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Multicenter Study
. 2018 Dec 27;6(1):159.
doi: 10.1186/s40425-018-0482-z.

Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders

A Boilève  1 , M I Carlo  2 , P Barthélémy  3 , S Oudard  4   5   6 , D Borchiellini  7 , M H Voss  2 , S George  8 , C Chevreau  9 , J Landman-Parker  10 , M-D Tabone  10 , D D Chism  11 , A Amin  12 , M A Bilen  13 , D Bosse  14 , A Coulomb-L'hermine  15 , Xiaoping Su  16 , T K Choueiri  14 , Nizar M Tannir  17 , Gabriel G Malouf  18   19   20   21
Affiliations
Multicenter Study

Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders

A Boilève et al. J Immunother Cancer. .

Abstract

Background: Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population.

Patients and methods: This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients.

Results: Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10- 6).

Conclusions: MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.

Keywords: Antiangiogenic agents; Bromodomain-containing genes; O-glycosylation; Parallel evolution; TFE3; TFEB.

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Conflict of interest statement

Ethics approval and consent to participate

Patient data were collected in compliance with the IRB guidelines of each participating institution. All study protocols were performed in accordance with the ethical tenets of the Declaration of Helsinki.

Consent for publication

Written informed consent was obtained from all patients for whom genomic testing was performed. Oral informed consent was obtained from all other patients.

Competing interests

Dr. Malouf reports consultancy fees from BMS, Pfizer, Ibsen, Novartis, Astellas, and grants from Novartis and Pfizer, outside the submitted work. Dr. Barthélémy reports consultancy fees from BMS, Pfizer, Novartis, outside the submitted work. Dr. Chevreau reports consultancy fees from BMS, Ipsen, Pfizer, Novartis,outside the submitted work. Dr. Borchiellini reports consulting fees from Bristol-Myers Squibb, Ipsen, Novartis, Pfizer, outside the submitted work. Dr. Voss reports consulting fees from Exelixis, Novartis, Eisai, Calithera, Alexion, grants from Genentech, BMS, outside the submitted work. Dr. George reports consultancy fees from Bristol-Myers Squibb, Novartis, Bayer, Pfizer, Exelixis, AstraZeneca, Janssen Oncology, Corvus Pharmaceuticals, Genentech/Roche, and research grants from Pfizer, Acceleron Pharma, Merck, Agensys, Novartis, Bristol-Myers Squibb, Bayer. Dr. Chism reports consultancy fees from Karyopharm Inc., Pfizer, Exelixis outside the submitted work. Dr. Tannir reports consulting fees from BMS, Exelixis, Nektar, Novartis, Pfizer, Argos, Calithera and grants from BMS, Exelixis, Epizyme, Novartis, Miranti, outside the submitted work, outside the submitted work. Dr. Choueiri has reports 1) research grants (Institutional and personal) from AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Takeda. 2) Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics. • 3) Consulting or Advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group. • No speaker’s bureau • No leadership or employment in for-profit companies (other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney cancer Association Medical and Scientific Steering Committee) • No Patents, royalties or other intellectual properties • Travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria • Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies • The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter.Dr. Boilève, Dr. Carlo, Dr. Oudard, Dr. Landman-Parker, Dr. Tabone, Dr. Amin, Dr. M. A Bilen, Dr. Bosse, Dr. A. Coulomb-L’hermine and Dr. Su have nothing to disclose.

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Figures

Fig. 1
Fig. 1
Responses to tyrosine kinase inhibitors and immune checkpoint inhibitors in 24 patients with metastatic MITF family translocation renal cell carcinoma. Blue/purple/cyan: first-line therapy; red: second-line therapy. S, sunitinib; P, pazopanib; So, sorafenib; N, nivolumab; I, ipilimumab; A, atezolizumab; X, combination MEDI4736 + tremelimumab; 41BB + Pembro, 41BB agonist and pembrolizumab; E, everolimus; T, temsirolimus; H, high-dose IL2; NA, Not available
Fig. 2
Fig. 2
Kaplan-Meier curves for progression-free survival (PFS) of patients with metastatic MITF family translocation renal cell carcinoma treated with (a) a tyrosine kinase inhibitor (TKI) or (b) an immune checkpoint inhibitor (ICI)
Fig. 3
Fig. 3
Genomic correlates of response to immune checkpoint inhibitor (ICI) therapy in a subset of 8 patients with metastatic MITF family translocation renal cell carcinoma (tRCC). The identified mutations and mutational load were assessed by either whole-exome sequencing or targeted sequencing. Numbers of mutations and genes mutated in each sample are given. a Genes mutated in the 4 samples assessed by whole-exome sequencing. b Box-plots depicting mutational load in tRCC patients (n = 4) assessed by whole-exome sequencing as compared to that in patients with clear-cell RCC (ccRCC) from the TCGA dataset (n = 420). c Genes mutated in the 4 samples assessed by targeted sequencing
Fig. 4
Fig. 4
Genomic evolution of a tumor from a patient who had an exceptional response to ipilimumab. a Numbers of somatic mutations in the primary tumor and in the 2 resistant clones following ipilimumab treatment reveal an increase of mutational load. Blue indicates shared mutations across all 3 samples; orange indicates private mutations. b String network analysis of 17 genes showing parallel evolution reveals 5 genes (in red) linked to the O-glycosylation process. c List of somatic mutations in the primary tumor and resistant clones showing mutations lost in resistant clones as compared to primary tumor and mutations in genes with parallel evolution
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