Invited discussant of the ClarIDHy trial, Rachna T. Shroff, MD, Associate Professor of Medicine, University of Arizona, and Chief of GI Medical Oncology at the University of Arizona Cancer Center, said positive findings for ivosidenib support the notion that “biliary cancer is a perfect example of precision medicine at its finest.”
“Progress is being made, while gemcitabine/cisplatin remains the front-line choice and FOLFOX (fluorouracil, leucovorin, oxaliplatin), the second-line choice, we now have specifically targetable molecular alterations in cholangiocarcinoma, including IDH1 and FGFR2 [fibroblast growth factor receptor] fusions,” she said. Numerous agents targeting these two mutations are in development.
Rachna T. Shroff, MD
Primary and Secondary Endpoints
As noted by Dr. Shroff, the primary endpoint was progression-free survival rather than overall survival, as crossover was allowed upon radiographic disease progression.1 Of 59 patients in the placebo arm, 43 (70.5%) ultimately received ivosidenib, and the median treatment duration paralleled that of the larger cohort. “This absolutely impacted the overall survival data,” she indicated. “Of the 25 patients who remained on ivosidenib for 1 year or more, 6 had crossed over from placebo. There’s no debate. The primary endpoint hit the target.”
For the secondary endpoint of overall survival, the final analysis was not statistically significant but did indicate numerical improvement. Whether this “missed the mark” or not “depends on how you define the mark. Is it overall survival in the intent-to-treat population? That would be difficult, when you have crossover,” explained Dr. Shroff. She pointed out that the crossover population created “noise” for the analysis, as they received treatment with ivosidenib for quite some time.
Prespecified use of the rank-preserving structural failure time model to account for the heavy crossover resulted in a lower overall survival in the placebo arm, 5.1 months. The difference between placebo and ivosidenib then became highly significant (HR = 0.49; P < .0001).
Dr. Shroff acknowledged that the control arm of ClarIDHy was not ideal, as it was placebo, but the study was designed before the ABC-06 trial showed the benefit of modified FOLFOX vs active symptom control alone,2 she explained. With FOLFOX, the numerical improvement in survival was less than 1 month: 6.2 vs 5.3 months (HR = 0.69; P = .031).
Other Key Metrics
Regardless of the survival analysis, Dr. Shroff said there are other important metrics beyond P values, namely toxicity and quality of life. Treatment discontinuation due to adverse events was actually more frequent among placebo recipients. “And, in quality-of-life metrics, ivosidenib was favored for physical functioning and pain—important things that we as clinicians recognize with our patients who have cholangiocarcinoma and when it comes to drug development and approval,” she said.
Dr. Shroff said she welcomes a relatively well-tolerated oral agent that improves symptoms, as an alternative to second-line chemotherapy. She further pointed out that although ivosidenib is the first marketed IDH1 inhibitor (for acute myeloid leukemia, so far), others are in clinical trials for the treatment of cholangiocarcinoma.
DISCLOSURE: Dr. Shroff has served as a consultant or advisor to Agios, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Debio Pharma, Exelixis, Incyte, Merck, QED Therapeutics, Seattle Genetics, and Taiho Pharmaceutical and has received research funding from Agios, Exelixis, Halozyme, Merck, Pieris Pharmaceuticals, QED Therapeutics, Rafael Pharmaceuticals, and Taiho Pharmaceutical.
REFERENCES
1. Zhu AX, Macarulla T, Javle MM, et al: Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib versus placebo in patients with previously treated cholangiocarcinoma and an isocitrate dehydrogenase 1 (IDH1) mutation. 2021 Gastrointestinal Cancers Symposium. Abstract 266. Presented January 17, 2021.
2. Lamarca A, Palmer DH, Wasan HS, et al: ABC-06. 2019 ASCO Annual Meeting. Abstract 4003. Presented June 2, 2019.
