Abstract
Pertuzumab plus trastuzumab and real-world standard of care (SOC) for patients (pts) with treatment refractory metastatic colorectal cancer (mCRC) with HER2 (ERBB2) amplification (amp) confirmed by tumor tissue or ctDNA analysis (TRIUMPH, EPOC1602).
Author
person
Wataru Okamoto
Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
info_outline
Wataru Okamoto, Yoshiaki Nakamura, Takeshi Kato, Taito Esaki, Masato Komoda, Ken Kato, Yoshito Komatsu, Toshiki Masuishi, Tomohiro Nishina, Kentaro Sawada, Hiroya Taniguchi, Nozomu Fuse, Shogo Nomura, Makoto Fukui, Steven R. Olsen, Justin Iver Odegaard, Akihiro Sato, Satoshi Fujii, Atsushi Ohtsu, Takayuki Yoshino
Full text
Authors
person
Wataru Okamoto
Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
info_outline
Wataru Okamoto, Yoshiaki Nakamura, Takeshi Kato, Taito Esaki, Masato Komoda, Ken Kato, Yoshito Komatsu, Toshiki Masuishi, Tomohiro Nishina, Kentaro Sawada, Hiroya Taniguchi, Nozomu Fuse, Shogo Nomura, Makoto Fukui, Steven R. Olsen, Justin Iver Odegaard, Akihiro Sato, Satoshi Fujii, Atsushi Ohtsu, Takayuki Yoshino
Organizations
Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan, Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan, Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan, Department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan, Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Japan, Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan, Division of Cancer Center, Hokkaido University Hospital, Sapporo, Japan, Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan, Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Kashiwa, Japan, Guardant Health AMEA, Minato-Ku, Tokyo, CA, Japan, Guardant Health, Inc., Redwood City, CA, Department of Molecular Pathology, Yokohama City University Graduate School of Medicine., Yokohama, Japan, National Cancer Center Hospital East, Kashiwa, Japan
Abstract Disclosures
Research Funding
Other Government Agency
Japan Agency for Medical Research and Development
Background:
HER2
amp occurs in 1-4% of mCRC pts. Two single arm phase 2 studies, HERACLES and MyPathway, showed efficacy for dual HER2-targeted therapy in pts with
RAS
wild type (
RAS
wt) mCRC with
HER2
amp detected in tumor tissue; however, efficacy for pts prospectively enrolled with
HER2
amp identified in ctDNA is unknown. Furthermore, the efficacy of real-world non-HER2-targeted SOC for
HER2
amplified
RAS
wt mCRC pts is not clear.
Methods:
We conducted a phase 2 trial to evaluate the efficacy of pertuzumab (P) plus trastuzumab (T) in
RAS
wt mCRC pts with
HER2
amp centrally confirmed by tissue (IHC and/or FISH) and/or ctDNA (Guardant360) who had progressed on SOC including EGFR blockade. Pts received intravenous P (840 mg loading dose followed by 420 mg) and T (8 mg/kg loading dose followed by 6 mg/kg) every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) by investigator assessment, analyzed for two primary populations: pts with
HER2
amp in tissue (tissue
+
) or in ctDNA (ctDNA
+
). Efficacy of real-world non-HER2-targeted SOC for
HER2
amplified
RAS
wt mCRC pts was prospectively assessed in a concurrent registry: the SCRUM-Japan registry.
Results:
Among 75 pts screened, concordance of
HER2
amp between tissue and ctDNA was 83%. The primary endpoint was met in each cohort of TRIUMPH, with confirmed ORR of 30% (95% CI 14-50%) in 27 tissue
+
pts and 28% (12-49%) in 25 ctDNA
+
pts. In contrast, ORR in first salvage SOC after EGFR blockade was 0% (0.0-24.7%) in the real-world cohort. Median progression free and overall survival were 4.0 months (1.4-5.6) and 10.1 months (4.5-16.5) in the tissue
+
pts and 3.1 months (1.4-5.6) and 8.8 months (4.3-12.9) in the ctDNA
+
pts. One pt withdrew due to an adverse event (grade 3 decreased ejection fraction), but no treatment related deaths occurred. In exploratory analyses, pts without ctDNA mutations of
RAS
/
BRAF
V600/
PIK3CA
/
HER2
were more likely to respond to P+T than those with a ctDNA mutation in at least one of these genes (ORR 44% vs. 0% in tissue
+
and 37% vs. 0% in ctDNA
+
). Decreased ctDNA fraction and
HER2
plasma copy number at 3 weeks after treatment initiation corresponded to P+T response. At least one actionable alteration emerged after progression in 16 (62%) of 26 pts with ctDNA results at both baseline and progression. Among 5 pts who achieved response and had ctDNA results at both time points, 4 pts acquired actionable alteration at progression.
Conclusions:
We demonstrate promising efficacy and safety of P+T for
RAS
wt mCRC pts with
HER2
amp in either tumor tissue or ctDNA. Our results show that complete ctDNA genotyping identifies pts most likely to benefit from dual HER2 blockade and can be used to monitor response and detect actionable resistance biomarkers. Clinical trial information: UMIN000027887 and UMIN000028058.