Abstract
Background: Mucosal and acral melanoma respond worse to immune checkpoint inhibitors (ICI) than cutaneous melanoma. MDM2/4 as well as EGFR amplifications are supposed to be associated with hyperprogression on ICI in diverse cancers. We therefore investigated the response of metastatic acral and mucosal melanoma to ICI in regard to MDM2/4 or EGFR amplifications and melanoma type. Methods: We conducted a query of our melanoma registry, looking for patients with metastatic acral or mucosal melanoma treated by ICI. Whole exome sequencing, FISH and immunohistochemistry on melanoma tissue could be performed on 45 of the total cohort of 51 patients. Data were correlated with patients’ responses to ICI and survival. Results: 22 out of 51 patients had hyperprogressive disease (an increase in tumor load of >50% at the first staging). Hyperprogression occurred more often in case of MDM2/4 or EGFR amplification or <1% PD-L1 positive tumor cells. Nevertheless, this association was not significant. Interestingly, the anorectal melanoma type and the presence of liver metastases were significantly associated with worse survival. Conclusions: So far, we found no reliable predictive marker for patients who develop hyperprogression on ICI, specifically with regard to MDM2/4 or EGFR amplifications. Nevertheless, patients with anorectal melanoma, liver metastases or melanoma with amplified MYC seem to have an increased risk of not benefitting from ICI.
Highlights
The introduction of anti-CTLA-4 and anti-PD-1 antibodies has significantly improved the prognosis of metastatic melanoma, primary therapy resistance is still present in about 40%–50% of patients [1,2,3,4,5,6,7]
In an ex post power analysis, we found that hazard ratios of 2.7 or higher and differences in frequencies of 42% could have been detected with 80% power in our sample
We could not see a statistically significant association between amplification of MDM2, MDM4 or EGFR and the response to checkpoint inhibitors, we found a trend towards a lower chance of disease control in case of either MDM2, MDM4 or EGFR
Summary
The introduction of anti-CTLA-4 and anti-PD-1 antibodies has significantly improved the prognosis of metastatic melanoma, primary therapy resistance is still present in about 40%–50% of patients [1,2,3,4,5,6,7]. Patients with mucosal and acral melanoma respond worse to immunotherapy than patients with cutaneous melanoma [16,17]. The response rate to anti-PD-1 therapy in patients with mucosal melanoma is only about 23%, and is approximately 37% to combined immunotherapy [16]. Acral melanoma patients show a reduced objective response rate to anti-PD-1 therapy of around 32% [17]. Mucosal and acral melanoma respond worse to immune checkpoint inhibitors (ICI) than cutaneous melanoma. We investigated the response of metastatic acral and mucosal melanoma to ICI in regard to MDM2/4 or EGFR amplifications and melanoma type
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