Nivolumab regimen misses PFS endpoint but shows promise in metastatic colorectal cancer
First-line nivolumab plus standard of care chemotherapy failed to prolong 1-year PFS among patients with metastatic colorectal cancer, according to study results presented at ASCO Gastrointestinal Cancers Symposium.
However, findings from the phase 2/phase 3 CheckMate 9x8 trial showed the immune checkpoint inhibitor nivolumab (Opdivo, Bristol Myers Squibb) plus FOLFOX and bevacizumab (Avastin, Genentech) conferred higher PFS rates after 1 year compared with standard-of-care chemotherapy alone.
“Although the primary endpoint was not met, the PFS curves overlapped up until 1 year and then separated, showing better PFS rates in the nivolumab combination at 15 months and 18 months, and response rates were also higher with the nivolumab combination,” Heinz-Josef Lenz, MD, FACP, professor of medicine at USC Norris Comprehensive Cancer Center, told Healio.
Rationale
Nivolumab, an anti-PD-1-antibody, may increase antitumor activity when combined with standard-of-care first-line treatment for patients with metastatic colorectal cancer, according to Lenz.
“The addition of immunotherapy to chemotherapy showed some benefit in previous research,” he added. “We, therefore, wanted to see whether nivolumab combined with standard chemotherapy would benefit this patient population.”
Methods
The CheckMate 9x8 study included 195 patients with previously untreated, unresectable metastatic colorectal cancer.
Researchers randomly assigned patients to 240 mg nivolumab plus FOLFOX and bevacizumab every 2 weeks (n = 127) or standard of care (FOLFOX and bevacizumab) every 2 weeks (n = 68).
PFS served as the primary endpoint. Secondary endpoints included objective response rate, disease control rate, time to response, duration of response, OS and safety.
The nivolumab combination group had median follow-up of 23.7 months and median duration of treatment of 9.9 months compared with 23.2 months and 7.7 months for the standard-of-care group.
Key findings
Results showed median 1-year PFS of 11.9 months for both treatment groups (HR = 0.81; 95% CI, 0.53-1.23).
However, the nivolumab combination conferred a PFS rate at 15 months of 45% (95% CI, 35.4-54.8) compared with 21.5% (95% CI, 9.7-36.4) for standard of care. Moreover, the combination conferred an 18-month PFS rate of 28% (95% CI, 19-38.4) vs. 9% (95% CI, 2.4-21.8) for standard of care.
Researchers additionally observed an ORR of 60% and median duration of response of 12.9 months with the nivolumab combination compared with an ORR of 46% and median duration of response of 9.3 months with standard of care.
“Exploratory analyses further showed interesting findings of a benefit in patients with tumors that expressed CMS1 and CMS3, as well as tumors that expressed more than 2% CD8 cells,” Lenz said.
The nivolumab combination group had higher rates of grade 3 to grade 4 adverse events, but researchers found no new safety signals.
Implications
“These [results] have no direct impact on clinical decision-making but raise important findings that a subgroup of patients benefit from the nivolumab combination with standard of care chemotherapy,” Lenz said. “We need to better understand what patient population benefits. This is the first time that CMS3 is identified in microsatellite-stable patients to demonstrate benefit for nivolumab plus chemotherapy and warrants further investigation and testing.”
For more information:
Heinz-Josef Lenz, MD, can be reached at USC Norris Comprehensive Cancer Center, 1520 San Pablo St., Los Angeles, CA 90033; email: lenz@med.usc.edu.
Perspective
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Microsatellite-stable colorectal cancer is resistant to immune checkpoint inhibitors. Hypothetically, cytotoxic chemotherapy can overcome this resistance via tumor cell death and exposure to neoantigens. Therefore, a combination of chemotherapy and an immune checkpoint inhibitor is a reasonable approach as exercised in CheckMate 9x8.
The study design had a 1/2 randomization to standard of care treatment (FOLFOX/bevacizumab) vs. standard of care plus nivolumab with the primary endpoint of PFS. The study failed to show an improvement in PFS in the nivolumab-plus-standard of care group. However, subtleties in the results suggest that treatment can be effective in a subset of patients. Notably, both arms had a PFS of 11.9 months. Yet, the CI in the experimental group is wider than that of standard of care. Given that the experimental group was two times bigger than the standard-of-care group, it is unlikely that the larger CI is due to small sample size. Rather, these results suggest that there are at least two groups in the experimental group, one with detrimental effects of immunotherapy and the other with significant benefit from immunotherapy.
Future efforts should focus on identification of disease presentation, molecular characteristics and treatment paradigms that predict sensitivity to immune checkpoint inhibitors and to use this information for design of confirmatory trials.
Perspective
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Unlike many other malignancies, colorectal cancer has not seen a great deal of success in the utility of immunotherapy agents for OS and PFS improvement, outside of the patient population with microsatellite instability-high tumors.
Although the long-term prognosis for patients with colorectal cancer has improved during the past several decades, largely due to the incorporation of colonoscopy screening into preventive care plans, the 5-year OS rate for patients with distant metastatic disease remains approximately 14%.
The CheckMate 9x8 study aimed to evaluate combination immunotherapy with standard-of-care chemotherapy in the metastatic colorectal cancer population. Unfortunately, results did not show a significant difference in median 1-year PFS. However, the 15-month PFS rate was 45% with the combination vs. 21.5% with standard of care alone, and this difference was also observed at 18 months.
In subgroup analysis of PFS, there seemed to be a numerical trend favoring PFS in the combination therapy arm, and the disease control, durability and ORR were higher and responses more durable in the nivolumab arm.
This study suggests there may be some utility to nivolumab plus standard-of-care therapy in certain patient populations. However, more research is needed to better understand which patient populations may benefit from this combination therapy.
HemOnc Today Editorial Board Member
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Lenz HJ, et al. Abstract 8. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 20-22, 2022; San Francisco.
