As Kras inhibition fast moves away from monotherapy and towards the promise of combinations, Amgen has played up its development plan for Lumakras. The move is a shot across the bow of Mirati, which has promised investors an adagrasib/Keytruda combo update next week, but which is mired in a highly distracting C-suite upheaval.
On a third-quarter call yesterday Amgen said that in the first half of 2022 it would report findings from Lumakras combos with Keytruda and Shp2 inhibition, as well as from its confirmatory phase 3 lung cancer trial. The confirmatory study also has the potential to cause Mirati a major headache.
This is because, despite much hype and a multi-billion dollar market cap, Mirati has still not filed adagrasib, its Kras G12C contender. An accelerated filing for NSCLC is due by the end of 2021, but swift conversion of Lumakras’s own accelerated green light into full approval could scupper Mirati’s chances to get adagrasib approved without controlled phase 3 data.
For now Mirati investors are focused on adagrasib’s potential in colorectal cancer, where data at this year’s Esmo meeting impressed, and where Amgen has deprioritised Lumakras. And first-line NSCLC data for adagrasib in combination with Keytruda, expected along with next Monday’s third-quarter release, are also seen as a way for Mirati to leapfrog its rival.
Still, nothing is known about how much efficacy data Mirati actually plans to provide, or indeed whether it will be possible to parse adagrasib’s contribution from this uncontrolled dataset. Leerink analysts reckon a 50% remission rate with favourable safety and signs of activity in PD-L1-low subjects would suggest a head start for adagrasib against Lumakras in front-line NSCLC.
Among the clinical updates Amgen has promised in the first half of next year are Keytruda/Lumakras combo data in solid tumours, but this phase 1 study does not include first-line patients. Amgen is also planning a first-half update on solid tumours other than NSCLC or colorectal, where so far data on just three subjects have been available.
| Mirati and Amgen's duelling development plans | ||||
|---|---|---|---|---|
| Adagrasib (Mirati) | Lumakras (Amgen) | |||
| Study | Status | Study | Status | |
| ≥2L NSCLC monoRx | Krystal-1 | Esmo21 update, filing due Q4 2021 | Codebreak-100 | Accelerated approval for 2L NSCLC |
| ≥2L colorectal monoRx | Esmo21 update, discussion with FDA expected Q4 2021 | Disappointed at Asco21 | ||
| ≥2L colorectal, EGFR combo | Krystal-10* | Esmo21 data (Erbitux combo) | Codebreak-101 | Esmo21 data (Vectibix combo) |
| Keytruda combo | Krystal-7 | 1L NSCLC update due Q4 2021 | Solid tumour data H1 2022 | |
| Shp2 combo | Krystal-2 | First data (TNO155 combo) H1 2022 | First data (RMC-4630 combo) H1 2022 | |
| Non-NSCLC/colorectal monoRx | – | – | First data H1 2022 | |
| BI 1701963 (Sos1) combo | Krystal-14 | First data H1 2022 | Unclear | Collaboration Sep 2021 |
| 2L NSCLC confirmatory ph3, monoRx vs docetaxel | Krystal-12* | Started Q1 2021 | Codebreak-200* | Data H1 2022 |
| 1L NSCLC (STK11 co-mutation), monoRx | Unclear | Started Q1 2021 | Codebreak-201 | Starting Nov 2021 |
| Note: selected studies only; *phase 3 trial. Source: Mirati, Amgen & clinicaltrials.gov. | ||||
All is by no means lost for Mirati, but the inescapable impression is that, while Amgen has made hay and grabbed a speedy Lumakras approval, Mirati has sat on its hands and presided over a senior management falling-out.
After months of its share price bleeding away value, Mirati unexpectedly appointed David Meek chief executive in September, replacing the founder, Charles Baum. Then two days ago its chief operating officer, Daniel Faga, and chief medical officer, Joseph Leveque, were shown the door. The shares took another 14% hit.
Mirati is still worth nearly $9bn, but investors are desperate for the group to execute, and one hope is that next Monday’s update will also include further clarity on a regulatory filing strategy.
It should also be stressed that while Amgen might be winning the Kras battle it is early days, and numerous other big players are advancing fast. And Amgen has troubles of its own, too: Lumakras may carry 2026 revenue consensus of $2bn, according to Evaluate Pharma, but Bernstein expects biosimilars to erode $13.5bn of the group’s current revenue in 2025-28.
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