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)

3555 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 RASwt mCRC pts is not clear. Methods: We conducted a phase 2 trial to evaluate the efficacy of pertuzumab (P) plus trastuzumab (T) in RASwt 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 RASwt 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/ BRAFV600/ 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 RASwt 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.