Nivolumab (NIVO) + 5-fluorouracil/leucovorin/oxaliplatin (mFOLFOX6)/bevacizumab (BEV) versus mFOLFOX6/BEV for first-line (1L) treatment of metastatic colorectal cancer (mCRC): Phase 2 results from CheckMate 9X8.

Abstract

8 Background: Standard 1L therapies for mCRC include a fluoropyrimidine with oxaliplatin and/or irinotecan, and a biologic agent. NIVO may enhance antitumor activity in combination with 1L standard therapies within a subset of patients (pts) with mCRC. CheckMate 9X8 evaluated NIVO + mFOLFOX6/BEV vs mFOLFOX6/BEV in 1L mCRC (NCT03414983). Methods: Adults with previously untreated, unresectable, mCRC were randomized 2:1 to NIVO 240 mg + mFOLFOX6/BEV Q2W (NIVO + standard-of-care [SOC]) or mFOLFOX6/BEV Q2W (SOC). Primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), overall survival (OS), and safety. Results: 195 pts were randomized to NIVO + SOC (n = 127) or SOC (n = 68). Median (range) follow-up was 23.7 (0–33.2) months (mo; NIVO + SOC) vs 23.2 (0–32.3) mo (SOC). Median (range) duration of therapy was 9.9 (0.1–31.8+) mo (NIVO + SOC) and 7.7 (0.1–26.7+) mo (SOC). The HR (95% CI) for PFS was 0.81 (0.53–1.23; P = 0.30), which did not meet the prespecified threshold for statistical significance (median PFS, 11.9 mo in both arms; Table). PFS rates after 12 mo were higher with NIVO + SOC vs SOC (Table). ORR was 60% (NIVO + SOC) and 46% (SOC; odds ratio 1.72 [95% CI 0.96–3.10]) and median (95% CI) DOR was 12.9 (9.0–13.1) mo (NIVO + SOC) and 9.3 (7.5–11.3) mo (SOC; Table). Rates of grade 3−4 treatment-related adverse events (TRAEs) were higher with NIVO + SOC; however, no new safety signals were identified (Table). Biomarker analyses, including tumor mutational burden and baseline CD8 levels, will be presented. Conclusions: The primary endpoint of PFS was not met; however, NIVO + SOC showed higher PFS rates after 12 mo, a higher response rate, and more durable responses compared with SOC, along with acceptable safety, in 1L mCRC. Clinical trial information: NCT03414983. [Table: see text]

Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer

“…The trial achieved its primary endpoint of median PFS (4.4 vs 3.6 months) in the overall population with a non-significant PFS improvement among the MSS subgroup (5.3 vs 3.3 months) ( 93 ).⁠⁠ Another study, the phase III CheckMate9X8, evaluated the addition of nivolumab to standard first-line chemotherapy with FOLFOX-bevacizumab vs FOLFOX-bevacizumab in patients with previously untreated, unresectable, mCRC. However, the primary endpoint of PFS was not met, with the same median PFS of 11.9 months in both arms ( 64 )⁠.⁠ Finally, the phase II MEDITREME trial evaluated the efficacy and safety of mFOLFOX6 (6 cycles) in combination with durvalumab and tremelimumab as induction therapy followed by maintenance therapy with durvalumab in patients with previously untreated RAS -mutated mCRC. ORR was 61% and mPFS was 8.4 months.…”

Drug Resistance in Colorectal Cancer: From Mechanism to Clinic

“…Therefore, using VEGF inhibitors while inducing more immunogenicity of MSS tumors may be a promising approach. Phase 2 study results of CheckMate 9X8 show nivolumab plus standard of care (SOC, fluorouracil/leucovorin/oxaliplatin/bevacizumab) This shows higher response rates in first-line treatment of mCRC compared to SOC [ 344 ].…”

Clinical Updates for Colon Cancer Care in 2022

“…Data presented at the ASCO GI 22 symposium failed to show a statistically significant benefit to the addition of nivolumab to standard of care (PFS 11.9 months in both arms) where the vast majority enrolled did not have dMMR/MSI-H mCRC. 26 The treatment horizon for patient with dMMR/MSI-H disease looks bright. This is a sub-group that has dramatic responses to checkpoint inhibitor therapy.…”