Esmo 2022 – Mirati needs some colorectal cancer urgency

Adagrasib data hold up, but filing timelines are still unclear.

This time last year it looked like colorectal cancer could be Mirati’s golden ticket in its ongoing Kras battle with Amgen. At this year’s Esmo meeting, the biotech again outdid its bigger rival – but it is still no clearer when Mirati’s lead project, adagrasib, will be filed in this setting.

The group has pledged to “provide additional clarity” on its colorectal cancer regulatory strategy later this year, but this is a long overdue promise. Discussions with the FDA over colorectal cancer were to have taken place by the end of 2021, and an update on filing plans was then promised in the first half of 2022. Mirati’s investors will have to hope that this will not end up being another case of good data being let down by poor execution.

Adagrasib and Amgen’s Lumakras are not the only Kras contenders taking aim at colorectal cancer, with phase 1 results on Roche’s GDC-6036 also due to be presented at Esmo. The overall response rate outlined in an abstract looks promising, and with a later cut of the data including more patients likely to emerge at the conference, it will be interesting to see if this holds up.

Krystal clear?

For now, though, Mirati appears to have the edge in late-line colorectal cancer patients with a Kras G12C mutation. Data just unveiled in a late-breaking abstract come from Krystal-1, which tested both adagrasib monotherapy and an Erbitux combo.

The results look similar to last year’s update on the same trial (Esmo 2021 – colorectal cancer could be Mirati’s golden ticket, September 17, 2021).

The adagrasib/Erbitux combo still looks better than a combination of Lumakras and Vectibix, updated results on which will also be available at Esmo. Amgen has deprioritised Lumakras monotherapy in colorectal after disappointing results.

Cross-trial comparison of Kras inhibitors in colorectal cancer
Project (company) Adagrasib (Mirati) Lumakras (Amgen) GDC-6036 (Roche)
Trial Krystal-1 Codebreak-101 NCT04449874
Cutoff Jun 16, 2022 Mar 25, 2022 Jan 28, 2022
  Adagrasib mono Adagrasib + Erbitux Lumakras + Vectibix GDC-6036 mono
Median prior therapies 3 3 2 3
ORR 19% (8/43) 46% (13/28) 30% (12/40) 20% (8/41)
All TRAEs - - 93% -
Grade 1/2 TRAEs 59% 84% - -
Grade 3/4 TRAEs* 34% 16% 23%** -
*No grade 5 AEs seen; **no grade 4 AEs seen. Source: Esmo abstracts LBA24, 315O & poster 362P.

Elsewhere, monotherapy data with GDC-6036 appear in line with solo adagrasib, and act as another reminder that the Kras space is getting crowded.

Still, efficacy is not the only consideration with Kras projects, with toxicity also high on the agenda, especially after liver enzyme elevations were recently seen with Lumakras and PD-(L)1 inhibitors in lung cancer.

The Esmo abstracts do not give a breakdown of adverse events, so it will be worth keeping an eye on these when the data are presented over the weekend.

As for future plans, Amgen is enrolling into a phase 3 trial of the Lumakras/Vectibix combo, Codebreak-300, in third-line disease, and this is due to complete next year.

Mirati, meanwhile, has said that an accelerated approval for late-line colorectal cancer could be on the cards, although it has been promising an update here for some time. The group expects full approval to be supported by the second-line Krystal-10 trial, testing an adagrasib/Erbitux combo against chemo.

The Esmo conference takes place in Paris on September 9-13. A recording of a discussion between Jacob Plieth and the biotech investor Brad Loncar about the meeting's themes is available below:

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