Blow for Novartis as PD-1 drug spartalizumab flunks trial

Novartis’ hopes of catching up with other companies in immuno-oncology have been dented after PD-1 inhibitor spartalizumab failed a phase 3 trial in skin cancer.

Novartis had hoped the COMBI-i trial would allow it to file for approval of the ‘me-too’ PD-1 inhibitor before the end of this year as part of a triple therapy for BRAF-mutated malignant melanoma alongside its targeted drugs Tafinlar (dabrafenib) and Mekinist (trametinib).

As it turned out, adding spartalizumab to treatment with the two targeted drugs failed to provide any improvement in the time patients lived without progression of their cancer.

Tafinlar/Mekinist are a blockbuster treatment regimen for BRAF-positive melanoma that added $737 million to Novartis’ coffers in the first half of the year, the third-largest oncology therapy in the company’s product line.

The Swiss drugmaker had hoped – despite spartalizumab coming to market well behind other PD-1/PD-L1 checkpoint inhibitors – that piggybacking on its established therapy would give it a rapid route to market and an indication free of competition from other drugs in the class like Merck & Co’s Keytruda (pembrolizumab) and Bristol-Myers Squibb’s Opdivo (nivolumab).

Prospects for the triplet therapy looked good as recently as this year’s virtual ASCO congress, when preliminary data from COMBI-I showed that the regimen eliminated tumours in 44% of patients, with an overall response rate of 78%.

Those results came from an open-label portion of the trial, however, and at the time Novartis said the results couldn’t be considered conclusive.

Novartis has not released the figures from the latest, randomised portion of the study, but said in a statement that the data “give us valuable insights into the role the investigational immunotherapy spartalizumab may play in future cancer therapy combinations.”

Merck has also tested the combination of Keytruda with Tafinlar/Mekinist in the KEYNOTE-022, which also involved BRAF-positive melanoma patients and used a similar design. Results released in 2018 showed some signs of efficacy, but also failed to reach statistical significance and on the basis of overall response rates the triple did worse than Tafinlar/Mekinist.

There’s no shortage of other trials on the go that could resurrect spartalizumab’s fortunes, but there’s no question that the COMBI-I failure has slammed the brakes on its progress to market.

The company has mid-stage trials of the PD-1 inhibitor on the go as a combination therapy with CSF-1 inhibitor BLZ945 in solid tumours, c-Met inhibitor capmatinib in liver cancer, and Palobiofarma’s adenosine A2A receptor inhibitor taminadenant (NIR178) in various cancer indications.

With six PD-1/PD-L1 inhibitors on the market – and the most recent entrants struggling to make headway sales-wise – there has been speculation that latecomers like Novartis, Eli Lilly and GlaxoSmithKline will be consigned to niche status.