The phase 3 COMBI-i trial demonstrated that spartalizumab plus dabrafenib and trametinib has modest efficacy in BRAF V600-positive metastatic melanoma, but no progression-free survival benefit when compared with dabrafenib and trametinib alone.
Modest efficacy was demonstrated with spartalizumab plus dabrafenib (Tafinlar) and trametinib (Mekinist) or sparta-DabTram in patients with BRAF V600-positive metastatic melanoma. However, the combination showed no progression-free survival (PFS) advantage vs placebo plus DabTram (placebo-DabTram), according to results from the phase 3 COMBI-I clinical trial.
“The trial did not meet its primary end point of improved progression-free survival with sparta-DabTram versus placebo-DabTram. [The] combination of dabrafenib plus trametinib with spartalizumab was associated with higher rates of adverse events and dose modifications than dabrafenib plus trametinib alone, wrote the study authors led by Reihard Drummer, MD, vice president of dermatology and director of CCCZ Clinical Trial at the Comprehensive Cancer Center Zurich.
The median PFS observed with sparta-DabTram was 16.2 months (95% CI, 12.7-23.9) compared with 12.0 months (95% CI, 10.2-15.4) in the placebo-DabTram arm (Hazard ratio [HR], 0.82; 95% CI, 0.66-1.03; 1-sided P =.042), demonstrating insignificance according to a stratified log-rank test at an overall 1-sided 2.5% level.
COMBI-i is a global, randomized clinical trial (NCT02967692) conducted to potentially improve survival in the unresectable or metastatic melanoma patient population. Although overall survival (OS) in patients with unresectable or metastatic melanoma has been significantly improved with BRAF and MEK-targeted therapies and immunotherapies, the majority of patients die after 5 years. The BRAF V600-mutated subgroup, in particular, accounts for roughly 40% of all melanoma cases.
The current standard-of-care treatment for BRAF V600-positive disease is the sequential use of 2 treatment strategies. Preclinical evidence suggests, however, that combining an immune checkpoint inhibitor like spartalizumab with BRAF and MEK inhibition may lead to better outcomes in these patients. Further, studies like the phase 2 KEYNOTE-022 study (NCT02130466) and the phase 3 IMspire150 study (NCT02908672) signaled promise for the anti-PD-1 and BRAK-MEK combination strategy.
In COMBI-i, 532 patients were randomized to receive either sparta-DabTram or placebo-DabTram. In the sparta-containing arm, 267 patients were administered 400 mg of the agent once every 4 weeks in combination with Dab 150 mg twice a day and Tram 2 mg once daily. In the comparator arm, 265 patients were administered matching placebo-DabTram. All patients in the spart-containing arm were included in both the intention-to-treat (ITT) and safety population. All patients in the control arm were also included in the ITT population, but 1 was excluded from the safety analysis.
At baseline, the investigational population had a median age of 56 years (range, 46-66) and the control arm had a median age of 55 years (range 47-65). Disease characteristics were similar between the 2 treatment arms. The most common disease stage at baseline was IV M1c, and most patients had BRAF V600E rather than V600K or another BRAF status.
PD-L1 status at baseline was positive for 37% of the experimental arm vs 43% of the control arms, and it was positive for 52% vs 48%, respectively. The tumor mutational burden status was low for 43% of the spartaDabTram arm vs 46% of the placebo plus DabTram arm, and it was high for 33% vs 34%, respectively. LDH levels in the study population as a whole were most commonly < 1 x the upper limit of normal. Most patients in both treatment arms had < 3 organ sites with disease. Prior adjuvant therapy was received by 2% of patients in each arm.
Results showed a PFS rate of 55% in the sparta-DabTram arm compared with 62% in placebo-DabTram arm (HR, 0.82; 95 % CI, 0.66-1.03; 1-sided P = 0.42). Interim analysis findings from COMBI-i showed an estimated OS rate of 68% (95% CI, 61%-73%) in the sparta-DabTram group compared with 62% (95% CI, 55%-67%) in the placebo-DabTram group. OS could not be formally tested in the study given its negative primary end point result.
In terms of response, sparta-DabTram achieved an ORR of 69% (95% CI, 62.6%-74.1%) with complete response (CRs) observed in 20% of patients. In comparison, the placebo-DabTram arm had an ORR of 64% (95% CI, 58.1%-69.9%) with an 18% CR rate. The median duration of response was not reached with sparta-DabTram vs 20.7 months with placebo-DabTram. The estimated DOR rate at 24 months were 55% (95% CI, 47%-62%) in the experimental arm vs 49% (95% CI, 39%-56%) in the control arm.
Patients in the study were exposed to the sparta-DabTram combination for a median duration of 13.2 months (interquartile range [IQR], 6.4-25.2) and to placebo-DabTram for 11.8 months (IQR, 6.4-24.9). Any-grade adverse events (AEs) were observed in 99% of the sparta-DabTram arm vs 97% of the placebo-DabTram arm. AEs were grade 3 or higher in 70% of the sparta-DabTram population vs 57% of the placebo-DabTram group.
Treatment-related AEs of any grade were observed in 99% of the experimental arm vs 88% of the control arm, and treatment-related grade ≥ 3 AEs occurred in 55% vs 33%, respectively. Any-grade serious AEs were observed in 52% of the sparta-DabTram group compared with 42% of the placebo-DabTram group. Grade ≥ 3 serious AEs occurred in 34% of the sparta-DabTram arm compared with 29% of the placebo-DabTram arm.
Seventy-six patients in the sparta-DabTram vs 103 patients in the placebo-DabTram arm discontinued treatment due to either progressive disease (PD), AEs, physician decision, withdrawal of consent protocol deviation, or being lost to follow up. Ten deaths occurred in the sparta-DabTram arm compared with 8 in the control arm. At the time of data cutoff, treatment was ongoing for 86 patients in the experimental arm and 82 in the control arm.
“Although COMBI-i did not reach the primary end point, the results provide further insight into the optimal use of checkpoint inhibitors and targeted therapies in the treatment of BRAF V600–mutant metastatic melanoma. Treatment with both a checkpoint inhibitor and targeted therapy in the first-line setting would leave few options for subsequent therapeutic lines in patients who experience PD,” wrote Drummer et al. “Instead, because upfront combination of a checkpoint inhibitor plus targeted therapy appears not to be an ideal therapeutic strategy for most patients, continued evaluation of sequencing approaches may be warranted.”
Drummer R, Long GV, Robert C, et al. Randomized phase 3 trial evaluating spartalizumab plus dabrafenib and trametinib for BRAF V600–mutant unresectable or metastatic melanoma. J Clin Oncol. 2022; 40(13):1428-1438. doi. 10.1200/JCO.21.01601