CR With Dabrafenib/Trametinib Linked to Long-Term Survival in BRAF+ Melanoma

Patients with unresectable or metastatic BRAF V600-mutant melanoma who achieve a complete response to dabrafenib (Tafinlar) plus trametinib (Mekinist) are more likely to have improved survival outcomes at 5 years.

Georgina Long, BSc, PhD, MBBS

Patients with unresectable or metastatic BRAF V600-mutant melanoma who achieve a complete response (CR) to dabrafenib (Tafinlar) plus trametinib (Mekinist) are more likely to have improved survival outcomes at 5 years, according to a pooled analysis of data from the phase III COMBI-d and COMBI-v studies.1

Patients who have CR are more likely to live for a long time and less likely to progress, are more likely to have low-volume disease, and are more likely to have normal LDH at baseline, said study co-author Georgina V. Long, MBBS, PhD, co-medical director of the Melanoma Institute Australia (MIA) and chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital.

“In the pooled analysis of the COMBI-v and COMBI-d studies, 50% of those complete responders had not progressed at 5 years. Over 70% of the complete responders were alive at 5 years,” she said during an interview at the 16th International Congress of the Society for Melanoma Research. The data were presented in a poster at the meeting.

“This was in marked contrast to those who had a partial response or only stable disease,” she added. “Complete responders were more likely to have fewer metastases and a normal LDH as well.”

The double-blind COMBI-d trial randomized patients with unresectable or metastatic BRAF V600E/K mutation—positive cutaneous melanoma to dabrafenib plus trametinib or dabrafenib alone. The open-label COMBI-v trial compared dabrafenib/trametinib with vemurafenib (Zelboraf) monotherapy in patients with BRAF V600E/K mutation—positive unresectable or metastatic melanoma.

The pooled analysis included 563 patients, 211 from COMBI-d and 352 from COMBI-v. Across the studies, there were 109 patients who achieved a CR, comprising 39 from COMBI-d and 70 from COMBI-v. In the CR group, 50% of patients had ongoing CR at the data cutoff.

The median follow-up for the 109 patients who achieved a CR was 64.0 months (range, 5.0-74.0). Among patients who had a CR, 46% were male, and 39% had stage IV M1c disease as compared with 70% of patients who did not have CR. Patients with CR were more likely to have normal LDH levels (90% vs 59%) and more likely to have an ECOG performance status of 0 (86% vs 68%).

Patients who did not have CR were more likely to have at least 3 disease sites (57% vs 16%). These patients also tended to have larger tumors (69.0 mm vs 34.0 mm sum of lesion diameters).

The median time to response was 5.6 months (95% CI, 4.0-7.3) for complete responders. Eighty-eight (81%) patients with CR discontinued at least 1 treatment drug, most often for disease progression.

In data first reported in the New England Journal of Medicine, the 5-year OS rate for patients who had CR was 71% compared with 32% for partial response (PR) and 16% for stable disease (SD).2 The 5-year progression-free survival (PFS) rate was 49% for those who had CR compared with 16% for PR and 1% for SD. The 5-year OS rate for the entire population of the pooled analysis was 34% and the 5-year PFS rate was 19%.

The median duration of response for patients with CR was 36.7 months (95% CI, 24.1 months-not reached).

Forty-six (42%) complete responders discontinued dabrafenib or trametinib while still in response. The most common reason was adverse events.

Fifty-four patients with CR experienced disease progression and 48 experienced new lesions, most often in the central nervous system (54%), lung (17%), and lymph nodes (17%). Those findings were similar to sites of new lesions observed in the overall population.

References

  1. Robert C; Grob J-J; Stroyakovskiy D, et al. Characteristics of patients (pts) with a complete response (CR) treated with dabrafenib plus trametinib (D+T) combination therapy: findings from COMBI-d and COMBI-v 5-year analysis. Presented at: the 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.
  2. Robert C; Grob J-J; Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626-636. doi: 10.1056/NEJMoa1904059.

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