Change in Longitudinal Level of EGFR ctDNA May Predict Benefit of Savolitinib Plus Osimertinib in NSCLC Patient Subset

Clearance of EGFR-mutant circulating tumor DNA (ctDNA) was associated with longer progression-free survival (PFS) in patients with EGFR-tyrosine kinase inhibitor (TKI)–pretreated advanced non-small cell lung cancer (NSCLC) characterized by an EGFR-sensitizing mutation and evidence of MET amplification who were treated with the combination of savolitinib and osimertinib. These findings were presented at the American Association of Cancer Research (AACR) Virtual Annual Meeting II.¹

For patients with advanced EGFR-mutant NSCLC, acquired resistance to EGFR-targeted therapy associated with modifications in MET related to MET amplification or other MET-based mechanisms has been reported in up to 10% of patients treated with a first- or second-generation EGFR-TKI, and up to 25% of those receiving a third-generation EGFR-TKI, respectively.²

In the phase 1b TATTON study (ClinicalTrials.gov Identifier: NCT02143466), the combination of the oral c-MET inhibitor, savolitinib, and the third-generation EGFR-TKI, osimertinib, was studied in several cohorts of patients with advanced NSCLC and disease progression on an EGFR-TKI that was characterized by either MET amplification according to next-generation sequencing or fluorescence in situ hydridization, or MET overexpression on immunohistochemistry. Osimertinib, a third-generation EGFR-TKI, has previously been shown to be active in advanced EGFR-sensitizing mutation-positive NSCLC, such as disease characterized by EGFR del 19 or EGFR L858R, as well as disease characterized by an EGFR T790M resistance mutation.²

A previous report of an interim analysis of results of the TATTON study, which had a primary endpoint of safety and tolerability, was consistent with the acceptable risk-benefit profile and promising antitumor activity found for the combination of savolitinib and osimertinib in this population of patients.²

In this post-hoc analysis, longitudinal measurements of ctDNA were investigated in dose-expansion cohorts B and D of the TATTON study. Cohort B consisted of 3 prespecified subcohorts characterized by pretreatment with a third-generation EGFR-TKI (B1), pretreatment with a first-/second-generation EGFR-TKI, and either EGFR T790M-negative (B2) or -positive disease (B3), respectively. Most patients in cohort B received savolitinib (600 mg) plus osimertinib (80 mg) with the remaining patients treated with 300 mg savotitinib and 80 mg of osimertinib. Those patients included in cohort D had the same disease characteristics as cohort B2 but received 300 mg of savolitinib in combination with 80 mg of osimertinib.¹

Objective response rates (ORR) and median PFS were 30% and 5.4 months for subcohort B1 where patients had been previously exposed to a third-generation EGFR-TKI. In contrast, for patients without prior treatment with a third-generation EGFR-TKI, these efficacy findings were 65% and 9 months for subcohort B2, 67% and 11 months for subcohort B3, and 64% and 9.1 months for patients in cohort D.¹

Of the 49 patients in cohort B treated with 600 mg savolitinib and 80 mg osimertinib who were evaluable for efficacy at data cutoff (B1:24; B2: 20; B3:5), 38 (79%) had at least 1 longitudinal ctDNA measurement at the start of cycle 3 or 4, and 34 (69%) had both detectable ctDNA at baseline and a ctDNA measurement at the start of cycle 3/4. Similarly, at data cutoff, 20 patients in cohort D were evaluable for efficacy with a ctDNA measurement at the start of cycle 4, and baseline ctDNA was detectable in 16 (80%) of these patients.¹

A key study finding was that most patients responding to treatment with the combination of savolitinib and osimertinib showed a large percentage decrease in the allele frequency of EGFR-sensitizing mutations measured at the start of cycle 3 or cycle 4 compared with baseline.¹

Specifically, for the 34 patients in cohort B with both detectable ctDNA at baseline and a ctDNA measurement at the start of cycle 3/4, the median PFS for those showing ctDNA clearance was 9.1 months compared with 3.4 months for those without ctDNA clearance (hazard ratio [HR], 0.34; 95% CI, 0.14-0.81; P =.0148).

In addition, the ctDNA clearance rate (cycle 3/4 compared with baseline) for evaluable patients in cohorts B2 and D were 50% and 65%, respectively.¹

The study authors concluded that these results support use of the lower dose of savolitinib in combination with osimertinib, and suggest that clearance of EGFR ctDNA over time may correlate with PFS in patients with EGFR-mutant advanced NSCLC characterized by MET amplification.¹ 

Disclosures: Research funding was provided for this study by AstraZeneca. For a full list of disclosures, please refer to the original study.

References

1. Hartmaier R, Han J-Y, Ahn M-J, et al. The effect of savolitinib plus osimertinib on ctDNA clearance in patients with EGFR mutation positive (EGFRm) MET-amplified NSCLC in the TATTON study. Presented at: American Association of Cancer Research (AACR) Virtual Annual Meeting II. June 22-24, 2020. Abstract CT303.
2. Sequist LV, Han J-Y, Ahn J-M, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: Interim results from a multicentre, open-label, phase 1b study. Lancet Oncol. 2020;21:373-386.