Birabresib achieved partial responses in 3 of 10 patients with NUT midline carcinoma.

  • Major finding: Birabresib achieved partial responses in 3 of 10 patients with NUT midline carcinoma.

  • Concept: Birabresib did not achieve responses in patients with prostate cancer or non–small cell lung cancer.

  • Impact: BET inhibition with birabresib may be beneficial in patients with NUT midline carcinoma.

The bromodomain and extraterminal (BET) proteins (including BRD2, BRD3, BRD4, and BRDT) are essential epigenetic regulators of transcription, and BET inhibition has antitumor activity in a variety of preclinical tumor models including nuclear protein in testis (NUT) midline carcinoma (NMC), which is characterized by BRD4–NUT fusions, non–small cell lung cancer (NSCLC), and androgen-resistant and androgen-sensitive prostate cancer. A selective small-molecule BET inhibitor, birabresib (OTX015), demonstrated antitumor activity in patients with hematologic malignancies, but has not yet been evaluated in solid tumors. Lewin and colleagues evaluated the safety and efficacy of birabresib in an open-label phase Ib dose-escalation study. A total of 46 patients were treated with birabresib: 26 with castration-resistant prostate cancer (CRPC), 10 with NMC, and 10 with NSCLC. Twenty-four patients were enrolled in cohort A and received continuous birabresib (starting at 80 mg per day), and the 22 patients in cohort B received 100 mg birabresib for 7 consecutive days in 21-day cycles. The primary objective was determination of dose-limiting toxicities and the recommended phase II dose, and secondary objectives were assessment of the safety, efficacy, and pharmacokinetics of birabresib. In the 42 evaluable patients, there was a 67% disease control rate, with partial responses achieved in 3 of 10 patients with NMC. Overall, 38 patients (83%) experienced treatment-related adverse events, including grade 3–4 treatment-related adverse events in 35% of patients and serious adverse events in 22% of patients. Pharmacokinetic analysis showed that birabresib had a dose-proportional increase in exposure and rapid absorption. Collectively, the results of this phase Ib trial indicate that birabresib has a favorable safety profile in solid tumors and warrants further investigation for the treatment of patients with NMC.

Lewin J, Soria JC, Stathis A, Delord JP, Peters S, Awada A, et al. Phase Ib trial with birabresib, a small-molecule inhibitor of bromodomain and extraterminal proteins, in patients with selected advanced solid tumors. J Clin Oncol 2018 May 7 [Epub ahead of print].

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