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J Clin Oncol: Phase III clinical study evaluating the efficacy of PD-1 inhibitor Spartalizumab combined with Dabrafenib (dabrafenib) + Trametinib (trametinib) in the treatment of BRAF V600-mutated unresectable or metastatic melanoma

 Last Update: 2022-01-23
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Recently, the Journal of Clinical Oncology published the results of a phase III clinical study COMBI-i, designed to evaluate the PD-1 inhibitor Spartalizumab combined with Dabrafenib (dabrafenib) + Trametinib (trametinib) in the treatment of BRAF V600 mutations Efficacy and safety of unresectable or metastatic melanoma
.

COMBI-i (NCT02967692) is a global, randomized, Phase III trial evaluating the anti-PD-1 inhibitor spartalizumab in combination with dabrafenib+trametinib (sparta-DabTram) versus placebo in combination with dabrafenib+trametinib (placebo-DabTram) and security
.
The primary endpoint was investigator-assessed progression-free survival (PFS)
.
Secondary endpoints included OS, ORR, duration of response (DOR), disease control rate (DCR) and safety
.

Between September 13, 2017, and July 4, 2018, 532 patients were randomly assigned to receive sparta-DabTram (n=267) or placebo-DabTram (n=265)
.

At the data cutoff point (July 1, 2020), the median follow-up was 27.
2 months (interquartile range [IQR], 25.
4-29.
0 months)
.
The median progression-free survival was 16.
2 months (95% CI, 12.
7 - 23.
9 months) and 12.
0 months (95% CI, 10.
2 - 15.
4 months), respectively, and was not statistically different (HR, 0.
82 [ 95% CI, 0.
66 to 1.
03]; P=0.
042 [one-sided; nonsignificant])
.
The 24-month progression-free survival rates were 44% (95% CI, 37 - 50) and 36% (95% CI, 30 - 42) in the two groups, respectively
.
The median progression-free survival was 16.
2 months (95% CI, 12.
7 - 23.
9 months) and 12.
0 months (95% CI, 10.
2 - 15.
4 months), respectively, and was not statistically different (HR, 0.
82 [ 95% CI, 0.
66 to 1.
03]; P=0.
042 [one-sided; nonsignificant])
.
The 24-month progression-free survival rates were 44% (95% CI, 37 - 50) and 36% (95% CI, 30 - 42) in the two groups, respectively
.
The median progression-free survival was 16.
2 months (95% CI, 12.
7 - 23.
9 months) and 12.
0 months (95% CI, 10.
2 - 15.
4 months), respectively, and was not statistically different (HR, 0.
82 [ 95% CI, 0.
66 to 1.
03]; P=0.
042 [one-sided; nonsignificant])
.
The 24-month progression-free survival rates were 44% (95% CI, 37 - 50) and 36% (95% CI, 30 - 42) in the two groups, respectively
.
statistics

PFS and subgroup analysis

PD-L1 and TMB status did not affect the prognosis of treatment
.
The 24-month OS rates were 68% (95% CI, 61 - 73) and 62% (95% CI, 55 - 67), respectively, with and without a statistically significant difference (HR, 0.
79 [95% CI, 0.
59 to 1.
05])
.

PD-L1 and TMB status did not affect the prognosis of treatment
.
PD-L1 and TMB status did not affect the prognosis of treatment
.
The 24-month OS rates were 68% (95% CI, 61 - 73) and 62% (95% CI, 55 - 67), respectively, with and without a statistically significant difference (HR, 0.
79 [95% CI, 0.
59 to 1.
05])
.

PD-L1 and TMB Status Hierarchical PFS Analysis

In patients treated with sparta-dabtram, the ORR was 69% (95% CI, 62.
6-74.
1), of which 53 (20%; 95% CI: 15.
2-25.
1) achieved complete remission
.
In contrast, the ORR in the placebo group was 64% (95% CI, 58.
1 to 69.
9), with 47 (18%; 95% CI, 13.
3 to 22.
9) achieving a complete response
.

In patients treated with sparta-dabtram, the ORR was 69% (95% CI, 62.
6-74.
1), of which 53 (20%; 95% CI: 15.
2 to 25.
1) achieved complete remission
.
In contrast, the ORR in the placebo group was 64% (95% CI, 58.
1 to 69.
9), with 47 (18%; 95% CI, 13.
3 to 22.
9) achieving a complete response
.
In patients treated with sparta-dabtram, the ORR was 69% (95% CI, 62.
6-74.
1), of which 53 (20%; 95% CI: 15.
2 to 25.
1) achieved complete remission
.
In contrast, the ORR in the placebo group was 64% (95% CI, 58.
1 to 69.
9), with 47 (18%; 95% CI, 13.
3 to 22.
9) achieving a complete response
.

Efficacy assessment

The median DOR was not reached in the Sparta-DabTram group (95% CI, 18.
6 months - not estimable), while the median DOR in the placebo-DabTram group was 20.
7 months (95% CI, 13.
0 months - not estimable)
.
The 24-month DOR rates for the two groups were 55% (95% CI, 47 - 62) and 48% (95% CI, 39 - 56), respectively
.
The median DOR was not reached in the Sparta-DabTram group (95% CI, 18.
6 months - not estimable), while the median DOR in the placebo-DabTram group was 20.
7 months (95% CI, 13.
0 months - not estimable)
.
The 24-month DOR rates for the two groups were 55% (95% CI, 47 - 62) and 48% (95% CI, 39 - 56), respectively
.
The median DOR was not reached in the Sparta-DabTram group (95% CI, 18.
6 months - not estimable), while the median DOR in the placebo-DabTram group was 20.
7 months (95% CI, 13.
0 months - not estimable)
.
The 24-month DOR rates for the two groups were 55% (95% CI, 47 - 62) and 48% (95% CI, 39 - 56), respectively
.

Differences in DOR between the two groups

The incidence of ≧ grade 3 adverse reactions in the two groups was ≧ 55% (146 / 267) and 33% (88 / 264), respectively
.

AEs

In conclusion, the study showed that the combination of PD-1 inhibitor Spartalizumab with Dabrafenib (dabrafenib) + Trametinib (trametinib) did not significantly improve the prognosis of patients with BRAF V600-mutated unresectable or metastatic melanoma
.
Studies have shown that the PD-1 inhibitor Spartalizumab combined with Dabrafenib (dabrafenib) + Trametinib (trametinib) did not significantly improve the prognosis of patients with BRAF V600-mutated unresectable or metastatic melanoma
.
Studies have shown that the PD-1 inhibitor Spartalizumab combined with Dabrafenib (dabrafenib) + Trametinib (trametinib) did not significantly improve the prognosis of patients with BRAF V600-mutated unresectable or metastatic melanoma
.

Original source:

Dummer R, Long GV, Robert C, Tawbi HA, Flaherty KT, Ascierto PA, Nathan PD, Rutkowski P, Leonov O, Dutriaux C, Mandalà M, Lorigan P, Ferrucci PF, Grob JJ, Meyer N, Gogas H, Stroyakovskiy D , Arance A, Brase JC, Green S, Haas T, Masood A, Gasal E, Ribas A, Schadendorf D.
Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600-Mutant Unresectable or Metastatic Melanoma.
J Clin Oncol.
2022 Jan 14: JCO2101601.
doi: 10.
1200/JCO.
21.
01601.
Epub ahead of print.
PMID: 35030011.
Dummer R, Long GV, Robert C, Tawbi HA, Flaherty KT, Ascierto PA, Nathan PD, Rutkowski P, Leonov O, Dutriaux C, Mandalà M, Lorigan P, Ferrucci PF, Grob JJ, Meyer N, Gogas H, Stroyakovskiy D , Arance A, Brase JC, Green S, Haas T, Masood A, Gasal E, Ribas A, Schadendorf D.
Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF BRAF V600-Mutant Unresectable or Metastatic Melanoma.
J Clin Oncol.
2022 Jan 14: JCO2101601.
doi: 10.
1200/JCO.
21.
01601.
Epub ahead of print.
PMID: 35030011.
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