COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma1

Research summary edited by Pierre Fabre

With a median follow-up duration of 100 months, the seven-year analysis from the COLUMBUS trial’s part 1 confirms the long-term, sustained efficacy and known safety profile of encorafenib + binimetinib in patients with BRAFV600-mutant metastatic melanoma. This is the longest follow-up analysis from a phase 3 trial of combined BRAF and MEK inhibition in this patient population.

COLUMBUS is a randomized, two-part, multicentre, open-label phase III trial assessing the safety and efficacy of encorafenib plus binimetinib compared to vemurafenib or encorafenib monotherapy in patients with BRAFV600E/K-mutant metastatic melanoma. Primary endpoint is PFS by BICR.2,3

 

 

a In part 2, patients were randomized 3:1 to receive encorafenib + binimetinib vs encorafenib alone.4
b Prior first-line immunotherapy replaced BRAF mutation status as a stratification factor after protocol amendment.

 

Part 1 included 577 patients with advanced, unresectable or metastatic BRAFV600-mutant melanoma: 192 were randomized to encorafenib + binimetinib, 191 to vemurafenib alone and 194 to encorafenib alone. Patients were either treatment-naïve or had progressed following first-line immunotherapy; no prior BRAF/MEK inhibitor therapy was allowed.

In this analysis, efficacy and safety were assessed at seven years, with data cutoff  on January 13, 2023, whereas time to overall response for the overall population is based on the March 31, 2023, data cutoff.

 

Extended PFS and OS

Results showed that combination therapy increased both PFS and OS compared to monotherapy. Median PFS was 14.9 months (95 % CI, 11.0–20.2 months) in the encorafenib + binimetinib arm, 7.3 months (95 % CI, 5.6–7.9 months) in the vemurafenib alone arm and 9.6 months (95 % CI, 7.4–14.8 months) in the encorafenib alone arm. Median OS was 33.6 months (95 % CI, 24.4–39.2 months) with encorafenib + binimetinib, 16.9 months (95 % CI, 14.0–24.5 months) with vemurafenib alone and 23.5 months (95 % CI, 19.6–33.6 months) with encorafenib alone.

 

 

Progression-free survival (PFS) in all patients.1

 

Overall survival (OS) in all patients.1

 

Subsequent therapy

Median time from randomization to end of next line of treatment was 21.2 months (95 % CI, 17.4–27.9 months) in the encorafenib + binimetinib arm, 12.5 months (95 % CI, 10.5–15.8 months) in the vemurafenib alone arm and 19.3 months (95 % CI, 12.8–22.3 months) in the encorafenib alone arm.

Among patients who received subsequent therapy, median OS since start of first antineoplastic systemic therapy following study drug discontinuation was 17.2 months (95 % CI, 11.7–23.8 months) for those initially in the encorafenib + binimetinib arm, 11.6 months (95 % CI, 8.1–15.1 months) for those initially in the vemurafenib alone arm, and 12.3 months (95 % CI, 9.0–20.5 months) for those initially in the encorafenib alone arm.

For patients initially treated with encorafenib + binimetinib, median OS since start of first subsequent therapy was also analysed. For the 16 patients who received ≥1 subsequent targeted therapy, OS was 38.3 months [95 % CI, 15.4 months–not evaluable (NE)]. For the 63 patients who received ≥1 subsequent immunotherapy OS was 17.1 months (95 % CI, 7.4–21.4 months), and for the eight patients who received ≥1 subsequent chemotherapy, it was 12.3 months (95 % CI, 0.9 months–NE).

 

Safety

The encorafenib + binimetinib combination had a manageable safety profile consistent with known class effects. TEAEs (seen in ≥30%) were nausea, diarrhoea, vomiting, arthralgia, and fatigue. Across the three arms, 16–20% of patients discontinued treatment due to adverse events.

Dose adjustments or interruptions occurred in 56.8% of patients in the encorafenib plus binimetinib arm, 62.4 % of patients in the vemurafenib arm, and 72.9% of patients in the encorafenib monotherapy arm.

 

Conclusions

With a median duration of follow-up of approx. 100 months, the seven-year analysis of the COLUMBUS trial confirms the long-term, sustained efficacy of encorafenib + binimetinib, with more than 20% of patients free of progression. The safety profile of the combination was consistent with what was previously reported, with no new safety signals emerging.

 

Abbreviations

AJCC, American Joint Committee on Cancer; BID, twice daily; BICR; blinded independent central review, Bini, binimetinib; CPK, creatine phosphokinase; DCR, disease control rate; DOR, duration of response; EGOC PS, performance status assessed by using ECOG (Eastern Cooperative Oncology Group) score; Enco, encorafenib; ORR, objective response rate; OS, overall survival; PFS; progression-free survival; PK, pharmacokinetics; QD, once daily; QoL, quality of life; R, randomization; TEAEs, treatment-emergent adverse events; TTR, time to response; Vemu, vemurafenib

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Uppdaterad: 28 juni, 2024
Referenser
1 Schadendorf D et al. COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma. Eur J Cancer 2024; 204: 114073.
2 Dummer R et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2018; 19: 603–15.
3 Dummer R et al. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma. J Clin Oncol 2022; 40: 4178–88.
4 Ascierto PA et al. Contribution of MEK Inhibition to BRAF/MEK Inhibitor Combination Treatment of BRAF-Mutant Melanoma: Part 2 of the Randomized, Open-Label, Phase III COLUMBUS Trial. J Clin Oncol 2023; 41: 4621–31).
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