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Spartalizumab, an anti–PD-1 antibody, in combination with Dabrafenib and Trametinib in advanced BRAF V600–mutant melanoma: efficacy and safety findings from parts 1 and 2 of the phase III COMBI-i trial


Treatment with checkpoint inhibitors or targeted therapy improves outcomes in patients with BRAF V600–mutant advanced melanoma; however, many patients subsequently progress and die.
Preliminary evidence suggests that targeted therapy may enhance the impact of checkpoint inhibitors and improve efficacy compared with either treatment alone.

COMBI-i is investigating first-line Spartalizumab 400 mg every 4 wk + Dabrafenib [ Tafinlar ] 150 mg twice daily + Trametinib [ Mekinist ] 2 mg once daily in patients with unresectable or metastatic BRAF V600–mutant melanoma.

Researchers have reported efficacy and safety data from parts 1 ( run-in cohort ) and 2 ( biomarker cohort ), with a median follow-up of 24.3 months.
Response was assessed per RECIST v1.1.
The randomized part 3 is ongoing.

36 patients were enrolled ( part 1: n = 9; part 2: n = 27 ); 20 ( 56% ) had stage IV M1c disease and 15 ( 42% ) had elevated lactate dehydrogenase ( LDH ) levels ( greater than or equal to upper limit of normal ).

At the data cutoff ( August 19, 2019 ), treatment was ongoing in 10 patients ( 28% ).

The confirmed investigator-assessed objective response rate ( ORR ) was 78% ( n = 28 ), with 16 complete responses ( CRs; 44% ) and 12 partial responses ( 33% ).

Median duration of response ( DOR; 10/28 responders with events ) was not reached ( NR ); 24-months DOR rate was 53.4% ( 95% CI, 29-73% ).

Median progression-free survival ( PFS ) was 22.7 months; 24-months PFS rate was 41.4% ( 95% CI, 23-59% ).

At the cutoff, median overall survival ( OS ) was NR, with a 24-months OS rate of 74.1% ( 95% CI, 56-86% ).

In patients with elevated LDH, ORR was 67%, with 4 CRs ( 27% ); median PFS was 10.7 months ( 95% CI, 4.6-19.1 months ), and median OS was NR. The estimated 24-months PFS and OS rates in these patients were 26.7% and 52.5%, respectively.

All patients had greater than or equal to 1 treatment-related adverse event ( TRAEs ); 26 ( 72% ) had grade greater than or equal to 3 TRAEs.
The most common grade greater than or equal to 3 TRAEs were pyrexia ( 17% ), increased lipase (11% ), neutropenia ( 11% ), increased blood creatine phosphokinase ( 8% ), and increased γ-glutamyltransferase ( 8% ).
Adverse effects leading to discontinuation of all 3 study drugs occurred in 6 patients ( 17% ). All-causality grade greater than or equal to 3 adverse effects requiring immunosuppressive medication occurred in 19 patients ( 53% ).
One patient died of cardiac arrest that was not considered treatment related.

In conclusion, the combination of Spartalizumab + Dabrafenib + Trametinib resulted in high objective response rate and complete response rates, with a high frequency of durable responses, including in patients with poor prognostic factors. ( Xagena )

Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020

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