FDA Updates Highlighting the Latest Cancer Treatments

Fam-Trastuzumab Deruxtecan-Nxki for drome was observed in 1 of 12 patients. No AEs resulted in permanent Unresectable or Metastatic HER2-Positive discontinuation of treatment. Breast Cancer The FDA granted accelerated approval to fam-trastuzumab deruxtecan- Enzalutamide for Metastatic Castration- nxki for patients with unresectable or metastatic HER2-positive breast Sensitive Prostate Cancer cancer who have received two or more prior anti-HER2-based regimens The FDA approved enzalutamide for patients with metastatic in the metastatic setting. ­castration-sensitive prostate cancer (mCSPC). The organization pre- Efficacy was investigated in DESTINY-Breast01 (NCT03248492), viously approved enzalutamide for patients with castration-resistant a multicenter, single-arm trial enrolling 184 female patients with prostate cancer. HER2-positive, unresectable, and/or metastatic breast cancer who Efficacy was investigated in ARCHES (NCT02677896), a trial en- had received two or more prior anti-HER2 therapies. Patients re- rolling 1,150 patients with mCSPC randomized (1:1) to receive either ceived fam-trastuzumab deruxtecan-nxki 5.4 mg/kg by intrave- enzalutamide orally 160 mg once daily (N=574) or placebo orally once nous infusion every 3 weeks until unacceptable toxicity or disease daily (N=576). All patients received a GnRH analog or had a prior progression. bilateral orchiectomy. The main efficacy outcome measures were confirmed objective The main efficacy outcome measure was radiographic progression- response rate (ORR) assessed by independent central review using free survival (rPFS). Based on blinded independent central review, RECIST 1.1 and response duration. ORR was 60.3 percent (95% CI: rPFS was defined as the time from randomization to radiographic 52.9, 67.4), with a 4.3 percent complete response rate and a 56 per- disease progression at any time or death within 24 weeks after drug cent partial response rate. Median response duration was 14.8 months discontinuation. (95% CI: 13.8, 16.9). Radiographic disease progression was defined by identification The safety was evaluated in a pooled analysis of 234 patients of 2 or more new bone lesions on a bone scan with confirmation with unresectable or metastatic HER2-positive breast cancer (Prostate Cancer Working Group 2 criteria) and/or progression in who received at least one dose of fam-trastuzumab deruxtecan- soft tissue disease. Time to new antineoplastic therapy was an ad- nxki 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101 ditional endpoint. (NCT02564900). Median rPFS was not reached (NR) in the enzalutamide arm com- The most common adverse reactions (frequency ≥20%) were nau- pared to 19.4 months (95% CI: 16.6, NR) in the placebo arm (HR 0.39; sea, fatigue, vomiting, alopecia, constipation, decreased appetite, ane- 95% CI: 0.30, 0.50; p<0.0001). A statistically significant improvement mia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia. was also reported on the enzalutamide arm compared to placebo in The prescribing information includes a Boxed Warning to advise time to initiation of a new antineoplastic therapy (HR 0.28; 95% CI: health professionals of the risk of interstitial lung disease (ILD) and 0.20, 0.40; p<0.0001). Overall survival data were not mature at the embryo-fetal toxicity. Fatal outcomes due to ILD occurred in 2.6 per- time of rPFS analysis. cent of patients. The most common adverse reactions (≥ 5%) that occurred more The recommended fam-trastuzumab deruxtecan-nxki dose is 5.4 frequently (≥ 2% over placebo) in enzalutamide-treated patients in mg/kg given as an intravenous infusion once every 3 weeks (21-day ARCHES were hot flush, asthenia/fatigue, hypertension, fractures, and cycle) until disease progression or unacceptable toxicity. musculoskeletal pain. The recommended dose is 160 mg (four 40 mg capsules) adminis- Breakthrough Therapy Designation tered orally once daily, with or without food. for Ivosidenib in R/R Myelodysplastic Syndrome Breakthrough Therapy Designation for The FDA has granted Breakthrough Therapy Designation for ivo- Tucatinib in HER2-Positive Breast Cancer sidenib for the treatment of adult patients with relapsed or refractory The FDA has granted Breakthrough Therapy designation to tuca- myelodysplastic syndrome (MDS) with a susceptible IDH1 mutation tinib, in combination with trastuzumab and capecitabine, for treat- as detected by an FDA-approved test. MDS is a group of bone mar- ment of patients with locally advanced unresectable or metastatic row disorders that can cause severe complications, such as infections HER2-positive breast cancer, including patients with brain metas- and uncontrolled bleeding, and can lead to the development of acute tases, who have been treated with trastuzumab, pertuzumab and myelogenous leukemia (AML). T-DM1. Results from the MDS arm of the ongoing ivosidenib phase I The positive topline results of the pivotal HER2CLIMB clinical dose-escalation and expansion study in hematologic malignan- trial were announced in October 2019, and additional data were pre- cies were presented at the 2019 Society of Hematologic Oncology sented at the 2019 San Antonio Breast Cancer Symposium (SABCS) Annual Meeting. These demonstrate that ivosidenib administered and were simultaneously published in the New England Journal of as a monotherapy was well-tolerated and associated with durable Medicine. Tucatinib is an oral, small molecule tyrosine kinase inhibi- remissions as well as the achievement and maintenance of transfu- tor (TKI). sion independence in patients with relapsed or refractory MDS with This Breakthrough Therapy Designation was based on data from an IDH1 mutation. the pivotal HER2CLIMB clinical trial, which compared tucatinib in Among the 12 patients who received 500 mg of oral ivosidenib daily, combination with trastuzumab and capecitabine to trastuzumab and the median treatment duration was 11.4 months. The median age was capecitabine alone in patients with locally advanced unresectable or 72.5 years, and 42 percent of patients were age 75 or older. As of the metastatic HER2-positive breast cancer. Nov. 2, 2018, data cut-off, 75 percent (9/12) of patients had a response Patients had previously received trastuzumab, pertuzumab, and and 42 percent (5/12) had a complete response (CR). The median du- ado-trastuzumab emtansine (T-DM1). Patients had received a median ration of CR had not been reached (95% CI, 2.8 months, NE). Of the of four prior lines of therapy overall and three in the metastatic set- patients who had a CR, 60 percent remained relapse-free at 12 months. ting. Forty-seven percent of the patients enrolled in the trial had brain In addition, nine (75%) patients were transfusion-­independent for 56 metastases at the time of enrollment. days or longer during study treatment. Data presented at SABCS and published in NEJM include The most common adverse events (AEs) of any grade were back the primary endpoint of progression-free survival (PFS) as as- pain, diarrhea, fatigue, and rash. Grade 2 IDH differentiation syn- Continued on page 37

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OT_January_20-20_Layout.indd 36 03/01/20 2:23 PM tinib and placebo due to adverse events was 5.7 percent in the tuca- FDA Updates tinib arm and 3.0 percent in the control arm. continued from page 36 Greater than or equal to grade 3 diarrhea was seen in 12.9 percent of the patients in the tucatinib arm versus 8.6 percent in the con- trol arm. Antidiarrheal prophylaxis was not required per protocol. sessed by blinded independent central review in the first 480 pa- Antidiarrheals were used in less than half of all cycles where diarrhea tients enrolled in the trial. The primary endpoint of PFS showed was reported. In both treatment arms, when used, the duration of that the addition of tucatinib was superior to trastuzumab and antidiarrheal treatment was short (median of 3 days/cycle). capecitabine alone, with a 46 percent reduction in the risk of Greater than or equal to grade 3 aspartate aminotransferase disease progression or death (HR=0.54 (95% CI: 0.42, 0.71); (AST) was seen in 4.5 percent of the patients in the tucatinib arm p<0.00001). The trial met the two key secondary endpoints at versus 0.5 percent in the control arm, and alanine aminotrans- interim analysis. ferase (ALT) elevation in 5.4 percent vs. 0.5 percent, respectively. The tucatinib arm demonstrated an improvement in overall sur- Discontinuations due to liver transaminase elevations were in- vival, with a 34 percent reduction in the risk of death (HR=0.66 [95% frequent in both arms (ALT: 1.0 vs. 0.5 percent; AST: 0.7 vs. 0.5 CI: 0.50, 0.88]; p=0.0048), compared to the control arm. For patients percent). OT with brain metastases at baseline, the tucatinib arm also demonstrated superior PFS, with a 52 percent reduction in the risk of disease pro- gression or death, compared to the control arm (HR=0.48 [95% CI: FDA Alerts & Updates 0.34, 0.69]; p<0.00001). Find the latest approvals, designations, and Tucatinib in combination with trastuzumab and capecitabine was new indications from the U.S. Food and Drug generally well tolerated. The most common adverse events occurring Administration for oncology drugs. Go online for the in more than 20 percent of patients in the tucatinib arm versus the latest news: https://bit.ly/39q0TuL control arm included diarrhea, palmar-plantar erythrodysaesthesia syndrome, nausea, fatigue, and vomiting. Discontinuation of tuca-

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