Osimertinib is unlikely to have any clinically relevant interaction with CYP3A substrates and has a weak inhibitory effect on BCRP. No new safety concerns were identified in either study.

Background: Most pts with epidermal growth factor receptor mutation-positive (EGFRm) NSCLC treated with osimertinib, a third-generation, irreversible, CNS-active EGFR-tyrosine kinase inhibitor (TKI), eventually develop resistance. MET alterations are common resistance mechanisms to osimertinib. The phase II ORCHARD platform study (NCT03944772) aims to characterise 1L osimertinib resistance mechanisms and identify optimal post-progression therapies. This interim analysis reports use of osimertinib + savolitinib, an oral, potent and highly selective MET-TKI, in adults with EGFRm advanced NSCLC and MET alterations (MET amplification / MET exon 14 skipping).Methods: Pts were allocated to treatment cohorts after disease progression on 1L osimertinib, based on molecular profiling of a tumour biopsy with NGS. Pts whose tumours harbour MET alterations were allocated to osimertinib 80 mg qd + savolitinib 300 or 600 mg qd. Primary endpoint: investigator assessed objective response rate (ORR; RECIST v1.1). Other endpoints include duration of response and safety / tolerability. Interim data cut-off (DCO): Jan 2021.Results: Of 20 pts that received osimertinib + savolitinib, median duration on prior 1L osimertinib was 414 (197e1722) days. At DCO, 17 pts were evaluable for confirmed response. ORR was 41% (n¼7; 80% CI: 25, 59); 7 pts (41%) had partial response, 7 (41%) had stable disease and 1 (6%) had disease progression as their best response; 2 pts (12%) were not evaluable. Overall, 6 / 20 pts (30%) reported a grade 3 adverse event (AE), most commonly pneumonia and decreased neutrophil count (each n¼2; 10%); 6 / 20 pts (30%) reported a serious AE. Three pts (15%) discontinued combination treatment due to AEs. No deaths due to AEs were reported.Conclusions: Osimertinib + savolitinib showed preliminary activity in pts with MET alterations after 1L osimertinib. Based on interim efficacy, enrolment will continue to 30 pts as pre-specified per protocol. The safety profile was acceptable and consistent with known profiles of osimertinib / savolitinib. Further exploration of this combination is underway in the SAVANNAH study (NCT03778229).Clinical trial identification: NCT03944772.

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