Therapies for EGFR-Mutated NSCLC Current Approvals and Indications1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
First-Generation Second-Generation Reversible EGFR TKIs Irreversible EGFR TKIs
Ge tinib Erlotinib Afatinib Dacomitinib
• 1L for EGFR exon 19 • 1L for EGFR exon 19 • 1L for EGFR exon 19 • 1L for EGFR exon 19 deletions or L858R, S768I, deletions or L858R deletions or L858R deletions or L858R L861Q, and/or G719X mutations mutations mutations mutations
Metastatic
Third-Generation EGFR TKI + VEGFR2 Irreversible EGFR TKI Antagonist
Osimertinib Erlotinib + Ramucirumab
• 1L for EGFR exon 19 deletions or L858R mutations • Treatment of T790M-positive NSCLC with progression • 1L for EGFR exon 19 deletions or L858R mutations on or after EGFR TKI therapy
Early Stage Third-Generation Irreversible EGFR TKI • Adjuvant therapy after tumor resection in patients with stage IB-IIIA NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations Osimertinib
1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications. Molecular Testing Guidelines for NSCLC Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
Why Test Lung Cancer Patients for Genomic Alterations?
• Genomic alterations are common in nonsquamous NSCLC (approximately 50%) • Targeted therapies produce better treatment outcomes (eg, higher response rates, improved quality of life) compared with chemotherapy as treatment of NSCLC with genomic alterations • Immunotherapy has low e cacy and a high risk of serious adverse events in patients with NSCLC with molecular driver alterations
Which Molecular Targets Are Relevant for Testing in NSCLC?
Molecular alterations to test for in patients with newly diagnosed stage IV NSCLC
Genotypes with approved Genotypes with emerging targeted therapies targeted therapies
q EGFR mutations q EGFR exon 20 mutations q ALK rearrangements q HER2 mutations q ROS1 rearrangements q KRAS G12C mutations q BRAF V600E mutations q MET amplifications q NTRK fusions q Many other promising targets with q MET exon 14 skipping mutations matched therapies are undergoing q RET fusions investigation in trials
Molecular alterations to test for in patients with resectable stage IB-IIIA NSCLC • EGFR mutations (exon 19 deletions or exon 21 L858R mutations)
Which Molecular Testing Techniques Should Be Used for Detection of Di erent Molecular Alterations in NSCLC?1
EGFR MET HER2 BRAF KRAS ALK ROS1 MET RET PD-L1 Protein NTRK (Sensitizing Exon 14 Mutation Mutation Mutation Rearrangement Rearrangement Ampli cation Rearrangement Expression Fusion and T790M) Mutation
Tissue PCR + + – + + – – – – – – sequencing
Tissue allele–speci c ++ ++ ++ ++ ++ – – – – – – PCR sequencing
Tissue FISH – – – – – ++ ++ ++ ++ – ++ Tissue IHC – – – – – ++ – – – ++ + Tissue NGS ++ ++ ++ ++ ++ + + + + – + ctDNA PCR + + + + + + – – + – – ctDNA NGS + + + + + + + + + – + Tissue RNA + + ++ + + ++ ++ + ++ – ++
++: Highest sensitivity +: Lower sensitivity (higher chance of false negative) –: Not useful
The speci c genes covered vary by assay; therefore, it is important to know which genes/alterations are covered by each assay Molecular Testing Guidelines for NSCLC Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
When Should Liquid Biopsies Be Considered for Use?
• NCCN guidelines recommend plasma-based testing for all patients with advanced-stage, treatment-naïve lung cancer for whom tissue sampling may be infeasible or insufficient 75% • Recent studies found that simultaneously adding plasma ctDNA analysis to tissue testing more actionable enhanced the chances of detecting a relevant actionable mutation mutations found • Based on these findings, it is reasonable to consider plasma-based testing for every patient with with tissue + advanced-stage, treatment-naïve lung cancer who has a tissue biopsy plasma vs • A new tissue biopsy and/or ctDNA plasma test also needs to occur when patients with tissue alone genotype-directed NSCLC develop resistance/disease progression while on targeted TKI therapy
cfDNA Use liquid biopsy when • Biopsy is insufficient • Biopsy is not feasible • cfDNA is a more suitable sample than biopsy Timing considerations
Plasma Body Fluids
Benefits ü Minimally invasive, highly accessible ü Multiple sampling easy: enables real-time monitoring ü Systemic approach: may effectively capture tumor heterogeneity
Staging and Therapy Screening Diagnosis Monitoring prognosis selection Molecular Testing Guidelines for NSCLC Latest Updates, Best Practices, and Patient-Reported Insights1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
Why should patients be educated about the importance of molecular testing and informed about their results?
Shortcomings exist in current molecular testing rates as well as patient awareness about testing and their testing results
Real-World, Patient-Reported Biomarker Data2,a
2018, % 2019, % 2020 (Q1-Q3), % Molecular Testing/Biomarker Testing (n) (n) (n)
27.21 21.22 21.75 I don't know if the cancer was tested (151) (222) (122) 12.25 10.13 10.16 The cancer was not tested (68) (106) (57) 48.11 56.12 58.65 The cancer was tested and I know the results (267) (587) (329) 12.43 12.52 9.45 The cancer was tested and I don't know the results (69) (131) (53) 100 21.22 100 Total (555) (1,046) (561)
a Patient self-reported data obtained from GO2 Foundation for Lung Cancer's 1-800 help line. Population comprised mostly of US-based patients (approx. 95%) and includes those being treated at community cancer centers and academic centers.
1. https://www.uptodate.com/contents/personalized-genotype-directed-therapy-for-advanced-non-small-cell-lung-cancer. 2. Provided courtesy of GO2 Foundation for Lung Cancer. Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC New Role for Adjuvant EGFR-Targeted Therapy1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
Localized/early stage Regional/locally advanced
Stage IB Stage II Stage IIIA
• About 30% of patients with NSCLC present with resectable disease at diagnosis1-3 • Surgery with curative intent is the primary treatment for these patients4 • Adjuvant cisplatin-based chemotherapy is recommended for patients with resectable stage II-IIIA NSCLC and select patients with stage IB disease5 • Adjuvant impact depends on stage, and there is much room for improvement6 • Rates of disease recurrence following surgery remain high across disease stages, regardless of postoperative chemotherapy use7
On December 18, 2020, the FDA approved osimertinib NSCLC 5-Year Overall Survival New for adjuvant therapy after tumor resection in patients with NSCLC whose tumors have EGFR exon 19 deletions Stage I (IB) Stage II Stage III Approval or exon 21 L858R mutations, as detected by an CALGB 34 57 9 Death (%) with/without chemotherapy Survival without chemotherapy FDA-approved test JBR.10 30 7 63 32 45 23 Survival due to chemotherapy Death due to chemotherapy ALPI 36 60 4 53 32 15 76 19 5
IALT 33 65 2 53 43 4 55 30 15
ANITA 36 4 60 43 39 18 51 26 23
LACE 33 64 3 51 39 10 61 26 13 Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC New Role for Adjuvant EGFR-Targeted Therapy1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
• EGFR TKIs are standard of care for patients with EGFRmut advanced NSCLC • Previous studies have suggested there may be a role for EGFR TKIs in the resected setting, but results have been inconclusive8,9 • ADAURA: Based on e cacy and safety data, and the new FDA approval, adjuvant osimertinib represents a big opportunity to improve outcomes in more patients with early-stage NSCLC10
ADAURA: Phase 3 Double-Blind Studya Patients with completely resected stageb IB, II, IIIA NSCLC, with or without adjuvant chemoc
Patients Planned treatment duration: 3 y • ≥18 y (Japan/Taiwan, ≥20 y) Osimertinib Treatment continues until • WHO PS 0/1 Strati ed by 80 mg, once daily • Disease recurrence • Con rmed primary nonsquamous NSCLC • Treatment completed d • Stage (IB vs II vs IIIA) • Ex19del/L858R • EGFRmut (ex19del • Discontinuation criteria met 1:1 randomization • Brain imaging, if not completed vs L858R) Follow-up preoperatively • Race (Asian • Until recurrence: wk 12 and 24, • Complete resection with negative marginse vs non-Asian) Placebo then every 24 wk to 5 y, then yearly • Maximum interval between surgery and once daily • After recurrence: every 24 wk for randomization: 10 wk without adjuvant 5 y, then yearly chemo; 26 wk with adjuvant chemo
• Primary endpoints: DFS by investigator assessment in stage II/IIIA patients; designed for superiority under the assumed DFS HR of 0.70 • Secondary endpoints: DFS in the overall population;f DFS at 2, 3, 4, and 5 years; OS; safety; QoL DFS According to Investigator Assessment10
Stage I to IIA Disease Stage IB to IIIA Disease
Osimertinib Osimertinib 90% DFS 89% DFS
Placebo Placebo 44% DFS 52% DFS • In the overall population, 89% of patients treated with osimertinib (95% CI, 85-92) • At 24 mo, 90% of patients treated with osimertinib (95% CI, 84-93) and 44% and 52% of patients treated with placebo (95% CI, 46-58) were alive and disease free of patients treated with placebo (95% CI, 37-51) were alive and disease free at 24 mo • HR = 0.17; 99.06% CI, 0.11-0.26; P < .001; 83% reduction in risk of disease • HR = 0.20; 99.12% CI, 0.11-0.26; P < .001; 80% reduction in risk of disease recurrence or death recurrence or death Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC New Role for Adjuvant EGFR-Targeted Therapy1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
Subgroup Analysis of DFS by Investigator10 CNS DFS by Investigator in the Overall Population10
Osimertinib DFS bene t was observed across all prede ned subgroups Osimertinib was associated with fewer local/regional and distant Subgroup HR 95% CI relapses, with a lower incidence of metastatic disease in patients with Strati ed log-rank 0.21 0.16 -0.28 recurrence, including fewer CNS recurrence events Overall (N = 682) Unadjusted Cox PH 0.20 0.14 -0.29 Male (n = 204) 0.21 0.11 -0.38 Sex Female (n = 478) 0.20 0.12 -0.30 Adjuvant osimertinib <65 y (n = 380) 0.18 0.10 -0.28 Age ≥65 y (n = 302) 0.24 0.14 -0.38 demonstrated a clinically Smoker (n = 194) 0.14 0.06 -0.27 Smoking status meaningful improvement in Nonsmoker (n = 488) 0.23 0.15 -0.34 CNS DFS compared Asian (n = 434) 0.22 0.14 -0.33 Race Non-Asian (n = 248) 0.17 0.08 -0.31 with placebo Stage IB (n = 212) 0.50 0.25 -0.96 Stage Stage II (n = 236) 0.17 0.08 -0.31 82% Stage IIIA (n = 234) 0.12 0.07 -0.20 reduction Exon 19 deletion (n = 378) 0.12 0.07 -0.20 EGFRmut L858R (n = 304) 0.35 0.21 -0.55 in CNS DFS Yes (n = 378) 0.18 0.11 -0.29 Adjuvant chemo No (n = 304) 0.23 0.13 -0.38
0.01 0.1 1 Adjuvant osimertinib HR for DFS (95% CI) Favors osimertinib Favors placebo HR = 0.18 (95% CI, 0.10-0.33; P < .0001) is the first targeted agent to show a statistically significant and clinically DFS by Investigator ± Adjuvant Chemo10 meaningful improvement Adverse Events10 in DFS in patients with stage IB/II/IIIA EGFRmut
Consistent improvement in DFS was seen regardless of whether NSLC10 Safety pro le was consistent with the established safety pro le patients received prior adjuvant chemotherapy of osimertinib, with mild EGFR TKI class e ects reported
Osimertinib (N = 337), N (%) Placebo (N = 343), N (%) 1.0 1.0 Adverse Event Any Grade Grade 1 Grade 2 Grade 3 Any Grade Grade 1 Grade 2 Grade 3
Diarrhea 156 (46) 116 (34) 32 (19) 8 (2) 68 (20) 54 (16) 13 (4) 1 (<1) 0.8 0.8
S Paronychia 85 (25) 31 (9) 50 (15) 3 (1) 5 (1) 3 (1) 2 (1) 0 S F F D
D
f Dry skin 79 (23) 75 (22) 3 (1) 1 (<1) 22 (6) 18 (5) 4 (1) 0
f 0.6
0.6 o
o
y y Pruritus 65 (19) 49 (15) 16 (5) 0 30 (9) 28 (8) 2 (1) 0 ili t ili t b b 0.4 0.4 Cough 62 (18) 43 (13) 19 (6) 0 57 (17) 42 (12) 15 (4) 0 ob a ob a r r P
P Stomatitis 59 (18) 35 (10) 18 (5) 6 (2) 14 (4) 10 (3) 4 (1) 0
0.2 0.2 Nasopharyngitis 47 (14) 30 (9) 17 (5) 0 35 (10) 25 (7) 10 (3) 0 Osimertinib Osimertinib Upper respiratory infection 45 (13) 24 (7) 19 (6) 2 (1) 35 (10) 19 (6) 16 (5) 0 Placebo HR = 0.16 (95% CI, 0.10-0.26) Placebo HR = 0.23 (95% CI, 0.13-0.40) 0 0 Decreased appetite 44 (13) 29 (9) 13 (4) 2 (1) 13 (4) 9 (3) 4 (1) 0 0 6 12 18 24 30 36 42 48 56 0 6 12 18 24 30 36 42 48 Time, mo Time, mo Mouth ulceration 39 (12) 32 (9) 7 (2) 0 8 (2) 6 (2) 2 (1) 0 Dermatitis acneiform 37 (11) 29 (9) 8 (2) 0 16 (5) 12 (3) 4 (1) 0
a NCT0251106; ADAURA data cutoff: January 17, 2020. b AJCC, 7th edition. c Prior, post, and planned radiotherapy was not allowed. d Centrally confirmed in tissue. e Patients received a CT after resection and within 28 days before treatment. f Stage IB/II/IIIA. 1. Datta D, Lahiri B. Chest. 2003;123:2096-2103. 2. Le Chevalier T. Ann Oncol. 2010;21(suppl 7):vii196-vii198. 3. Cagle PT et al. Arch Pathol Lab Med. 2013;137:1191-1198. 4. Chansky K et al. J Thorac Oncol. 2017;12:1109-1121. 5. Postmus PE et al. Ann Oncol. 2017;28(suppl 4):iv1-iv21. 6. Kris MG et al. J Clin Oncol. 2017;35:2960-2974. 7. Pignon J et al. J Clin Oncol. 2008;26:3552-3559. 8. Wu Y-L et al. J Clin Oncol. 2020;38(suppl 15):9005. 9. Huang Q et al. Chest. 2016;149:1384-1392. 10. Wu Y et al. N Engl J Med. 2020;383:825-835. The Emerging Role of EGFR Exon 20 Insertions in NSCLC A New Era of Targeted Therapy Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
• EGFR exon 20 insertion mutations represent the third most common EGFR mutation in NSCLC1 • First- and second-generation EGFR TKIs have limited e cacy in patients with NSCLC harboring EGFR exon 20 insertions1 • Advances with EGFR TKIs and bispeci c antibodies may establish a new standard of care in NSCLC for patients with EGFR exon 20 insertions1
Impact of Deletions and Insertions on EGFR Activation1,2 Incidence of EGFR Exon 20 Insertions in NSCLC1-3
“Classical” EGFR mutations WT EGFR WT EGFR
Deletions Exon 19 deletions L858R Trans- Extracellular membrane Tyrosine kinase β3 β3 domain domain domain
Exon Exon Exon Exon Exon Exon β4 β4 EGFR I/II III/IV 18 19 20 21 22 23 “C-helix “C-helix Exon 18 Exon 20 insertions out” in” 3%
Insertions C-helix Loop following C-helix
Exon 21 Exon 19 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 Inactive Active 42% 45% D E A Y V M A S V D N P H V C A767-S768 insX V765-M766 insX V769-D770 insX D770 N771 insX H773-V774 insX A763-Y764 insX V774-C775 insX D761-E762 insX P772-H773 insX N771-P772 insX S768-V769 insX Y764-V765 insX Percentage of Total Exon
Exon 19 Deletion Exon 20 Insertion Exon 20 20 EGFR Insertions 10% 0.3% 0.3% (n = 349) 0.9% 1.4% β3 • Insertions: 6% 1.7% 4.3% β3 4.6% • S768I: 1% 5.4%
• T790M (de novo): 5% 8.3% β4 β4 • 4%-10% of all EGFR-mutant NSCLC - This could be limited by testing type • First/second-generation EGFR TKIs have 22.6%
limited activity 24.6% 25.5% - Erlotinib/ge tinib: mPFS, 1.5-2 mo Active Active - Afatinib: mPFS, 2.9 mo • Worse prognosis than other types of EGFR-mutant NSCLC The Emerging Role of EGFR Exon 20 Insertions in NSCLC A New Era of Targeted Therapy Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
Emerging Treatment Strategies for NSCLC With EGFR Exon 20 Insertions1
EGFR/MET bispeci c antibody
Osimertinib Amivantamab Mobocertinib
Third-generation EGFR TKI EGFR/HER2 exon 20ins TKI C-lobe Exon 19 deletions Gly719 A-loop Exon 20 Leu858 insertions Leu861
N-lobe Hypoxia-activated EGFR TKI EGFR/HER2/HER4 TKI EGFR
Tarloxotinib Poziotinib CLN-081a
Pan-EGFR-mutation TKI The Emerging Role of EGFR Exon 20 Insertions in NSCLC A New Era of Targeted Therapy Full abbreviations, accreditation, and disclosure information available at PeerView.com/CWE40
Overview of Emerging Targeted Therapies for NSCLC With EGFR Exon 20 Mutations
Dose Discontinuation FDA BT Drug MOA n ORR mPFS Major Toxicities Reduction Due to Toxicity Therapy
82% diarrhea; 26% gr 3+ Poziotinib3,4 TKI 115 15% 4.2 mo 78% 12% – 68% rash; 30% gr 3+ 88% diarrhea; 22% gr 3+ Mobocertinib5 TKI 28 43% 7.3 mo 25% rash; 1% gr 3+ NR NR Targeted (TAK-788) 49% nausea; 4% gr 3+ Therapies 8.3 mo 72% rash; 0% gr3 for EGFR Amivantamab6 EGFR/ 39 36% (95% CI, 60% infusion reaction 10% 6% Exon 20 (JNJ-372) MET Ab Insertions 3.0-14.8) 34% paronychia 76% diarrhea; 0% gr 3+ 38% rash; 0% gr 3+ Osimertinib7 TKI 17 24% 9.6 mo NR 1/17 – 10% gr 3+ plts, 10% gr 3+ QTc 35% 60% rash; 0% gr 3+ CLN-0818 TKI 22 (uncon- NR 9% 0% – 13% stomatitis, 0% gr 3 rmed) Other Emerging Hypoxia- 61% QTc prolonged; 35% gr 3+ Therapies Tarloxotinib9 activated 11 0% – 43% rash; 4% gr 3+ 5/23 (22%) 1/23 (4%) – for EGFR TKI 21% diarrhea; 4% gr 3+ Exon 20 Insertions Oral allosteric BDTX-18910 Phase 1 study ongoing (NCT04209465) ErbB inhibitor
a Other name: TAS6417. 1. Remon J et al. Cancer Treat Rev. 2020;90:102105. 2. Vyse S, Huang PH. Signal Transduct Target Ther. 2019;4:5. 3. Le X et al. 2020 American Association for Cancer Research Annual Meeting (AACR 2020). Abstract CT081. 4. Socinski M et al. European Society for Medical Oncology Congress 2020 (ESMO 2020). Abstract LBA60. 5. Riely G et al. ESMO 2020. Abstract 1261MO. 6. Park K et al. 2020 American Society of Clinical Oncology Annual Meeting (ASCO 2020). Abstract 9512. 7. Piotrowska Z et al. ASCO 2020. Abstract 9513. 8. Piotrowska Z et al. ESMO 2020. Abstract 1345P. 9. Liu S et al. ESMO 2020. Abstract LBA61. 10. Hamilton EP et al. ASCO 2020. Abstract TPS3665.