OA02.07 Updated Results of Phase 1 Study of DS-8201a in HER2-Expressing or –Mutated Advanced Non-Small-Cell Lung Cancer

Abstract

and 40 patients were evaluated for response. 65.1% of patients had received at least two prior lines of therapy for metastatic disease. 60% of patients had grade 3 adverse events; most common were skin-rash (27.5%) and diarrhea (12.5%). 45.0% of patients required dose reduction to 12mg, while 17.5% required dose reduction to 8mg. One patient stopped treatment due to grade 3 skin rash. ORR at eight weeks was 58% (95%-CI 40.9-73.0) and the DCR was 90% (95%-CI 76.3-97.2). Among 23 patients who achieved partial response, 15 responses were confirmed with subsequent scans, five responses were unconfirmed, and three patients are pending confirmation. Responses were observed in 8/13 (62%) patients that were previously treated with TKI. Median PFS was 5.6mo (95%-CI 5.06-NA). Furthermore, 13 patients were enrolled in HER2 cohort. Toxicities were similar to EGFR cohort except one case of grade 5 pneumonitis, assessed to be possibly drug related. Twelve patients were evaluated for response with ORR of 50% (95% CI 21.1-78.9) at eight weeks and DCR of 83%. Conclusion: In heavily pre-treated population with EGFR and HER2 exon 20 mutant NSCLC, poziotinib demonstrated encouraging antitumor activity in both TKI-naive and -refractory patients, and manageable toxicity profile.

Advanced-Stage Non–Small Cell Lung Cancer: Advances in Thoracic Oncology 2018

“…The combination of dabrafenib (a BRAF TKI) and trametinib (a MEK TKI) is the SoC treatment according to the FDA and EMA in patients with BRAF V600E-mutant NSCLC regardless of prior treatment, 114,115 as BRAF TKI monotherapy has been reported to have limited efficacy, such as in AcSé trial (RR ¼ 45%, PFS ¼ 5.2 months, and OS ¼ 9.3 months [ Table 6]). [114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] The recent functional classification of BRAF mutations (class I, V600 mutations; class II, non-V600 mutations; and class III, ERK-signaling amplification) demonstrated that class II and III tumors have unfavorable prognosis and suggested that class-specific therapies are necessary. 133 BRAF-mutant NSCLC overlaps with PD-L1 expression in 60% of cases (45% with PD-L1 expression !50%), low or intermediate TMB, and microsatellite-stable status, 134 but ICI efficacy is similar to that in patients with wild-type BRAF.…”

“…138 DS-8201a is a new HER2-targeting antibody-drug conjugate incorporating a novel topoisomerase I inhibitor. In HER2-mutant patients, it gave a clinically significant RR of 73% and a median PFS of 14.2 months 125 ; and a phase II trial (NCT03505710) is ongoing (see Table 6).…”

<p>Recent Progress in Rare Oncogenic Drivers and Targeted Therapy For Non-Small Cell Lung Cancer</p>

“…Poziotinib showed promising preclinical and early clinical activity in NSCLC patients with HER2 or EGFR exon 20 ins,105 in an ongoing phase II study (NCT03066206), initial responses of 50% and a median PFS of 5.1 months were observed in 12 evaluable advanced HER2 exon 20 ins NSCLC patients 106. An ongoing phase I study of another novel HER2-targeted drug, trastuzumab deruxtecan (DS-8201a), demonstrated an ORR of 62.5% and DCR of 75% in 12 patients with HER2-expressing or -mutated NSCLC 107. A phase II study for this drug against the same condition recently began accrual (NCT03505710).…”

Emergence of ERBB2 Mutation as a Biomarker and an Actionable Target in Solid Cancers

“…Subsequent expansion of the NSCLC cohort ( n = 18) reported confirmed response rate of 58.8% (10 of 17 patients). The median duration of response was 9.9 months, and grade 3 or higher toxicities were reported in 25% of patients with one patient death because of interstitial lung disease (Table 2) . The response rate in patients with confirmed ERBB2 mutations was 72.7% (8 of 11 patients), and median duration of response was 11.9 months.…”