ATC is a rare, aggressive malignancy with a dismal prognosis and median overall survival (OS) of < 6 mo. One-fourth of ATCs harbor activating BRAF V600E mutations. Initial data from this trial demonstrated strong efficacy of combined D (BRAF inhibitor) + T (MEK inhibitor) treatment in pts with BRAF V600–mutated ATC. Among 16 pts, overall response rate (ORR) was 69%, and median duration of response (DOR), progression-free survival (PFS), and OS were not reached (NR) due to insufficient progression and death events. D + T was recently approved by the U.S. Food and Drug Administration for the treatment of BRAF V600E-mutant ATC.
In this phase II, open-label basket trial (NCT02034110), pts with BRAF V600E mutations in 9 rare tumor types, including ATC, received continuous D (150 mg BID) + T (2 mg QD) until unacceptable toxicity or disease progression. Eligible pts had advanced or metastatic cancer with no standard-of-care treatment options. The primary endpoint was investigator-assessed ORR. Secondary endpoints included DOR, PFS, OS, and safety. We report updated data from the ATC cohort.
27 of 28 pts with ATC had evaluable data. BRAF V600E mutations were centrally confirmed in 25/28 pts. Median age was 70 y; 23/28 (82%) pts had undergone prior tumor radiation, and 13/28 pts (46%) had received ≥ 1 prior line of chemotherapy. Investigator-assessed confirmed ORR was 67% (18/27; 95% CI, 46%-84%), with 8/18 responses ongoing at data cutoff. 12/18 patients (67%) had a DOR of ≥ 6 months. Median PFS and OS were 1.2 y (95% CI, 0.4-NR) and 1.7 y (95% CI, 0.7-NR). The safety population comprised 163 pts enrolled in 8/9 histologies. Among all pts, 96% had an adverse event (AE). Common AEs of any grade for all histologies were pyrexia (50%) and fatigue (36%). In the ATC cohort, the most common grade 3/4 events were anemia (25%), hyponatremia (21%), and pneumonia (21%). Biomarker and quality-of-life analyses are ongoing and will be presented.
D + T combination therapy continues to significantly improve outcomes in ATC, with a favorable safety profile. This regimen represents a clinically meaningful therapeutic advance for pts with advanced/metastatic BRAF V600–mutated ATC.
Clinical trial identification
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
Medical writing assistance was provided by William Fazzone, PhD (ArticulateScience LLC), funded by Novartis Pharmaceuticals Corporation.
B. Keam, A. Italiano, J.Y. Cho, J.H.M. Schellens: Assistance with abstract preparation. R.J. Kreitman: Research funding: GlaxoSmithKline (CRADA with NIH regarding research support for patients enrolled). Z.A. Wainberg: Consultancy: Novartis, Merck, EMD Serno, Lilly, Five Prime. M.E. Cabanillas: Research funding: Exelixis, Genentech, Kura; Membership on board of directors or advisory committees: Loxo, Ignyta. D.C. Cho: Consultancy: Bristol-Myers Squibb, Genentech, Exelixis, Pfizer, Prometheus. A. Stein: Research funding: German Cancer Aid, Sanofi, Roche, Merck, GBA Innovationfond, Bristol-Myers Squibb; Advisory board: Sanofi, Amgen, Merck, Roche, Bristol-Myers Squibb, MSD, Servier, Sirtex; Speakers’ fees: Sanofi, Merck, Roche, Servier, Bayer, Lilly. P.Y. Wen: Research support: AbbVie, Agios, Angiochem, Ariad, AstraZeneca, Genentech/Roche, GlaxoSmithKline, Immunocellular Therapies, Karyopharm, Merck, Novartis, Oncoceutics, Sanofi-Aventis, Vascular Biogenics; Advisory board, consulting, honoraria: AbbVie, AstraZeneca, Aurora Biopharma, Cavion, Gamestop Inc, Genentech/Roche, GW Pharmaceuticals, Immunomic Therapeutics, Insys, Kadmon, Lilly, Monteris, Novogen, Novartis, Puma, Vascular Biogenics, VBI Vaccines, Vivus, Ziopharm; Speakers' bureau: Merck. C.C. Zielinski: Honoraria: Novartis, Roche, Bristol-Myers Squibb, MSD, AstraZeneca. A.D. Boran, P. Burgess, F. Rangwala: Employment: Novartis. B. Mookerjee: Employment: Novartis; Stock ownership: Novartis, Glaxo Smith Kline, AstraZeneca. V. Subbiah: Research funding: Novartis.