Combination Immunotherapy Efficacy in Lung Cancer May Differ by Patient Sex

Women with advanced lung cancer appeared to benefit more than men from the combination of chemotherapy and a programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor, a systematic review and meta-analysis found. The findings were recently published in the Journal of the National Cancer Institute.

“It’s important to look at sex and sex differences and understand that responses may not be the same,” said Karen Reckamp, MD, co-director of the Lung Cancer and Thoracic Oncology Program at City of Hope, during an interview with Cancer Network. Reckamp, who was not involved in the study, said these findings support previous data that, in general, women do better with chemotherapy.

The study authors previously reported in the LancetOncology in 2018 that immune checkpoint inhibitor monotherapy was more effective in men with cancer than women, according to their systematic review and meta-analysis of 20 randomized controlled trials of various cancer types. Conflicting results emerged in early 2019 when a study published in JAMA Oncology by a different group of researchers reported that the efficacy of immune checkpoint inhibitors did not differ by patient sex, according to their systematic review and meta-analysis of 23 randomized controlled trials.

The current study had two meta-analyses. The first meta-analysis aimed to determine differences in treatment efficacy on the basis of patient sex and included 8 randomized controlled trials that evaluated PD-1 or PD-L1 inhibitors plus chemotherapy vs chemotherapy for advanced solid tumors. The second meta-analysis aimed to determine differences in efficacy between immunotherapeutic strategies on the basis of patient sex and included 6 randomized controlled trials that evaluated first-line systemic treatment with PD-1 or PD-L1 inhibitors as a single-agent or in combination with chemotherapy for advanced non–small-cell lung cancer.

The first meta-analysis revealed a pooled-ratio of the overall survival (OS) hazard ratios (HR) of 1.56 (95% CI, 1.21–2.01), in favor of women deriving greater benefit than men from the combination of chemotherapy and a PD-1 or PD-L1 inhibitor. The second meta-analysis showed a pooled-ratio of the OS-HRs of 0.83 (95% CI, 0.65–1.06) for PD-1 inhibitor monotherapy, suggesting that immune checkpoint inhibitor monotherapy confers greater benefit in men. The analysis also showed a pooled-ratio of the OS-HRs of 1.70 (95% CI, 1.16–2.49) for a PD-1 or PD-L1 inhibitor plus chemotherapy, suggesting that combination therapy confers greater benefit in women.

Ultimately, the findings suggest responses to immunotherapy may differ by sex, with women who have advanced lung cancer benefiting more than men from the addition of chemotherapy to PD-1 or PD-L1 inhibitor therapy.

Reckamp cautioned that, in lung cancer in particular, there may be confounding factors related to gender, and this could affect the results. For instance, women tend to get lung cancer earlier than men, have better treatment outcomes, and be nonsmokers. “I think likely there are some confounding factors that are playing a part here,” she said.

When asked how these study findings would apply in the clinic, Reckamp explained that the biology of the tumor will still guide decisions. “There is no specific factor to the patient’s sex that would change how you treat that would trump understanding the biology,” said Reckamp. “We’re in the era of precision medicine, and it’s really about the biology of the tumor, which is genderless, so that’s what’s important.”