Immunotherapy Not Additive to Standard of Care for Untreated Metastatic CRC

SAN FRANCISCO — Immunotherapy’s limited activity against microsatellite stable (MSS) colorectal cancer (CRC) failed to improve when added to standard-of-care (SOC) therapy, a phase II randomized trial showed.

Patients had a median progression-free survival (PFS) of 11.9 months regardless of whether they received nivolumab (Opdivo) in addition to FOLFOX6 chemotherapy, and bevacizumab (Avastin). Median overall survival (OS) had yet to be reached in patients who received FOLFOX6 and bevacizumab but leveled off at 29.2 months with the addition of nivolumab.

PFS landmark analyses at 15 and 18 months showed clear advantages for the nivolumab arm, and a subgroup analysis suggested a trend favoring the addition of immunotherapy, reported Heinz-Josef Lenz, MD, of the USC Norris Comprehensive Cancer Center in Los Angeles, at the Gastrointestinal Cancers Symposium.

“Higher objective response rate and more durable responses were observed with nivolumab plus standard of care, said Lenz. “In exploratory subgroup analyses, benefit was observed with the addition of nivolumab to standard of care in CMS1 [consensus molecular subtype for CRC] and CMS3 patients and in patients with CD8 count ≥2%.”

“Results from this phase II exploratory study suggest that a subgroup of patients with metastatic colorectal cancer may experience benefit from the addition of nivolumab to standard of care in the first-line setting,” Lenz added. “However, further investigation is warranted to identify characteristics of these patients.”

The collective data from multiple studies “do not support concurrent chemotherapy plus immune checkpoint inhibition in either MSI-H [microsatellite instability-high] or MSS in metastatic colorectal cancer,” said invited discussant Rona Yaeger, MD, of Memorial Sloan Kettering Cancer Center in New York City. “Immune checkpoint inhibition does not improve outcomes in MSS in metastatic colorectal cancer. Patients should be encouraged to enroll in clinical trials to identify new combinations with increased activity.”

With respect to the current trial, biomarker analyses could provide insight into why immune checkpoint inhibitors (ICIs) are not beneficial in metastatic CRC, she said. However, even if a subpopulation of patients might be more sensitive to ICIs, “we need new approaches and combination regimens to achieve meaningful clinical activity with immune checkpoint inhibition with metastatic colorectal cancer.”

ICIs have substantial activity in MSI-H metastatic CRC but little activity in MSS disease. Some evidence suggests immunotherapy may enhance antitumor activity in metastatic CRC when combined with standard treatment, said Lenz.

Nivolumab has FDA approval as a single agent or in combination with ipilimumab (Yervoy) for previously treated MSI-H or mismatch repair-deficient (dMMR) metastatic CRC. The current CheckMate 9X8 randomized trial investigated the efficacy of nivolumab in combination with standard-of-care therapy as first-line treatment for unselected patients with metastatic CRC.

The trial involved 195 patients who were randomized 2:1 to FOLFOX6 plus bevacizumab with or without nivolumab. More than 90% of the patients had MSS/MMR-proficient tumors. The primary endpoint was PFS, and OS was a key secondary endpoint.

With a minimum follow-up of 21.5 months, the results showed no significant difference between treatment groups in either the primary endpoint or OS. PFS in the MSS/pMMR subgroup was identical to the overall results. Landmark PFS analyses favored the nivolumab arm at 15 months (45% vs 21.5%) and at 18 months (28% vs 9%).

The addition of nivolumab led to a higher response rate (60% vs 46%) and to more prolonged responses (median duration 12.9 months vs 9.3 month). A majority of responses in the nivolumab arm persisted for at least 12 months as compared with 31% in the standard-of-care group.

An exploratory analysis showed that patients with CMS1 and CMS3 tumors derived a PFS benefit from nivolumab after 12 months. The same was true of patients who had baseline tumor CD8 ≥2%.

The nivolumab arm had a higher incidence of grade 3/4 treatment-related adverse events (75% vs 48%), but no new or unexpected safety issues arose during the study, said Lenz.