Triplet Therapy Effective in BRAF-mutant mCRC

Chloe E. Atreya, MD, PhD

The combination of dabrafenib (Tafinlar), trametinib (Mekinist), and panitumumab (Vectibix) demonstrated an objective response rate (ORR) of 26% and a median progression-free survival (PFS) of 4.1 months in pretreated patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC), according to findings from a phase I/II study presented at the 2015 ASCO Annual Meeting.¹

“Triplet therapy with dabrafenib, panitumumab, and trametinib appears to be more active in BRAF-mutated colorectal cancer than dabrafenib plus panitumumab or dabrafenib plus trametinib,” lead investigator Chloe E. Atreya, MD, PhD, assistant clinical professor in the Department of Medicine, University of California, San Francisco, said during her presentation. "Dermatologic toxicities are significant, resulting in dose reductions, interruptions, and delays. A nuance to this is that dabrafenib may lessen skin-related toxicity due to panitumumab and trametinib."

BRAF mutations are found in approximately 8% of patients with mCRC and are associated with a poor prognosis. The median overall survival in patients with BRAF-mutant mCRC is 13.4 months compared with 37.1 months in those with BRAF wild-type disease, Atreya explained.

Prior studies have shown that single-agent inhibition of BRAF inhibition was largely ineffective in CRC, with MEK plus BRAF inhibition only moderately more effective. The rationale behind the study was that the addition of panitumumab to dabrafenib and trametinib would provide a more effective blockade of phospho-ERK signaling.

In the first arm of the phase I/II study, 20 patients received dabrafenib at 150 mg twice daily and panitumumab at 6 mg/kg every 2 weeks. Thirty-five patients received dabrafenib, trametinib, and panitumumab, with 24 receiving the phase II recommended dose of dabrafenib at 150 mg twice daily, panitumumab at 6 mg/kg every 2 weeks, and trametinib at 2 mg daily. Additionally, in two separate arms panitumumab plus trametinib was administered to patients with BRAF-mutant mCRC (n = 12) and those with acquired resistance to EGFR inhibition (n = 2).

Following progression on the doublet arms, patients were allowed to cross over to receive triplet therapy. At the data cutoff of March 16, 2015, six patients had crossed over from the doublet arms to receive the triplet therapy. However, data on the outcomes for these patients were not yet available.

In the triplet arm, the majority of patients were female (63%) with an ECOG performance status of 0 (57%) or 1 (43%). As is common with BRAF-mutant CRC, the majority of tumors had originated in the right colon (71.4%). All patients were pretreated, with 54% having received three or more prior lines of therapy. The primary endpoint of the study was ORR, with secondary measures focused on PFS.

In the dabrafenib plus panitumumab arm the ORR was 10%, comprised of one complete response (CR) and one partial response (PR). In the triplet arm, the ORR was 26%, with one CR and eight PRs. Additionally, 21 patients (60%) had stable disease with the triplet, for an overall disease control rate of 86%. The unconfirmed response rate with the triplet was 34%, Atreya added.

In the dabrafenib doublet arm, 25% of patients remained on treatment for >6 months. In the triplet arm, 26% of patients were on treatment >6 months and 11% of patients remained on therapy for longer than a year. The median duration of response with the triplet therapy was 5.4 months.

“Triplet therapy has produced more durable disease control than the dabrafenib plus panitumumab doublet, with four triplet patients on study for over a year and 4 patients receiving ongoing treatment,” said Atreya.

The median PFS in the dabrafenib and trametinib doublet arms, respectively, were 3.4 months (95% CI 2.6-5.8) and 4.1 months (95% CI, 2.6-4.5). In the triplet arm, the median PFS was 4.1 months (95% CI, 2.8-5.5).

In the triplet arm, patients in the dose escalation portion of the study who received panitumumab at a lower dose of 4.8 mg/kg every 2 weeks experienced better outcomes. At this lower dose, the ORR was 67% and the median PFS was 10.1 months in those who received 1.5 mg daily of trametinib with dabrafenib (n = 2). In those who received trametinib at 2 mg daily (n = 2) with the lower dose panitumumab in the triplet, the ORR was 50% and the median PFS was 9.0 months.

“Although numbers are very small, we note that patients in this cohort achieved higher panitumumab drug compliance and were exposed to fewer lines of prior therapy. This will be further investigated,” Atreya explained.

The most common all-grade adverse events with the triplet therapy were diarrhea (77%), dermatitis acneiform (57%), fatigue (51%), nausea (49%), dry skin (49%), pyrexia (46%), decreased appetite (46%), and hypomagnesaemia (37%). Grade 3 diarrhea and dermatitis acneiform were each seen in 9% of patients in the triplet arm. In the dabrafenib doublet arm, dermatitis acneiform was evident in 60% of patients and diarrhea in 45% (all grade 1/2).

Dermatologic toxicity was seen in 94% of patients treated with the triplet regimen. Overall, 36% of patients in the triplet arm required a dose reduction or delay to alleviate this toxicity.

“Dermatologic toxicities were the most significant reason for dose interruptions, delays, and interruptions. Patients who received both panitumumab and trametinib and a wide range of skin-related toxicity,” Atreya said. “Although numbers are small, we have noted the greatest proportion of serious dermatologic toxicities with the combination of panitumumab and trametinib without the BRAF inhibitor, suggesting that addition of dabrafenib may lessen skin-related toxicity.”

A pharmacokinetic analysis across the study arms revealed significantly lower phosphorylated ERK (p-ERK) staining in the triplet arm compared with the dabrafenib doublet. However, while the triplet level was lower than seen with either doublet in mCRC, it was still higher than single-agent dabrafenib in melanoma, Atreya added.

“Triplet therapy inhibited MAP kinase signaling more strongly than the dabrafenib doublet therapies, but to a lesser degree than what was observed with dabrafenib monotherapy in BRAF-mutated melanoma,”Atreya said. “We have several correlative science studies planned to elucidate mechanisms of response and resistance to BRAF and MEK-targeted therapies.”

Both dabrafenib and trametinib are approved as monotherapy for patients with BRAF-mutant metastatic melanoma. Additionally, the combination of the two drugs became the first FDA-approved combination therapy for patients with metastatic melanoma in January 2014. This approval was based on early phase data, with additional trials conducted to support the approval.

In the phase III COMBI-d trial, which was also presented at the ASCO meeting, dabrafenib plus trametinib demonstrated superior overall survival compared with dabrafenib alone.² In the final analysis of the study, the median OS with the combination was 25.1 months compared with 18.7 months for dabrafenib alone.

The ongoing phase I/II study will continue to enroll patients with BRAF-mutant mCRC to the panitumumab-plus-trametinib arm. The study is being expanded to compare 4.8 mg/kg of panitumumab with the 6-mg/kg dose as a first-line therapy and in later lines of treatment (2-4) in approximately 60 additional patients.

References

1. Atreya CE, Van Cutsem E, Bendell JC, et al. Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC). J Clin Oncol. 2015;33 (suppl; abstr 103).
2. Long GV, Stroyakovskiy D, Gogas H, et al. Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. J Clin Oncol. 2015;33 (suppl; abstr 102).