Spartalizumab Plus Dabrafenib/Trametinib Misses PFS End Point in BRAF V600+ Melanoma


Spartalizumab in combination with dabrafenib and trametinib failed to meet the primary end point of investigator-assessed progression-free survival in treatment-naïve patients with unresectable or metastatic BRAF V600 mutation–positive cutaneous melanoma.

John Tsai, MD

Spartalizumab in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) failed to meet the primary end point of investigator-assessed progression-free survival (PFS) in treatment-naïve patients with unresectable or metastatic BRAF V600 mutation–positive cutaneous melanoma, according to an update on the phase 3 COMBI-i trial (NCT02967692).1

“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 [dabrafenib plus trametinib] for these patients,” John Tsai, MD, head of Global Drug Development and chief medical officer at Novartis, stated in a press release.

The pharmaceutical company will continue to examine the data from the trial, along with the study investigators, and the results will be submitted for presentation at an upcoming medical meeting.

Previous pooled results from the trial presented during the 16th International Congress of the Society for Melanoma Research (SMR) showed that the triplet resulted in a 12-month overall survival (OS) rate of 86.1% in treatment-naïve patients with advanced BRAF V600–mutated melanoma.2 Moreover, the regimen was found to have encouraging efficacy in those with elevated lactate dehydrogenase (LDH) levels and stage IV M1c disease, populations that are known to have poor outcomes.

Previous findings from other trials demonstrated that the addition of the PD-1 inhibitor to the BRAF/MEK inhibitor combination resulted in improved objective response rates (ORRs) versus the doublet alone.3

In the randomized, double-blind, placebo-controlled phase 3 COMBI-i trial, investigators set out to examine spartalizumab at a dose of 400 mg given every 4 weeks in combination with dabrafenib at 150 mg twice daily and a daily 2-mg dose of trametinib in patients with unresectable or metastatic BRAF V600-mutant melanoma. Treatment was given until progressive disease, death, intolerable toxicity, loss to follow-up, or withdrawal of consent.

The first portion of the trial was a safety run-in phase, while the second portion was a biomarker cohort. Pooled baseline characteristics from both portions of the trial showed that the median age of participants was 55 years, with the majority being male (61%) and white (92%). Sixty-nine percent of patients had an ECOG performance status of 0 and more than half, or 56%, of patients had 3 or more disease sites.

Data presented during the 2019 ASCO Annual Meeting showed that the triplet regimen elicited an ORR of 78% per investigator assessment in the overall patient population; this included a complete response (CR) rate of 42% at a median follow-up of 19.9 months.4 Notably, the CR was found to be ongoing in 10 of 15 patients. Moreover, the median duration of response (DOR) was 20.7 months, with a 12-month DOR rate of 80.3%. OS was not yet evaluable at the time of that presentation.

Updated data presented at the 2019 SMR showed a 12-month OS rate of 86.1% in a total of 36 patients (9 for the first portion of the trial and 27 from the second portion) at a data cutoff of April 8, 2019. Additionally, the 12-month DOR rate was 80.3%.

In 15 patients with elevated LDH, the 12-month DOR rate was 64.8%, the 12-month PFS rate was 33.3%, and the 12-month OS rate was 66.7%. In 20 patients with stage IV M1c disease, the 12-month DOR rate was 67.7%, the 12-month PFS rate was 50.0%, and the 12-month OS rate was 75.0%.

Notably, results indicated that patients who had elevated circulating tumor DNA, low tumor mutational burden, high levels of immunosuppressive factors in the tumor microenvironment, and/or low T-cell–inflamed gene expression levels had a higher likelihood of experiencing a PFS event in the first 12 months of treatment (n = 5; 23%).

With regard to safety, all patients who received the triplet had 1 or more any-grade adverse effects (AEs); the most common toxicities reported included pyrexia (n = 32), cough (n = 18), arthralgia (n = 18), rash (n = 17), chills (n = 17), and fatigue (n = 16). Six patients had grade 3 or higher pyrexia. Serious AEs associated with the treatment were experienced by 36% of participants (n = 13). No treatment-related deaths were reported.

“Novartis remains committed to [patients with] melanoma through ongoing research, and we continue to deliver the approved combination therapy [dabrafenib plus trametinib] to patients around the world,” added Tsai in the release. “We extend our gratitude to 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.”


  1. Novartis provides update on phase III study evaluating investigational spartalizumab (PDR001) in combination with Tafinlar + Mekinist in advanced melanoma. News release. Novartis. August 22, 2020. Accessed August 22, 2020.
  2. Dummer R, et al. Spartalizumab (S) + dabrafenib (D) + trametinib (T) in first-line treatment (tx) of BRAF V600-mutant melanoma: clinical outcomes and biomarker analyses from COMBI-1 parts 1 and 2. Presented at: 16th International Congress of the Society for Melanoma Research; November 20-23, 2019; Salt Lake City, UT.
  3. Long GV, Weber JS, Infante JR, et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J Clin Oncol. 2016;34:871-878. doi:10.1200/JCO.2015.62.9345
  4. Long GV, Lebbe C, Atkinson V, et al. The anti–PD-1 antibody spartalizumab (S) in combination with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600–mutant melanoma: updated efficacy and safety from parts 1 and 2 of COMBI-i. J Clin Oncol. 2019;37(suppl 15):9531. doi:10.1200/JCO.2019.37.15_suppl.9531.
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