Platinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All “BRCAness” Is Created Equal

Abstract

Preclinical data suggest that IDH1/2 mutations result in defective homologous recombination repair (HRR). We hypothesized that patients with IDH1/2mt intrahepatic cholangiocarcinoma (IHCC) would benefit more from 1 L platinum chemotherapy than patients with wildtype (WT) tumors. We performed a multicenter retrospective study of 81 patients with unresectable IHCC treated with 1 L platinum with a primary endpoint of clinical benefit rate (CBR). Patients with IDH1/2mt tumors had a similar CBR and objective response rate compared to those with IDH WT disease (59 versus 54%; p = 0.803), suggesting that a relationship between platinum sensitivity and HRR gene defects may be specific to tumor context.

Keywords:

• Cholangiocarcinoma
• platinum sensitivity
• DNA damage repair
• isocitrate dehydrogenase

Author contributions

D. Doroshow: Conception and design, provision of study material/patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. W. Wei: Conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript. M. Mehrotra: Collection and/or assembly of data, final approval of manuscript. D. Sia: Provision of study material/patients, manuscript writing, final approval of manuscript. J. Eder: Provision of study material/patients, manuscript writing, final approval of manuscript. R. Bindra: Conception and design, manuscript writing, final approval of manuscript. J. Houldsworth: Conception and design, collection and/or assembly of data, final approval of manuscript. P. LoRusso: Conception and design, provision of study material/patients, manuscript writing, final approval of manuscript. Z. Walther: Conception and design, provision of study material/patients, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript

Declaration of interest

D. Doroshow: Consulting/Advisory role: Mirati Therapeutics, AstraZeneca, Sonata Therapeutics, G1 Therapeutics, Summit Therapeutics. Research funding, Conquer Cancer Foundation and Bristol Myers Squibb Foundation. J. Eder: Stock and other ownership interests: Parthenon. Honoraria: Roche Molecular Diagnostics. Consulting or Advisory Role: Roche/Genentech. Employment: Parthenon Therapeutics. R. Bindra: Leadership: Cybrexa Therapeutics, Athena Therapeutics. Stock and other ownership interests: Cybrexa Therapeutics, Athena Therapeutics. Consulting or Advisory Role: Cybrexa Therapeutics, Novocure, Syros Pharmaceuticals, Third Bridge Group, AstraZeneca, Prelude Therapeutics; Research Funding: Cybrexa Therapeutics, Athena Therapeutics; Patents: Patent filed on on PPM1D as a biomarker NAMPTi sensitivity Patent filed on use of IDH1/2 as a biomarker for PARPi sensitivity. P. LoRusso: Consulting/advisory role: Genentech, CytomX Therapeutics, Roche/Genentech, Halozyme, Five Prime Therapeutics, Agenus, Agios, Cybrexa Therapeutics, Sotio, Abbvie, Genmab, Takeda, TYME, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GlaxoSmithKline, QED Therapeutics, Astrazeneca, EMD Serono, Shattuck Labs, Astellas Pharma, Salarius Pharmaceuticals, Silverback, Macrogenics, Kyowa Kirin International, Kineta, Zentalis, Molecular Templates, ABL Bio, SK Life Sciences, ST Cube, Bayer, I-Mab, Seagen, ImCheck Therapeutics, Relay Therapeutics, Stemline Therapeutics, Mekanistic Therapeutics, Compass Therapeutics, BaxK Therapeutics. Research funding: Genentech (institutional). Travel/accommodations/expenses: Genentech. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

Additional information

Funding

This research was funded by a Young Investigator Award from the Conquer Cancer Foundation [2019YIA-6153320947].