Nivolumab Plus Standard of Care Misses Primary End Point in mCRC

Results from the CheckMate 9X8 trial (NCT03414983), which evaluated nivolumab (Opdivo) plus 5-fluorouracil/leucovorin/oxaliplatin (mFOLFOX6)/bevacizumab (Avastin; BEV) (standard of care [SOC]) vs SOC failed to meet statistical significance in previously untreated patients with metastatic colorectal cancer (mCRC). These findings were presented by Heinz-Josef Lenz, MD, at the 2022 Gastrointestinal Cancers Symposium.¹

“PFS [progression free survival] curves overlapped before separating at approximately 12 months, after which numerically higher PFS rates were observed for the [nivolumab] combination,” said Lenz of the University of Southern California, Norris Comprehensive Cancer Center.

CheckMate 9X8, a randomized, open label, phase 2/3 study failed to meet its primary end point of PFS per blinded independent central review (BICR). Patients administered nivolumab plus SOC showed a PFS of 11.9 months (95% CI, 8.9-15.7) vs 11.9 months (95% CI, 10.1-12.2) for SOC (HR = 0.81; 95% CI, 0.53-1.23; P = 0.3). However, at 15 months, the PFS rate for nivolumab plus SOC was 45% (95% CI, 35.4%-54.8%) vs SOC at 21.5% (95% CI, 9.7%-36.4%). At 18 months, the PFS was 28% (95% CI, 19.0%-38.4%) for nivolumab plus SOC vs 9.0% (95% CI, 2.4%-21.8%) for SOC.

The study enrolled 195 patients and randomized them 2:1. In the treatment arm, 127 patients received 240 mg of nivolumab every 2 weeks and SOC every 2 weeks. In the control arm, 68 patients received SOC every 2 weeks. The trial’s primary end points were PFS, and the secondary end points were objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), overall survival, and safety. At the data cutoff, the minimum follow up was 21.5 months.

Eligible patients needed to have histologically confirmed mCRC, no prior chemotherapy for mCRC, no prior treatment with checkpoint inhibitors, and an ECOG performance status of 0 to 1.

In the nivolumab plus SOC group, the median age was 58 years (range, 24-85), 55% were male, and 40% had an ECOG score of 1. In the SOC group, the median age was 56 years (range, 24-78), 72% were male, and 40% had an ECOG score of 1. Overall, baseline characteristics were generally balanced between the 2 arms.

Median treatment duration lasted 9.9 months (range, 0.1-31.8+) in the nivolumab plus SOC group. For the 123 patients in this group, 119 (97%) discontinued treatment. Disease progression (59%) was the most common reason for treatment discontinuation. The median treatment duration for the SOC group was 7.7 months (range, 0.1-26.7+). For these 62 patients, 60 (97%) discontinued treatment. Disease progression (44%) was also the most common reason for discontinuation.

Lenz stated, “54% of patients received more than 90% of the planned relative dose intensity of [nivolumab]. In the standard of care treatment [arm], the relative dose intensity of FOLFOX/BEV was higher than in the [nivolumab] combination.”

In subgroup analysis of PFS, there was a numerical trend favoring PFS in the treatment arm. Regarding responses, disease control, and durability, the ORR was higher and responses were more durable in the treatment arm compared with the control arm.

Median OS was 29.2 months for the treatment arm and not reached in the control arm (HR, 1.03; 95% CI, 0.64-1.66).

In exploratory analysis, a benefit was seen in patients with baseline tumor CD8 levels of 2% or greater after 12 months with nivolumab plus SOC. Median PFS in this subgroup was 13.2 months (95% CI, 8.25-NE) vs 10.4 months (95% CI, 9.1-NE) in the nivolumab plus SOC and SOC groups, respectively. With CD8 levels less than 2%, median PFS rates were similar among the two groups. The nivolumab plus SOC median PFS was 11.8 months (95% CI, 10.0-15.7) vs. 11.9 months (95% CI, 10.25-14.2) in the SOC group.

The microsatellite stable (MSS) patient population PFS was comparable with all randomized patients. MSS patients receiving nivolumab plus SOC had a PFS of 11.8 months (95% CI, 8.9-15.7). MSS patients receiving SOC had a PFS of 11.9 months (95% CI, 10.1-12.2).

ORR was 60% in the nivolumab plus SOC group vs 46% in the SOC group. The nivolumab plus SOC group saw a DCR of 91% vs 84% in the SOC group. The median TTR both nivolumab plus SOC and SOC was 2.8 months. The median DOR for the nivolumab plus SOC group was 12.9 months vs 9.3 months in the SOC group.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 75% of the nivolumab plus SOC group and in 48% of the SOC group. Any grade TRAEs occurring in 25% or more of patients in the treatment arm were fatigue (46%), nausea (46%), and peripheral neuropathy (42%). In the control arm these were 47%, 37%, and 32%, respectively. Researchers identified no new safety signals.

These findings suggest that a subgroup of patients with mCRC can benefit with the nivolumab plus SOC combination in the first line, but further research is required to identify these patients’ characteristics.

_Reference

_{Lenz H, Parikh A, Spigel D, et al. 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. Rapid abstract presented at: 2022 Gastrointestinal Cancers Symposium; January 20-22, 2022, San Francisco, California. Accessed January 22, 2022.}