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

Ikeda, Sadakatsu; Goodman, Aaron M.; Cohen, Philip R.; Jensen, Taylor J.; Ellison, Christopher K.; Frampton, Garrett M.; Miller, Vincent A.; Patel, Sandip Pravin; Kurzrock, Razelle

doi:10.1038/npjgenmed.2016.37

Cited by 109 publications

(105 citation statements)

References 34 publications

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“…In agreement with our findings on immune checkpoint expression profiles of murine BCC-like lesions, first proof-of-concept studies support a therapeutic benefit of anti-PD-1 treatment for patients with advanced or metastatic and SMO inhibitor resistant BCC (Chang et al, 2019, Ikeda et al, 2016, Lipson et al, 2017. These positive initial results underline the importance of predictive mouse models of BCC that allow the evaluation of innovative combination therapies including immunotherapeutics.…”

Section: Overexpression Of Active Gli2 In T Cells Can Cell-autonomoussupporting

confidence: 88%

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

Aberger

Grund-Groeschke

Ortner

et al. 2019

Preprint

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Genetic activation of Hedgehog (HH)/GLI signaling causes basal cell carcinoma (BCC), a very frequent non-melanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) proved an efficient medical therapy of BCC, although lack of durable responses and frequent development of drug resistance pose major challenges to anti-HH treatments. In light of the recent breakthroughs in cancer immunotherapy, we analyzed in detail the possible immunosuppressive mechanisms in HH/GLI-induced BCC. Using a genetic mouse model of BCC, we identified profound differences in the infiltration of BCC lesions with cells of the adaptive and innate immune system. Epidermal activation of HH/GLI led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including PD-1/PD-L1. Anti-PD1 monotherapy, however, did not reduce tumor growth, presumably due to the lack of immunogenic mutations in common BCC mouse models, as shown by whole-exome sequencing. BCC lesions also displayed a marked infiltration with neutrophils, the depletion of which unexpectedly promoted BCC growth. The results provide a comprehensive survey of the immune status of murine BCC and provide a basis for the design of efficacious rational combination treatments. This study also underlines the need for predictive immunogenic mouse models of BCC to evaluate in vivo the efficacy of immunotherapeutic strategies.

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Section: Overexpression Of Active Gli2 In T Cells Can Cell-autonomoussupporting

confidence: 88%

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

Aberger

Grund-Groeschke

Ortner

et al. 2019

Preprint

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“…Utilizing TMB as a biomarker may help select such patients for immunotherapy. For example, in our study, patients with cervical high-grade neuroendocrine carcinoma, metastatic basal cell carcinoma(42), and undifferentiated pleomorphic sarcoma, all of whom had failed multiple prior treatments and had intermediate to high TMB, responded to PD-1/PD-L1 blockade (Supplemental Table 19). Prospective basket trials evaluating patients with uncommon tumors harboring high TMB are needed.…”

Section: Discussionmentioning

confidence: 89%

“…NGS also has the ability to recognize alterations that can predict response to immunotherapy by identifying mutations in mismatch repair genes (21), microsatellite instability (MSI) (24,25,30,38,39), and PD-L1 amplification (40). …”

Section: Discussionmentioning

confidence: 99%

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Goodman

Kato

Bazhenova

et al. 2017

Molecular Cancer Therapeutics

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Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = <0.0001); median OS, not reached vs. 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB.

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“…1 patient of this series with PD-L1 positivity showed objective tumor response to pembrolizumab. Other reports described the exceptional response to nivolumab in basal cell carcinoma harboring PD-L1 amplification [19] and disease stabilization in a patient with basal cell carcinoma and pulmonary metastases who was also given nivolumab [20]. …”

Section: Discussionmentioning

confidence: 99%

Anti-PD-1 Therapy Leads to Near-Complete Remission in a Patient with Metastatic Basal Cell Carcinoma

et al. 2018

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Background: Metastatic basal cell carcinoma is rare and the prognosis is poor, with a lack of established treatment options for patients progressing on or after treatment with inhibitors of the hedgehog signaling pathway. Case Report: A man with pulmonary metastases of a basal cell carcinoma progressing after treatment with sonidegib and vismodegib was started on treatment with the anti-PD-1 antibody pembrolizumab. Upon treatment, rapid clinical improvement occurred, and after 5 cycles, the computed tomography scan showed near-complete remission of all tumor lesions. The tumor cells showed the absence of PD-L1 expression. Discussion: We report the first case of a patient with metastatic basal cell carcinoma experiencing an exceptional response to treatment with pembrolizumab in the absence of PD-L1 expression on the tumor cells. Immune checkpoint inhibition seems a promising treatment strategy for metastatic basal cell carcinoma. Our case suggests that the lack of PD-L1 expression does not rule out potential benefit from checkpoint inhibitor treatment.

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

Cited by 109 publications

References 34 publications

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Anti-PD-1 Therapy Leads to Near-Complete Remission in a Patient with Metastatic Basal Cell Carcinoma

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