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Background The benefit of immune checkpoint blockade in mCRC is currently limited to mismatch repair (MMR) deficient tumours. Increasing evidence suggests that the vascular endothelial growth factor (VEGF) pathway plays a role in cancer immune evasion. Co-targeting the PD-1/PD-L1 and VEGF axes may result in clinical activity in mCRC. Methods 133 patients (pts) were randomized 2:1 to receive C/B/P (Arm A) or C/B/A (Arm B), stratifying by ECOG and RAS. Pts had progressed on 5-FU, oxaliplatin, irinotecan, bevacizumab, and anti-EGFR therapy (if RAS wt). Prior anti-PD-1/PD-L1 therapy was not permitted. Doses were C 850 or 1000 mg/m² d1-14, B 7.5 mg/kg d1, and A 1200 mg d1 in 21 day cycles. Primary endpoint was progression free survival (PFS). 110 events were required to detect PFS hazard ratio (HR) of 0.65 at 1-sided α = 0.1 with 80% power. Secondary endpoints were objective response rate (ORR), overall survival (OS), and safety/tolerability. Primary and secondary efficacy analyses were performed using modified intent to treat analysis (mITT). Results Analysis includes 46 pts (Arm A) and 82 pts (Arm B) with median age 58 yo, 40% female, 47% ECOG 0. As of 4/12/19, median follow-up was 12.35 months (mo). Proficient MMR or microsatellite stable (MSS) is present in 86.7% vs 85.7%. In mITT analysis, median PFS is 3.3 mo (2.1-6.2) vs 4.4 mo (4.1-6.4) with a HR of 0.725 (0.491-1.07), 1-sided log-rank p-value 0.051. In MSS only pts, HR for PFS is 0.67 (0.44-1.03). ORR is 4.35% (0.5-14.8) vs 8.54% (3.5-16.8), p = 0.5. The 12 mo OS is 43% (29-63) vs 52% (42-65), HR 0.94 (0.56-1.56), p = 0.4. Most common grade > = 3 related adverse events are hypertension (7% vs 9%), hand-foot syndrome (4% vs 6%), and diarrhea (2% vs 7%). Conclusions The study reached its prespecified primary endpoint and the addition of A to CB results in a significantly longer PFS. No new or increased safety signals are identified. Further investigation in a larger phase III study may be warranted. This is the first positive study co-targeting PD-1/PD-L1 and VEGF axes in mCRC and correlative analyses may help identify predictors of benefit. Clinical trial identification NCT0287319. Legal entity responsible for the study ACCRU. Funding Genentech Roche. Disclosure H.J. Lenz: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb. P.M. Boland: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Hemispherx; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Isofol Medical; Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Athenex; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Clinical Genomics. A.B. Nixon: Research grant / Funding (self): Seattle Genetics; Research grant / Funding (self): MedPacto; Research grant / Funding (self): Genentech Roche; Advisory / Consultancy, Research grant / Funding (self): Tracon Pharma; Research grant / Funding (self): Acceleron Pharma; Research grant / Funding (self): Leadiant Biosciences; Research grant / Funding (self): Sanofi-Aventis; Advisory / Consultancy: Eli Lilly. H. Hurwitz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech Roche. M.G. Fakih: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Advisory / Consultancy: Array; Advisory / Consultancy: Bayer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Novartis. All other authors have declared no conflicts of interest.

Background HER2 (ERBB2) amplification is present in 5-10% of patients (pts) with KRAS and NRAS (RAS) WT mCRC. Tucatinib (Seattle Genetics, Bothell, WA) is a potent, highly selective oral tyrosine kinase inhibitor of the HER2 receptor. In patient-derived xenograft models of HER2+ mCRC, the combination of tucatinib and trastuzumab showed significantly greater antitumor activity compared with tucatinib or trastuzumab alone. Here we present initial results from a trial of tucatinib and trastuzumab in pts with HER2 amplified mCRC. Methods MOUNTAINEER is a multicenter open-label single-arm phase II trial. Pts with RAS WT mCRC had HER2 amplification/overexpression by NGS, FISH, or IHC (3+ or 2+ and amplified by FISH). Prior treatment with 5FU, oxaliplatin, irinotecan, and an anti-VEGF antibody was required. Prior anti-HER2 therapy was excluded. Pts received tucatinib 300mg PO bid and standard doses of trastuzumab (IV, Q3 weeks). The primary endpoint was objective response rate (ORR) per RECIST v1.1. Using a 2-Stage Fleming design, this study compared ORR of 20% (null) vs 40% (alt) in 10 or 25 evaluable pts (1-sided α = 0.11; β=.16). At least 8 responses were needed to meet the primary efficacy endpoint. Results As of 26 April 2019, 26 pts enrolled, and 22 pts completed ≥1 evaluation of response. 16/26 pts (62%) were male. Median age= 52.5 (range 24-70). The primary tumor site of origin included right colon (N = 4), left colon/rectum (N = 17), transverse colon (N = 3), and overlapping (N = 2). Among 22 evaluable pts, ORR= 55% (CR/PR= 12; SD = 5; PD = 5). Clinical benefit rate (CR+PR+SD≥4 months) = 64%. At a median follow-up of 10.6 months, median PFS= 6.2 months (95% CI 3.5-NE). Median OS = 17.3 months (95% CI 12.3-NE). Median duration of response has not been reached. There were 2 (9%) grade 3 treatment-related adverse events (TRAEs) and no grade 4/5 TRAEs. The most common TRAEs were AST elevation (48%; all G1), ALT elevation (30%; all G1), and diarrhea (26%; G1/G2/G3=4%/17%/4%). Conclusions The combination of tucatinib and trastuzumab is well tolerated and has met its primary efficacy endpoint. Based on these results, further expansion of the MOUNTAINEER trial in pts with HER2 amplified mCRC is justified. Updated results will be presented. Clinical trial identification NCT03043313. Legal entity responsible for the study Academic and Community Cancer Research United. Funding Seattle Genetics. Disclosure J.H. Strickler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Chugai; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: OncoMed; Advisory / Consultancy: Celgene; Advisory / Consultancy: Proteus Digital Health; Advisory / Consultancy: Chengdu Kanghong Biotechnology Ltd; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Leap Therapeutics. A. Cercek: Advisory / Consultancy: Bayer; Advisory / Consultancy: Proteus; Research grant / Funding (institution): Seattle Genetics. C. Wu: Research grant / Funding (institution): Vaccinex; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): FLX Bio. J. Hubbard: Research grant / Funding (institution): Seattle Genetics; Honoraria (institution), Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Treos Bio; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Senhwa pharmaceuticals. N. Kemeny: Research grant / Funding (institution): Amgen. P.M. Boland: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Hemispherx; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Isofol Medical; Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): Athenex; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Clinical Genomics. K. Ng: Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Tarrex Biopharma; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Trovagene; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Pharmavite; Research grant / Funding (institution): Consano. T. Bekaii-Saab: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics. All other authors have declared no conflicts of interest.