1523P Phase II dose optimization results from MOUNTAINEER-02: A study of tucatinib, trastuzumab, ramucirumab, and paclitaxel for HER2+ gastroesophageal cancer (GEC)

Approximately 12%-23% of pts with GEC have HER2+ tumours. Ramucirumab (R) + paclitaxel (P) is commonly used in the 2L setting for GEC; however, overall response and survival rates remain low. Tucatinib (TUC) is a highly selective, HER2-directed TKI. Here, we report safety and efficacy results from the dose optimization phase of MOUNTAINEER-02 (NCT04499924), a trial evaluating TUC in combination with trastuzumab (T), P, and R. MOUNTAINEER-02 is a global trial evaluating TUC 300 mg BID + T (6 then 4 mg/kg D1,15) + P (D1, 8, 15) + R (8 mg/kg D1, 15) every 28 days in pts with previously treated, locally advanced unresectable or metastatic HER2+ GEC. In the open-label phase II dose optimization stage, two P doses were explored (60 mg/m2 and 80 mg/m2). HER2+ status was confirmed by ctDNA or IHC/ISH assay. The primary endpoint is safety/tolerability of TUC+T+P+R. Secondary endpoints are ORR, confirmed ORR (cORR), DOR, DCR, PFS (all investigator-assessed), and PK. As of Jan 20, 2023, 17 pts (median age 59 yrs) received study tx (n=8 in 60 mg/m2 vs n=9 in 80 mg/m2). Ten pts (58.8%) remain on study after a median of 8 TUC cycles. All pts treated with 80 mg/m2 P were DLT-evaluable; 2 experienced a DLT event (1 pt with G3 mucositis and 1 pt with G2 fatigue and diarrhea leading to dose holds). No DLTs were observed in 7 DLT-evaluable pts treated with 60 mg/m2 P. TEAEs stratified by two P doses are summarized in the table. ORR was 76.5% (95% CI, 50.1-93.2), with cORR of 70.6% (44-89.7) and DCR of 94.1% (71.3-99.9). Median DOR was 10.6 months (95% CI, 6.7-inestimable), and median PFS was 11.9 months (4.1-inestimable) after 7 PFS events. Plasma concentrations of P were not affected by TUC administration.Table: 1523PMost Common TEAEs (≥30%)60 mg/m280 mg/m2TotalAny GG ≥3Any GG ≥3Any GG ≥3Any Event8 (100)6 (75.0)9 (100)8 (88.9)17 (100)14 (82.4) Diarrhea4 (50.0)2 (25.0)7 (77.8)1 (11.1)11 (64.7)3 (17.6) Nausea2 (25.0)07 (77.8)09 (52.9)0 Epistaxis2 (25.0)06 (66.7)08 (47.1)0 Fatigue2 (25.0)06 (66.7)2 (22.2)8 (47.1)2 (11.8)Peripheral sensory neuropathy1 (12.5)07 (77.8)2 (22.2)8 (47.1)2 (11.8) Stomatitis2 (25.0)06 (66.7)1 (11.1)8 (47.1)1 (5.9) Constipation3 (37.5)03 (33.3)06 (35.3)0 Neutropenia1 (12.5)1 (12.5)5 (55.6)4 (44.4)6 (35.3)5 (29.4) Pyrexia3 (37.5)03 (33.3)06 (35.3)0 Weight decreased2 (25.0)1 (12.5)4 (44.4)1 (11.1)6 (35.3)2 (11.8) Open table in a new tab Coadministration with TUC did not impact the PK of P. Based on the preliminary data from MOUNTAINEER-02, the combination of TUC+T+P+R was tolerable with encouraging antitumor activity in pts with previously treated HER2+ GEC.