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Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy.

ABSTRACT: Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burden (> 50 mutations per megabase; 19 functional alterations in tissue next-generation sequencing (NGS; 315 genes)) as well as PDL1/PDL2/JAK2 amplification (as determined by both tissue NGS and by analysis of plasma-derived cell-free DNA). The latter was performed using technology originally developed for the genome-wide detection of sub-chromosomal copy-number alterations (CNAs) in noninvasive prenatal testing and showed numerous CNAs including amplification of the 9p24.3-9p22.2 region containing PD-L1, PD-L2 and JAK2. Of interest, PD-L1, PD-L2 and JAK2 amplification is a characteristic of Hodgkin lymphoma, which is exquisitely sensitive to nivolumab. In conclusion, selected SMO antagonist-resistant metastatic basal cell carcinomas may respond to nivolumab based on underlying molecular genetic mechanisms that include PD-L1 amplification and high tumour mutational burden.

SUBMITTER: Ikeda S

PROVIDER: S-EPMC5142752 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy.

Ikeda Sadakatsu S Goodman Aaron M AM Cohen Philip R PR Jensen Taylor J TJ Ellison Christopher K CK Frampton Garrett G Miller Vincent V Patel Sandip P SP Kurzrock Razelle R

NPJ genomic medicine 20161019

Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burde ...[more]

PMID: 27942391

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Project description:BackgroundSalvage nivolumab and ipilimumab after prior anti-PD-1/PD-L1 therapy is frequently used off-label for clear cell metastatic renal cell carcinoma (mRCC). However, limited data are available to guide such therapy. We performed a meta-analysis to characterize further the safety and efficacy of salvage nivolumab and ipilimumab.MethodsWe conducted a systematic review in accordance with PRISMA. Studies of salvage nivolumab and ipilimumab in patients with mRCC published in English before June 1, 2021 were included. We also included patients treated at the Ohio State University from 2012 to 2020 through a retrospective chart review. The included studies were further stratified into adaptive and standard groups based on their designs. We calculated objective response rate (ORR) and adverse events (AEs) via pooled data and quantitative synthesis using the Stata metaprop procedure. A conservative random effect model was used to combine values.ResultsA total of 7 studies and 310 patients were included. Salvage nivolumab and ipilimumab had an ORR of 14% (95% CI, 0.09-0.21) and median progression-free survival ranged between 3.7 and 5.5 months. Four out of the seven studies were standard design, whereas the other three studies were adaptive. The ORR was numerically higher in the standard group compared with the adaptive group (21% and 9-10%, respectively). The responses to salvage nivolumab and ipilimumab did not correlate with the initial anti-PD-1/PD-L1 responses (odds ratio = 1.45; p = 0.5). Grade ≥3 AEs occurred in 26% of the patients (95% CI, 0.19-0.33). There were no new safety signals observed in this study.ConclusionSalvage nivolumab and ipilimumab demonstrated moderate antitumor activity and a manageable safety profile in patients with mRCC who had prior anti-PD-1/PD-L1 therapy.Implication for practicePatients with metastatic renal cell carcinoma have limited treatment options after progressive disease on anti-PD-1/PD-L1 therapy. The role of salvage nivolumab and ipilimumab in this patient population is poorly defined. The studies on this highly important and clinically relevant topic are limited by small sample sizes. The results from our meta-analysis suggest that nivolumab and ipilimumab are feasible in the salvage setting with moderate efficacy and acceptable toxicity profile. The response rates differ with different treatment designs. This information will be beneficial to guide clinical decision-making and accurately estimating toxicity.

Project description:Combination anti-PD-(L)1/CTLA-4 blockade is approved in patients with hepatocellular carcinoma (HCC) in the first-line setting or after sorafenib, but whether this treatment has efficacy after prior anti-PD-(L)1 therapy is unknown. We performed a multicenter retrospective review of patients with advanced HCC treated with ipilimumab plus nivolumab after prior anti-PD-(L)1 therapy, excluding patients with prior anti-CTLA-4 treatment. Of the 32 patients who met our inclusion criteria, prior anti-PD-(L)1 regimens included atezolizumab plus bevacizumab (50%, n = 16), other anti-VEGF plus anti-PD-(L)1 combinations (31%, n = 10), and anti-PD-(L)1 monotherapy (19%, n = 6). The median number of prior systemic therapies was 2 (range, 1-8). The objective response rate with ipilimumab plus nivolumab by RECIST 1.1 was 22% [1 complete response (3%), 6 partial response (19%), 8 stable disease (25%), 16 progressive disease (50%), and 1 not evaluable (NE) (3%)], and objective response was associated with improved progression-free survival and overall survival. Immune-related adverse events were reported in 13 patients (41%), with no new safety signals. This study demonstrates that ipilimumab plus nivolumab has efficacy in patients with HCC who have received prior anti-PD-(L)1 therapy, suggesting that failure to respond to prior PD-(L)1 blockade should not preclude treatment with salvage ipilimumab plus nivolumab. Prospective studies are needed to define the optimal sequence of therapies.SignificanceAnti-PD-(L)1 containing regimens are the preferred first-line treatment for advanced HCC, but whether salvage with PD-(L)1/CTLA-4 blockade is effective in patients who have failed prior anti-PD-(L)1 therapy is unknown. Our study demonstrates that ipilimumab plus nivolumab has clinical activity in patients with advanced HCC previously treated with anti-PD-(L)1 therapy, supporting the continued use of this regimen in the late-line setting after prior anti-PD-(L)1 exposure.

Dataset Information

Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy.

Publications

Metastatic basal cell carcinoma with amplification of PD-L1: exceptional response to anti-PD1 therapy.

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