Tumor mutational burden predicts treatment response among women, not men, with melanoma
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Tumor mutational burden predicted immune checkpoint inhibitor response among women, but not men, with melanoma, according to findings presented during the virtual American Association for Cancer Research Annual Meeting.
“Recent studies have suggested tumor mutational burden levels, strength of immune selection and response to immune checkpoint inhibitor treatment differ between male and female [patients with melanoma],” Neelam Sinha, MS, researcher at NCI’s Center for Cancer Research, told Healio. “Hence, when the FDA approved pembrolizumab [Keytruda, Merck] for all solid tumors with a tumor mutational burden of 10 or more mutations/megabase [Mb], we hypothesized that use of this single threshold for both sexes may introduce an unwarranted sex bias when selecting patients.”
Sinha and colleagues sought to identify the potential sex-specific implications of this threshold in selecting patients for immune checkpoint inhibitor treatment.
The researchers pooled data from Memorial Sloan Kettering Cancer Center’s MSK-IMPACT tumor profiling panel, which included 1,286 patients who received anti-PD-1/PD-L1 monotherapy, 99 patients who received anti-CTLA-4 monotherapy and 255 patients who received a combination of both.
The analysis focused on nine types of cancer with tumor mutational burden and clinical response data for 50 or more patients.
Median follow-up was 19 months.
Among 130 patients with melanoma, men had higher median tumor mutational burden than women (11.81 mutations/Mb vs. 6.51 mutations/Mb). A meta-analysis of four melanoma cohorts using a weighted Z test showed significantly higher median tumor mutational burden values among men (P < .006).
Researchers additionally found that among women, those with tumor mutational burden of 10 or more mutations/Mb had 81% longer OS with immune checkpoint inhibition than those with tumor mutational burden below the threshold (P < .03).
Conversely, no significant difference in treatment response was observed among men with tumor mutational burden above vs. below the threshold, Sinha said during her presentation.
“We found that among female patients with melanoma, the current tumor mutational burden threshold can successfully stratify [women]with better survival, but this was not the case with male patients,” Sinha said.
Results of the meta-analysis showed a consistently lower HR among women vs. men treated with anti-PD-1/PD-L1 monotherapy (P < .027) but not for anti-CTLA-4 treatment, combined anti-PD-1 and anti-CTLA-4 therapy, or non-immune checkpoint inhibitor treatments.
“We performed this analysis in other patient cohorts but did not observe this sex bias in those cohorts,” Sinha said. “After observing these results in the melanoma cohort, we expanded our analysis to seven other cancer types.”
Results showed that despite the large sample size in the lung cancer cohort, no differences existed in HRs between men and women based on the tumor mutational burden threshold. However, researchers did observe a trend toward improved responses based on the threshold among women vs. men for glioblastoma and cancer of unknown primary.
“These differences were insignificant, which could be due to small sample size,” Sinha said.
Use of the FDA-approved high tumor mutational burden threshold as a biomarker may introduce a sex bias in glioblastoma and cancers of unknown origin, but this requires further careful testing in larger data sets, Sinha added.
“Another important point that we observed from our analysis is that this biomarker can successfully stratify [women with metastatic melanoma] but fails to do so in male patients,” she said. “Even though this biomarker is not currently an FDA prerequisite for anti-PD-1 treatment [for patients with melanoma], clinicians may consider it when recommending therapies.”
Researchers are currently investigating the underlying mechanisms potentially driving these sex-dependent differences and analyzing patient data to characterize different immune cell activity in the tumors of men vs. women.
Perspective
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Jennifer A. Doherty, MS, PhD
This is a fascinating study that shows us how important it is to understand other characteristics of cases for these important and potential treatment guidelines, although they are not being used as treatment guidelines right now. Regarding the lung cancer finding, it is my understanding that these types of therapies are much more effective among smokers compared with never-smokers. It might be interesting to look at this in future research.
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Sinha N, et al. Abstract 29. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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