Targeted Combos Improve QoL as Well as Survival in CRC

SAN FRANCISCO — Further analysis of data from the large phase 3 BEACON trial in colorectal cancer (CRC) shows that targeted drug combinations are associated with a better quality of life in addition to improved survival compared with standard chemotherapy.

However, an expert questions whether the modest benefits are worth the increased cost.

The BEACON trial was conducted in patients with BRAF V600E–mutated metastatic CRC and investigated targeted therapy with encorafenib (Braftovi, Array BioPharma) and cetuximab (Erbitux, Eli Lilly), with or without binimetinib (Mektovi, Array BioPharma). This was compared with standard-of-care chemotherapy regimens that included irinotecan plus cetuximab or FOLFIRI (leucovorin, calcium folinate, fluorouracil, and irinotecan) with cetuximab.

Efficacy results showed better outcomes for the targeted therapy regimens, which were presented at the World Conference on Gastrointestinal Cancers (WCGC) 2019 and subsequently published in the New England Journal of Medicine.

Now a secondary analysis shows that there was less deterioration in quality of life with the targeted therapies compared with chemotherapy.

"Encorafenib plus cetuximab with or without binimetinib significantly approved overall survival and response rate compared to the standard of care," commented author Scott Kopetz, MD, PhD, from the University of Texas MD Anderson Cancer Center, Houston.

"This is a population with poor outcomes and an unmet need," he added.

"The targeted combination — either the doublet or the triplet — maintained longer quality of life by patient-reported outcomes," he said. "There was no discernible difference in quality of life between triplet and doublet groups across the four instruments used."

These new quality of life data were presented here at the Gastrointestinal Cancers Symposium (GICS) 2020.

Ground Shot and Moon Shot

The abstract's discussant, however, questioned the cost of the targeted drug regimens, and whether they represent real value, given the modest benefit.

"There has been increasing concern that many of our therapies offer very modest benefits," said Christopher Booth, MD, of Queen's University in Kingston, Ontario, Canada.

For the BEACON trial, the elephant in the room is the cost, he said. Based on Red Book costs, Booth estimated that the cost per month for the doublet and triplet therapies would be about $20,000 to $30,000, for a total annual cost of more than $300,000.

"That is a large number, and we have to ask ourselves the extent to which it offers benefit," he said.

Booth then discussed the idea of "ground shot" and "moon shot" treatment initiatives. "A ground shot is what we can do today and we need things that can be implemented in cancer care today," he said. "The BEACON trial is a moon shot — modest outcomes and high cost. The concept is more than just price and of benefit for people in this protocol — we need to strike a better shot between ground shot and moon shot."

He noted that the treatment regimen applies to a very small number of patients and only a very small number of health systems can afford it. "It has a modest effect size and significant financial cost," Booth emphasized. "Value includes more than just drug price and we need to take ownership of value. As more data come out, we will learn the magnitude of benefit with the BEACON protocol."

Updated Outcomes

Initial efficacy data from the BEACON trial showed that the median overall survival was 9.0 months in the triplet-therapy group versus 5.4 months with chemotherapy (hazard ratio [HR] for death, 0.52; 95% CI, 0.39 - 0.70; P < .001).

Similarly, median overall survival in the doublet-therapy group was 8.4 months (HR for death vs control, 0.60; 95% CI, 0.45 - 0.79; P < .001).

The objective response rate was 26% in the triplet-therapy group vs 2% for chemotherapy (P < .001), and 20% in the doublet-therapy group.

Grade 3 or higher adverse events occurred in 58% of patients in the triplet-therapy group, 50% in the doublet-therapy group, and 61% in the chemotherapy group.

At the meeting, Kopetz also briefly presented updated efficacy data accrued after the manuscript was submitted for publication (cutoff of November 2019). At a median follow-up of 12.8 months, the overall response rate was 27% for the triplet group, 20% for doublet, and 2% for controls.

Median overall survival was 9.3 months in both the triplet and doublet treatment groups, compared with 5.9 months for controls.

"The full updated results with subgroup analysis will be presented at a future congress," said Kopetz, adding that the data have been submitted for regulatory approval.

Maintaining Quality of Life

Quality of life, a secondary endpoint, and was assessed using several standardized tools including the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), Functional Assessment of Cancer Therapy – Colorectal (FACT-C), EuroQol 5D-5L, and Patient Global Impression of Change (PGIC).

On the QLQ-C30, 10% deterioration occurred at 4.96 months in the triplet therapy group (HR, 0.55; 95% CI, 0.43 - 0.70), 4.60 months with the doublet (HR, 0.54; 95% CI, 0.43 - 0.69), and 2.2 months in the control group.

Analysis of the FACT-C questionnaire showed that time to deterioration occurred at 5.56 months with the triplet regimen (HR, 0.48; 95% CI, 0.38 - 0.62), 5.36 months with the doublet (HR, 0.46; 95% CI, 0.36 - 0.59), and 2 months among controls.

Similar outcomes were seen with the EuroQol 5D-5L, which measures mobility, ability to care for self or engage in usual activities, pain or discomfort, and anxiety or depression. The time to deterioration was 5.59 months for the triplet-therapy group (HR, 0.49; 95% CI, 0.38 - 0.63), 5.36 months for the doublet (HR, 0.49; 95% CI, 0.39 - 0.63), and 2.37 months among controls.

On the PGIC, which measures self-reported assessment of symptoms, the perception of improvement in symptoms was reported by most patients in the doublet and triplet groups, noted Kopetz.

The study was funded by Pfizer. Kopetz has reported relationships with Roche, Genentech, EMD Serono, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire, Symphogen, Holy Stone Healthcare, Biocartis, Amgen, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, MolecularMatch, Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, and MedImmune.

Gastrointestinal Cancers Symposium (GICS) 2020. Abstract 8. Presented January 25, 2020.

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