With Lumakras the first drug specifically approved for KRAS-mutated cancer, Amgen is examining various combination options to expand its reach. But new data underline the difficulty in finding the right partner.
In a small group of heavily pretreated patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC), Lumakras shrunk tumors in 35% of individuals when paired with a high dose of Boehringer Ingelheim’s Gilotrif. Altogether, 74% of patients had their disease under control, Amgen unveiled at the AACR-NCI-EORTC virtual International Conference on Molecular Targets and Cancer Therapeutics.
Separately, Amgen presented early data for a cocktail of Lumakras and Novartis’ MEK inhibitor Mekinist. In patients with pretreated NSCLC, the combo achieved partial response in 20% of patients who were new to KRAS inhibitors, with 87% disease control rate. In three patients who had previously got a KRAS inhibitor, two achieved disease control.
The data, from the phase 1b CodeBreaK 101 trial, are disappointing because the numbers are roughly the same or even lower than the 37% response rate and 91% disease control rate that single-agent Lumakras has historically shown, Bernstein analyst Ronny Gal and Jefferies analyst Michael Yee noted in their separate notes Thursday.
Admittedly, the Gilotrif group also included some patients with prior Lumakras treatment who might have dragged down the overall performance. But results from KRAS drug-naïve patients didn’t look great, either, Yee noted.
Besides NSCLC, some colorectal cancer data was also reported for the Mekinist combo. There, only one of 11 KRAS-naïve patients (9%) achieved partial response, with 82% achieving disease control. One of seven patients (14%) who had previously been treated with a KRAS inhibitor achieved partial response while on the cocktail, with the disease control rate checking in at 86%.
Once again, these data are similar to Lumakras monotherapy’s 12% response rate and 80% disease control rate in colorectal cancer.
As a result, Gal expects Amgen will discontinue both combinations for Lumakras.
Jefferies’ Yee was previously counting on the Mekinist combo data as a potential opportunity for higher sales projection for Lumakras, especially as Amgen’s close rival Mirati Therapeutics had decided not to pursue MEK based on its own preclinical findings.
But despite the lackluster data, Amgen has recently signed on Verastem Oncology’s investigational MEK inhibitor, VS-6766, for pairing with Lumakras in NSCLC. “Perhaps Amgen feels a better MEK with improved antiresistance mechanisms could unlock more efficacy and still drive a point of differentiation over Mirati,” Yee wrote in his note.
Amgen has launched testing for different Lumakras combinations, following the logic that tumors might mutate in multiple ways to compensate for KRAS inhibition. For CodeBreaK 101, the company has about a dozen potential partner drugs for Lumakras, including Merck & Co.’s PD-1 inhibitor Keytruda, Roche’s PD-L1 inhibitor Tecentriq, Pfizer’s CDK inhibitor Ibrance, Novartis’ mTOR inhibitor Afinitor, different chemo regimens, among others.
At the recent ESMO 2021 conference, Amgen reported encouraging Lumakras combo data with its own EGFR inhibitor Vectibix. The pairing reached an unconfirmed response rate of 33% in previously treated, KRAS drug-naïve patients with KRAS G12C-mutated colorectal cancer. And Amgen is moving the regimen into phase 3 testing.
Mirati is trailing closely behind Amgen with its own KRAS contender adagrasib. At ESMO 2021, adagrasib posted competitive monotherapy data, showing an overall response rate of 22% in KRAS-mutant colorectal cancer patients with a median of three prior lines of therapy. And the drug’s combination with Eli Lilly’s EGFR inhibitor Erbitux reported a 39% response rate in the same disease setting.
Lumakras’ latest setback with Gilotrif or Mekinist doesn’t mean combination with other mechanisms wouldn’t work. “With a broad effort by Amgen and others to find the right combination, we see it as reasonably likely some combinations will provide added efficacy, especially in targeted segments,” Gal said in his note. However, he did point out that Amgen competitors now have a better chance at playing catch-up.