A triplet combining the PD-1 inhibitor spartalizumab with dabrafenib and trametinib led to a 12-month overall survival rate of 86.1% for patients with previously untreated advanced BRAF V600–mutant melanoma.
Georgina V. Long, BSc, PhD, MBBS, FRACP
A triplet combining the PD-1 inhibitor spartalizumab with dabrafenib (Tafinlar) and trametinib (Mekinist) led to a 12-month overall survival (OS) rate of 86.1% for patients with previously untreated advanced BRAF V600—mutant melanoma, according to pooled findings from the phase III COMBI-i trial presented during the 16th International Congress of the Society for Melanoma Research.1
Furthermore, the 3-drug regimen showed promising efficacy in patients with elevated lactate dehydrogenase (LDH) levels and stage IV M1c disease—populations that generally have poor outcomes.
“With that combination, we saw that everybody had some tumor reduction—which was incredible,” 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, stated in an interview with OncLive. “That does give us the idea that this triplet could be used in patients who have the poorest of poor prognosis, particularly when we saw that no one actually progressed, everyone had some tumor reduction or at least stable disease, and a very good response rate.”
Results from previous trials showed that adding spartalizumab to treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib led to improved objective response rates (ORRs) compared with the doublet alone.2
In the ongoing COMBI-i trial (NCT02967692), investigators are evaluating 400 mg of spartalizumab administered every 4 weeks plus 150 mg of twice-daily dabrafenib and 2 mg of daily trametinib in patients with unresectable or metastatic BRAF V600—mutant melanoma. Treatment is continued until disease progression, death, unacceptable toxicity, loss to follow-up, or withdrawal of consent.
Part 1 of the phase III trial is a safety run-in phase, and part 2 is a biomarker cohort. The median follow-up was 19.9 months (range, 16.5-25.1), and treatment was ongoing in 36% of patients (n = 13).
Pooled baseline characteristics from part 1 and part 2 showed that the median age was 55 years (range, 23-76), 61% of patients were male, and 92% of patients were white. Most (69%) patients had an ECOG performance status of 0, and 56% of patients had ≥3 disease sites.
In data presented at the 2019 ASCO Annual Meeting, the triplet was associated with an ORR of 78% by investigator assessment in the overall population and a complete response (CR) in 42% (15/36) at a median follow-up of 19.9 months.3 CR was ongoing in 10 of 15 patients. The median duration of response (DOR) was 20.7 months and the 12-month DOR rate was 80.3%. OS was not evaluable in results presented at the 2019 ASCO Annual Meeting.
The updated findings presented at SMR, which include the 86.1% (95% CI, 70-94) 12-month OS rate, are from the total 36 patients (9 from part 1 and 27 from part 2), with a data cutoff of April 8, 2019. Overall, the 12-month PFS rate was 66.7% (95% CI, 49-80) and the 12-month DOR was 80.3% (59-91).
Among those with elevated LDH (n = 15), the 12-month DOR rate was 64.8% (95% CI, 25-87). At 12 months, the progression-free survival (PFS) rate was 33.3% (95% CI, 12-56) and the OS rate was 66.7% (95% CI, 37.5-85).
In patients with stage IV M1c disease (n = 20), the DOR rate was 67.7% (95% CI, 35-86.5) at 12 months, with a 12-month PFS rate of 50.0% (95% CI, 27-69) and an OS rate of 75.0% (95% CI, 50-89).
Moreover, investigators determined that patients with elevated circulating tumor DNA, low tumor mutational burden (TMB), high levels of immunosuppressive factors in tumor microenvironment (TME), and/or low T-cell—inflamed gene expression levels were more likely to experience a PFS event in the first 12 months (n = 5; 23%). In their poster, they noted that the predictive implications of linking TMB and T-cell–inflamed gene expression levels with other TME markers require further validation.
Updated safety findings showed that all patients experienced ≥1 any-grade adverse event (AE), the most common being pyrexia (n = 32), cough (n = 18), arthralgia (n = 18), rash (n = 17), chills (n = 17), and fatigue (n = 16). Six patients experienced grade ≥3 pyrexia, and treatment-related serious AEs occurred in 36% (n = 13) of patients. There were no treatment-related deaths.