Christopher M. Booth, MD

Patients with BRAF-mutated metastatic colorectal cancer “pose clinical challenges for us every day,” said Christopher M. Booth, MD, Professor of Medical Oncology and the Canada Research Chair in Population Cancer Care at Queen’s University, Kingston, Ontario, the invited discussant of the BEACON-CRC quality-of-life findings. He applauded the investigators for choosing overall survival and quality of life as endpoints in a trial that benefits a “vulnerable patient population with unmet needs.”

Dr. Booth continued: “Any intervention in health care should help patients live longer and live better lives. Accordingly, the endpoints that matter in randomized control trials are overall survival and quality of life.”

Is Magnitude of Benefit Meaningful?

However, although BEACON-CRC showed improved survival and better maintenance of quality of life with the targeted regimens, Dr. Booth questioned whether the magnitude of benefit was truly meaningful. “I think, as a community, we need to have an honest conversation about what constitutes a meaningful magnitude of benefit. There are at least two things to consider: What is the endpoint, and what is the effect size?” he said.

“On first look, the curves of the European Organisation for Research and Treatment of Cancer global health status look impressive. The doublet and triplet have a 2-month difference in the median time to definitive deterioration of quality of life (defined as a 10% decrease in the median score). However, the time-to-event endpoint analysis that was used in BEACON-CRC is somewhat unusual. This method is restrictive, offering a snapshot of a single point in time. The analysis is also unidirectional, which makes it overly sensitive and may exaggerate the quality-of-life benefit,” commented Dr. Booth.

“A more conventional analysis would be a repeated measures approach, where mean change scores are reported at 2 months, 3 months, etc. Another way of doing this is to report the proportion of patients with a substantial improvement in quality of life or decreased quality of life at specific times,” Dr. Booth maintained. “With the quality-of-life results reported thus far, we could debate whether the effect size is clinically meaningful.”

Cost: ‘The Elephant in the Room’

Dr. Booth concluded by referencing “the elephant in the room: cost.” The cost of treatment with the doublet and triplet regimens is reported to be in the range of $20,000 to $30,000 per month, totaling about $300,000 per course of treatment. “That’s a very large number to put in the denominator of the value paradigm,” he suggested. “When one considers that the numerator might be of modest benefit, we need to ask ourselves, as a community, about the extent to which this offers high-value care.”

“The BEACON-CRC study is an example of aspirational, ‘moonshot’ research, but it applies to a much smaller cohort of patients in a small number of health systems globally that can afford this care, has a modest effect size, and has significant financial cost,” Dr. Booth concluded. “As more data come out in subsequent publications, we’ll learn the true extent of the magnitude of quality-of-life benefit with the BEACON-CRC protocol,” he said. The aim, explained Dr. Booth, “is to strike a better balance between cancer moonshot and ‘cancer groundshot’ initiatives.” 

DISCLOSURE: Dr. Booth reported no conflicts of interest.