ESMO 2024 – Amgen’s PRMT5 still looks lacklustre
So much for hopes that efficacy with Amgen’s PRMT5 inhibitor AMG 193 might have improved. Enthusiasm had been spurred by the presentation's last-minute change to a presidential slot at ESMO, but updated results from the project’s first-in-human study look even worse than the first disappointing cut, at last year’s Triple Meeting. The phase 1/2 trial, in various MTAP or CDKN2A-deleted cancers, has now produced a confirmed ORR of 11% with doses deemed to be active: 800mg and 1200mg daily, and 600mg twice daily. The project previously saw an ORR of 28% at the higher doses tested. Amgen is moving forward with 1200mg once daily; however, there were two dose-limiting toxicities at this dose, of vomiting and hypokalaemia. Combination trials are also ongoing, including one with Ideaya’s MAT2A inhibitor IDE397, and combos might now be the only hope for AMG 193. Amgen’s biggest rival in PRMT5 is Bristol Myers Squibb, via its acquisition of Mirati; that group’s MRTX1719 has produced an ORR of 33% in its phase 1/2 trial. Also active here are Tango Therapeutics, which is set to report phase 1/2 data with TNG462 this year, and AstraZeneca, which took AZD3470 into the clinic last year.
The evolving dataset with AMG 193 in phase 1/2
| Triple Meeting 2023 | ESMO 2024 presentation | |
|---|---|---|
| Cutoff date | 1 Sep 2023 | 23 May 2024 |
| ORR | 14% ORR in 14 patients given 40-1600mg; 28% ORR among 18 patients given ≥800mg | Confirmed ORR with 800, 1200mg QD & 600mg BID: 11% (7/65); NSCLC 12% (2/17), PDAC 9% (2/23), BTC 11% (2/19), E/G 17% (1/6) |
| Safety | 21% serious TEAEs, leading to discontinuation in 6%; 1600mg dose “intolerable” owing to gr3 nausea & fatigue | Gr3 TRAEs 18% with 1200mg QD; 8 DLTs at various doses (2 at 1200mg QD) |
Notes: QD=once daily; BID=twice daily; BTC=biliary tract cancer; E/G=oesophageal/gastric cancer; NSCLC=non-small cell lung cancer; PDAC=pancreatic ductal adenocarcinoma. Source: ESMO & OncologyPipeline.
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