FDA Grants Priority Review to Encorafenib Doublet for the Treatment of Advanced BRAF V600E-Mutant mCRC


The FDA has accepted a supplemental new drug application for the combination of encorafenib and cetuximab for the treatment of patients with advanced&nbsp;BRAF&nbsp;V600E-mutant metastatic colorectal cancer, following 1 or 2 lines of therapy, Pfizer, Inc. reported in a press release.<br /> &nbsp;

BRAFV600E-mutant metastatic colorectal cancer (mCRC), following 1 or 2 lines of therapy, Pfizer, Inc reported in a press release.1&nbsp;

The decision to grant priority review to the combination was prompted by the results of the phase III BEACON trial, which evaluated the efficacy and safety of the encorafenib-plus-cetuximab doublet compared with the doublet regimen plus binimetinib (Mektovi) or investigator&rsquo;s choice of a control-group combination, which consisted of cetuximab with either irinotecan or FOLFIRI (folinic acid, fluorouracil, and irinotecan).

The triplet regimen achieved the longest median overall survival (OS) at 9.0 months compared with 5.4 months in the control group (HR, 0.52; 95% CI, 0.39-0.70;P<.001). In the doublet group, the median OS was 8.4 months which was a significant improvement over the control (HR, 0.60; 95% CI, 0.45-0.79;&nbsp;P<.001).2

OS analysis according to subgroups for the triplet versus control arms showed consistent benefit across groups. The study also included a descriptive analysis, which compared patients who received the triplet combination with patients given the doublet combination. This analysis showed an estimated 71% survival at 6 months with the triplet versus 65% in patients treated with the doublet combination (HR, 0.79; 95% CI, 0.59-1.06). The estimated 6-month survival in the control group was 47%.

Treatment with the encorafenib/binimetinib/cetuximab combination performed better than the other groups in terms of the objective response rate (ORR). The confirmed ORR observed in the 331 patients who were treated the triplet was 26% (95% CI, 18%-35%) compared with 2% (95% CI, 0-7) in the control group, (P<.001). The ORR detected in the doublet group was also significantly higher than the control group at 20% (95% CI, 13-29), with aP-valueof .001.

Differences in the depth of the responses were seen and differed according to the type of assessment, including local investigator assessment and central review. Responses were also influenced by the number of prior lines of therapy, with higher rates observed in those patients who received fewer prior therapies.

In terms of progression-free survival (PFS), the triplet combination showed the greatest response compared with both the doublet combination and the control group. The median PFS in the triplet group was 4.3 months (95% CI, 4.1-5.2) , 4.2 months (95% CI, 3.7-5.4) in the doublet arm, and just 1.5 months (95% CI, 1.5-1.7) in the control group. Disease progression or death was reduced by 62% in the triplet-therapy group when compared with the control regimen (HR 0.38; 95% CI, 0.31-0.52;P<.001). As of the data cutoff date of February 11, 2019, the median follow-up for PFS was 5.4 months.

Investigators saw 217 adverse events (AEs) in the triplet group (98%), 128 of which were grade 3 or higher (58%). Among patients who receive the doublet regimen, there was a total of 212 AEs (98%), with 108 being grade &ge;3 (50%). In the control arm, 188 AEs were observed (97%), 117 of which were grade &ge;3 (61%).

The most common any-grade AEs in the triplet-regimen group were diarrhea (62%), acneiform dermatitis (49%), nausea (45%), vomiting (38%), and fatigue (33%). In the doublet group, the events occurred at lower rates of 33%, 29%, 34%, 21%, and 30%, respectively. The control arm had the lowest occurrence of any-grade AEs overall. In some cases, however, the number of events exceeded those observed in the doublet group. The corresponding rates in the control group were 48%, 39%. 41%,29%, and 27%, respectively.

Abnormal laboratory (lab) values of any-grade occurred across all study groups. With the triplet combination, patients experienced abnormal alanine aminotransferase (23%), aspartate aminotransferase (23%), bilirubin (5%), creatinine kinase (23%), creatinine (75%), and hemoglobin (56%). With the doublet combination, these rates were 17%, 14%, 7%, 3%, 50%, and 32%, respectively. In the control group, 26%, 20%, 8%, 7%, 34%, and 44% of patients, respectively, presented with abnormal labs.

Seven percent who were treated with the triplet regimen discontinued treatment due to an AE. Treatment was also discontinued by 8% of patients in the doublet group, and 11% of individuals in the control group. AEs were fatal for 4%, 3%, and 4% of these patients, respectively. The study investigators determined that 3 deaths were treatment-related. Thee treatment-related causes of death were colonic perforation in the triplet group, anaphylaxis in the control group, and respiratory failure in the control group.

Patients were exposed to the drugs in the triplet for a median of 21 weeks. The doublet was given for a median of 19 weeks, and the control group drugs were given for an average of 7 weeks.

The BEACON CRC trial is a global, multicenter, randomized, open-label trial, which enrolled patients with advancedBRAFV600E-mutant mCRC after 1 or 2 previous treatment regimens and randomized them 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 in the doublet group; or an identical dose of cetuximab plus FOLFIRI in the control group. Treatment went on for 28-day cycles until time of disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.

The primary end point of the study was OS in the triplet group versus the control group. An amendment to the trail protocol also brought on a coprimary end point of ORR. The secondary end points included OS in the doublet group versus the control group, PFS, duration of responses, and safety, which were evaluated in all study groups.

According to Pfizer, these data are encouraging and serve an unmet need in the area of mCRC treatment.1

&ldquo;The FDA&rsquo;s acceptance of our application for the Braftovi doublet is highly encouraging news for patients with mCRC harboring aBRAFV600E mutation,&rdquo; said Chris Boshoff, MD, PhD., chief development officer, Oncology, Pfizer Global Product Development. &ldquo;Currently, there are no FDA-approved treatments specifically for patients with&nbsp;BRAF-mutant mCRC who have received prior treatment. If approved, the Braftovi doublet would become the first targeted regimen for this patient population, who typically have a poor prognosis. We also look forward to continuing to explore this targeted Doublet regimen with or without Mektovi in earlier lines of&nbsp;BRAF-mutant mCRC, including in the ongoing, Phase II ANCHOR study in previously untreated patients.&rdquo;

The BEACON CRC results are also being reviewed by the European Medicines Agency for approval in the European Union.


  1. U.s. fda accepts and grants priority review to sNDA for Braftovi (encorafenib) in combination with Erbitux (cetuximab) (Braftovi doublet) for the treatment of BRAFV600e-mutant metastatic colorectal cancer after prior therapy [press release]. Pfizer; December 18, 2019. https://bit.ly/35EKgJi. Accessed December 18, 2019
  2. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E
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