E-News - July 2023
Alliance Trial In Print


Alliance Study Shows Promise for Patients with Rare Brain Tumors

Papillary craniopharyngiomas (PCPs) are a rare type of brain tumor that cause substantial morbidity for patients. While surgery and radiation are often used to treat PCPs, incomplete removal of the tumor and toxicity from radiation can leave patients with life-long health challenges after treatment, including neuroendocrine dysfunction or vision or memory loss.

Investigators from the Alliance Neuro-Oncology Committee have developed and led the first multicenter treatment trial in this rare tumor – Alliance A071601: Phase II trial of BRAF/MEK inhibitors in papillary craniopharyngiomas. Noting that genotyping shows that more than 90 percent of PCPs carry a BRAF V600E mutation, and that therapies that inhibit BRAF and MEK have been approved by the U.S. Food and Drug Administration for treating melanoma and other cancers, investigators hypothesized that a BRAF-MEK inhibitor might also be effective for treating papillary craniopharyngioma.

In findings published in the New England Journal of Medicine, investigators treated 16 patients with a BRAF/MEK inhibitor and found that tumors shrank by an average of 91 percent. Eligible patients had histologically proven BRAF V600E–mutant papillary craniopharyngiomas, had not undergone previous radiation or systemic therapy for craniopharyngioma, and had measurable disease. Their median age was 49.5 years, median baseline tumor volume was 2.75 cm, and 15 of the 16 had an ECOG performance status of 0 or 1.

Sixteen patients at nine centers were enrolled in the study, and 15 ultimately completed at least one, 28-day cycle of the therapy. Over the course of four cycles, the median reduction in tumor size was 91 percent, with a range of 68 to 99 percent. Seven patients received no other treatment after discontinuing vemurafenib/cobimetinib and six have not demonstrated evidence of tumor progression at a median follow-up of nearly two years. No patient's tumor progressed while on vemurafenib/cobimetinib, and none have died.

“The results of this study represent a paradigm shift in the clinical management of patients with papillary craniopharyngioma,” said Priscilla Brastianos, MD, the study’s lead investigator and Director of the Central Nervous System Metastasis Program and Associate Professor of Medicine at Harvard Medical School and Massachusetts General Hospital. “Targeted therapy should now be part of the armamentarium of treatments for this patient population, which historically was in need of improved therapies.”

Notably, patients did experience adverse reactions to the drugs. Three patients discontinued treatment due to adverse events, with one patient discontinuing therapy after eight days due to anaphylaxis and acute kidney injury. The most common adverse events were rashes, reported by six patients. Still, many patients tolerated the drugs well, electing to continue therapy beyond the four prescribed cycles because of their positive response to it.

Future research may determine the optimal number of cycles of vemurafenib/cobimetinib for patients with PCP. “This study highlights that we can truly move the needle forward in brain tumors with multidisciplinary and multi-institutional collaborations,” Dr. Brastianos said.

"These results illustrate the practice changing impact when scientific breakthroughs get translated to the clinical forefront and there would not have been possible without the critical collaboration of our neurosurgery and radiation oncology colleagues," said Eva Galanis, MD, Alliance Neuro-Oncology Committee Chair and Group Chair Elect. "This is the type of approach we want to support in Alliance trials both in the precision oncology space and beyond."

Priscilla K. Brastianos, MD; Erin Twohy, MS; Susan Geyer, PhD; Elizabeth R. Gerstner, MD; Timothy J. Kaufmann, MD; Shervin Tabrizi, MD; Brian Kabat, BS, Julia Thierauf, MD; Michael W. Ruff, MD; Daniela A. Bota, MD, PhD; David A. Reardon, MD; Adam L. Cohen, MD; Macarena I. De La Fuente, MD; Glenn J. Lesser, MD; Jian Campian, MD, PhD; Pankaj K. Agarwalla, MD; Priya Kumthekar, MD; Bhupinder Mann, MB, BS; Shivangi Vora, MS; Michael Knopp, MD, PhD; A. John Iafrate, MD, PhD; William T. Curry, Jr., MD; Daniel P. Cahill, MD, PhD; Helen A. Shih, MD; Paul D. Brown, MD; Sandro Santagata, MD, PhD; Fred G. Barker, II, MD; and Evanthia Galanis, MD.

Author Affiliations
From Massachusetts General Hospital Cancer Center, Harvard Medical School (P.K.B., E.R.G., S.T., J.T., A.J.I., W.T.C., D.P.C., H.A.S., F.G.B.), Dana–Farber Cancer Institute (D.A.R.), and Brigham and Women’s Hospital, Harvard Program in Therapeutic Science, Dana–Farber Partners CancerCare (S.S.) — all in Boston; Alliance Statistics and Data Management Center (E.T., S.G., B.K.), Mayo Clinic (T.J.K., M.W.R., P.D.B., E.G.), Rochester, MN; UC Irvine–Chao Family Comprehensive Cancer Center, Orange, CA (D.A.B.); Huntsman Cancer Institute, University of Utah, Salt Lake City (A.L.C.); Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami (M.I.D.L.F.); Wake Forest University School of Medicine, Winston-Salem, NC (G.J.L.); Washington University School of Medicine, St. Louis (J.C.); Rutgers Cancer Institute, New Brunswick, NJ (P.K.A.); Northwestern University, Chicago (P.K.); the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD (B.M.); and Ohio State University Comprehensive Cancer Center, Columbus (S.V., M.K.).