Esmo IO – Mirati struggles to keep the first-line dream alive

 When it comes to adagrasib's chances in the potentially lucrative first-line lung cancer setting, Mirati still has some convincing to do. Amgen set a low bar earlier this year at World Lung: adding its rival Kras inhibitor, Lumakras, to checkpoint inhibition came with worrying levels of liver toxicity and a meagre 29% overall response rate. Standard-of-care Keytruda presents a much bigger challenge, and topline data in an abstract, released ahead of a full presentation at the Esmo Immuno-Oncology conference tomorrow, point to adagrasib coming up short. SVB analysts described a 49% ORR for adagrasib plus Keytruda as “relatively modest” and in-line with Keynote-189, which tested the Merck & Co MAb plus chemo. Adagrasib needs to do much better for any hope of justifying front-line usage; Stifel analysts described a 56% ORR generated in six patients treated for more than six months as “trending in the right direction”. Responses stratified by patients’ PD-L1 expression levels will be scrutinised tomorrow, and perhaps point to a way forward. Mirati plans to launch a phase 3 trial in patients with low PD-L1 expression “soon”, according to Reuters. But with Mirati shares opening down 17%, it seems the market was expecting a lot more.

Cross-trial comparison of combination first-line non-small cell lung cancer trials
	ORR	ORR in TPS >50%	ORR in TPS 1-49%	ORR in TPS<1%
Krystal-7 (ph2, adagrasib + Keytruda)	49% (26/53)*	?	?	?
Krystal-1 (ph1b portion, adagrasib + Keytruda)	57% (4/7)**	?	?	?
Keynote-189 (ph3, Keytruda + chemo)	48% (184/387)***	61%	48%	32%
*In patients with at least one on-study scan, median treatment duration two months, includes 5 unconfirmed partial responses. **median follow-up 19.3 months. ***median follow-up 10.5 months Source: Esmo-IO 2022 abstract, NEJM Gandhi et al, 2018. https://www.evaluate.com/vantage/articles/events/conferences-snippets/esmo-io-mirati-struggles-keep-first-line-dream-alive