Hutchmed, AZ file Orpathys for lung cancer on ESMO data

Hutchmed and AstraZeneca's Orpathys is now under review in Europe and Japan for MET-driven, EGFR-mutated lung cancer, a few weeks after the drug was filed in the US.

The marketing applications come on the back of results from the SAFFRON trial of MET inhibitor Orpathys (savolitinib) and AZ's EGFR inhibitor Tagrisso (osimertinib) – presented at the ESMO congress last month – which showed that the combination significantly reduced the risk of death by 32% versus chemotherapy in the study, involving patients with non-small cell lung cancer (NSCLC) who had progressed after prior Tagrisso treatment.

The targeted regimen extended median overall survival (OS) by nearly five months to 17.8 months, and also extended progression-free survival (PFS) by 45% to 7.6 months compared to doublet chemo. Alongside their presentation at ESMO, the results were also published in the New England Journal of Medicine.

According to AZ and Hutchmed, SAFFRON was the first global phase 3 trial to show a significant PFS and OS benefit over chemo in this setting, and the results are a "decisive step forward" in targeting MET-driven resistance, which is a longstanding challenge in EGFR-mutated lung cancer.

Around one in three patients with EGFR-mutated lung cancer develop MET mutations after treatment with third-generation EGFR inhibitors like Tagrisso, primarily as an acquired resistance mechanism to escape their therapeutic effects.

Orpathys was originally approved in China in 2021 for treating NSCLC patients whose tumours have MET exon 14 skipping mutations who have previously had systemic treatment or are unable to receive chemotherapy, after showing efficacy in a phase 2 trial in a Chinese patient population.

Its label in China has since been extended to include second-line treatment of MET-driven, EGFR-positive NSCLC, on the strength of the SACHI study, as well as certain forms of MET-amplified advanced gastric or gastroesophageal junction adenocarcinoma. Meanwhile, Orpathys has also been approved in Switzerland for MET-driven, EGFR-positive NSCLC after Tagrisso therapy.

The filings in the US, Europe, and Japan are an attempt to expand Orpathys' role on the international stage and, if approved, the drug would consolidate AZ's position in EGFR-positive lung cancer, where Tagrisso is currently the market-leading therapy.

The two partners are looking at extending the use of the MET inhibitor into the first-line setting as a dual therapy with Tagrisso, and recently reported encouraging topline results from the Chinese SANOVO trial, which showed the combination was better than Tagrisso alone at extending PFS.

Orpathys was discovered by Hutchmed and has been partnered with AZ since 2011. Hutchmed takes the lead on the product in China, with AZ responsible elsewhere for development and regulatory activities elsewhere, along with having global commercial rights.

The UK-headquartered group also extended its position in the sector recently by taking a global license to Dizal's Zegfrovy (sunvozertinib), an irreversible EGFR inhibitor which is approved in China and the US as a second-line treatment for adults with locally advanced or metastatic NSCLC with exon 20 insertion mutations who have previously had platinum-based chemo.