AstraZeneca shores up its Tagrisso defences
The Hutchmed-originated savolitinib moves towards its first US approval.
The Hutchmed-originated savolitinib moves towards its first US approval.
AstraZeneca has been defending its kinase inhibitor Tagrisso against Johnson & Johnson’s Rybrevant in EGFR-mutant NSCLC, and its next efforts could involve the Hutchmed-originated cMet inhibitor savolitinib.
The companies on Wednesday toplined a win in the global phase 2 Savannah trial, testing savolitinib plus Tagrisso in post-Tagrisso patients. Detailed results aren’t yet available, but assuming that they stand up to scrutiny a US accelerated approval filing could follow later this year, based on comments previously made by Hutchmed.
Savolitinib already has conditional approval in China – where it’s branded Orpathys – in second-line NSCLC patients with Met exon 14 skipping alterations. Hutchmed is also seeking the go ahead there in first-line disease. These de novo mutations are seen in around 3-4% of NSCLC.
Resistance
Savannah, meanwhile, enrolled patients with EGFR mutations and Met amplification or overexpression, who had previously received Tagrisso.
Tagrisso is approved for first-line EGFR-mutant NSCLC, both with and without chemotherapy, and Met alterations are a key resistance mechanism. The hope, therefore, is that combining savolitinib with Tagrisso could help overcome this resistance.
One question is how broadly savolitinib might be used: Astra and Hutchmed said that, among patients screened for Savannah, 62% had Met overexpression and/or amplification, with 34% having high levels, defined as IHC90+ and/or FISH10+.
However, the partners only specified that a “high, clinically meaningful and durable” objective response rate was seen in those with high levels of Met aberrations.
This appears to be backed up by early data from Savannah, reported at the World Lung meeting in 2022: across all 193 patients (IHC50+ and/or FISH5+) ORR was 32%, rising to 49% in the IHC90+ and/or FISH10+ subgroup.
A confirmatory global trial in the same setting, Saffron, is ongoing; here patients are being selected using the high Met cutoff, and data are expected next year. Hutchmed also has various trials under way in China, including a first-line study, Sanovo.
Savolitinib’s registrational studies in NSCLC
| Trial | Location | Setting | Regimen | Note |
|---|---|---|---|---|
| Savannah | Global | 2nd/3rd-line, post-Tagrisso, EGFRm, Met amplified/overexpressed | Savolitinib + Tagrisso, vs savolitinib + placebo | First results at WCLC 2022; toplined positive Oct 2024; NDA filing planned in 2024 |
| Saffron | Global | 2nd/3rd-line, post-Tagrisso, EGFRm, Met amplified/overexpressed (high) | Savolitinib + Tagrisso, vs chemo | Data expected H2 2025 |
| China confirmatory trial | China | 1st/2nd-line, Met exon 14 mutations | Savolitinib, uncontrolled | Data at WCLC 2023; China sNDA accepted Mar 2024 |
| Sachi | China | 2nd-line, post-EGFR TKI, EGFRm, Met amplified | Savolitinib + Tagrisso, vs chemo | Enrolment to complete YE 2024 |
| Sanovo | China | 1st-line, EGFRm, Met overexpressed | Savolitinib + Tagrisso, vs placebo | Primary completion Nov 2024 |
Note: global trials sponsored by Astra, China trials sponsored by Hutchmed. Source: OncologyPipeline & Hutchmed July 2024 presentation.
If savolitinib is approved in the US it could go up against J&J’s anti-EGFR x cMet MAb Rybrevant, which recently got the FDA nod in second-line EGFRm NSCLC, as part of a chemo combo, backed by the Mariposa-2 trial.
For Rybrevant Met mutation testing isn’t necessary, working in J&J’s favour; however, Rybrevant plus chemo was described as “toxic and expensive” at the ESMO meeting last month.
Still, J&J believes that Rybrevant is one of its most underappreciated assets, and that it could become a $5bn drug. Investors should soon get a sense of whether the product can live up to these lofty expectations: J&J plans to start disclosing Rybrevant sales in the first quarter of 2025.
Other cMet-targeting projects are also in development, including AbbVie’s ADC telisotuzumab vedotin, recently filed in Met-overexpressing disease – although, unlike Astra and Hutchmed, that group is taking aim at EGFR wild-type disease.
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