Colorectal cancer
Dictionary definition of Colorectal cancer

Patient-reported outcomes improved with double- and triple-drug treatments compared with the current standard of care options for patients with a particular type of colorectal cancer. This the conclusion of a study funded by Pfizer.

Patients with colorectal cancer that has a BRAFV600E mutation, treated with encorafenib and cetuximab with or without binimetinib were able to maintain their quality of life longer than those treated with one of two standard of care regimens, consisting of irinotecan plus cetuximab or FOLFIRI, a combination of chemotherapeutic drugs including leucovorin, calcium folinate, fluorouracil, and irinotecan, with cetuximab.

The BRAFV600E mutation occurs in about 10% of colorectal cancer patients [1] but accounts for more than 90% of BRAF mutations in the disease. The mutation results in a poor prognosis. One study demonstrated that this BRAF mutation was negatively associated with Overal Survival (HR 3.055, P = 0.00004). [2] In contrast, colorectal cancer without a BRAFV600E mutation have a different prognosis, and a significantly longer Overall Survival (62 vs. 12.6 months, P = 0.002). [3]

“The findings highlight that with these novels targeted therapy regimens, not only was the disease controlled longer, but patient-reported quality of life was maintained longer,” noted lead author Scott Kopetz, MD, Ph.D., FACP, who is a professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

BEACON CRC trial
The findings come from the open-label, phase-III BEACON CRC trial (NCT02928224; Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer), which included 655 patients. Binimetinib and encorafenib are inhibitors of proteins involved in cancer cell growth.

Efficacy data were previously published in the New England Journal of Medicine (NEJM).[4] The median overall survival was 9.0 and 8.4 months with the triplet and doublet targeted treatments, compared to 5.4 months in the control group of patients, which received irinotecan plus cetuximab or FOLFIRI plus cetuximab (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001).

The study results published in the NEJM also demonstrated a confirmed response rate of 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, 50% in the doublet-therapy group, and in 61% in the control group.[4]

Health-related Quality of Life
During the 2020 Gastrointestinal Cancers Symposium, held January 23-25, 2020 in San Francisco, California, researchers reported on the health-related Quality of Life, which was a secondary endpoint of the study.

Health-related Quality of Life (hrQoL) was assessed at baseline and after every treatment cycle using four validated measurement tools: the European Organisation for Research and Treatment of Cancer (EORTC) QOL Questionnaire, Functional Assessment of Cancer Therapy, EuroQol 5D 5L, and the Patient Global Impression of Change.

Researchers looked at the time to 10% or greater deterioration between the study arms, which is considered to represent a clinically meaningful decline in health-related Quality of Life. Patients treated with the triplet had a roughly 44-45% reduction in the risk of quality of life deterioration compared with patients in the standard of care group, based on two of the measures.

Patients receiving the doublet had a roughly 46% reduction in risk. Similar results were seen with the EuroQuol 5D 5L and Patient Global Impression of Change. There was no significant difference in the quality of life for patients in the triplet and doublet groups.

Clinical trials
Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer (BEACON CRC) – NCT02928224

Reference
[1] Muzny DM, Bainbridge MN, Chang K, et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330-7.
[2] Tosi F, Magni E, Amatu A, et al. Effect of KRAS and BRAF Mutations on Survival of Metastatic Colorectal Cancer After Liver Resection: A Systematic Review and Meta-Analysis. Clin Colorectal Cancer. 2017;16(3):e153–e163. doi:10.1016/j.clcc.2017.01.004
[3] Cremolini C, Di Bartolomeo M, Amatu A, et al. BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol. 2015;26(10):2092–2097. doi:10.1093/annonc/mdv290
[4] Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019;381(17):1632–1643. doi:10.1056/NEJMoa1908075

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