Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Expanded efficacy analysis from CheckMate 8HW.

person Heinz-Josef Lenz Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA info_outline Heinz-Josef Lenz, Sara Lonardi, Elena Elez, Eric Van Cutsem, Lars Henrik Jensen, Jaafar Bennouna, Guillermo Mendez, Michael Schenker, Christelle De La Fouchardiere, Maria Luisa Limon, Takayuki Yoshino, Jin Li, Jose Luis Manzano, Giampaolo Tortora, Rocio Garcia-Carbonero, Rohit Joshi, Elvis Cela, Tian Chen, Lixian Jin, Thierry Andre

Authors person Heinz-Josef Lenz Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA info_outline Heinz-Josef Lenz, Sara Lonardi, Elena Elez, Eric Van Cutsem, Lars Henrik Jensen, Jaafar Bennouna, Guillermo Mendez, Michael Schenker, Christelle De La Fouchardiere, Maria Luisa Limon, Takayuki Yoshino, Jin Li, Jose Luis Manzano, Giampaolo Tortora, Rocio Garcia-Carbonero, Rohit Joshi, Elvis Cela, Tian Chen, Lixian Jin, Thierry Andre Organizations Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy, Vall d’Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain, University Hospitals Gasthuisberg and University of Leuven (KU Leuven), Leuven, Belgium, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark, Centre Hospitalier Universitaire de Nantes, Nantes, France, Hospital Universitario Fundacion Favaloro, Buenos Aires, Argentina, Centrul de Oncologie Sf. Nectarie, Craiova, Romania, Institut Paoli-Calmettes, Marseille, France, Hospital Universitario Virgen del Rocio, Seville, Spain, National Cancer Center Hospital East, Chiba, Japan, Shanghai East Hospital, Shanghai, China, Instituto Catalán de Oncología, Badalona, Spain, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, Medical Oncology Department. Hospital Universitario 12 de Octubre, Imas12, UCM, Madrid, Spain, Cancer Research SA, Adelaide, Australia, Bristol Myers Squibb, Princeton, NJ, Sorbonne Université, and Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris, Paris, France Abstract Disclosures Research Funding Bristol Myers Squibb Background: NIVO + IPI demonstrated superior progression-free survival (PFS) vs chemo in patients (pts) with previously untreated MSI-H/dMMR mCRC in the randomized phase 3 CheckMate 8HW study (NCT04008030). We report expanded efficacy analysis from the prespecified interim analysis of NIVO + IPI vs chemo in the 1L setting. Methods: Pts with unresectable or mCRC and MSI-H/dMMR status by local testing were enrolled across different lines of therapy and randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms) or for up to 2 years (NIVO ± IPI arms). In pts with blinded independent central review (BICR)–documented progression with chemo, crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) was a key exploratory endpoint. Results: Among 303 pts randomized to NIVO + IPI (n = 202) or chemo (n = 101), 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR. At 31.5-months (mo) median follow-up (range 6.1–48.4), NIVO + IPI demonstrated superior PFS vs chemo (HR 0.21; 97.91% CI 0.13–0.35; P< 0.0001). Subsequent systemic therapy was received by 20 (12%) and 57 (68%) pts in the NIVO + IPI and chemo arms, respectively. In the chemo arm, 56 (67%) pts received subsequent immunotherapy (39 [46%] crossed over to NIVO + IPI on study; 17 [20%] received non-study immunotherapy). Median PFS2 was not reached (NR) with NIVO + IPI and 29.9 mo with chemo (HR 0.27; 95% CI 0.17–0.44; Table). Any grade and grade 3/4 treatment-related adverse events (TRAEs) are presented (Table). Treatment-related deaths were reported for 2 pts in the NIVO + IPI arm. Conclusions: Clinical benefit with 1L NIVO + IPI vs chemo was maintained after subsequent therapy, as shown by improved PFS2 in pts with centrally confirmed MSI-H/dMMR mCRC. No new safety concerns were identified with NIVO + IPI. These results further support NIVO + IPI as a standard-of-care 1L treatment option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030. 1L Centrally Confirmed MSI-H/dMMR NIVO + IPI (n = 171) Chemo (n = 84) Median PFS (95% CI), mo NR (38.4–NE) 5.9 (4.4–7.8) HR (97.91% CI); P value 0.21 (0.13-0.35); P< 0.0001 Median PFS2 (95% CI), mo NR (NE–NE) 29.9 (14.8–NE) HR (95% CI) 0.27 (0.17–0.44) 12-mo PFS2 rate (95% CI), % 89 (83–93) 65 (53–75) 1L all treated NIVO + IPI (n = 200) Chemo (n = 88) Any grade/grade 3–4 TRAEs, n (%) 160 (80)/46 (23) 83 (94)/42 (48) NE, not evaluable.

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