Resistance to the combination of osimertinib plus savolitinib is predominantly mediated by acquired mutations in either MET, EGFR, or KRAS in patients with EGFR-mutated metastatic non–small-cell lung cancer (NSCLC).
Up to 22% of patients with EGFR mutation–positive non–small-cell lung cancer (NSCLC) after progression on osimertinib have a MET amplification as a resistance mechanism.1 In the expansion cohorts (parts B and D) of the phase 1b TATTON study, patients with MET-amplified EGFR-mutated advanced NSCLC who progressed on a prior EGFR tyrosine kinase inhibitor (TKI) received osimertinib (80 mg) plus savolitinib (300 mg or 600 mg once daily). Osimertinib is a third-generation, irreversible, oral EGFR TKI. Savolitinib is an oral highly selective MET TKI.
The part B group of TATTON was split into 3 cohorts by prior therapy and tumor T790M status. Patients in part D had not received a third-generation EGFR TKI and were T790M negative. For patients who eventually develop resistance to the osimertinib plus savolitinib combination, it is not known which driver mutation(s) mediate this resistance.1
In the analysis presented at the American Association of Cancer Research Annual Meeting 2021, researchers assessed paired plasma samples (collected at baseline) upon disease progression and/or treatment discontinuation up to a data cutoff date (March 4, 2020). Next-generation sequencing using either Guardant Health (Guardant360 73-gene panel) or Omni 500-gene panel was used to analyze the plasma ctDNA samples. All 73 genes on the Guardant360 panel were included in the Omni 500-gene panel. Analyses from each patient were reported only for genes included across the panels used. Genomic alterations were identified using Guardant Health’s pipeline, which included mutations and amplifications of EGFR and MET.1
Disease progression was assessed by the investigator, according to RECIST version 1.1. Assessments were completed for patients with progression-free survival (PFS) of >2 months.1
Of 180 patients who received treatment with osimertinib plus savolitinib, 70 provided plasma samples at baseline and at progression or discontinuation. Of these, 45 patients were used for the analysis: 18 of 70 were not evaluable for ctDNA detection and 7 of 70 had a PFS of ≤2 months.1
Among evaluable samples, the following acquired mutations were recorded with exclusivity between genes in most patients: MET D1228X, Y1230X, L1212X – 20% (9 of 45); EGFR C797X – 16% (7 of 45); KRAS G12X, G13X – 11% (5 of 45); PIK3CA E545K – 4% (2 of 45).1
Seven of 9 patients who developed MET-based resistance developed more than 1 MET mutation, suggesting polyclonal resistance. Across both parts B and D, the resistance profiles appeared similar by prior EGFR-TKI status and by savolitinib dose.1
In this analysis, approximately half of all evaluable patients had an identifiable acquired resistance mechanism. Resistance to osimertinib plus savolitinib appeared to be predominantly mediated by either MET, EGFR, or KRAS. Co-occurring mutations across multiple genes were rare. However, multiple acquired mutations were often detected in a specific gene, particularly MET, which suggests to researchers that individual tumors showed inherent resistance dependencies.1
1. Markovets A, Han J-Y, Cho BC, et al. Acquired resistance in patients with EGFRm NSCLC following treatment with osimertinib plus savolitinib in the Ph1b TATTON study Parts B and D. Presented at: American Association of Cancer Research Annual Meeting 2021; April 10-15, 2021. Abstract CT024.