Combination of Targeted Therapies Improves Survival in Advanced Colorectal Cancers

The ceramic dragon fountain in the Parc Guell designed by Antoni Gaudi, Barcelona, Spain.
The ceramic dragon fountain in the Parc Guell designed by Antoni Gaudi, Barcelona, Spain.

Data presented at the European Society of Medical Oncology’s World Congress on Gastrointestinal Cancer, held July 3 – 6, 2019 in Barcelona, Spain, suggests that a three-drug combination with encorafenib, binimetinib and cetuximab, should replace chemotherapy for the one in seven patients with metastatic colorectal cancer who have a BRAF mutation.

The data demonstrates for the first time that a combination of these targeted therapies can improve survival in patients with advanced or metastatic colorectal cancer and are based on the BEACON CRC phase III trial (NCT02928224). The trial, sponsored by Array BioPharma in collaboration with Merck KGaA, Pierre Fabre Medicament and Ono Pharmaceutical Co., confirms that triple therapy targeting BRAF mutations in progressive metastatic colorectal tumors significantly improved overall survival and objective response compared to standard care. [1]

The global BEACON CRC study included 665 patients with BRAF V600E-mutant colorectal cancer who had progressed after one or two prior regimens in the metastatic setting were randomized to receive triplet therapy, doublet therapy (encorafenib and cetuximab) or the investigator’s choice of irinotecan or folinic acid, fluoruracil and irinotecan (FOLFIRI) and cetuximab.

In this trial patients were randomly assigned to receive either the triplet combination (n=224), doublet combination (n=220), or one of the control regimens (n=221).

Median overall survival of the patients participating in the trial was 9 months (95% confidence interval [CI]: 8, 11,4) for the triplet targeted therapy compared to 5.4 months (95% CI: 4.8, 6.6) for standard therapy (hazard ratio [HR] 0.52; 95% CI: 0.39, 0.7, p<0.0001).

Confirmed objective response rate by blinded central review for the triplet targeted therapy was 26% (95% CI: 18, 35) compared to 2% (95% CI: 0,7, p<0.0001) for standard therapy.

Median overall survival for the doublet combination was 8.4 months (95% CI: 7.5, 11) compared to standard therapy (HR 0.6; 95% CI: 0.45, 0.79, p<0.0003).

The study was not powered to compare triplet and doublet therapies but future analyses will explore which patients are most likely to benefit from triplet versus doublet combinations.

BRAF V600E targeted treatment was well tolerated, with Grade 3 or higher adverse events seen in 58% of patients on triplet treatment, 50% of those in the doublet group and 61% of those in the standard therapy group.

Exciting results
BRAF V600E mutations are identified in up to 15% of patients diagnosed with metastatic colorectal cancer (mCRC).  This diagnosis generally confer a poor prognosis. In patients who are refractory to initial therapy, objective response rates (ORR) to standard chemotherapy and biologic combinations are generally less than 10%, with median progression-free survival (PFS) and overall survival (OS) approximately 2 and 4-6 months, respectively.

Scott Kopetz
Scott Kopetz, MD, Ph.D., FACP

“[Overall ] These are very exciting results because we’ve been trying to target BRAF-mutant colorectal cancer for many years. It’s encouraging to see such a significant improvement in overall survival and response in patients with such aggressive tumour biology. Hopefully, this will soon lead to increased access to this treatment for patients where there is currently such a large unmet need,” said study author Scott Kopetz, MD, Ph.D., FACP from the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at the University of Texas, MD Anderson Cancer Center in Houston, USA.

Growing understanding
Kopetz explained that the three-drug combination builds on growing understanding of the activation of cancer genes such as BRAF and the effects of targeted therapies.

“Colorectal cancer does not respond to BRAF therapy alone because tumour cells adapt through other mechanisms after initial treatment. With this triple targeted therapy, we are using a very scientifically logical combination to inhibit BRAF and these other mechanisms,” Kopetz pointed out.

“We now have a specific treatment that can change the natural course of the disease in patients with BRAF mutations and is better than previous therapy, so it is essential that patients are routinely tested.”

Andres Cervantes, MD, Ph.D

Relevance
Commenting on the relevance of the new presented during the World Congress on Gastrointestinal Cancer, Professor Andrés Cervantes, MD, Ph.D, from the Biomedical Research Institute INCLIVA, University of Valencia in Spain, stressed that it will be important for all patients with colorectal cancer to be tested for BRAF mutations in the light of the BEACON CRC findings.

Cervantes also highlighted the chemotherapy-free nature of the targeted combination used in the study.

“In many other types of cancer, and particularly in colorectal cancer, it is common for biological targeted therapies to be used in combination with chemotherapy. The fact that we can give this targeted combination without the need for chemotherapy is very good news for patients, not least because of the side effects that they typically experience with chemotherapy,” he added.

“At present, targeted therapy should probably be limited to the patient group treated in the BEACON CRC trial who had progressed after one or two previous lines of chemotherapy. However, it is important that we investigate its use in other settings where more patients with BRAF mutations may also benefit, including those with less advanced metastatic disease and possibly in the adjuvant setting after primary surgery with curative intent,” Cervantes concluded.

An ongoing study (ANCHOR-CRC) is investigating the effects of triplet therapy as first line treatment for patients with metastatic BRAF V600E-mutant colorectal cancer.

Clinical trial
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] Kopetz S, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, et al. LBA-006 ‘BEACON CRC: a randomized, 3-Arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E–mutant metastatic colorectal cancer.  Annals of Oncology 30 (Supplement 4): iv137–iv151, 2019. Data presented by Scott Kopetz during Session XX: Colorectal Cancer (Part I) on Saturday, 6 July 09:20-10:05 CEST.