Contrary to Previous Studies, Sex May Not Impact Efficacy of Immunotherapy

Despite previous findings, the response to immune checkpoint inhibitors does not differ between men and women, according to a systemic review and meta-analysis published in JAMA Oncology.

These findings, conducted at the University of Toronto, contradict a number of recent studies — including a study from Fabio Conforti, M.D., and colleagues, published in The Lancet Oncology in June 2018, that found men derive greater benefits from immune checkpoint inhibitors than women. However, the researchers in this study noted that the previous study did have its limitations.

“First, the (previous) meta-analysis included a limited subset of approved immunotherapeutic agents,” the researchers wrote. “Second, several comprehensive and updated studies that met the inclusion criteria, including those with a more robust representation of female patients, have been published since the Conforti et al literature review.”

To address these limitations in their own analysis, the researchers took a broader and more updated approach. They began by revisiting the search criteria used by Conforti and colleagues, this time including a broader range of treatment agents, and adding all new data that has been generated since the initial study. They then scoured the MEDLINE (PubMed), Embase and Scopus databases for phase 2 or 3 randomized clinical trials that took place from the inception of said databases through Oct. 2, 2018.

Their analysis included data from trials that involved the use of Yervoy (ipilimumab), tremelimumab, Opdivo (nivolumab), Keytruda (pembrolizumab), Tecentriq (atezolizumab), Imfinzi (durvalumab) and Bavencio (avelumab).

When the data was combined and duplicate studies and/or patients were removed, the researchers were left with a total of 23 studies and 13,721 patients. Of this total, 9,322 (67.9 percent) were men and 4,399 (32.1 percent) were women. Most patients were in their 70s, and all studies enrolled patients within the past decade. The majority of studies were published in the past three years.

The analysis also included patients with a wide variety of advanced cancer types. Out of the 23 studies, 11 (48 percent) were for patients with non-small cell lung cancer (NSCLC), four (17 percent) for melanoma, two (9 percent) for clear cell renal cell carcinoma, two for small cell lung cancer (SCLC) and one (4 percent) each for urothelial carcinoma, head and neck squamous carcinoma, mesothelioma and gastric or gastroesophageal carcinoma.

While most trials examined the efficacy of immunotherapy after previous systemic therapy failure, 11 trials (48 percent) assessed it in the first-line setting. In all but two studies, overall survival was the primary endpoint.

Of the 23 studies, 17 evaluated the use of immunotherapy compared to standard of care, but six trials (26 percent) evaluated the combination of immunotherapy and standard of care compared to standard of care alone. Additionally, 17 used a PD-L1 or PD-1 inhibitor while only six trials (26 percent) used a CTLA-4 inhibitor.

The meta-analysis of the data showed, as expected, that immunotherapy offered a statistically significant advantage in overall survival versus other therapies. However, the researchers noted, unlike the analysis by Conforti and colleagues, there was no evidence of improved overall survival when comparing men to women.

“Contrary to the published meta-analysis by Conforti et al, which suggested a greater immunotherapy advantage compared with standard of care systemic therapy for men than women,” he explained, “the present analysis found no difference in overall survival from immune checkpoint inhibitors when comparing the efficacy of these treatments between the sexes.”

To explain these conflicting results, the study noted that updated data and the inclusion of additional immunotherapy agents in the analysis may have played a role. Additionally, the researchers excluded three trials initially included in the Conforti et al trial that compared various immunotherapy regimens, focusing instead only on trials that compared immunotherapy with a non-immunotherapy control.

“Contrary to findings of a previous analysis, we found no evidence that sex should be considered when deciding whether to offer immunotherapy to patients with advanced cancers,” the researchers concluded.