COMBI-i Regimen Does Not Improve PFS in Unresectable or Metastatic BRAF V600E-Mutant Melanoma

Progression-free survival (PFS) was not improved with the combination of spartalizumab (PDR001), dabrafenib (Tafinlar), and trametinib (Mekinist) when administered as treatment of untreated patients with unresectable or metastatic BRAF V600E-mutant cutaneous melanoma compared with dabrafenib plus trametinib alone, missing the primary end point of the phase 3 COMBI-I clinical trial.¹

The negative trial result was announced in a press release from the spartalizumab developer, Novartis. Investigators will continue to review data from the trial, and results will be presented at an upcoming medical meeting.

“While the COMBI-I trial did not reach its primary end point, the study’s findings give us valuable insights into the role the investigational immunotherapy spartalizumab may play in future cancer therapy combinations and underscore the previously established importance of Tafinlar plus Mekinist for these patients,” said John Tsai, MD, Head of Global Drug Development and Chief Medical Officer, Novartis, in a statement. “Novartis remains committed to melanoma patients through ongoing research, and we continue to deliver the approved combination therapy Tafinlar + Mekinist to patients around the world. We extend our gratitude to the patients and investigators who participated in the COMBI-I study. Their partnership has expanded our understanding of spartalizumab and its potential role in future cancer treatments.”

The PFS outcome represents a downward trajectory for the COMBI-I trial, which originally showed promise in terms of inducing responses in patients with BRAF-mutant melanoma in parts 1 and 2 of the 3-part study.²

In the part 1 safety run-in phase of the study, 9 patients with unresectable or metastatic disease who were previously untreated, had no history of central nervous system metastasis, aspartate aminotransferase alanine transaminase level of <2.5 upper limit normal (ULN), and an ECOG performance status of ≤ 1.

The 27 patients included in the part 2 biomarker cohort also had unresectable or metastatic disease, were previously untreated with no active brain metastasis, had an ECOG performance status of 2 or lower, and had at least 2 cutaneous, subcutaneous, or nodal lesion for tumor sample collection.

All patients in the study received spartalizumab at a dose level of 400 mg every 8 weeks, in addition to dabrafenib 150 mg twice daily, and trametinib 2 mg twice daily. Treatment was continued until progression of disease or unacceptable toxicity. The primary end point for parts 1 and 2 of COMBI-I was changed in PD-L1 level and CD8 cells upon treatment. The study also explored PFS, overall survival (OS), duration of response (DOR), disease control rate (DCR), and pharmacokinetics as secondary end points.

Efficacy and safety analyses were performed on all patients from parts 1 and 2 (n = 36). The confirmed objective response rate among all patients was 78% (95% CI, 61%-90%), which included complete responses in 16 patients (44%), partial responses in 12 patients (33%), and stable disease in 6 patients (17%). There was also 1 patient who had progressive disease, and another patient with an unknown response to treatment. The DCR observed in the study was 94% (95% CI, 81%-99%). The median DOR was not reached (95% CI, 17-not reached [NR]).

At the time these efficacy data were reported by Georgina V. Long, MD, during the American Society of Clinical Oncology Virtual Annual Meeting, Kaplan-Meier estimates of PFS were also presented based on local investigator review. It was estimated that the 12-month PFS rate would be 67% (95% CI, 49-80%) and the 24-month PFS rate would be 41% (95% CI, 23%-59%). The estimated median PFS was 23 months (95% CI, 12-NR).

Among the 19 patients with LDH level less than ULN, the 12-month PFS rate was estimated as 95% (95% CI, 68%-99%) and the estimated 24-month PFS rate was 46% (95% CI, 14%-73%). The estimated median PFS was 24 months (95% CI, 20 months-NR).

Estimates were also made for OS in the overall population, as well as the low and high LDH level population. In all 36 patients, the estimated 12-month OS rate was 86% (95% CI, 70%-94%), and the 24-months PFS rate was 74% (95% CI, 56%-86%). The median OS was estimated as NR (95% CI, NR to NR).

Among the 19 patients with low LDH levels, the estimated OS rate at 12 months was 100%. The estimated 24-months OS was 88% (95% CI, 59%-97%). The median OS was estimated as NR in this group (95% CI, NR to NR).

Finally, among the 15 patients whose LDH levels were ≥ than ULN, the estimated 12-month OS rate was 67% (95% CI, 38%-85%), and the 24-month OS rate was 95% CI, 25%-74%). Similar to the other groups, the estimated median OS was NR (95% CI, 7 months-NR).

The safety analysis showed that adverse events (AEs) of any-grade were seen in all patients. Grade 3 or higher AEs were observed in 29 patients (81%). All any-grade AEs were treatment-related, but only 72% of the grade 3 or higher AEs were considered to be treatment-related. Trametinib caused the highest number of treatment-related AEs ([TRAEs], n = 12), whereas the spartalizumab triplet caused the least (n = 6).

TRAEs leading to dose interruptions were caused by dabrafenib in 94% of patients, trametinib in 94% of patients, and spartalizumab in 64% of patients. There were no deaths related to treatment in the study. The median exposure to treatment was 13 months (range, 0.8-29) with dabrafenib and trametinib. Spartalizumab treatment exposure was a median of 9 months (range, 0.9-29). The most common TRAEs of any grade included pyrexia (86%), arthralgia (44%), chills (42%), rash (42%), and fatigue (36%).

Long et al concluded from these data that spartalizumab plus dabrafenib, and trametinib may have led to a high frequency of durable response in patients with unresectable or metastatic BRAF-mutant melanoma, with a manageable safety profile.

COMBI-I is an ongoing randomized, double-blind, placebo-controlled trial with a target enrollment of 500 patients (NCT02967692). The study was launched to improve upon the 30% to 50% survival rate observed with dabrafenib plus trametinib in patients with unresectable or metastatic BRAF-mutant melanoma.^1,2

_References:

_{1. Novartis provides update on Phase III study evaluating investigational spartalizumab (PDR001) in combination with Tafinlar® + Mekinist® in advanced melanoma. News release. August 22, 2020. Accessed August 24, 2020. https://bit.ly/32jg1XX}

_{2. Long GV, Lebbe C, Atkinson V, et al. The anti–PD-1 antibody spartalizumab 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. J Clin Oncol. 38: 2020 (suppl; abstr 10028). doi:10.1200/JCO.2020.38.15_suppl.10028}