ESMO 2023 – Lumakras still looks like a colorectal also-ran

In the new KRAS battleground of colorectal cancer, Amgen’s G12C inhibitor Lumakras had already risked falling behind Mirati’s Krazati and, more recently, Roche’s divarasib. More combo data released last night in an ESMO late-breaking abstract confirm Lumakras’s status as a likely also-ran in this setting.

But perhaps more worrying for Amgen were the first detailed results with a low Lumakras dose, which were particularly lacklustre. With doubts swirling about the chances of the drug getting full approval, this is another headache that Amgen doesn’t need. 

The company had already deprioritised Lumakras monotherapy in colorecal cancer. The latest trial, Codebreak-300, evaluated a combination of Lumakras, dosed at 960mg or 240mg per day, and Vectibix, in patients with third-line disease. 

Dose questions

The 960mg dose is marketed in KRAS G12C-mutated NSCLC under accelerated approval. However, the FDA asked Amgen to also investigate a lower, 240mg dose; later, hints of liver toxicity with Lumakras emerged. There had been speculation ahead of a recent adcom that the FDA might be pushing the company towards this low dose, but in the event this was not a major point of discussion.

If the FDA is considering restricting Lumakras to a low dose, this could be disastrous for Amgen, the Codebreak-300 data suggest. 

Although the abstract notes that the study met the primary endpoint, with both dose arms showing significantly superior PFS versus standard of care, the low-dose data looked particularly disappointing. 

Even the 26% ORR seen with the high dose fell short of the 30% reported in the late-line Codebreak-101 study at ESMO last year – which had already been seen as lacklustre versus the competition. 

There are still unanswered questions ahead of the full Codebreak-300 presentation on Sunday, not least around toxicity, which has been an issue for the KRAS G12C inhibitors. 

The abstract notes that there were no fatal treatment-related adverse events, but has few other details.

So far, Roche’s divarasib/Erbitux combo has looked the most impressive in terms of efficacy, but also the most toxic, with a 41% rate of grade 3/4 treatment-related adverse events in its phase 1 trial. 

In regulatory terms Mirati is ahead, with plans to file Krazati in third-line colorectal cancer this year, although it has taken a long time to get to this point. Amgen has not given detailed filing plans, which will be another thing to look out for in the coming days.

Cross-trial comparison of KRAS G12C inhibitor combos in colorectal cancer

Source: ESMO 2023, AACR 2023 & ESMO 2022.