In a meta-analysis of studies that included 1727 patients with 8 types of advanced cancers other than melanoma, the differences detected in overall survival (OS) and progression-free survival (PFS) between nivolumab plus ipilimumab and nivolumab alone were not clinically meaningful, even though statistical significance was detected in PFS. Treatment-related higher-grade side effects and discontinuations were substantially higher with the combination treatment.
Nivolumab or other anti-PD1 alone may deliver equivalent clinical outcomes with lower toxicity (clinical and financial) in many advanced cancers other than melanoma according to Dr. Niraj K. Shenoy of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and Dr. Anthony V. Serritella of the Northwestern University Feinberg School of Medicine in Chicago, IL, US who published the findings in a brief report on 31 August 2023 in the JAMA Oncology.
The authors wrote in the background that relatively few studies to date have directly compared nivolumab plus ipilimumab with nivolumab monotherapy, and currently no summative analyses have compared the combination therapy with nivolumab alone for advanced cancers other than melanoma. They searched systematically electronic databases (PubMed, EBSCO Information Services, Embase, and Cochrane Library) from database inception to 31 October 2022 for studies of standard-dose nivolumab plus ipilimumab versus nivolumab alone in the treatment of advanced cancers other than melanoma.
A total of 8 studies with 1727 included patients (854 in nivolumab plus ipilimumab group and 873 in nivolumab monotherapy group) met the selection criteria. Patients had squamous cell lung cancer (Lung-MAP S1400I), non-small cell lung cancer with PD-L1 level of 1% or higher (CheckMate 227), small cell lung cancer (CheckMate 032), pleural mesothelioma (IFCT-1501 MAPS2), urothelial carcinoma (CheckMate 032), oesophagogastric carcinoma (CheckMate 032), sarcoma (Alliance A091401), or glioblastoma multiforme (CheckMate 143).
For comparison of OS and PFS outcomes, estimation of log hazard ratios (HRs) and SEs was initially performed for OS and PFS of each included study based on summary statistics extracted from individual Kaplan-Meier curves. Inverse-variance weighting was then used to compute pooled HRs (95% confidence intervals [CIs]). For comparison of dichotomous data (treatment-related grade 3 to 4 side effects and discontinuations), odds ratios (ORs) were used, and the Mantel-Haenszel method was used to estimate pooled ORs (95% CIs).
Treatment with nivolumab plus ipilimumab was not associated with improvement in OS over treatment with nivolumab alone (pooled HR 0.95, 95% CI 0.85-1.06; p = 0.36), with 4 of the 8 studies having numerically lower median OS with the combination. Nivolumab plus ipilimumab combination therapy was associated with marginal, but not clinically meaningful, improvement in PFS over nivolumab alone (pooled HR 0.88, 95% CI 0.79-0.98; p = 0.02).
The combination was associated with substantially higher treatment-related grade 3 to 4 side effects (pooled OR 1.84; 95% CI 1.47-2.31; p < 0.001) and treatment-related discontinuations (pooled OR 1.96, 95% CI 1.44-2.65; p < 0.001). This finding was recapitulated in meta-analyses of individual grade 3 to 4 hepatotoxicity, gastrointestinal toxicity, pneumonitis, endocrine dysfunction, dermatitis, fatigue.
The authors commented that it is possible that certain immunogenic non-melanoma cancers (such as renal cell carcinoma and triple-negative breast cancer) or specific subsets of populations (such as sarcomatoid renal cell carcinoma or squamous cell lung cancer with high tumour mutational burden and low PD-L1) may have survival benefit with the combination over single-agent nivolumab, although this remains to be determined.
In advanced Merkel cell carcinoma, a rare immunogenic cutaneous cancer, nivolumab and ipilimumab combination therapy has demonstrated substantial benefit with objective response rate (ORR) of 31% even after prior anti-PD1/anti-PD-L1 exposure and ORR of 100% in the immune checkpoint inhibitor naïve setting, establishing the superiority of the combination in treatment of this cancer type. Future randomised investigations in immunogenic cancers and biomarker-driven studies may identify combination-responsive cancers and subsets.
The authors underlined that the data from this meta-analysis indicate that investigations of anti-PD1 plus anti-CTLA4 therapies in any non-melanoma advanced cancer should be conducted along with anti-PD1 monotherapy to ensure that the net effect of the addition of anti-CTLA4 to anti-PD1 can be clearly established for that cancer and setting and that unnecessary CTLA4 inhibition with related toxicity (clinical and financial) can be avoided. Furthermore, in cancers in which nivolumab and ipilimumab combination therapy has been approved without comparison with nivolumab, non-inferiority studies should be considered.
