Novartis Announces Phase III COMBI-i Trial of Spartalizumab Triple Combination Misses Primary Endpoint in Advanced Melanoma

Compiled by Keke

Over the weekend, Novartis shared the results of the Phase 3 COMBI-i clinical trial evaluating the combination therapy of spartalizumab (PDR001) + Tafinlar (dabrafenib) + Mekinist (trametinib) at the 2020 ESMO Virtual Congress. The trial primarily assessed this triple-drug regimen in previously untreated patients with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600 mutation-positive cutaneous melanoma. The results showed that the study did not meet its primary endpoint of progression-free survival (PFS). The efficacy of this triple combination was similar to that previously observed with the dual-drug combination of Tafinlar and Mekinist; however, the difference in efficacy did not reach statistical significance.

After previously observing evidence that spartalizumab could complement the efficacy of targeted therapies such as Tafinlar and Mekinist, researchers initiated the COMBI-i trial, a randomized, double-blind, placebo-controlled Phase 3 clinical study evaluating the three-drug regimen as first-line treatment in 500 patients with advanced melanoma. The control group received dual therapy with Tafinlar and Mekinist. The researchers hypothesized that this triple-combination therapy could disrupt the MAP kinase signaling pathway, leading to tumor shrinkage and upregulation of antigens. Theoretically, this effect could enhance the efficacy of agents such as spartalizumab, which primarily functions to coordinate immune attacks against cancer cells.

Spartalizumab is a humanized monoclonal antibody targeting the human cell surface receptor programmed death-1 (PD-1, PCD-1), an immune checkpoint inhibitor with antitumor activity. Upon administration, spartalizumab binds to PD-1 expressed on activated T cells and blocks its interaction with its ligands, namely programmed death-ligand 1 (PD-L1, PD-1L1) and programmed death-ligand 2 (PD-L2, PD-1L2). Inhibition of ligand binding prevents PD-1-mediated signaling, leading to T-cell activation and the induction of T-cell-mediated immune responses against tumor cells. PD-1 is a transmembrane protein and inhibitory receptor belonging to the immunoglobulin (Ig) superfamily, which negatively regulates T-cell activation.

Previously, Novartis collaborated with Merck & Co. to seek evidence for the aforementioned hypothesis, with Merck providing the checkpoint inhibitor Keytruda required for a Phase 2 clinical study. This study helped Novartis confirm melanoma as a therapeutic indication for spartalizumab; however, the drug still failed in Phase 3 trials.

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Novartis presented the following specific trial data at this year’s ESMO Congress:

The triple therapy showed numerically superior outcomes across multiple endpoints compared with the dual targeted therapy of Tafinlar and Mekinist, but the differences were not statistically significant. The results indicated a hazard ratio for progression-free survival (PFS) of 0.82, with a one-sided p-value of 0.042. However, the statistical significance required by the trial design necessitated a p-value below 0.025.

Due to the efficacy of Tafinlar and Mekinist in tumor shrinkage, the curves for the triplet and doublet therapy arms were similar during the first 6 months but diverged thereafter. The 1-year progression-free survival (PFS) rate was 58.4% in the triplet combination group versus 50.1% in the doublet group. At 2 years, the PFS rates were 43.7% and 36.1% for the triplet and doublet groups, respectively. The median PFS was also numerically longer in the triplet group than in the doublet group, at 16.2 months versus 12.0 months.

Spartalizumab, Tafinlar, and Mekinist also demonstrated superior performance across other endpoints. A greater number of patients survived two years after receiving the triple-drug combination therapy, and responses to the three-drug regimen were more durable. However, one issue is that the durability of response to Tafinlar and Mekinist was longer than expected; this study showed a median duration of response of 20.7 months, compared with the historical benchmark of 12 months observed in other studies.

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Despite the setback, Novartis has stated that it will continue to “bet on” spartalizumab. The company is currently analyzing the data to understand the reasons for the trial’s failure and to gather lessons learned for other development programs. Specific efforts include subgroup analyses, which have generated hypotheses regarding the causes of the trial failure; one such analysis will focus on patients with certain prognostic factors.

Novartis’s analysis of patients with high PD-L1 expression or high tumor mutational burden supports this hypothesis. In these patients, spartalizumab appears to confer benefit. Jeff Legos, Global Program Head of Novartis Oncology, stated that Novartis is advancing the development of spartalizumab, supported by “many other signals,” in the absence of safety concerns.

The failure of this melanoma trial has delayed the approval timeline for this checkpoint inhibitor, but Novartis is evaluating approximately 30 combinations involving spartalizumab, leaving ample opportunity to obtain positive pivotal data on the drug.

Reference Source:

1. NIH Official Website

2. ESMO: Novartis posts data from failed spartalizumab phase 3, reaffirms commitment to PD-1 combos

3. Novartis provides update on Phase III study evaluating investigational spartalizumab (PDR001) in combination with Tafinlar® + Mekinist® in advanced melanoma