Novartis drops out of KRAS

Yet more signs of of how hard companies have to push to compete in the crowded KRAS G12C inhibitor space has emerged this morning, with Novartis discontinuing its contender, opnurasib, just three months after saying it was planning to start a new phase 3 trial.

The decision has been taken shortly after Novartis’s Swiss rival Roche moved its KRAS G12C inhibitor divarasib into a pivotal second-line NSCLC trial head to head against Lumakras or Krazati, with plans to go into the front line next year. Lung cancer was always the key setting for opnurasib, but recent developments have shut off various avenues for Novartis.

The formal reason for opnurasib’s discontinuation is so Novartis can prioritise “other key programmes”, but it’s noteworthy that just three months ago the group was reiterating plans for a “seamless phase 2/3 trial” in first-line NSCLC as part of an undisclosed combo. Meanwhile, the phase 3 Kontrast-02 study was continuing to dose second-line NSCLC patients.

Competition

It’s important to appreciate the competition that, as a result of aggressive moves into pivotal trials, Novartis had come up against with opnurasib.

Amgen’s Lumakras and Bristol Myers Squibb’s Krazati are already in pivotal first-line NSCLC studies, as are Lilly’s olomorasib and Merck & Co’s MK-1084, the latter since less than two months ago. Roche plans to move divarasib into a pivotal first-line NSCLC trial next year.

It’s also worth noting the second-line NSCLC space, where Lumakras and Krazati, whose confirmatory studies have already read out, are approved. Lilly and Merck have decided to bypass this setting entirely and head straight into the front line; Roche, meanwhile, has pitted divarasib against Lumakras or Krazati, reckoning that the Amgen and Bristol drugs will soon be fully approved, and that nothing short of a head-to-head trial will do.

This second-line plan at Roche exposed the hopeless position in which Novartis had found itself with the Kontrast-02 trial in second-line NSCLC. Kontrast-02 began in mid-2022 (when Lumakras was newly approved, and Krazati had yet to reach the market), and was testing opnurasib not against other KRAS inhibitors but against docetaxel.

Novartis realised the futility of this last month, when Kontrast-02 stopped recruitment early after enrolling only 95 of a planned 360 patients, according to clinicaltrials.gov. That was an early heads-up for today’s discontinuation, though not long before that Novartis was still playing up “emerging data” backing opnurasib’s combination with PD-1 blockade in the front line.

But another factor that might have weighed heavy is that Novartis earlier discontinued spartalizumab, and pulled out of a deal with BeiGene for tislelizumab, as well as separately deprioritising its SHP2 inhibitor TNO155. These developments left the company without a readily available in-house compound with which to combine opnurasib.

And, while other KRAS players still have the option of colorectal cancer and perhaps other uses to turn to, beyond phase 1 basket trials Novartis had only pursued NSCLC with opnurasib. Now the group has decided that its money will be better spent elsewhere.

Phase 3 trials of KRAS G12C inhibitors in lung cancer

Source: OncologyPipeline.