FDA Approves Encorafenib Plus Cetuximab in BRAF V600E+ mCRC

The FDA has approved the combination of encorafenib (Braftovi) and cetuximab (Erbitux) as treatment of patients with metastatic colorectal cancer (mCRC) with aBRAFV600E mutation, as detected by an FDA-approved test, after prior therapy, according to a press release from Pfizer.

“We are pleased by the FDA’s approval of Braftovi in combination with cetuximab, as we are committed to developing targeted medicines that can help people living with certain mutation-driven cancers,” said Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development, in a statement. “We are grateful to the patients and study investigators who participated in the phase III BEACON CRC trial and are proud to now be able to offer a targeted treatment option for people withBRAFV600E-mutant metastatic CRC who have received prior therapy. Looking ahead, we’re committed to continuing to investigate this treatment regimen across earlier lines of therapy.”

The approval was granted based on positive results from the phase III BEACON CRC trial of encorafenib, binimetinib (Mektovi), and cetuximab inBRAFV600E mCRC, which were published in October 2019 in theNew England Journal of Medicine. The study showed that encorafenib, cetuximab, and binimetinib significantly improved overall survival (OS) and achieved a higher response than the standard treatment.The triplet combination was previously granted Priority Review by the FDA, based on the results of this study.

A total of 665 patients were randomized to receive a triplet combination of encorafenib, binimetinib, and cetuximab (n = 224), the encorafenib/cetuximab doublet (n = 220), or the control, which included the investigator’s choice of either irinotecan plus cetuximab or FOLFIRI (Irinotecan, fluorouracil (5-FU), and folinic acid [leucovorin]) plus cetuximab.

The median follow-up at data cutoff was 7.8 months for all treatment groups. The higher median OS was achieved in the triplet group, which was 9.0 months (95% CI, 8.0-11.4) compared with 5.4 months (95% CI, 4.8-6.6) in the control group. Additionally, the risk of death was significantly decreased (48%) with the triplet combination compared with the control arm (HR, 0.52; 95% CI, 0.39-0.70;P<.001). These findings were consistent with what was observed in the subgroup analysis, which revealed a median OS of 8.4 months (95% CI, 7.5 to 11.0) in the doublet-therapy group and significant decrease in the risk of death as compared with the control group (HR, 0.60; 95% CI, 0.45-0.79;&nbsp;P<.001). A comparison of survival between the doublet arm and triplet arm at 6 months was analyzed and showed 71% survival in the triplet arm versus 65% in the doublet arm (HR for death 0.79; 95% CI, 0.59-1.06). The control group had a 6-month survival rate of 47%.&nbsp;

An independently reviewed confirmed objective response rate (ORR) was measured in the first 331 patients who were randomized. Patients in the triplet arm had a confirmed ORR of 26% (95% CI, 18%-35%) versus only 2% (95% CI, 0%-7%) in the control arm (P<.001). Participants in the doublet arm also had a significantly higher ORR than the control arm at 20% (95% CI, 13%-29%). The difference was deemed significant (P<.001).&nbsp;

Median follow-up for progression-free survival (PFS) as of data cutoff was 5.4 months. The doublet and triplet arms surpassed the control arm in terms of PFS also. With the triplet, the median PFS was 4.3 months (95% CI, 4.1-5.2) and with the doublet, the median PFS was 4.2 months (95% CI, 3.7-5.4), both compared with 1.5 months (95% CI, 1.5-1.7) in the control group. In the triplet arm, the HR for disease progression or death was 0.38 (95% CI, 0.29-0.49) versus the control group (P<.001). The doublet arm had a HR of 0.40 for disease progression or death (95% CI, 0.31-0.52) compared with the control arm (P<.001).

In terms of safety, adverse events (AEs) were observed in all study arms. In the triplet arm, 98% of patients experienced any grade AEs (n = 217), and 58% had grade 3 or higher AEs. The most common AEs of any grade in the triplet arm were diarrhea (62%), acneiform dermatitis (49%), nausea (45%), and vomiting (38%). In the doublet arm, 98% of patients experienced AEs of any grade (n = 212), and 50% had grade 3 or higher AEs. Finally, in the control arm, any-grade AEs were seen in 97% of patients (n = 188), and grade 3 or higher AEs occurred in 61% of patients (n = 117).

Altogether, 7% of patients in the triplet arm, 8% in the doublet arm, and 11% in the control arm discontinued treatment due to AEs. In 4%, 3%, and 4% of patients, respectively, AEs were fatal.

Patients were exposed to the triplet regimen for a median of 21 weeks, the doublet for 19 weeks, and the control regimens for 7 weeks. The doublet combination had the highest median relative dose intensity at 98%. In the triplet group, the median dose intensity was 91%. &nbsp;

The BEACON CRC trial is a global, multicenter, randomized, open-label trial, which randomized patients 1:1:1 to receive encorafenib at 300 mg daily, binimetinib at 45 mg twice daily, and cetuximab at 400 mg/m²as the initial dose then weekly at 250 mg/m²in the triplet group; the same doses of encorafenib plus cetuximab were received in the doublet group or an identical dose of cetuximab plus FOLFIRI in the control group. Treatment lasted for 28-day cycles until time of disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.

The study&rsquo;s primary end point was OS in the triplet group compared with the control group. ORR was a coprimary end point. Secondarily, the study assessed OS in the doublet group versus the control group, PFS, duration of responses, and safety, which were evaluated in all study groups.

References

1. U.S. FDA approves Braftovi (encorafenib) in combination with cetuximab for the treatment of brafv600e-mutant metastatic colorectal cancer (crc) after prior therapy [news release]. New York, New York: Pfizer, Inc; April 8, 2020.https://bit.ly/2JQOcgR. Accessed April 8, 2020.
2. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in braf&nbsp;v600e—mutated colorectal cancer.N Engl J Med2019; 381:1632-1643. DOI: 10.1056/NEJMoa1908075