A phase II study of trastuzumab monotherapy in pretreated patients with non-small cell lung cancers (NSCLCs) harboring HER2 alterations: HOT1303-B trial

Background: About 5% of NSCLCs have high level of overexpression and/or amplification of HER2 or its mutations, mostly exon 20 insertions. Retrospective studies suggest some activity of a Her2-targeted antibody, trastuzumab, for HER2-altered NSCLCs. However, no clinical trial data of trastuzumab monotherapy for HER2-altered NSCLCs are available so far. Methods: HOT1303-B was a multicenter, single-arm phase II study of trastuzumab for NSCLC patients who were pretreated with two or more regimens and had HER2-altered tumors (IHC 3+ or IHC 2+/dual color in situ hybridization [DISH] +, and/or presence of mutations) identified by a HER2 screening study HOT1303-A and a nationwide genomic screening study LC-SCRUM-Japan. Eligible patients (pts) were treated with trastuzumab 6 mg/kg every 3 weeks (loading dose 8 mg/kg). The primary endpoint was the overall response rate (ORR) using RECIST v1.1. This study required ten pts, with ORR of 10% considered non-promising and 40% promising (one-sided alpha = 0.10; beta = 0.2). Results: Ten pts were recruited in this trial. The median age was 59 (range 44-74), three pts were female, three pts were never smokers, nine pts had performance status 0-1, and all had adenocarcinomas. The median lines of prior systemic therapy were 3 (range 2-6). There were two pts with IHC 3+, one pt with IHC 2+/DISH +, five pts with exon 20 insertions (four A755_G776insYVMA and one G776>VC) and two pts with S310F mutations without overlapping cases. ORR was 0% (95% CI, 0-26%). Disease control ratio (DCR) was 70% (95% CI, 39-91%). Median progression-free survival was 5.2 months (95% CI, 1.4-6.3). Grade ≥ 3 adverse events occurred only in a patient with grade 3 pneumonitis, which was judged as organizing pneumonia related with tumor progression. OS data will be presented at the meeting. Conclusions: Trastuzumab monotherapy did not produce response for HER2-altered NSCLCs in this cohort, although DCR and PFS seemed favorable for the heavily treated pts. Additional approaches including combination therapy are required for HER2-targeted therapy using trastuzumab. Clinical trial identification: UMIN000012551. Legal entity responsible for the study: Hirotoshi Dosaka-Akita. Funding: Ministry of Health, Labor and Welfare, Japan. Disclosure: I. Kinoshita: Honoraria: Chugai Phama, Novartis. M. Maemondo: Advisory role: Chugai Pharma, AstraZeneca, Boehringer Ingelheim, MSD, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Pfizer, Novartis, Taiho Pharmaceutical, Lilly Japan; Research funding: Boehringer Ingelheim, Chugai Pharma, AstraZeneca, Novartis, Sanofi, MSD, Lilly Japan. S. Oizumi: Honoraria: AstraZeneca Japan, Lilly Japan; Research funding: Kyowa Hakko Kirin, Pfizer, BMS UK, Ono Pharmaceuticals. Y. Hatanaka: Advisory role: GeneticLab, Medicinal Chemistry Pharmaceutical Co.; Speakers' bureau: Merck Sharp & Dohme, Chugai Pharma, Pfizer; Honoraria: Ono Pharmaceutical, AstraZeneca KK.; Research funding: Roche, Taiho Pharmaceutical, Eisai, Merck Sharp & Dohme. T. Harada: Honoraria: Taiho Pharmaceutical, AstraZenea KK, Boehringer Ingelheim, Hisamitsu Pharmaceutical. K. Goto: Advisory role: Otsuka; Honoraria: Daiichi Sankyo, Bristol-Myers Squibb, AstraZeneca, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Ono Pharmaceutical, Novartis, Lilly, Boehringer Ingelheim, Quintiles, Merck Serono, SRL Diagnostics, Life Technologies, F. Hoffmann La Roche AG, MSD, AbbVie, RIKEN GENESIS, Nippon Kayaku; Research funding: MSD, AstraZeneca, Taiho Pharmaceutical, Chugai Pharma, Boehringer Ingelhiem, Ono Pharmaceutical, OxOnc, Sumitomo Dainippon, Takeda, Novartis, Daiichi Sankyo, Kyowa Hakko Kirin, Astellas Pharma, Eisai, Lilly, Pfizer, Riken Genesisi, Bristol-Myers Squibb, Merck Serono, Abbvie, Ignyta. H. Isobe: Speakers' Bureau: Chugai Pharma, Bristol-Myers Squibb Japan, Pfizer. All other authors have declared no conflicts of interest.