Modified FOLFOX6 plus bevacizumab with and without nivolumab for first-line treatment of metastatic colorectal cancer: phase 2 results from the CheckMate 9X8 randomized clinical trial

Abstract

Background: Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8).

Methods: CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed.

Results: From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3-4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified.

Conclusions: The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted.

Trial registration number: NCT03414983.

Keywords: gastrointestinal neoplasms; immune checkpoint inhibitors; immunotherapy; nivolumab; tumor biomarkers.

Figure 1

Consolidated Standards of Reporting Trials diagram. ^aOther reasons included poor/non-compliance (n=1), and additional reasons (n=19). ^bMedian (range) follow-up was 23.7 (0–33.2) months in the nivolumab plus SOC arm and 23.2 (0–32.3) months in the SOC arm. ^cOther reasons included completion of treatment per protocol (n=8), withdrawal of consent (n=4), poor/non-compliance (n=2), and additional reasons (n=4). ^dOther reasons included withdrawal of consent (n=3), death (n=2), lost to follow-up (n=1), and additional reasons (n=2). AE, adverse event; NIVO, nivolumab; OS, overall survival; PFS, progression-free survival; SOC, standard of care.

Figure 2

Kaplan-Meier estimates of progression-free survival by BICR in all randomized patients. ^aMinimum follow-up of 21.5 months. BICR, blinded independent central review; NIVO, nivolumab; PFS, progression-free survival; SOC, standard of care.

Figure 3

Subgroup analysis of progression-free survival by BICR. ^a13 patients (NIVO+SOC: n=10; SOC: n=3) were ≥75 years. ^bTumor sidedness was unknown in 21 patients (NIVO+SOC: n=12; SOC: n=9). ^cHR is not computed for categories with less than 10 patients per treatment group. ^dLiver metastases status was not evaluable in 10 patients (NIVO+SOC: n=5; SOC: n=5). ^eSix MSI-L-patients (NIVO+SOC, n=1; SOC: n=5) included in the MSS/pMMR category; two patients with dMMR per IHC (one from each arm) are included in the MSS/pMMR category based on their PCR result of MSS. ^fKRAS mutation status was not reported in one patient in the SOC arm. ^gPD-L1 expression was not quantifiable in one patient in the NIVO+SOC arm. ^hAll treated patients. ⁱPD-L1 CPS was not evaluable in one patient in the NIVO+SOC arm. ^jCMS category was unknown, not available, or not reported in 64 patients (NIVO+SOC, n=41; SOC, n=23). ^kEvaluated only in patients with sufficient tumor samples for sequencing analyses. ^lBaseline TMB levels were generally low in this study; therefore, a lower TMB threshold was used to classify patients into subgroups instead of the threshold of 200 mutations/exome used in other tumor types. ^mTMB status was not evaluable in 73 patients (NIVO+SOC: n=44; SOC: n=29). BICR, blinded independent central review; CMS, consensus molecular subtype; CPS, combined positive score; dMMR, mismatch repair deficient; ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; IRT, interactive response technology; KRAS, Kirsten rat sarcoma viral oncogene homolog; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; NA, not applicable; NIVO, nivolumab; PD-L1, programmed death ligand 1; pMMR, mismatch repair-proficient; SOC, standard of care; TMB, tumor mutational burden.

Figure 4

Kaplan-Meier estimates of overall survival in all randomized patients. ^aMinimum follow-up of 21.5 months. NIVO, nivolumab; NE, not evaluable; OS, overall survival; SOC, standard of care.

Figure 5

Kaplan-Meier estimates of progression-free survival by BICR in patient subgroups. Progression-free survival in all randomized MSS/pMMR patients (A), all treated patients with CMS status at baseline (B), all treated MSS/pMMR patients with CMS status at baseline (C), all treated MSS/pMMR patients by CMS subsets at baseline (D), and all treated MSS/pMMR patients with PD-L1 CPS≥1 at baseline (E). ^aSix MSI-L patients (nivolumab plus SOC, n=1; SOC, n=5) are included in the MSS/pMMR category; two patients with dMMR per IHC (one from each arm) are included in the MSS/pMMR category based on their PCR result of MSS. ^b13 patients (nivolumab plus SOC, n=6; SOC, n=7) were MSI-H and were excluded from this analysis. ^cCMS status was evaluated only in patients with sufficient tumor samples for sequencing analyses. ^dCMS classifier random forest method was used for CMS classification. ^ePatients with unknown CMS status were excluded from the analyses. BICR, blinded independent central review; CMS, consensus molecular subtype; CPS, combined positive score; IHC, immunohistochemistry; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; NE, not evaluable; PD-L1, programmed death ligand 1; PFS, progression-free survival; pMMR, mismatch repair-proficient; SOC, standard of care.