A SPECIAL MEETING REVIEW EDITION

Highlights in Early and Metastatic From the 2020 San Antonio Breast Cancer Symposium A Review of Selected Presentations From the 2020 SABCS Virtual Symposium • December 8-11, 2020

Special Reporting on: • Continued Efficacy of Neratinib in Patients With HER2-Positive Early-Stage Breast Cancer: Final Overall Survival Analysis From the Randomized Phase 3 ExteNET Trial • First Results From a Phase 3 Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- in Patients With 1 to 3 Positive Nodes, Hormone Receptor–Positive and HER2-Negative Breast Cancer With Recurrence Score <25: SWOG S1007 (RxPONDER) • Bringing Diarrhea Under CONTROL: Dose Escalation Reduces Neratinib-Associated Diarrhea and Improves Tolerability in HER2-Positive Early-Stage Breast Cancer • Phase III Study of Combined With Endocrine Therapy in Patients With Hormone Receptor–Positive, HER2-Negative Primary Breast Cancer and With High Relapse Risk After Neoadjuvant Chemotherapy: First Results From PENELOPE-B • Impact of Neratinib on Outcomes in HER2-Positive Metastatic Breast Cancer Patients With Central Nervous System Disease at Baseline: Findings From the Phase 3 NALA Trial • Results From CONTESSA: A Phase 3 Study of Tesetaxel Plus a Reduced Dose of Versus Capecitabine Alone in Patients With HER2–, Hormone Receptor+ Metastatic Breast Cancer Who Have Previously Received a • Cost-Effectiveness of Neratinib for the Extended Adjuvant Treatment of Adult Patients With Early-Stage, HR+, HER2-Overexpressed/Amplified Breast Cancer Who Initiated Neratinib Within 1 Year of Completing Trastuzumab in the US • Primary Outcome Analysis of Invasive Disease–Free Survival for MonarchE: Combined With Adjuvant Endocrine Therapy for High-Risk Early Breast Cancer • The Neat-HER Virtual Registry: Results on HER2+ Breast Cancer Patients Receiving Neratinib as Extended Adjuvant Therapy • E2112: Randomized Phase 3 Trial of Endocrine Therapy Plus /Placebo in Patients With Hormone Receptor–Positive Advanced Breast Cancer: A Trial of the ECOG-ACRIN Cancer Research Group

PLUS Meeting Abstract Summaries With Expert Commentary by: Joyce A. O’Shaughnessy, MD Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center Director, Breast Cancer Research Program, Texas Oncology US Oncology Dallas, Texas

ON THE WEB: hematologyandoncology.net

Indexed through the National Library of Medicine (PubMed/MEDLINE), PubMed Central (PMC), and EMBASE * In patients randomized to NERLYNX ≤1 year from completing trastuzumab-based therapy. Results of ExteNET are supported by an exploratory analysis of 5-year follow-up, with 74.5% (2117/2840) of patients reconsented. 95% of the HR+ study population received concurrent endocrine therapy. Recurrence is defined as time from randomization to first occurrence of invasive ipsilateral tumor THE FIRST AND ONLY HER2-DIRECTED SMALL MOLECULE APPROVED recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence, or death from any cause. †4.7% absolute benefit in distant disease-free survival vs placebo at 5 years in early-stage HER2+ HR+ breast cancer patients within IN BOTH EARLY AND METASTATIC HER2+ BREAST CANCER 1 year of completing trastuzumab-based therapy. Distant disease-free survival was a secondary endpoint in the clinical trial. ‡Median PFS of 5.6 months with NERLYNX + capecitabine vs 5.5 months with lapatinib + capecitabine (HR=0.76; 95% CI: 0.63, 0.93; P=0.0059). §Select exclusion criteria: clinically significant cardiac, GI, or psychiatric comorbidities; inability to swallow pills. |Invasive disease-free survival defined as the time between the date of randomization to the first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up.

CI: confidence interval; eBC: early breast cancer; HER: human epidermal growth factor receptor; HR: hazard ratio; HR+: hormone receptor–positive; PREVENT PROTECT iDFS: invasive disease-free survival; mBC: metastatic breast cancer; PFS: progression-free survival. RECURRENCE1,2,* AGAINST PROGRESSION3 IMPORTANT SAFETY INFORMATION To report SUSPECTED ADVERSE REACTIONS, contact Puma (REDUCE THE RISK OF RECURRENCE IN eBC)† (INCREASE PFS IN mBC)‡ CONTRAINDICATIONS: None Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) or WARNINGS AND PRECAUTIONS: FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. • Diarrhea: Aggressively manage diarrhea. If diarrhea occurs DRUG INTERACTIONS: despite recommended prophylaxis, treat with additional • Gastric acid reducing agents: Avoid concomitant use with anti-diarrheals, fluids, and electrolytes as clinically proton pump inhibitors. When patients require gastric indicated. Withhold NERLYNX in patients experiencing acid reducing agents, use an H2-receptor antagonist or severe and/or persistent diarrhea. Permanently discontinue antacid. Separate NERLYNX by at least 3 hours with antacids. NERLYNX in patients experiencing Grade 4 diarrhea or Grade Separate NERLYNX by at least 2 hours before or 10 hours after ≥ 2 diarrhea that occurs after maximal dose reduction. H2-receptor antagonists. • Hepatotoxicity: Monitor liver function tests monthly for • Strong CYP3A4 inhibitors: Avoid concomitant use. the first 3 months of treatment, then every 3 months while • Moderate CYP3A4 and P-glycoprotein (P-gp) dual inhibitors: on treatment and as clinically indicated. Withhold NERLYNX Avoid concomitant use. in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing • Strong or moderate CYP3A4 inducers: Avoid concomitant use. ACTUAL PATIENTS Grade 4 liver abnormalities. • P-glycoprotein (P-gp) substrates: Monitor for adverse • Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX. ExteNET was a pivotal phase 3, global, multicenter, randomized, double-blind, placebo-controlled study Advise patients of potential risk to a fetus and to use involving 2840 women with early-stage HER2+ breast cancer and locally confirmed HER2 status who had effective contraception. USE IN SPECIFIC POPULATIONS: received prior trastuzumab-based therapy.1,2,§ Of the patients with HER2+, hormone receptor-positive (HR+) ADVERSE REACTIONS: The most common adverse reactions • Lactation: Advise women not to breastfeed. disease, 95% of the HR+ study population received concurrent endocrine therapy.2 The primary endpoint (reported in ≥ 5% of patients) were: || Please see brief summary of Full Prescribing Information was iDFS. • NERLYNX as a single agent: diarrhea, nausea, abdominal pain, on next page. NALA was a pivotal phase 3, global, multicenter, randomized, open-label study of NERLYNX + capecitabine fatigue, vomiting, rash, stomatitis, decreased appetite, References: 1. Gnant M, Martin M, Holmes FA, et al. Efficacy of neratinib in (n=307) vs lapatinib + capecitabine (n=314) in adults with HER2+ mBC. All patients had ≥2 prior lines of muscle spasms, dyspepsia, AST or ALT increased, nail hormone receptor-positive patients who initiated treatment within 1 year of 3,4 disorder, dry skin, abdominal distention, epistaxis, weight completing trastuzumab-based adjuvant therapy in HER2+ early stage breast HER2-directed therapy for mBC. Asymptomatic and stable brain metastases were permitted. cancer: subgroup analysis from the phase III ExteNET trial. Poster presented decreased, and urinary tract infection. at: 2018 San Antonio Breast Cancer Symposium (SABCS); December 4-8, 2018; San Antonio, TX. 2. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib • NERLYNX in combination with capecitabine: diarrhea, after trastuzumab-based adjuvant therapy in HER2-positive breast cancer INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated: (ExteNET): 5-year analysis of a randomized, double-blind, placebo-controlled, • As a single agent, for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer, to follow nausea, vomiting, decreased appetite, constipation, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. 3. NERLYNX [package fatigue/asthenia, weight decreased, dizziness, back pain, insert]. Los Angeles, CA; Puma Biotechnology, Inc. 4. Saura C, Oliveira M, adjuvant trastuzumab-based therapy. Feng Y-H, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine • In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer arthralgia, urinary tract infection, upper respiratory tract in HER2-positive metastatic breast cancer previously treated with ≥2 HER2- directed regimens: phase III NALA trial. J Clin Oncol. Published online July 17, who have received two or more prior anti-HER2 based regimens in the metastatic setting. infection, abdominal distention, renal impairment, and 2020. doi:10.1200/JCO.20.00147 muscle spasms. NERLYNX is a registered trademark of Puma Biotechnology, Inc. Please see IMPORTANT SAFETY INFORMATION and brief summary of Full Prescribing Information on the following pages. © 2020 Puma Biotechnology, Inc. All Rights Reserved. PRC-US-NER-1854 08/20 * In patients randomized to NERLYNX ≤1 year from completing trastuzumab-based therapy. Results of ExteNET are supported by an exploratory analysis of 5-year follow-up, with 74.5% (2117/2840) of patients reconsented. 95% of the HR+ study population received concurrent endocrine therapy. Recurrence is defined as time from randomization to first occurrence of invasive ipsilateral tumor THE FIRST AND ONLY HER2-DIRECTED SMALL MOLECULE APPROVED recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence, or death from any cause. †4.7% absolute benefit in distant disease-free survival vs placebo at 5 years in early-stage HER2+ HR+ breast cancer patients within IN BOTH EARLY AND METASTATIC HER2+ BREAST CANCER 1 year of completing trastuzumab-based therapy. Distant disease-free survival was a secondary endpoint in the clinical trial. ‡Median PFS of 5.6 months with NERLYNX + capecitabine vs 5.5 months with lapatinib + capecitabine (HR=0.76; 95% CI: 0.63, 0.93; P=0.0059). §Select exclusion criteria: clinically significant cardiac, GI, or psychiatric comorbidities; inability to swallow pills. |Invasive disease-free survival defined as the time between the date of randomization to the first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up.

CI: confidence interval; eBC: early breast cancer; HER: human epidermal growth factor receptor; HR: hazard ratio; HR+: hormone receptor–positive; PREVENT PROTECT iDFS: invasive disease-free survival; mBC: metastatic breast cancer; PFS: progression-free survival. RECURRENCE1,2,* AGAINST PROGRESSION3 IMPORTANT SAFETY INFORMATION To report SUSPECTED ADVERSE REACTIONS, contact Puma (REDUCE THE RISK OF RECURRENCE IN eBC)† (INCREASE PFS IN mBC)‡ CONTRAINDICATIONS: None Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) or WARNINGS AND PRECAUTIONS: FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. • Diarrhea: Aggressively manage diarrhea. If diarrhea occurs DRUG INTERACTIONS: despite recommended prophylaxis, treat with additional • Gastric acid reducing agents: Avoid concomitant use with anti-diarrheals, fluids, and electrolytes as clinically proton pump inhibitors. When patients require gastric indicated. Withhold NERLYNX in patients experiencing acid reducing agents, use an H2-receptor antagonist or severe and/or persistent diarrhea. Permanently discontinue antacid. Separate NERLYNX by at least 3 hours with antacids. NERLYNX in patients experiencing Grade 4 diarrhea or Grade Separate NERLYNX by at least 2 hours before or 10 hours after ≥ 2 diarrhea that occurs after maximal dose reduction. H2-receptor antagonists. • Hepatotoxicity: Monitor liver function tests monthly for • Strong CYP3A4 inhibitors: Avoid concomitant use. the first 3 months of treatment, then every 3 months while • Moderate CYP3A4 and P-glycoprotein (P-gp) dual inhibitors: on treatment and as clinically indicated. Withhold NERLYNX Avoid concomitant use. in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing • Strong or moderate CYP3A4 inducers: Avoid concomitant use. ACTUAL PATIENTS Grade 4 liver abnormalities. • P-glycoprotein (P-gp) substrates: Monitor for adverse • Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX. ExteNET was a pivotal phase 3, global, multicenter, randomized, double-blind, placebo-controlled study Advise patients of potential risk to a fetus and to use involving 2840 women with early-stage HER2+ breast cancer and locally confirmed HER2 status who had effective contraception. USE IN SPECIFIC POPULATIONS: received prior trastuzumab-based therapy.1,2,§ Of the patients with HER2+, hormone receptor-positive (HR+) ADVERSE REACTIONS: The most common adverse reactions • Lactation: Advise women not to breastfeed. disease, 95% of the HR+ study population received concurrent endocrine therapy.2 The primary endpoint (reported in ≥ 5% of patients) were: || Please see brief summary of Full Prescribing Information was iDFS. • NERLYNX as a single agent: diarrhea, nausea, abdominal pain, on next page. NALA was a pivotal phase 3, global, multicenter, randomized, open-label study of NERLYNX + capecitabine fatigue, vomiting, rash, stomatitis, decreased appetite, References: 1. Gnant M, Martin M, Holmes FA, et al. Efficacy of neratinib in (n=307) vs lapatinib + capecitabine (n=314) in adults with HER2+ mBC. All patients had ≥2 prior lines of muscle spasms, dyspepsia, AST or ALT increased, nail hormone receptor-positive patients who initiated treatment within 1 year of 3,4 disorder, dry skin, abdominal distention, epistaxis, weight completing trastuzumab-based adjuvant therapy in HER2+ early stage breast HER2-directed therapy for mBC. Asymptomatic and stable brain metastases were permitted. cancer: subgroup analysis from the phase III ExteNET trial. Poster presented decreased, and urinary tract infection. at: 2018 San Antonio Breast Cancer Symposium (SABCS); December 4-8, 2018; San Antonio, TX. 2. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib • NERLYNX in combination with capecitabine: diarrhea, after trastuzumab-based adjuvant therapy in HER2-positive breast cancer INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated: (ExteNET): 5-year analysis of a randomized, double-blind, placebo-controlled, • As a single agent, for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer, to follow nausea, vomiting, decreased appetite, constipation, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. 3. NERLYNX [package fatigue/asthenia, weight decreased, dizziness, back pain, insert]. Los Angeles, CA; Puma Biotechnology, Inc. 4. Saura C, Oliveira M, adjuvant trastuzumab-based therapy. Feng Y-H, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine • In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer arthralgia, urinary tract infection, upper respiratory tract in HER2-positive metastatic breast cancer previously treated with ≥2 HER2- directed regimens: phase III NALA trial. J Clin Oncol. Published online July 17, who have received two or more prior anti-HER2 based regimens in the metastatic setting. infection, abdominal distention, renal impairment, and 2020. doi:10.1200/JCO.20.00147 muscle spasms. NERLYNX is a registered trademark of Puma Biotechnology, Inc. Please see IMPORTANT SAFETY INFORMATION and brief summary of Full Prescribing Information on the following pages. © 2020 Puma Biotechnology, Inc. All Rights Reserved. PRC-US-NER-1854 08/20 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary of the full prescribing information and does not include all the information needed to use NERLYNX® (neratinib) tablets safely and effectively. See full prescribing information for NERLYNX. NERLYNX® (neratinib) tablets, for oral use Initial U.S. Approval: 2017 INDICATION AND USAGE: NERLYNX is a kinase inhibitor indicated: • As a single agent, for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy. • In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting. CONTRAINDICATIONS: None. (See Section 4 of the full prescribing information.) WARNINGS AND PRECAUTIONS: • Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥2 diarrhea that occurs after maximal dose reduction. (See Sections 2.3, 5.1 of the full prescribing information.) • Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities. (See Sections 2.3, 5.2 of the full prescribing information.) • Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (See Sections 5.3, 8.1, 8.3 of the full prescribing information.) ADVERSE REACTIONS: The most common adverse reactions (reported in ≥ 5% of patients) were: • NERLYNX as a single agent: diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection. • NERLYNX in combination with capecitabine: diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms. To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS: • Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. When patients require gastric acid reducing agents, use an

H2-receptor antagonist or antacid. Separate NERLYNX by at least 3 hours with antacids. Separate NERLYNX by at least 2 hours before or 10 hours after H2-receptor antagonists. (See Sections 2.3, 7.1 of the full prescribing information.) • Strong CYP3A4 inhibitors: Avoid concomitant use. (See Section 7.1 of the full prescribing information.) • Moderate CYP3A4 and P-glycoprotein (P-gp) dual inhibitors: Avoid concomitant use. (See Section 7.1 of the full prescribing information.) • Strong or moderate CYP3A4 inducers: Avoid concomitant use. (See Section 7.1 of the full prescribing information.) • P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX. (See Section 7.2 of the full prescribing information.) USE IN SPECIFIC POPULATIONS: Lactation: Advise women not to breastfeed. (See Section 8.2 of the full prescribing information.)

Distributed by: Puma Biotechnology, Inc. 10880 Wilshire Blvd., Suite 2150 Los Angeles, CA 90024-4106 NERLYNX is a registered trademark of Puma Biotechnology, Inc. © 2020 Puma Biotechnology, Inc. All Rights Reserved. PRC-US-NER-1453 03/20 HIGHLIGHTS IN EARLY AND METASTATIC BREAST CANCER FROM THE 2020 SABCS

Continued Efficacy of Neratinib in Patients With HER2-Positive Early-Stage Breast Cancer: Final Overall Survival Analysis From the Randomized Phase 3 ExteNET Trial

eratinib is an irreversible mone receptor–positive disease who of patients who did not achieve a pCR tyrosine kinase inhibitor of initiated neratinib treatment within after neoadjuvant therapy (n=354). the human epidermal growth 1 year of completing trastuzumab, an The analysis cutoff date was July 2019. Nfactor receptors­ (HER) 1, 2, and 4. The absolute IDFS benefit of 5.1% and a After a median follow‑up of 8.1 phase 3 ExteNET trial enrolled 2840 DDFS benefit of 4.7% were seen at 5 years in the ITT population, deaths women with early-stage HER2-posi- years. In the subset of the population were reported in 8.9% of the neratinib tive breast cancer who had completed that did not achieve a pathologic com- arm and 9.6% of the placebo arm. The neoadjuvant or adjuvant trastuzumab plete response (pCR) after neoadjuvant 8-year OS rates were 90.1% (95% CI, plus chemotherapy. The patients were therapy, the absolute 5-year IDFS and 88.3-91.6) in the neratinib group and randomly assigned to oral neratinib DDFS benefits were 7.4% and 7.0%, 90.2% (95% CI, 88.4-91.7) in the at 240 mg/d or placebo for 1 year.1 respectively. placebo group (absolute difference Their median age was 52 years (range, The current OS analysis was at 8 years, –0.1%; stratified hazard 23-83). Dr Frankie Ann Holmes and event-driven and powered for the ITT ratio [HR], 0.95; 95% CI, 0.75-1.21; colleagues reported the final analysis of population, with a target of 248 events. P=.6914). In the hormone recep- overall survival (OS) from ExteNET.2 OS was defined as the time from tor–positive population, the absolute As previously reported, a 5-year randomization to the date of death difference in OS rates at 8 years was follow-up analysis in the intention- from any cause. Descriptive analyses 1.5% (HR, 0.80; 95% CI, 0.58- to-treat (ITT) population showed were performed in the population of 1.12). In the subgroup that initiated that neratinib was associated with an patients with hormone receptor–posi- neratinib treatment within 1 year of absolute invasive disease–free survival tive disease (n=1631), in those who completing trastuzumab, the absolute (IDFS) benefit of 2.5% and a distant initiated neratinib treatment within difference in OS rates at 8 years was disease–free survival (DDFS) benefit 1 year of completing trastuzumab 2.1% (HR, 0.79; 95% CI, 0.55-1.13), of 1.7%.3 Among patients with hor- (n=1334), and in the higher-risk subset whereas in the subgroup with no pCR

Figure 1. Overall survival among the N Events Median 95% Cl Median Duration of (months) (months) Follow-Up, months subgroup of patients (min, max) without a pathologic Part A: Brentuximab vedotin monotherapy 26 16 10.48 5.55-77.47 54.5 (4.6, 89.5) complete response after 100 Part B: Brentuximab vedotin + 20 8 46.75 11-68.7 63.6 (6.7, 77.0) neoadjuvant therapy in Part C: Brentuximab vedotin + 20 11 40.34 4.01-NR 39.2 (0.4, 66.0) the phase 3 ExteNET 90 Part D: Brentuximab vedotin + nivolumab 21 6 – 9.36-NR 26.2 (0.5, 41.7) trial, which compared 80 neratinib vs placebo in 70 patients with early-stage 60 HER2-positive breast cancer. HER2, human 50 epidermal growth factor 40 receptor 2. Adapted 30 from Holmes FA et al. 20 SABCS abstract PD3-03. Presented at the 2020 San 10 Antonio Breast Cancer 0

Symposium; December Subjects Free of Disease Progression or Death (%) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 8-11, 2020.2 Time (months) Number at Risk (events) Part A 26(0) 25(0) 17(7) 11(11)8(14) 8(14) 7(14) 7(14) 7(14) 7(14) 7(14) 7(14) 6(14) 6(14) 4(15) 4(15) 4(15) 4(15) 3(15) 3(15) 3(15) 3(15) 3(15) 3(15) 2(15) 2(15) 1(16) 1(16) 0(16) Part B 20(0) 19(0) 16(1) 13(2) 11(4) 11(4) 8(6) 8(6) 7(6) 7(6) 7(6) 7(6) 7(6) 7(6) 6(6) 6(6) 5(7) 5(7) 4(7) 3(7) 2(7) 2(7) 1(7) 0(8) Part C 20(0) 15(3) 12(6) 11(7) 11(7) 11(7) 10(8) 10(8) 10(8) 10(8) 10(8) 9(9) 8(9) 7(9) 5(10) 4(10) 3(11) 3(11) 1(11) 1(11) 0(11) Part D 21(0) 17(2) 16(3) 15(4) 10(5) 7(6) 6(6) 3(6) 2(6) 2(6) 0(6)

Clinical Advances in Hematology & Oncology Volume 19, Issue 2, Supplement 9 February 2021 5 SPECIAL MEETING REVIEW EDITION

after neoadjuvant therapy, the absolute statistically significant benefit in OS References difference at 8 years was 9.1% (HR, over placebo in the ITT population. 1. Chan A, Delaloge S, Holmes FA, et al; ExteNET Study Group. Neratinib after trastuzumab-based adju- 0.47; 95% CI, 0.23-0.92; Figure 1). However, an association between nera- vant therapy in patients with HER2-positive breast Neratinib did not appear to improve tinib treatment and OS benefit was cancer (ExteNET): a multicentre, randomised, double- OS rates for patients with hormone seen in the population of patients with blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. receptor–negative disease. In the ITT hormone receptor–positive disease, in 2. Holmes FA, Moy B, Delaloge S, et al. Continued group and hormone receptor–positive the subset of patients who initiated efficacy of neratinib in patients with HER2-positive disease subgroups, there were fewer neratinib treatment within 1 year of early-stage breast cancer: final overall survival analysis from the randomized phase 3 ExteNET trial. Abstract central nervous system (CNS) events completing trastuzumab, and in the presented at: the San Antonio Breast Cancer Sympo- in the neratinib arm compared with higher-risk subset of patients who did sium 2020 Virtual Meeting; December 8-11, 2020. placebo; however, these differences did not achieve a pCR after neoadjuvant Abstract PD3-03. 3. Martin M, Holmes FA, Ejlertsen B, et al; ExteNET not reach statistical significance. Safety therapy. These findings are consistent Study Group. Neratinib after trastuzumab-based results in this 8-year follow-up were with earlier results for IDFS and adjuvant therapy in HER2-positive breast cancer similar to those previously published.2 DDFS, and they support the use of (ExteNET): 5-year analysis of a randomised, double- blind, placebo-controlled, phase 3 trial. Lancet Oncol. The investigators concluded that neratinib in clinical practice for such 2017;18(12):1688-1700. neratinib was not associated with a patients.

First Results From a Phase 3 Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients With 1 to 3 Positive Nodes, Hormone Receptor–Positive and HER2- Negative Breast Cancer With Recurrence Score <25: SWOG S1007 (RxPONDER)

he phase 3 SWOG S1007 The baseline characteristics were 0.78-1.22; P=.82) for postmenopausal RxPONDER trial compared well balanced between the treatment women. In premenopausal patients, endocrine therapy vs chemo- arms. In both arms, 33.2% of women the 5-year IDFS was 94.2% with endocrineT therapy in women with were premenopausal. The Recurrence chemoendocrine therapy vs 89.0% hormone receptor–positive, HER2- Score was 0 to 13 in 42.7% of patients with endocrine therapy alone (HR, negative breast cancer, with 1 to 3 in the endocrine therapy arm and 0.54; 95% CI, 0.38-0.76; P=.0004; positive lymph nodes, and a 21-gene 42.9% of those in the chemotherapy Figure 2). Among premenopausal Oncotype DX Recurrence Score of arm. Previous axillary lymph node women, the addition of chemotherapy 0 to 25.1 Patients were randomly dissection was reported in 62.7% vs to endocrine therapy resulted in a assigned to receive endocrine therapy 62.5%, respectively. In both groups, 46% decrease in IDFS events. Benefits or chemoendocrine therapy. The pri- most patients had only 1 positive were seen across all subgroups. There mary endpoint was IDFS. The primary node (65.9% vs 65.0%). Disease risk was a 53% decrease in deaths, which hypothesis was that the benefit of che- was considered intermediate in most translated to an absolute improvement moendocrine therapy would increase patients (64.1% vs 66.1%). in 5-year OS of 1.3%. These data sug- as the Recurrence Score increased. After a median follow-up of 5.1 gest there is a significant differential Dr Kevin Kalinsky presented the years (447 IDFS events), the Recur- treatment effect of chemoendocrine results from the primary analysis.1 The rence Score did not predict the relative therapy over endocrine therapy alone analysis included 2506 patients treated benefit of chemoendocrine therapy based on the Recurrence Score for with endocrine therapy only and 2509 (P=.30). In a prespecified analysis by premenopausal women that requires patients treated with chemotherapy menopausal status, chemoendocrine further analysis. followed by endocrine therapy. Half of therapy did not provide statistically The investigators concluded that the patients treated with chemotherapy significant benefits over endocrine it is likely that adjuvant chemotherapy received and cyclophospha- therapy for postmenopausal patients. can be omitted from treatment for mide (4 or 6 cycles). Premenopausal The 5-year IDFS was 91.9% with endo- postmenopausal women with 1 to 3 women underwent ovarian function crine therapy vs 91.6% with chemoen- positive lymphoma nodes and a Recur- suppression. docrine therapy (HR, 0.97; 95% CI, rence Score of 0 to 25. In contrast,

6 Clinical Advances in Hematology & Oncology Volume 19, Issue 2, Supplement 9 February 2021 HIGHLIGHTS IN EARLY AND METASTATIC BREAST CANCER FROM THE 2020 SABCS

Figure 2. Invasive disease– N Events Median 95% Cl Median Duration of free survival at 5 years among (months) (months) Follow-Up, months premenopausal women with (min, max) a Recurrence Score of 0 to 25 Part A: Brentuximab vedotin monotherapy 26 11 82 40.1-NR 54.5 (4.6, 89.5) Part B: Brentuximab vedotin + dacarbazine 20 7 – 53.4-NR 63.6 (6.7, 77.0) in the phase 3 SWOG S1007 Part C: Brentuximab vedotin + bendamustine 20 11 46.9 6.8-NR 39.2 (0.4, 66.0) RxPONDER trial, which Part D: Brentuximab vedotin + nivolumab 21 3 – NR-NR 26.2 (0.5, 41.7) compared endocrine therapy 100 vs chemoendocrine therapy in 90 women with hormone receptor– 80 positive, HER2-negative breast 70 60 cancer. CET, chemoendocrine 50 therapy; ET, endocrine therapy; 40 HER2, human epidermal 30 growth factor receptor 2; HR, 20 Subjects Free of Death (%) hazard ratio; IDFS, invasive 10 0 disease–free survival. Adapted 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 from Kalinsky K et al. Abstract Time (months) GS3-00. Presented at: the 2020 Number at Risk (events) Part A 26(0) 26(0) 25(0) 23(1) 22(2) 20(3) 20(3) 19(4) 18(5) 18(5) 17(6) 17(6) 17(6) 17(6) 14(8) 13(9) 13(9) 13(9) 13(9) 13(9) 13(9) 13(9) 12(9) 11(9) 11(9) 11(9)10(10) 8(10) 3(11) 2(11)0(11) San Antonio Breast Cancer Part B 20(0) 20(0) 20(0) 19(0) 19(0) 18(0) 17(1) 17(1) 16(1) 16(1) 16(1) 16(1) 16(1) 16(1) 15(2) 15(2) 14(3) 13(3) 12(4) 12(4) 11(5) 11(5) 8(7) 5(7) 3(7) 2(7) 0(7) Symposium; December 8-11, Part C 20(0) 15(4) 15(4) 13(6) 13(6) 12(7) 12(7) 12(7) 11(8) 11(8) 11(8) 10(9) 10(9) 10(9) 10(9) 10(9) 9(10) 9(10) 8(11) 8(11) 8(11) 5(11) 0(11) 2020.1 Part D 21(0) 19(1) 18(1) 18(1) 17(2) 17(2) 14(3) 12(3) 11(3) 10(3) 9(3) 5(3) 3(3) 1(3) 0(3)

premenopausal women with positive Reference (HER2-) breast cancer (BC) with recurrence score (RS) <25: SWOG S1007 (RxPONDER). Abstract presented nodes and a Recurrence Score of 0 1. Kalinsky K, Barlow W, Meric-Bernstam F, et al. First results from a phase III randomized clinical trial of at: the San Antonio Breast Cancer Symposium 2020 to 25 will likely benefit from chemo- standard adjuvant endocrine therapy (ET) +/- chemo- Virtual Meeting; December 8-11, 2020. Abstract GS3- therapy. Future analysis of the study therapy (CT) in patients (pts) with 1-3 positive nodes, 00. will provide data for quality of life and hormone receptor-positive (HR+) and HER2-negative other outcomes. Bringing Diarrhea Under CONTROL: Dose Escalation Reduces Neratinib-Associated Diarrhea and Improves Tolerability in HER2- Positive Early-Stage Breast Cancer

iarrhea is the main tolerabil- neratinib-associated grade 3/4 diarrhea treatment proceeded in 28-day cycles ity concern with neratinib, were improved compared with rates for 1 year. particularly in the first 1 to reported in the ExteNET trial when There were 6 cohorts. The first 2D months of treatment. In the phase preemptive antidiarrheal prophylaxis cohort (n=137) received oral nera- 3 ExteNET trial, women with early- with loperamide alone or in combina- tinib 240 mg/d continuously, with a stage HER2-positive breast cancer tion with budesonide or colestipol was tapering schedule of oral loperamide who had completed neoadjuvant or used or when a dose-escalation strategy prophylaxis during cycles 1 and 2 fol- adjuvant trastuzumab plus chemo- for neratinib was adopted.2 Dr Manuel lowed by loperamide (≤16 mg/d) as therapy received either oral neratinib Ruiz-Borrego reported updated find- needed thereafter. The second cohort at 240 mg/d or placebo for 1 year. ings from 2 dose-escalation cohorts in (n=64) received neratinib at 240 mg/d No mandatory prophylaxis was used, the CONTROL trial.3 continuously, with budesonide at 9 and the rate of grade 3 diarrhea was The CONTROL trial enrolled mg/d during cycle 1 and loperamide 40%.1 The CONTROL trial is a phase adults with stage I to IIIc, HER2-pos- prophylaxis as described above. The 2, open-label study that is investigat- itive breast cancer who had received third cohort (n=136) received nera- ing several strategies to improve the trastuzumab-based adjuvant therapy. tinib at 240 mg/d continuously, with tolerability of neratinib. A previous The median age was between 49 and colestipol given at 2 g twice daily analysis of CONTROL showed that 53 years (depending on cohort; range, during cycle 1 and a tapering schedule the rate, severity, and duration of 26-86), and 99% were women. The of loperamide prophylaxis during the

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Table 1. Key Diarrhea Outcomes in All Cohorts in the CONTROL Trial

Neratinib Budesonide + Colestipol + Colestipol + Neratinib DE2 Loperamide DE1 Loperamide Loperamide Loperamide PRN + Loperamide (n=137) + Loperamide (n=64) (n=136) (n=104) PRNa (n=62) PRN (n=60)

Grade 3 diarrhea, 42 (30.7) 18 (28.1) 28 (20.6) 33 (31.7) 8 (13.3) 16 (25.8) n (%)

Discontinuations due to diarrhea, 28 (20.4) 7 (10.9) 5 (3.7) 8 (7.7) 2 (3.3) 3 (4.8) n (%) aThe data cutoff was October 19, 2020. DE, dose escalation; PRN, as needed. Adapted from Ruiz-Borrego M et al. SABCS abstract PS13-20. Presented at the 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020.3

Rash 13 3 1 Elevated AST/ALT 5 7 4 Nausea 12 2 Grade 1 Oral Mucositis 1 9 2 Fatigue 11 1 Grade 2 Headache 7 2 Grade 3 Diarrhea 4 2 Constipation 3 3 Hand-Foot Syndrome 4 1 Infusion-Related Reaction 5 Vomiting 4 1 Neutrophil Count Decreased 1 3 Peripheral Sensory Neuropathy 3 1 Super cial Thrombophlebitis 3 Fever 2 1

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 Figure 3. Treatment discontinuation owing to diarrhea according to treatmentNumber arm in of the Patients CONTROL trial. DE, dose escalation. Adapted from Ruiz-Borrego M et al. Abstract PS13-20. Presented at the 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020.3 first cycle only, followed by loperamide at 160 mg/d on days 1 to 14, 200 6 months of treatment and remained (≤16 mg/d) as needed thereafter. The mg/d on days 15 to 28, then 240 mg/d on treatment. Discontinuation for fourth cohort (n=104) received nera- thereafter, plus loperamide as needed diarrhea occurred in 3.3% and 4.8% tinib at 240 mg/d continuously, with throughout (n=62). The primary end- of patients in dose-escalation cohorts colestipol at 2 g twice daily during point was the incidence of grade 3 or 1 and 2, respectively (Table 1). Treat- cycle 1, plus loperamide as needed higher diarrhea. ment discontinuations owing to throughout treatment. The fifth cohort As of the data cutoff (October diarrhea tended to occur early among (dose-escalation 1) received neratinib 19, 2020), all patients in the dose- all cohorts (Figure 3). Escalation at 120 mg/d on days 1 to 7, 160 mg/d escalation 1 cohort were off-study, proceeded on schedule for 91.7% of on days 8 to 14, and then 240 mg/d with a completion rate of 78.3%. In patients in dose-escalation cohort 1 thereafter, plus loperamide as needed dose-escalation cohort 2, 38.7% of and 77.4% in dose-escalation cohort throughout (n=60). The sixth cohort patients completed, 24.2% discontin- 2. At least 1 dose hold was required by (dose-escalation 2) received neratinib ued, and 37.1% had received at least 11.7% of patients in dose-escalation

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cohort 1 and 14.5% in dose-escalation from the phase 3 ExteNET study, the vant therapy in patients with HER2-positive breast cohort 2. There were no grade 4 diar- regimen in dose-escalation cohort 1 cancer (ExteNET): a multicentre, randomised, double- blind, placebo-controlled, phase 3 trial. Lancet Oncol. rhea events. The incidence of grade 3 in the CONTROL study reduced the 2016;17(3):367-377. diarrhea was 13.3% in dose-escalation incidence, severity, and duration of 2. Barcenas CH, Hurvitz SA, Di Palma JA, et al; cohort 1 and 25.8% in dose-escalation neratinib-associated diarrhea.1-3 This CONTROL Study Investigators. Improved tolerability of neratinib in patients with HER2-positive early- cohort 2. The median cumulative dose-escalation strategy, combined stage breast cancer: the CONTROL trial. Ann Oncol. duration of grade 3 diarrhea over the with loperamide administered as 2020;31(9):1223-1230. 12-month treatment period was 2.5 needed, may improve treatment adher- 3. Ruiz-Borrego M, Chan A, Marx G, et al. Bringing diarrhea under CONTROL: dose escalation reduces days (range, 1-6 days) in dose-escala- ence and completion rates. neratinib-associated diarrhea and improves tolerability tion cohort 1 and 2 days (range, 1-7 in HER2-positive early-stage breast cancer. Abstract days) in dose-escalation cohort 2. References presented at: the San Antonio Breast Cancer Sympo- sium 2020 Virtual Meeting; December 8-11, 2020. Compared with reported data 1. Chan A, Delaloge S, Holmes FA, et al; ExteNET Study Group. Neratinib after trastuzumab-based adju- Abstract PS13-20.

Phase III Study of Palbociclib Combined With Endocrine Therapy in Patients With Hormone Receptor–Positive, HER2-Negative Primary Breast Cancer and With High Relapse Risk After Neoadjuvant Chemotherapy: First Results From PENELOPE-B

pproximately one-third of use of adjuvant endocrine therapy. Pal- Loibl reported final results from the patients with hormone recep- bociclib is a cyclin-dependent kinase PENELOPE-B trial of palbociclib.2 tor–positive, HER2‐negative (CDK) 4/6 inhibitor that has demon- This double-blind, placebo‐controlled, Aprimary breast cancer with residual strated highly relevant efficacy in meta- phase 3 study enrolled women with invasive disease after neoadjuvant static breast cancer when combined centrally confirmed, hormone recep- chemotherapy will relapse despite the with endocrine therapy.1 Dr Sibylle tor–positive, HER2-negative primary breast cancer who did not achieve a pCR after taxane‐containing neoadju- vant chemotherapy. The patients had ABSTRACT SUMMARY Double-Blind, Placebo-Controlled Randomized a baseline Clinical-Pathologic Stage + Phase III Trial Evaluating First-Line Ipatasertib Combined With Pacli- Estrogen/Grade (CPS+EG) score of 3 taxel for PIK3CA/AKT1/PTEN-Altered Locally Advanced Unresectable or higher (or 2 or higher if there were or Metastatic Triple-Negative Breast Cancer: Primary Results From lymph node metastases at the time of IPATunity130 Cohort A surgery). The CPS+EG score combines The IPATunity130 phase 3 trial enrolled 255 patients with chemotherapy-naive, locally clinical stage before neoadjuvant treat- advanced unresectable or metastatic triple-negative breast cancer that was PIK3CA/ ment, pathologic stage after neoadju- AKT1-altered and/or PTEN-altered (Abstract GS3-04). Patients were randomly assigned vant treatment, grading, and estrogen 3,4 2:1 to receive either ipatasertib at 400 mg or placebo (days 1-21), both combined with receptor status. at 80 mg/m2 (days 1, 8, and 15) in 28-day cycles until disease progression, In PENELOPE-B, patients who unacceptable toxicity, or withdrawal. Approximately 51% had received neoadjuvant had completed neoadjuvant chemo- chemotherapy, 59% had visceral disease, 51% had PIK3CA/AKT1-activating mutations, therapy and locoregional therapy were and 49% had PTEN alterations only. After a median follow-up of 8.3 months, 33% of randomly assigned to receive 13 cycles patients remained on treatment. The mean paclitaxel dose intensity was similar of palbociclib 125 mg/d (n=631) or between the groups. There was no significant difference in PFS between treatment placebo (n=619) on days 1 to 21 in a arms overall or in any prespecified subgroups. OS results are immature, but preliminary 28-day cycle in addition to standard 2 findings revealed no significant difference between the treatment arms. Similar propor- endocrine therapy. Randomization tions of patients in the study arms experienced grade 3/4 AEs, fatal AEs, or AEs leading was stratified by lymph node status (at to discontinuation of any treatment. AEs leading to dose reduction of any treatment surgery), age, Ki-67 expression level, were more common with ipatasertib. global region, and CPS+EG score. The primary endpoint was IDFS, and the main secondary endpoints were IDFS

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Figure 4. Invasive disease– 1.0 free survival in the phase 3 PENELOPE-B trial, which compared palbociclib vs placebo among patients 0.8 Censored with hormone receptor– positive, HER2-negative primary breast cancer who did not achieve a 0.6 pathologic complete response after taxane‐containing neoadjuvant chemotherapy. ET, endocrine therapy;

Probability 0.4 HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IDFS, 0.2 invasive disease–free survival; yr, year. Adapted from Loibl S et al. Abstract GS1-02. 0.0 Presented at the 2020 San Antonio Breast Cancer At Risk 59 54 51 40 11 4 1 Symposium; December 8-11, 2 0 6 12 18 24 30 36 2020. Time (months)

excluding second primary invasive palbociclib vs 90.5% with placebo). References 1. Turner NC, Slamon DJ, Ro J, et al. Overall survival nonbreast cancers, OS, and safety. An analysis showed that palbociclib with palbociclib and fulvestrant in advanced breast can- The median age of enrolled was not significantly superior to pla- cer. N Engl J Med. 2018;379(20):1926-1936. patients was 49.7 years (range, 19-79). cebo among any subgroups. 2. Loibl S, Marmé F, Martin M, et al. Phase III study of palbociclib combined with endocrine therapy (ET) Among these, 47.4% had grade 3 Therapy was completed by 80.5% in patients with hormone-receptor-positive (HR+), disease, 25.5% had a Ki-67 expression of patients in the palbociclib arm vs HER2-negative primary breast cancer and with high level greater than 15%, and 59.4% had 84.5% in the placebo arm. Approxi- relapse risk after neoadjuvant chemotherapy (NACT): first results from PENELOPE-B. Abstract presented at: a CPS+EG score of 3 or higher. After mately 88.6% vs 90.3% of patients, the San Antonio Breast Cancer Symposium 2020 Vir- a median follow-up of 42.8 months, respectively, received at least 7 cycles of tual Meeting; December 8-11, 2020. Abstract GS1-02. IDFS was not improved with palbo- study treatment. The relative total dose 3. Mittendorf EA, Jeruss JS, Tucker SL, et al. Validation of a novel staging system for disease-specific survival in ciclib compared with placebo (strati- intensity was 82% for palbociclib and patients with breast cancer treated with neoadjuvant fied HR, 0.93; 95% CI, 0.74-1.16; 99% for placebo. In the safety analysis, chemotherapy. J Clin Oncol. 2011;29(15):1956-1962. P=.525; Figure 4); similar results were the incidence of nonhematologic grade 4. Marmé F, Lederer B, Blohmer JU, et al. Utility of the CPS+EG staging system in hormone receptor-positive, seen for OS (stratified HR, 0.87; 95% 3/4 adverse events (AEs) did not differ human epidermal growth factor receptor 2-negative CI, 0.61-1.22; P=.420). The estimated significantly between the arms. The breast cancer treated with neoadjuvant chemotherapy. 3-year IDFS rates were similar between incidence of hematologic grade 3/4 Eur J Cancer. 2016;53:65-74. groups (81.2% with palbociclib vs AEs was significantly higher in the pal- 77.7% with placebo), as were the bociclib arm than in the placebo arm estimated 3-year OS rates (93.6% with (73% vs 1.3%; P<.001).

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Impact of Neratinib on Outcomes in HER2-Positive Metastatic Breast Cancer Patients With Central Nervous System Disease at Baseline: Findings From the Phase 3 NALA Trial

pproximately 30% to 55% the neratinib combination compared treatment duration was 5.7 months of patients with HER2-pos- with the lapatinib combination (HR, (range, 0.4-28.6) for the neratinib itive metastatic breast cancer 0.76; 95% CI, 0.63-0.93; P=.0059), as combination and 3.5 months (range, Adevelop CNS metastases, but there are was the use of interventions for CNS 0.5-20.8) for the lapatinib combina- few evidence-based treatments avail- disease (cumulative incidence, 22.8% tion. The endpoints for this analysis able.1 NALA is a randomized phase vs 29.2%; P=.043).3 The most com- were PFS, OS, time to intervention for 3 study comparing the combination mon AEs were diarrhea (83% with the metastatic CNS disease, and time from of neratinib plus capecitabine vs the neratinib combination vs 66% with randomization to disease progression combination of lapatinib, a reversible the lapatinib combination) and nausea in the brain or death from any cause dual tyrosine kinase inhibitor, plus (53% vs 42%). (CNS-PFS). capecitabine in patients with HER2- Dr Cristina Saura discussed data PFS was 7.8 months with the positive, metastatic breast cancer from an exploratory analysis of patients neratinib combination vs 5.5 months treated with at least 2 previous HER2- from NALA with CNS involvement with the lapatinib combination, but directed treatment regimens.2 As at enrollment.4 Baseline CNS disease this difference did not reach statisti- previously reported, NALA enrolled was documented in 51 patients in the cal significance (HR, 0.66; 95% CI, 621 patients who were randomly neratinib combination arm and 50 in 0.41-1.05; P=.0741; Figure 5). CNS- assigned to neratinib at 240 mg once the lapatinib combination arm; the PFS was 12.4 months vs 8.3 months, daily plus capecitabine at 750 mg/m2 mean age of this cohort was 54 years respectively, a difference that was not twice daily (with loperamide prophy- (range, 25-75). No significant imbal- significant (HR, 0.62; 95% CI, 0.32- laxis) or to lapatinib at 1250 mg once ances of baseline characteristics were 1.18; P=.143; Figure 6). There was daily plus capecitabine at 1000 mg/m2 noted between the treatment arms. no statistically significant difference twice daily. Neratinib and lapatinib Previous treatment with CNS radia- between the arms for OS (16.4 months were administered continuously, and tion included whole brain radiation in vs 15.4 months; HR, 0.90; 95% CI, capecitabine was administered on days 58% of patients and stereotactic radia- 0.59-1.38; P=.635). The 12-month 1 to 14 of 21-day cycles. Progression- tion in 17%. Five patients (5%) had cumulative incidence for CNS dis- free survival (PFS) was improved with undergone CNS surgery. The median ease was 25.5% vs 36.0% (P=.430).

Figure 5. Progression-free survival in an exploratory 1.0 analysis of patients with CNS involvement at enrollment in the phase 3 NALA trial, 0.8 which compared neratinib plus Censored capecitabine vs lapatinib plus capecitabine in patients with 0.6 HER2-positive, metastatic breast cancer treated with at least 2 previous HER2-directed 0.4 treatment regimens. CNS, Probability central nervous system; HER2, human epidermal growth 0.2 factor receptor 2. Adapted from Saura C et al. Abstract PD13-09. Presented at the 2020 0.0 San Antonio Breast Cancer 1 21 19 19 15 4 0 Symposium; December 8-11, 2 24 22 20 17 5 2 1 2020.4 3+ 14 13 12 8 2 2 0 0 6 12 18 24 30 36 Time (months)

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Figure 6. CNS progression- 100 free survival in an exploratory 4.3 Not evaluable analysis of patients with CNS 90 10.6 2.1 involvement at enrollment 80 Progressive disease in the phase 3 NALA trial, which compared neratinib 70 Stable disease plus capecitabine vs 60 44.7 lapatinib plus capecitabine Partial response in patients with HER2- 50 positive, metastatic breast Complete response 40 cancer treated with at least 2 previous HER2-directed Response (%) 30 regimens. CNS, central 20 38.3 nervous system; HER2, human epidermal growth 10 1 factor receptor 2. Adapted 0 from Saura C et al. Abstract a PD13-09. Presented at Camidanlumab Tesirine 45 µg/kg the 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020.4

gators. Neratinib plus capecitabine versus lapatinib plus at: the 2019 San Antonio Breast Cancer Symposium; The safety profile was similar to that capecitabine in HER2-positive metastatic breast cancer San Antonio, Texas; December 10-14, 2019. Abstract reported for the overall NALA trial.4 previously treated with ≥2 HER2-directed regimens: P2-20-01. phase III NALA trial. J Clin Oncol. 2020;38(27):3138- 4. Saura C, Ryvo L, Hurvitz S, et al. Impact of neratinib 3149. on outcomes in HER2-positive metastatic breast cancer References 3. Awada A, Brufsky A, Saura C, et al. Impact of nera- patients with central nervous system disease at baseline: 1. Witzel I, Oliveira-Ferrer L, Müller V. Brain metas- tinib on development and progression of central ner- findings from the phase 3 NALA trial. Abstract pre- tasis in breast cancer patients-need for improvement. vous system metastases in patients with HER2-positive sented at: the San Antonio Breast Cancer Symposium Cancers (Basel). 2020;12(11):3190. metastatic breast cancer: findings from the NALA, 2020 Virtual Meeting; December 8-11, 2020. Abstract 2. Saura C, Oliveira M, Feng YH, et al; NALA Investi- NEfERT-T, and TBCRC 022 trials. Abstract presented PD13-09.

Results From CONTESSA: A Phase 3 Study of Tesetaxel Plus a Reduced Dose of Capecitabine Versus Capecitabine Alone in Patients With HER2–, Hormone Receptor+ Metastatic Breast Cancer Who Have Previously Received a Taxane

esetaxel is a novel oral taxane cancer who had received no more than received endocrine therapy, 80% had given every 3 weeks that has 1 for advanced previously received an , demonstrated an objective disease and had received a taxane in the and approximately 50% had previ- responseT rate (ORR) of 45% in a phase adjuvant or neoadjuvant setting. ously received a CDK4/6 inhibitor. 2 trial of patients diagnosed with hor- CONTESSA randomly assigned Approximately 80% had visceral mone receptor–positive, HER2-nega- patients to receive tesetaxel at 27 mg/ disease. The primary endpoint was tive metastatic breast cancer.1 Dr Joyce m2 on day 1 plus capecitabine at 1650 independently assessed PFS. Second- O’Shaughnessy presented results from mg/m2 per day on days 1 to 14 of a ary endpoints included OS, ORR, and a protocol-specified primary analysis of 21-day cycle (n=343), or capecitabine disease control rate. CONTESSA, an international, multi- 2500 mg/m2 per day on days 1 to 14 The median PFS was 9.8 months center phase 3 trial comparing tesetaxel of a 21-day cycle (n=342). The median with the tesetaxel combination vs 6.9 plus a reduced dose of capecitabine vs age was 56 years (range, 23-85) in the months with single-agent capecitabine capecitabine monotherapy, given at tesetaxel combination arm (n=343) (HR, 0.716; 95% CI, 0.573-0.895; the approved dose.2 The trial enrolled and 57 years (range, 29-84) in the P=.003; Figure 7). The treatment patients with hormone receptor–posi- capecitabine arm (n=342). More effect was similar across the protocol- tive, HER2-negative metastatic breast than 90% of patients had previously specified subgroups, including patients

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Figure 7. Progression- 1.0 free survival in the phase 3 5-year PFS 82.2% (95% Cl, 79.0-85.0) CONTESSA trial, which 0.8 compared tesetaxel plus a 5-year PFS 75.3% reduced dose of capecitabine 0.6 (95% Cl, 71.7-78.5) vs capecitabine alone in Events HR (95% CI) Log-Rank Test P Value patients with HER2-negative, 0.4 hormone receptor–positive Brentuximab 112 0.681 .002

Probability of PFS vedotin + AVD (0.534-0.867) metastatic breast cancer 0.2 who had previously received ABVD 158

a taxane. HER2, human 0.0 epidermal growth factor 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 receptor 2. Adapted from Time From Randomization (months) Number of Patients at Risk O’Shaughnessy J et al. Abstract Brentuximab 664 620 562 535 518 505 492 474 446 414 333 201 102 38 2 0 GS4-01. Presented at the 2020 vedotin + AVD San Antonio Breast Cancer ABVD 670 613 521 500 478 456 432 423 397 360 292 179 73 22 4 0 Symposium; December 8-11, 2020.2

with a disease-free interval of less alone arm (P=.0002). The 24-week capecitabine vs 8.3% of those treated than 24 months after neoadjuvant disease control rate was 67% in the with capecitabine), diarrhea (13.1% vs or adjuvant taxane therapy, patients tesetaxel combination arm vs 50% in 8.9%), hand‑foot syndrome (6.8% vs who had been previously treated with the capecitabine-alone arm (P<.0001). 12.2%), febrile neutropenia (13.1% a CDK4/6 inhibitor, and patients in The most frequent grade 3/4 vs 1.2%), fatigue (8.6% vs 4.5%), each geographic region. The ORR treatment-emergent AEs were neu- hypokalemia (8.6% vs 2.7%), leuko- was 57% in the tesetaxel combina- tropenia (which occurred in 70.9% penia (9.8% vs 0.9%), anemia (8% vs tion arm vs 41% in the capecitabine- of patients treated with tesetaxel plus 2.4%), nausea (6.2% vs 2.1%), and neuropathy (5.9% vs 0.9%). Grade 2 alopecia occurred in 8% of patients ABSTRACT SUMMARY PRIME 2 Randomised Trial (Postoperative Radio- treated with tesetaxel plus capecitabine therapy in Minimum-Risk Elderly): Wide Local Excision and Adjuvant vs 0.3% of patients treated with Hormonal Therapy ±Whole Breast Irradiation in Women ≥65 Years With capecitabine alone. Treatment discon- Early Invasive Breast Cancer: 10-Year Results tinuation owing to any AE occurred in 23.1% of patients in the tesetaxel The PRIME 2 phase 3 trial enrolled 1326 women ages 65 years or older with hormone combination arm vs 11.9% of patients receptor–positive, unilateral invasive breast cancer with a tumor size of 3 cm or less and in the capecitabine monotherapy arm. no regional lymph node involvement (Abstract GS2-03). Patients underwent breast- Treatment-related deaths occurred in conserving surgery and received neoadjuvant endocrine therapy. They were randomly 1.8% vs 0.9%, respectively. assigned to receive whole breast radiotherapy (n=658) or not to receive radiotherapy (n=668). The mean age was approximately 71 years. Ipsilateral breast tumor recurrence References was the primary endpoint. The 10-year ipsilateral breast tumor recurrence rate was 1. Seidman AD, Schwartzberg LS, Gudena VK, et al. Activity of tesetaxel, an oral taxane, given as a single- 9.8% without radiotherapy and 0.9% with radiotherapy (HR, 0.12; 95% CI, 0.05-0.31; agent in patients (pts) with HER2-, hormone receptor P<.0001). Regional recurrence was reported in 2.3% vs 0.5%, respectively (P=.014). No + (HR+) locally advanced or metastatic breast cancer J differences were seen for subgroups such as patients with contralateral breast cancer (MBC) in a phase 2 study [ASCO abstract 1042]. Clin Oncol. 2018;36(15 suppl). (1% vs 2.2%; P=.20), distant metastases (1.4% vs 3.6%; P=.07), or new cancers (exclud- 2. O’Shaughnessy J, Schwartzberg L, Piccart M, et al. ing breast cancer; 10.2% vs 8.7%; P=.41). Metastasis-free survival was 98.1% without Results from CONTESSA: a phase 3 study of tesetaxel radiotherapy and 96.4% with radiotherapy (P=.28). OS at 10 years was 80.4% vs 81.0%, plus a reduced dose of capecitabine versus capecitabine alone in patients with HER2-, hormone receptor+ respectively (P=.68). Most deaths were not attributable to breast cancer recurrence. (HR+) metastatic breast cancer (MBC) who have previ- ously received a taxane. Abstract presented at: the San Antonio Breast Cancer Symposium 2020 Virtual Meet- ing; December 8-11, 2020. Abstract GS4-01.

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Cost-Effectiveness of Neratinib for the Extended Adjuvant Treatment of Adult Patients With Early-Stage, HR+, HER2-Overexpressed/ Amplified Breast Cancer Who Initiated Neratinib Within 1 Year of Completing Trastuzumab in the US

he phase 3 ExteNET study primary stages of disease in early breast calculated based on drug acquisition, reported improvements in cancer: disease-free, local recurrence, administration, and monitoring, com- OS and IDFS with neratinib remission, distant recurrence, and bined with the expenses associated with vsT placebo in patients with hormone dead. The model corresponded with AE-related and health state–related use receptor–positive, HER2-positive early the primary and secondary endpoints of medical resources. Quality-adjusted breast cancer who initiated neratinib in the ExteNET trial.1 The treatment life-years (QALYs) were estimated less than 1 year after they completed effect in the model was based on 5-year per health state, and disutilities were adjuvant trastuzumab-based therapy.1 data from ExteNET for IDFS, the pro- applied per AE independent of treat- Dr Thor-Henrik Brodtkorb presented portion of local and distant recurrence, ment. Utility values for IDFS health data from a cost-effectiveness study and the number of AEs. Statistical state and diarrhea were estimated using of neratinib vs placebo in this patient extrapolation of IDFS and post-distant the EQ-5D-3L quality-of-life data col- population from the perspective of recurrence survival were derived from lected in ExteNET.1 Additional health a third-party payer in the United the 5-year ExteNET clinical trial data state utilities and AE disutilities were States.2 Additional analyses evaluated to obtain lifetime transition prob- identified from the literature. Costs cost-effectiveness for the subgroup of abilities. OS was modeled based on were adjusted to 2020 US dollars. patients in this population who did a combination of post–distant recur- One-way and probabilistic sensitivity not achieve a pCR after neoadjuvant rence survival and general population analyses and scenario analyses were therapy. mortality, assuming all cancer-related performed to investigate the robust- The investigators constructed a mortality would occur through the ness of the results. Markov model of costs and health out- distant recurrence health state. Mor- The increased cost of neratinib comes of neratinib and placebo over a tality unrelated to breast cancer was compared with placebo was partially lifetime horizon. The model consisted derived from US life tables. offset by decreased costs of subsequent of 5 health states that represent the The costs per treatment arm were therapy owing to improved patient

10

0

–10

–20 3 mg/kg every 4 weeks Ph1 3 mg/kg every 2 weeks Ph1 Best Change From Baseline 1 mg/kg every 2 weeks Ph1 –30 Figure 8. The cost results breakdown in 0.5an analysis mg/kg of everycost-effectiveness 2 weeks ofPh1 neratinib for extended adjuvant treatment of early-stage breast cancer. Adapted from Brodtkorb T et al. Abstract PS9-33. Presented at the 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020.2 0.15 mg/kg every 2 weeks Ph1 Responder 14 Clinical–40 Advances in Hematology & Oncology Volume 19, Issue 2, Supplement 9 February 2021 HIGHLIGHTS IN EARLY AND METASTATIC BREAST CANCER FROM THE 2020 SABCS

outcomes (Figure 8). The results of QALYs compared with placebo, for References the base case analysis showed that, a resulting cost per QALY gained of 1. Chan A, Moy B, Mansi J, et al. Final efficacy results of neratinib in HER2-positive hormone recep- overall, neratinib treatment gener- $29,500. One-way sensitivity analyses tor–positive early-stage breast cancer from the phase ated an additional 0.89 incremental found that the parameters that most III ExteNET Trial. Clin Breast Cancer. 2020;S1526- QALYs compared with placebo, for influenced the results were variations 8209(20)30258-5. 2. Brodtkorb T, McDade C, Lalla D, et al. Cost-effec- a resulting cost per QALY gained in treatment-related costs, efficacy, and tiveness of neratinib for the extended adjuvant treat- of $62,172. The results were robust health state utility values. The proba- ment of adult patients with early-stage, HR+, HER2- across multiple scenario analyses, with bilistic sensitivity analysis indicated overexpressed/amplified breast cancer who initiated neratinib within 1 year of completing trastuzumab in incremental cost-effectiveness ratios that the probability of neratinib being the US. Abstract presented at: the San Antonio Breast below $70,000. Among patients who cost-effective at a $100,000 per QALY Cancer Symposium 2020 Virtual Meeting; December did not achieve a pCR after neoadju- threshold exceeded 74% overall, and 8-11, 2020. Abstract PS9-33. vant therapy, neratinib treatment gen- was higher than 78% in patients with- erated an additional 1.27 incremental out a pCR after neoadjuvant therapy.

Primary Outcome Analysis of Invasive Disease–Free Survival for MonarchE: Abemaciclib Combined With Adjuvant Endocrine Therapy for High-Risk Early Breast Cancer

pproximately 20% of patients therapy with or without abemaciclib was efficacy in the subpopulation who have hormone recep- at 150 mg twice daily for 2 years. The with high Ki-67 expression levels. tor–positive, HER2-negative, median age of enrolled patients was 51 The 2-year IDFS rate was 91.6% with Aearly breast cancer will develop disease years (range, 22-89). The high Ki-67 abemaciclib plus endocrine therapy vs recurrence within 10 years.1 Elevated subgroup included all patients with 87.1% with endocrine therapy alone expression levels of the nuclear anti- an expression level of at least 20% (HR, 0.691; 95% CI, 0.519-0.920; gen Ki-67 are associated with higher (n=2498). The primary endpoint was P=.0111) for this subpopulation. risk.2 Abemaciclib is an oral, continu- IDFS. Secondary endpoints included Treatment-emergent AEs that ously dosed, CDK 4/6 inhibitor that distant relapse–free survival, OS, and were more common with abemaciclib is approved for the treatment of this safety. included diarrhea (82.6% vs 7.8%), patient population in combination A previously reported interim neutropenia (45.2% vs 5.2%), fatigue with endocrine therapy.3 In the open- analysis found a 2-year IDFS rate of (39.2% vs 16.6%), leukopenia (37.2% label phase 3 monarchE trial, abemaci- 92.2% with abemaciclib plus endo- vs 6.3%), abdominal pain (34.4% clib combined with endocrine therapy crine therapy vs 88.7% with endocrine vs 9.0%), nausea (28.5% vs 8.3%), was compared with endocrine therapy therapy alone (HR, 0.747; 95% CI, anemia (23.5% vs 3.4%), venous alone in 5637 patients with node- 0.598-0.932; P=.0096).4 For the cur- thrombosis events (2.4% vs 0.6%), positive, hormone receptor–positive, rent analysis, the cutoff date was July and interstitial lung disease (2.9% vs HER2-negative, high-risk early breast 8, 2020. The 2-year IDFS rates were 1.2%). Treatment discontinuation cancer.4 The patients had undergone 92.3% with abemaciclib plus endo- was required by 27.7% of patients surgery and, as indicated, radiotherapy crine therapy and 89.3% with endo- who received abemaciclib plus endo- and/or adjuvant/neoadjuvant chemo- crine therapy alone (HR, 0.713; 95% crine therapy vs 14.6% of those who therapy. Dr Joyce A. O’Shaughnessy CI, 0.583-0.871; P=.0009; Figure received endocrine therapy alone. reported results from the primary 9). This benefit was consistently seen The investigators concluded that outcome analysis for IDFS.5 across prespecified subgroups, includ- abemaciclib combined with endocrine The eligibility criteria encom- ing baseline number of nodes, histo- therapy continued to confer a clinically passed patients with 4 or more posi- logic tumor grade, tumor size, and meaningful improvement in IDFS and tive nodes, 1 to 3 nodes plus either a tumor stage. Two-year distant relapse– distant relapse–free survival compared tumor size of at least 5 cm or histologic free survival rates were 93.8% with with endocrine therapy alone for grade 3 disease, or 1 to 3 nodes plus a abemaciclib plus endocrine therapy vs patients with hormone receptor–posi- centrally tested Ki-67 expression level 90.8% with endocrine therapy alone tive, HER2-negative, node-positive, of at least 20%. Patients were ran- (HR, 0.687; 95% CI, 0.551-0.858; high-risk early breast cancer, including domly assigned to adjuvant endocrine P=.0009). A key secondary endpoint those with Ki-67 expression levels of

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Common Toxicities

Thrombocytopenia Neutropenia Anemia

Hypercholesteremia Rash Grade 3/4 AST elevation Any Grade ALT elevation Hyperlipidemia Figure 9. Invasive disease–freeMucositis survival in the phase 3 monarchE trial, which compared abemaciclib plus endocrine therapy vs endocrine therapy alone in patients with high-risk early breast cancer. ET, endocrine therapy; HR, hazard ratio; IA2, second interim analysis; IDFS, invasive disease–free survival.Infection Adapted from O’Shaughnessy J et al. Abstract GS1-01. Presented at the 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020.5 Hypertension 20% or higher. The safety profile of in early breast cancer: patient-level meta-analysis of Committee Members and Investigators. Abemaciclib the combination therapy was tolerable the randomised trials. Lancet. 2015;386(10001):1341- combined with endocrine therapy for the adjuvant 1352. treatment of HR+, HER2-, node-positive, high- and similar to that reported in previ0%- 2. 20%Dowsett M, Nielsen40% TO, A’Hern 60%R, et al; Interna-80%risk, early100% breast cancer (monarchE). J Clin Oncol. ous analyses. The monarchE study is tional Ki-67 in Breast Cancer Working Group. Assess- 2020;38(34):3987-3998. ongoing, and will continue until the ment of Ki67 in breast cancer: recommendations from 5. O’Shaughnessy JA, Johnston S, Harbeck N, et al. the International Ki67 in Breast Cancer working group. Primary outcome analysis of invasive disease-free final assessment of OS. J Natl Cancer Inst. 2011;103(22):1656-1664. survival for monarchE: abemaciclib combined with 3. Corona SP, Generali D. Abemaciclib: a CDK4/6 adjuvant endocrine therapy for high risk early breast References inhibitor for the treatment of HR+/HER2- advanced cancer. Abstract presented at: the San Antonio Breast breast cancer. Drug Des Devel Ther. 2018;12:321-330. Cancer Symposium 2020 Virtual Meeting; December 1. Early Breast Cancer Trialists’ Collaborative Group 4. Johnston SRD, Harbeck N, Hegg R, et al; monarchE 8-11, 2020. Abstract GS1-01. (EBCTCG). Aromatase inhibitors versus tamoxifen

The Neat-HER Virtual Registry: Results on HER2+ Breast Cancer Patients Receiving Neratinib as Extended Adjuvant Therapy

eat-HER is a virtual registry from the first 22 patients enrolled.1 records from providers on their behalf. based in the United States that Patients ages 18 years and older Patient data are then extracted from is currently enrolling patients who are currently receiving neratinib medical records and organized into a Nwith HER2-positive, early-stage breast as extended adjuvant therapy for data schema using optical character can­cer who are receiving neratinib as HER2-positive, early-stage breast recognition and named entity recogni- extended adjuvant therapy. The Neat- cancer are eligible. Those participating tion. Medical records for breast cancer- HER registry is designed to assess the in a clinical trial or with metastatic related treatment are included from characteristics and treatment history disease are excluded. Recruitment is the time of diagnosis to 1-year after of these patients; evaluate treatment occurring through email, private social enrollment in the registry. The data patterns, such as diarrhea prophylaxis; media groups, treating clinicians, and collected include demographics, medi- and inform clinical practice and qual- a texting program. cal history, visit information, medica- ity of care. Dr Hope S. Rugo reported Enrolled patients authorize inves- tions, comorbid conditions, laboratory on the registry design and early data tigators to request and collect medical results, vital sign measures, procedures,

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imaging, tumor characteristics, breast and trastuzumab plus pertuzumab in sible and provides useful information cancer surgery, receipt of therapy 91% (all but 1 patient also received on patient/tumor characteristics and (eg, radiotherapy, adjuvant therapy), docetaxel). At month 12, 50% of treatment patterns in a real-world neratinib duration, and diarrhea pro- patients had completed neratinib treat- cohort of patients receiving extended phylaxis. Patients have digital access ment, whereas 23% had discontinued adjuvant neratinib. Validation of this to their own consolidated medical treatment early, and 27% were still method is needed and could be used records for the duration of the study. receiving ongoing treatment at the to evaluate important trends such as De-identified longitudinal patient data time of data cutoff. Dose holds were the frequency of neoadjuvant therapy sets will undergo statistical analysis. reported for 27%, and dose modifica- and associated outcomes in a larger Since December 2018, 22 patients tions were reported for 18% during the population. have been enrolled. The median age course of neratinib treatment. Most is 51 years (range, 32-73). Of these, patients (95%) had discussed diarrhea Reference 73% have hormone receptor–positive prophylaxis with their health care pro- 1. Rugo HS, Vidal GA, Oestreicher N, et al. The Neat-HER Virtual Registry: results on HER2+ breast disease, and 73% have node-positive viders before the start of neratinib. cancer patients receiving neratinib as extended adjuvant disease. Adjuvant therapies include The investigators concluded that therapy. Abstract presented at: the San Antonio Breast trastuzumab plus paclitaxel in 9%, the Neat-HER virtual registry is fea- Cancer Symposium 2020 Virtual Meeting; December 8-11, 2020. Abstract PS7-61.

E2112: Randomized Phase 3 Trial of Endocrine Therapy Plus Entinostat/Placebo in Patients With Hormone Receptor–Positive Advanced Breast Cancer: A Trial of the ECOG-ACRIN Cancer Research Group

reclinical models suggest that sion of the estrogen receptor.1 Previ- aromatase inhibitor, in patients with resistance to endocrine therapy ous results of the phase 2 ENCORE advanced hormone receptor–positive, can be overcome with the use of 301 study showed improvements HER2-negative breast cancer.2 Protein Phistone deacetylase (HDAC) inhibitors­ in PFS and OS with the addition of lysine acetylation in peripheral blood that inhibit growth factor signaling entinostat, an oral class I HDAC mononuclear cells was associated with pathways and normalize gene expres- inhibitor, to exemestane, a steroidal prolonged PFS in the entinostat arm.

Figure 10. Progression-free 1.0 survival for entinostat plus exemestane vs placebo plus exemestane in the phase 3 E2112 0.8 trial of patients with hormone receptor–positive advanced 0.6 breast cancer. Adapted from Connolly RM et al. Abstract 0.4

GS4-02. Presented at the 2020 Survival Probability PET2+/PET4– San Antonio Breast Cancer 0.2 PET2–/PET4– Symposium; December 8-11, P<.0001 PET4+ 3 2020. 0.0 PET2+/PET4– 62 50 48 45 43 31 15 4 PET2–/PET4– 654 626 602 589 558 407 167 40 PET4+ 43 20 20 20 17 11 3 1 0 1 2 3 4 5 6 7 Progression-Free Survival (years)

Number of Event Censored Median Survival Subjects (95% CI) PET2+/PET4– 62 24.2% (15) 75.8% (47) Not reached PET2–/PET4– 654 8.3% (54) 91.7% (600) Not reached PET4+ 43 53.5% (23) 46.5% (20) 0.4 (0.3-NA)

Clinical Advances in Hematology & Oncology Volume 19, Issue 2, Supplement 9 February 2021 17 SPECIAL MEETING REVIEW EDITION

Dr Roisin M. Connolly pre- to show benefit over placebo plus hypophosphatemia (14% vs 1%), sented results from E2112, a phase 3 exemestane in this study. The median anemia (8% vs 2%), leukopenia (6% study that enrolled 608 patients with PFS was 3.3 months in the entinostat vs 1%), fatigue (4% vs 1%), diarrhea hormone receptor–positive, HER2- arm vs 3.1 months in the placebo (4% vs <1%), and thrombocytopenia negative advanced breast cancer whose arm (HR, 0.87; 95% CI, 0.67-1.13; (3% vs 1%). disease had progressed during treat- P=.30; Figure 10). The median OS ment with a nonsteroidal aromatase was 23.4 months vs 21.7 months, References inhibitor in the adjuvant or metastatic respectively (HR, 0.99; 95% CI, 0.82- 1. Sabnis GJ, Goloubeva OG, Kazi AA, Shah P, Brodie AH. HDAC inhibitor entinostat restores responsive- setting. The median age was 63 years 1.21; P=.94). The ORR was 4.6% in ness of letrozole-resistant MCF-7Ca xenografts to aro- (range, 29-91).3 All patients received the entinostat arm and 4.3% in the matase inhibitors through modulation of Her-2. Mol exemestane at 25 mg daily; addition- placebo arm. Cancer Ther. 2013;12(12):2804-2816. 2. Yardley DA, Ismail-Khan RR, Melichar B, et al. ally, patients were randomly assigned The pharmacodynamic analysis Randomized phase II, double-blind, placebo-controlled to either entinostat 5 mg weekly or confirmed that HDAC inhibition was study of exemestane with or without entinostat in post- placebo. The patient characteristics increased in the entinostat arm. The menopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on were well balanced between the study median change from baseline in lysine treatment with a nonsteroidal aromatase inhibitor. J arms. The co–primary endpoints were acetylation in peripheral blood mono- Clin Oncol. 2013;31(17):2128-2135. PFS and OS. The secondary endpoints nuclear cells was approximately 1.5- 3. Connolly RM, Zhao F, Miller KD, et al. E2112: randomized phase 3 trial of endocrine therapy plus included safety, ORR, and changes fold in the entinostat arm and 1-fold entinostat/placebo in patients with hormone receptor– in protein lysine acetylation status in in the placebo arm (P<.001). Grade positive advanced breast cancer. A trial of the ECOG- peripheral blood mononuclear cells 3/4 AEs with a higher incidence in the ACRIN cancer research group. Abstract presented at: the San Antonio Breast Cancer Symposium 2020 Vir- from baseline. entinostat arm than the placebo arm tual Meeting; December 8-11, 2020. Abstract GS4-02. Entinostat plus exemestane failed included neutropenia (20% vs <1%),

Highlights in Early and Metastatic Breast Cancer From the 2020 San Antonio Breast Cancer Symposium: Commentary

Joyce A. O’Shaughnessy, MD Celebrating Women Chair in Breast Cancer Research Baylor University Medical Center Director, Breast Cancer Research Program Texas Oncology US Oncology Dallas, Texas

n December 2020, the San Early Disease After 5 years of follow-up, treatment Antonio Breast Cancer Sympo- Neratinib with neratinib led to an absolute ben- sium (SABCS) was presented in The phase 3 ExteNET trial evaluated efit in invasive disease–free survival aI virtual format. Important data in the efficacy and safety of 12 months (IDFS) of 2.5% and an improvement both early and metastatic disease were of neratinib administered after in distant disease–free survival of provided for treatments such as nera- trastuzumab-based adjuvant therapy 1.7%.2 tinib, the cyclin-dependent kinase 4/6 in patients with early-stage human At the 2020 SABCS, Dr Frankie (CDK4/6) inhibitors abemaciclib and epidermal growth factor receptor 2 Holmes presented the final overall palbociclib, tesetaxel, entinostat, and (HER2)-positive breast cancer.1,2 More survival analysis of the ExteNET trial.3 ipatasertib plus paclitaxel. Studies also than 2800 patients were randomly The median follow-up was 8 years. The evaluated optimal use of neo/adjuvant assigned to treatment with oral nera- key finding that is relevant to clinical chemotherapy and radiotherapy. tinib at 240 mg per day or placebo. practice concerns the group of patients

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with estrogen receptor (ER)-positive/ findings from the ExteNET trial.2,6 was approximately $29,000. This is a HER2-positive breast cancer who were The CONTROL trial is evaluating 2 favorable cost-effectiveness analysis receiving preoperative therapy and still dose-escalation strategies. Dr Ruiz- in a very high–risk population. The had residual disease. Within a year of Borrego provided data for the first results make sense; prevention of a finishing adjuvant trastuzumab, the regimen, which begins with 120 mg (3 metastatic recurrence should lead to patients received neratinib or placebo. pills), increases to 160 mg (4 pills), and a large cost savings. Although there is Among these patients, neratinib then continues with 240 mg (6 pills), additional expense associated with a was associated with a 9% absolute with loperamide given as needed. The year of treatment with neratinib, the improvement in overall survival. This dose was increased every week. There effect on the overall cost to the health finding is drawn from an exploratory was the option to increase the dose care system is favorable. analysis of a small cohort of patients more slowly, with increases made only Dr Hope Rugo is the principal (n=295). However, it is the key cohort if the patient was tolerating the lower investigator of the Neat-HER Virtual of clinical interest. This improvement dose. With this regimen, the rate of Registry.8 This prospective virtual in survival is important. One issue grade 3 diarrhea was 13%, as opposed registry is gathering data from patients with the ExteNET trial is that the to approximately 40% in the Exte- with early-stage HER2-positive breast patients had not received preoperative NET study,2 a dramatic reduction. The cancer treated with neratinib in the pertuzumab nor trastuzumab emtan- duration of grade 3 diarrhea was short, extended adjuvant setting. Patients are sine (T-DM1) in the adjuvant setting. at 2.5 days. The percentage of patients recruited from physicians’ practices or Data from the NALA trial showed that who had to stop neratinib because of through social media. Patients provide in the metastatic setting, neratinib is diarrhea was 3.3%. It is important for informed consent for the investigators non–cross-resistant with pertuzumab the patient to take loperamide after to compile medical records to assess and T-DM1.4 Based on these data in each loose stool. factors such as demographics, tumor the metastatic setting, it would there- The dose-escalation scheme has characteristics, treatments, outcomes, fore be expected that treatment with been a sea change in terms of the feasi- and dose modifications. Using artifi- a pan-HER tyrosine kinase inhibitor bility and tolerability of neratinib. An cial intelligence methods, the data are would be non–cross-resistant with important finding from the ExteNET extracted virtually from the patient’s antibody-based therapy. Extrapolat- trial is that, with just 1 year of adjuvant records and entered into this virtual ing the metastatic data to the curative neratinib, high-risk patients accrue a registry. setting, it appears likely that neratinib reduced risk of recurrence and death The goals are to examine real- would have a positive impact on out- that increases after completing nera- world evidence among patients receiv- come even after treatment with prior tinib.2 Therefore, patients continue to ing extended adjuvant neratinib. These pertuzumab and T-DM1 among high- receive more benefit as the years go on, data will be used to evaluate the feasi- risk hormone receptor (HR)-positive which is very important. This observa- bility of delivering neratinib, including patients. Given the improvement in tion speaks to the synergy of inhibiting the use of dose-escalation strategies survival, albeit in an exploratory subset the HER family along with the ER. and loperamide to ameliorate diarrhea, analysis, I believe that 1 year of nera- Neratinib represents an important the percentage of patients who reach tinib should be offered to high-risk therapeutic opportunity for high-risk and maintain the upper dose levels, the patients who have residual disease that patients who still have considerable duration of neratinib, the need for dose is node-positive or larger cancers that residual disease after standard preop- reductions and treatment discontinua- are node-negative after treatment with erative therapy. tion, and outcome. Now that there is preoperative chemotherapy, trastu- Dr Thor-Henrik Brodtkorb pre- an effective approach to decreasing the zumab, pertuzumab, and T-DM1, in sented a cost-effectiveness analysis of serious diarrhea that can interfere with combination with endocrine therapy. extended adjuvant neratinib, based administration of neratinib, it will be Dr Manuel Ruiz-Borrego pro­ on data from the ExteNET trial.7 interesting to see the data from this vided updated data from the CON- The analysis showed that neratinib is registry. TROL trial, which examined strate- cost-effective among patients in the gies to control diarrhea associated ExteNET trial at highest risk, meaning CDK4/6 Inhibitors with neratinib.5 An earlier report of those who are HR-positive/HER2- The monarchE trial was an important the CONTROL trial showed that positive and who had residual disease study of adjuvant treatment with the antidiarrheal prophylaxis or a dose- after prior adjuvant trastuzumab-based CDK4/6 inhibitor abemaciclib.9 My escalation schedule reduced the rate, therapy. These high-risk patients are colleagues and I presented the primary severity, and duration of grade 3 or those most relevant to clinical practice. outcome analysis of IDFS per protocol higher diarrhea, as compared with The cost of a quality-adjusted life-year specification. The median follow-up

Clinical Advances in Hematology & Oncology Volume 19, Issue 2, Supplement 9 February 2021 19 SPECIAL MEETING REVIEW EDITION

was 19 months. The 2-year rate of in monarchE are likely to have early benefit of chemotherapy was derived IDFS was 92.3% with abemaciclib recurrence of disease. Abemaciclib from ovarian suppression. In the plus endocrine therapy vs 89.3% with and palbociclib are different CDK4/6 RxPONDER trial, only 16% of endocrine therapy alone. The hazard inhibitors. Abemaciclib is adminis- patients in the endocrine therapy– ratio was 0.713, which was statistically tered continuously, and it has a broader alone arm received an LHRH agonist. significant (P=.0009). The analyses also spectrum of action beyond CDK4/6, Therefore, the patients did not receive showed that the Ki-67 level does not inhibiting other CDKs and additional the current definition of optimal impact the benefit seen with abemaci- kinases. Based on results from PENEL- endocrine therapy. It is necessary to clib. The level of Ki-67 was prognostic, OPE-B,10 as well as the PALLAS trial,11 individualize treatment for premeno- but not predictive of abemaciclib adjuvant palbociclib does not improve pausal patients because not all will benefit. The risk of early recurrence the outcome of early-stage breast can- require chemotherapy. Chemotherapy was increased in patients with a higher cer patients. Mature results are awaited will probably not benefit premeno- Ki-67 (≥20%) and decreased in those from monarchE, as well as the ongoing pausal women with 1 or 2 nodes with a lower Ki-67. These data from NATALEE trial evaluating 3 years of and an otherwise indolent biology the primary outcome analysis of IDFS adjuvant .12 of grade 1 or 2 disease, whose breast are encouraging. Longer follow-up cancers are strongly ER-positive/ is needed because at the time of this Adjuvant Chemotherapy progesterone receptor–positive and analysis, most patients were still and the Recurrence Score have a low Ki-67, and who are willing receiving adjuvant abemaciclib. The Dr Kevin Kalinsky provided results to undergo oophorectomy or receive investigators will assess outcome after from the SWOG S1007 RxPONDER an LHRH agonist together with an abemaciclib treatment ends. trial.13 This important phase 3 trial aromatase inhibitor, which is the Dr Sibylle Loibl presented results enrolled premenopausal and post- optimal endocrine therapy. Data from from the phase 3 PENELOPE-B trial, menopausal women with hormone the RxPONDER trial suggest that which evaluated the CDK4/6 inhibi- receptor–positive/HER2-negative dis- chemotherapy had a cytotoxic effect tor palbociclib plus endocrine therapy ease and 1 to 3 positive lymph nodes. on the ovaries in some premenopausal in patients with hormone-receptor– Patients had a recurrence score between patients. Interestingly, a recent study positive, HER2-negative primary 0 and 25. They were randomly assigned showed that high recurrence scores breast cancer at high risk of relapse to chemotherapy followed by endo- are driven by less sensitivity to endo- after neoadjuvant chemotherapy.10 crine therapy or endocrine therapy crine therapy, in other words, less ER These high-risk patients had received alone. The primary endpoint was to transcriptional activity in the breast preoperative chemotherapy for ER- determine the effect of chemotherapy cancer.14 This study showed that high positive/HER2-negative breast cancer on IDFS and to assess whether the recurrence scores are not driven pre- and had residual disease at definitive effect corresponds with the recurrence dominantly by proliferation, but rather surgery. They were randomly assigned score. In the overall population, IDFS by the expected endocrine therapy to receive endocrine therapy with 1 was 92.4% in the chemotherapy arm sensitivity of the cancer. The cassette year of palbociclib or placebo. The vs 91.0% in the control arm (P=.026). of ER-related genes in the recurrence primary endpoint was IDFS. The An analysis according to menopausal score are less highly expressed. There- results of PENELOPE-B showed an status showed that premenopausal fore, the higher the recurrence score, early improvement with palbociclib women benefited from chemotherapy. the less that patients will benefit from that was not sustained. Unfortunately, The absolute difference in the 5-year endocrine therapy and the more they there was no statistically significant rate of IDFS was 3.9% in premeno- will need the chemotherapy. Patients improvement. This sobering result pausal patients with a recurrence score with lower recurrence scores may still suggests that palbociclib appears to of 0 to 13 and 6.2% in those with a have a risk of recurrence because they lack a cytotoxic mechanism that would recurrence score of 14 to 25. Post- have node-positive disease, but they lead to a durable impact on IDFS. menopausal women did not derive any have higher expression and biologic It is not known whether the same benefit from adjuvant chemotherapy, activity of the ER pathway. In my view, outcome will be seen with abemaci- regardless of their recurrence score. data from the RxPONDER trial sug- clib, another CDK4/6 inhibitor. In These results raise the question gest that optimal endocrine therapy is the monarchE trial, abemaciclib will of whether treatment with endocrine an option for premenopausal patients be given for 2 years.9 The popula- therapy that included a luteinizing with 1 to 3 positive lymph nodes who tion enrolled in the monarchE trial hormone-releasing hormone (LHRH) have lower recurrence scores. is at even higher risk than that in the agonist would have decreased the Another point raised by the PENELOPE-B trial.9,10 The patients impact of chemotherapy if the main RxPONDER trial is that among the

20 Clinical Advances in Hematology & Oncology Volume 19, Issue 2, Supplement 9 February 2021 HIGHLIGHTS IN EARLY AND METASTATIC BREAST CANCER FROM THE 2020 SABCS

overall population, the magnitude of a healthy 65-year-old woman, a 10% not extruded from cells via P-glyco- the benefit of chemotherapy did not risk of in-breast recurrence over 10 protein (Pgp). Tesetaxel is absorbed correspond with rising recurrence years—with the potential for a contin- from the gastrointestinal (GI) tract scores. The data showed that prognosis ued increased risk out to 20 years—is and is not extruded back into the GI was worse among patients with higher too high. In contrast, for a 65-year-old tract by Pgp, leading to improved recurrence scores, and these patients woman with substantial comorbidi- oral bioavailability of tesetaxel. In the obtained a greater absolute benefit ties, with a life expectancy of less than CONTESSA trial, the addition of tes- from chemotherapy even though the 10 years, a 10% risk over 10 years may etaxel to capecitabine led to a signifi- proportional impact on disease-free be acceptable. For a woman ages 80 cant improvement in progression-free survival was the same across the years or older with grade 1 or 2, node- survival of approximately 3 months spectrum of the recurrence scores. negative breast cancer sized 3 cm or compared with capecitabine alone Among patients with a higher risk of less, with clear margins, the decision among patients with ER-positive, recurrence, chemotherapy will lead to forgo radiation therapy may be very HER2-negative metastatic breast can- to a higher absolute improvement in reasonable, as long as she is able to cer that is resistant to endocrine ther- disease-free survival, even though pro- tolerate endocrine therapy. Radiation apy. Tesetaxel was administered as 27 portional risk reduction is the same in therapy tends to be recommended to mg/m2 orally once every 3 weeks with women with high and low recurrence women who are younger and health- capecitabine 825 mg/m2 orally twice scores. In the RxPONDER trial, the ier, and who have a longer lifespan, daily for 14 days of a 21-day cycle. recurrence score was not predictive particularly now with the availability The safety profile was accept- of chemotherapy benefit, but it was of accelerated whole breast radiation able. Approximately 13% of patients prognostic. and partial breast irradiation options treated with tesetaxel plus capecitabine that shorten treatment duration. developed febrile neutropenia. This Breast Radiotherapy toxicity can be ameliorated by holding Dr Ian Kunkler presented results Metastatic Disease capecitabine during the neutrophil of the PRIME 2 trial, which evalu- Neratinib nadir if patients develop concomitant ated whether postoperative whole Dr Cristina Saura provided updated GI toxicity. Dose reductions of tesetaxel breast radiotherapy can be omitted in data from the phase 3 NALA trial of and/or the use of granulocyte colony– low-risk older patients.15 The study neratinib plus capecitabine vs lapa- stimulating factor in the capecitabine enrolled patients ages 65 years and tinib plus capecitabine in patients off-days were successful in preventing older with early breast cancer that was with HER2-positive metastatic breast treatment delays and discontinuations. HR-positive. Patients had grade 1 or 2 cancer.4,17 This analysis evaluated Tesetaxel was associated with low rates breast cancer that was node-negative. patients who entered the study with of neurotoxicity and alopecia (28% They had already undergone definitive stable treated brain metastases. Pro- overall, with grade 2 cases in 8%). surgery, and the breast cancer tumor gression-free survival was improved If tesetaxel is approved by the US was no larger than 3 cm. All patients with neratinib compared with lapa- Food and Drug Administration, it received adjuvant endocrine therapy tinib among patients with central will be helpful to have the combina- with wide local excision with clear nervous system (CNS) metastases. tion of capecitabine plus tesetaxel as margins. They were randomly assigned In addition, neratinib had a greater an all-oral therapeutic option in ER- to receive treatment with whole breast impact on control of CNS disease. positive, HER2-negative patients who radiation or no radiotherapy. The The overall analysis of the NALA trial require combination chemotherapy. A 10-year rate of local recurrence was found that progression-free survival second oral taxane regimen consists of 9.8% without radiotherapy vs 0.9% was significantly higher with neratinib oral paclitaxel plus oral encequidar.19 with radiotherapy. Therefore, the risk plus capecitabine.4 This improvement Encequidar inhibits Pgp, allowing of an in-breast recurrence was approxi- was maintained in patients with brain for GI absorption of paclitaxel. Cur- mately 1% per year among patients metastasis. This analysis of the NALA rently, oral paclitaxel with encequidar who did not receive whole breast radia- trial supports the combination of is administered 3 times weekly, and tion. There was no impact on overall neratinib and capecitabine as an effec- involves a higher pill burden. Tesetaxel survival. tive option for patients with CNS is given as a regimen of 2 to 5 pills once These data corroborate other stud- metastases. every 3 weeks. Overall, the oral ies and support the current standard of will be a welcome addition as treat- care,16 where we have the option to dis- Tesetaxel ment options, postponing the need for cuss omitting radiation therapy in low- The CONTESSA trial evaluated the central venous access and intravenous risk patients ages 70 years and older. In novel oral taxane tesetaxel,18 which is chemotherapy.

Clinical Advances in Hematology & Oncology Volume 19, Issue 2, Supplement 9 February 2021 21 SPECIAL MEETING REVIEW EDITION

Entinostat paclitaxel alone. This outcome differed 2017;18(12):1688-1700. 3. Holmes FA, Moy B, Delaloge S, et al. Continued Dr Roisin Connolly presented long- from that of the LOTUS trial, which efficacy of neratinib in patients with HER2-positive awaited results from the phase 3 E2112 demonstrated a favorable impact on early-stage breast cancer: final overall survival analysis trial, which compared entinostat plus progression-free survival, as well as a from the randomized phase 3 ExteNET trial. Abstract presented at: the San Antonio Breast Cancer Sympo- exemestane vs exemestane plus placebo trend toward improvement in overall sium 2020 Virtual Meeting; December 8-11, 2020. in patients with metastatic breast cancer survival with combined paclitaxel plus Abstract PD3-03. that was resistant to a nonsteroidal aro- ipatasertib.24 The negative results of 4. Saura C, Oliveira M, Feng YH, et al; NALA Investi- 20 gators. Neratinib plus capecitabine versus lapatinib plus matase inhibitor. Unfortunately, the the IPATunity130 trial do not neces- capecitabine in HER2-positive metastatic breast cancer addition of entinostat did not improve sarily mean that ipatasertib, and inhi- previously treated with ≥ 2 HER2-directed regimens: progression-free survival or overall bition of the AKT, is a failed strategy in phase III NALA trial. J Clin Oncol. 2020;38(27):3138- 3149. survival in this trial. The ENCORE triple-negative breast cancers. AKT is 5. Ruiz-Borrego M, Chan A, Marx G, et al. Bringing trial had previously shown that add- active and promotes therapy resistance diarrhea under CONTROL: dose escalation reduces ing the histone deacetylase (HDAC) in a majority of triple-negative breast neratinib-associated diarrhea and improves tolerability in HER2-positive early-stage breast cancer. Abstract inhibitor entinostat to exemestane cancers. An earlier phase 1b trial by presented at: the San Antonio Breast Cancer Sympo- favorably impacted survival in patients Professor Peter Schmid evaluated a sium 2020 Virtual Meeting; December 8-11, 2020. whose breast cancer was resistant to triplet combination of ipatasertib, Abstract PS13-20. 21 6. Barcenas CH, Hurvitz SA, Di Palma JA, et al; a nonsteroidal aromatase inhibitor. atezolizumab, and paclitaxel or nab- CONTROL Study Investigators. Improved tolerability Preclinically, entinostat remodels the paclitaxel as first-line therapy for of neratinib in patients with HER2-positive early- chromatin and can overcome endo- metastatic triple-negative breast cancer stage breast cancer: the CONTROL trial. Ann Oncol. 22 26 2020;31(9):1223-1230. crine therapy resistance. patients. The response rate was 73%, 7. Brodtkorb T, McDade C, Lalla D, et al. Cost-effec- The reason for the difference in which is encouraging, and additional tiveness of neratinib for the extended adjuvant treat- outcome between the E2112 trial and trials of this triplet utilizing nab- ment of adult patients with early-stage, HR+, HER2- overexpressed/amplified breast cancer who initiated the ENCORE trials is not known. paclitaxel are ongoing. Another AKT neratinib within 1 year of completing trastuzumab in Previous use of a CDK4/6 inhibitor inhibitor, capivasertib, is undergoing the US. Abstract presented at: the San Antonio Breast was reported in 37% of patients in the evaluation in combination with pacli- Cancer Symposium 2020 Virtual Meeting; December 8-11, 2020. Abstract PS9-33. entinostat arm and 33% of patients taxel in triple-negative breast cancer 8. Rugo HS, Vidal GA, Oestreicher N, et al. The in the placebo arm. The ENCORE patients in a phase 3 trial enrolling a Neat-HER Virtual Registry: results on HER2+ breast trial was conducted before the avail- nongenomically selected population.25 cancer patients receiving neratinib as extended adjuvant therapy. Abstract presented at: the San Antonio Breast ability of CDK4/6 inhibitors, while Cancer Symposium 2020 Virtual Meeting; December approximately one-third of patients Disclosure 8-11, 2020. Abstract PS7-61. in the E2112 trial had received a Dr O’Shaughnessy has received honoraria 9. O’Shaughnessy JA, Johnston S, Harbeck N, et al. Primary outcome analysis of invasive disease-free prior CDK4/6 inhibitor. Whether the for consulting and advisory boards from survival for monarchE: abemaciclib combined with weekly administration of entinostat AbbVie, Agendia, Amgen Biotechnol- adjuvant endocrine therapy for high risk early breast inhibited HDAC enough to increase ogy, AstraZeneca, Bristol Myers Squibb, cancer. Abstract presented at: the San Antonio Breast Celgene Corporation, Eisai, Genentech, Cancer Symposium 2020 Virtual Meeting; December the response to endocrine therapy will 8-11, 2020. Abstract GS1-01. be evaluated through analysis of blood Genomic Health, GRAIL, Immunomed- 10. Loibl S, Marmé F, Martin M, et al. Phase III study biomarkers of histone acetylation in ics, Heron Therapeutics, Ipsen Biophar- of palbociclib combined with endocrine therapy (ET) maceuticals, Jounce Therapeutics, Lilly, in patients with hormone-receptor-positive (HR+), patients who received entinostat. HER2-negative primary breast cancer and with high Merck, Myriad Genetics, Novartis, relapse risk after neoadjuvant chemotherapy (NACT): Ipatasertib and Paclitaxel Odonate Therapeutics, Pfizer, Puma first results from PENELOPE-B. Abstract presented at: Biotechnology, Prime Oncology, Roche, the San Antonio Breast Cancer Symposium 2020 Vir- Dr Rebecca Dent presented primary tual Meeting; December 8-11, 2020. Abstract GS1-02. results from cohort A of the phase 3 Seattle Genetics, Syndax Pharmaceuti- 11. Mayer EL, Dueck AC, Martin M, et al. Palboci- IPATunity130 trial, which evaluated cals, and Takeda. clib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, first-line therapy with the selective open-label, randomised, phase 3 study. Lancet Oncol. AKT inhibitor ipatasertib plus pacli- References 2021;22(2):212-222. taxel vs paclitaxel plus placebo.23 The 1. Chan A, Delaloge S, Holmes FA, et al; ExteNET 12. Slamon DJ, Fasching PA, Patel R, et al. NATALEE: Study Group. Neratinib after trastuzumab-based adju- phase III study of ribociclib (RIBO) + endocrine trial enrolled patients with a genomic vant therapy in patients with HER2-positive breast therapy (ET) as adjuvant treatment in hormone alteration that activated the phos- cancer (ExteNET): a multicentre, randomised, double- receptor–positive (HR+), human epidermal growth phoinositide 3-kinase pathway, includ- blind, placebo-controlled, phase 3 trial. Lancet Oncol. factor receptor 2–negative (HER2–) early breast can- 2016;17(3):367-377. PIK3CA AKT1 cer (EBC) [ASCO abstract TPS597]. J Clin Oncol. ing mutations in , , or 2. Martin M, Holmes FA, Ejlertsen B, et al; ExteNET 2010;37(5 suppl). PTEN. Ipatasertib plus paclitaxel did Study Group. Neratinib after trastuzumab-based 13. Kalinsky K, Barlow WE, Meric-Bernstam F, et al. not improve progression-free survival adjuvant therapy in HER2-positive breast cancer First results from a phase III randomized clinical trial of (ExteNET): 5-year analysis of a randomised, double- standard adjuvant endocrine therapy (ET) +/- chemo- or overall survival compared with blind, placebo-controlled, phase 3 trial. Lancet Oncol. therapy (CT) in patients (pts) with 1-3 positive nodes,

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hormone receptor-positive (HR+) and HER2-negative 18. O’Shaughnessy J, Schwartzberg L, Piccart M, et al. Clin Oncol. 2013;31(17):2128-2135. (HER2-) breast cancer (BC) with recurrence score (RS) Results from CONTESSA: a phase 3 study of tesetaxel 22. Connolly RM, Rudek MA, Piekarz R. Entinostat: a < 25: SWOG S1007 (RxPONDER). Abstract pre- plus a reduced dose of capecitabine versus capecitabine promising treatment option for patients with advanced sented at: the San Antonio Breast Cancer Symposium alone in patients with HER2-, hormone receptor + breast cancer. Future Oncol. 2017;13(13):1137-1148. 2020 Virtual Meeting; December 8-11, 2020. Abstract (HR+) metastatic breast cancer (MBC) who have previ- 23. Dent R, Kim SB, Oliveira M, et al. Double-blind GS3-00. ously received a taxane. Abstract presented at: the San placebo (PBO)-controlled randomized phase III trial 14. Dowsett M, Sestak I, Cuzick J. Calibration of Antonio Breast Cancer Symposium 2020 Virtual Meet- evaluating first-line ipatasertib (IPAT) combined with CTS5 in women with early estrogen receptor-positive ing; December 8-11, 2020. Abstract GS4-01. paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered breast cancer. J Clin Oncol. 2021;39(4):338-339. 19. Umanzor G, Rugo HS, Barrios FJ, et al. Oral locally advanced unresectable or metastatic triple- 15. Kunkler IH, Williams LJ, Jack W, et al. Prime 2 ran- paclitaxel and encequidar (oPac+E) versus IV paclitaxel negative breast cancer (aTNBC): primary results from domised trial (postoperative radiotherapy in minimum- (IVPac) in the treatment of metastatic breast cancer IPATunity130 Cohort A. Abstract presented at: the San risk elderly): wide local excision and adjuvant hormonal (mBC) patients (study KX-ORAX-001): progression Antonio Breast Cancer Symposium 2020 Virtual Meet- therapy +/- whole breast irradiation in women =/> 65 free survival (PFS) and overall survival (OS) updates. ing; December 8-11, 2020. Abstract GS3-04. years with early invasive breast cancer: 10 year results. Abstract presented at: the San Antonio Breast Cancer 24. Kim SB, Dent R, Im SA, et al; LOTUS investigators. Abstract presented at: the San Antonio Breast Cancer Symposium 2020 Virtual Meeting; December 8-11, Ipatasertib plus paclitaxel versus placebo plus paclitaxel Symposium 2020 Virtual Meeting; December 8-11, 2020. Abstract PD1-08. as first-line therapy for metastatic triple-negative breast 2020. Abstract GS2-03. 20. Connolly RM, Zhao F, Miller KD, et al. E2112: cancer (LOTUS): a multicentre, randomised, double- 16. Hughes KS, Schnaper LA, Bellon JR, et al. randomized phase 3 trial of endocrine therapy plus blind, placebo-controlled, phase 2 trial. Lancet Oncol. Lumpectomy plus tamoxifen with or without irradia- entinostat/placebo in patients with hormone receptor- 2017;18(10):1360-1372. tion in women age 70 years or older with early breast positive advanced breast cancer. A trial of the ECOG- 25. Schmid P, Abraham J, Chan S, et al. Capivasertib cancer: long-term follow-up of CALGB 9343. J Clin ACRIN cancer research group. Abstract presented at: plus paclitaxel versus placebo plus paclitaxel as first-line Oncol. 2013;31(19):2382-2387. the San Antonio Breast Cancer Symposium 2020 Vir- therapy for metastatic triple-negative breast cancer: the 17. Saura C, Ryvo L, Hurvitz S, et al. Impact of nera- tual Meeting; December 8-11, 2020. Abstract GS4-02. PAKT trial. J Clin Oncol. 2020;38(5):423-433. tinib on outcomes in HER2-positive metastatic breast 21. Yardley DA, Ismail-Khan RR, Melichar B, et al. 26. Schmid P, Loirat D, Savas P, et al. Phase Ib study cancer patients with central nervous system disease Randomized phase II, double-blind, placebo-controlled evaluating a triplet combination of ipatasertib (IPAT), at baseline: findings from the phase 3 NALA trial. study of exemestane with or without entinostat in post- atezolizumab (atezo), and paclitaxel (PAC) or nab-PAC Abstract presented at: the San Antonio Breast Cancer menopausal women with locally recurrent or metastatic as first-line (1L) therapy for locally advanced/metastatic Symposium 2020 Virtual Meeting; December 8-11, estrogen receptor-positive breast cancer progressing on triple-negative breast cancer (TNBC) [AACR abstract 2020. Abstract PD13-09. treatment with a nonsteroidal aromatase inhibitor. J CT049]. Can Res. 2019;79(13 suppl).

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