Mirati gets a combo coup

An adagrasib/Keytruda combo in front-line lung cancer looks promising, but patient numbers are small and Amgen looms large.

Amgen has sewn up the later-line non-small cell lung cancer Kras inhibitor segment. But Mirati investors saw reasons to be cheerful after first-line data from a combination of its contender adagrasib plus Keytruda beat expectations. 

It is not yet time to call a winner in first-line NSCLC: Amgen will report its first combo data in the same setting in the first half of next year. Analysts are already talking up adagrasib’s potential differentiation, but even if they turn out to be right Mirati will have to improve its execution if it is to compete. 

At least the group now has a decent chance. The data, released after hours yesterday during Mirati’s third-quarter call, come from one cohort of the phase 1/2 Krystal-1 trial. One reason to be cautious is the small number of patients involved – just seven evaluable subjects receiving adagrasib 400mg plus Keytruda. 

But among this group Mirati reported four confirmed partial responses. A fifth patient had 49% tumour regression that allowed surgery, and a response was later confirmed.

This 57% overall response rate – 71% if the final patient is counted – is above the 50% analysts had hoped for. It also exceeds the 48% ORR seen with Keytruda plus chemo in the Keynote-189 trial, in non-squamous disease, cited by Mirati. However, Stifel analysts noted that Keynote-407, a Keytruda chemo combo trial in squamous NSCLC, showed a 58% ORR

PD-L1 status and toxicity 

There are a couple of other caveats about the latest findings. For one, analysts had hoped to see data on how the adagrasib/Keytruda combo performed according to patients’ PD-L1 status, but Mirati did not give such details, saying this was not measured when patients joined Krystal-1. 

Secondly, Mirati only reported data with the 400mg twice-daily dose of adagrasib, and did not give any results with 600mg twice daily, the combo dose originally tested. According to Leerink, the full intent-to-treat population for the combo numbered 18 patients.  

Mirati switched to the 400mg dose because of toxicity seen with 600mg, execs said during a conference call yesterday. They added that adverse events were similar to those seen with adagrasib monotherapy, and cited gastrointestinal events as being of particular concern, as these side effects can also occur with Keytruda. 

In addition, Mirati’s project has been linked with liver enzyme elevations and QT prolongation, which carries a risk of sudden cardiac death. 

These issues did not appear to faze investors, who sent Mirati’s stock up 6% this morning.  

And, with the 400mg dose, the group said there were no grade 4 or 5 adverse events and no treatment-related discontinuations.  

Mirati’s chances in first-line disease should become clearer with data from the ongoing phase 2 Krystal-7 Keytruda combo trial, which will now focus on the 400mg dose and is stratifying patients by PD-L1 status. 

But Amgen also has a combo readout looming, with data from Codebreak-101 due in the first half of next year (Amgen strikes while its rival is down, November 3, 2021). 

Somewhat counterintuitively, Stifel analysts wondered whether Amgen would be able to find a therapeutic window for Lumakras plus Keytruda, given that drug’s shorter half-life versus adagrasib; they reckon more consistent exposure to drug could help adagrasib “thread the needle” between efficacy and toxicity. Still, Lumakras, at least as monotherapy, appears to have a better side-effect profile than adagrasib so far. 

For now, Mirati has a slight head start in first-line NSCLC. But it has dropped the ball in second-line disease, and the jury is out on whether, and how, it can make any advantage count. 

This story has been amended to clarify that Krystal-7 is the phase 2 adagrasib/Keytruda combo trial.

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