The invited discussant of the DeFi trial was Jean-Yves Blay, MD, PhD, General Director of the Center Bérard, Lyon, France, and President of Unicancer, the French Federation of Cancer Centers. He called the DeFi study a “rigorous trial” in a “representative population” that “introduces a new class of agents blocking a pathway [Notch] that is activated in many cancers.”

Jean-Yves Blay, MD, PhD

Dr. Blay explained that desmoid tumors are rare neoplasms with unpredictable behavior, ranging from “aggressive life-threatening neoplasms to indolent, spontaneously regressing tumors.” They affect all ages and body sites; although these tumors are potentially aggressive, they rarely metastasize. Some 90% are sporadic, involving beta-catenin–activating mutations, and 10% are germline, with APC mutations.

There are currently no approved therapies for desmoid tumors, and although treatment options are available, protocols are not well standardized. The guidelines recommend watchful waiting, surgery, and medical treatment, depending on the clinical presentation. The Desmoid Tumor Working Group has proposed a strategy whereby medical treatment is proposed when disease progresses; in this setting, sorafenib and pazopanib have been shown to be beneficial.

DeFi and Beyond

“This is a randomized placebo-controlled clinical trial, with the primary endpoint achieved by blinded independent central review. It shows a higher response rate, an improvement in quality-of-life parameters (including pain), and an acceptable toxicity profile. The hazard ratio [HR] is very low [HR = 0.29], with only a small proportion of patients experiencing disease progression during exposure to nirogacestat. In addition, it demonstrated activity in all subsets, including patients treated previously with a tyrosine kinase inhibitor [HR = 0.15],” Dr. Blay noted.

Dr. Blay continued: “It is also of importance to observe a significant impact on pain, given that pain is a major symptom presented by patients with desmoid tumors. This is probably the most significant observation of this trial, even though an improvement in pain was a secondary objective.”

However, additional studies are required to answer questions about the optimal integration of nirogacestat into current treatment strategies, the optimal duration of treatment, biomarkers of efficacy, mechanisms of resistance, long-term toxicity profile, ovarian dysfunction in women of childbearing age, and the drug’s effect on subsequent pregnancies, noted Dr. Blay. 

DISCLOSURE: Dr. Blay reported financial relationships with AbbVie, Amgen, ARIAD Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, DDB Health, Eisai, Genomic Health, Gilead Sciences GSK, Innate-Pharma Janssen, Lilly, Merck Serono, MSD, Nanobiotix, Novartis, Novex Pharma, Onxeo, Pfizer, PharmaMar, Roche, Sanofi-Aventis, Swedish Orphan, and Toray.