Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor-Mutated, MET-Amplified Non-Small Cell Lung Cancer: TATTON

Abstract

MET-inhibitor and EGFR tyrosine kinase inhibitor (EGFR-TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final phase Ib TATTON (NCT02143466) analysis (Part B, n = 138/Part D, n = 42) assessing oral savolitinib 600 mg/300 mg once daily (q.d.) + osimertinib 80 mg q.d. in patients with MET-amplified, EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An acceptable safety profile was observed. In Parts B and D, respectively, objective response rates were 33% to 67% and 62%, and median progression-free survival (PFS) was 5.5 to 11.1 months and 9.0 months. Increased antitumor activity may occur with MET copy number ≥10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib + savolitinib were mediated by MET, EGFR, or KRAS alterations.

Significance: The savolitinib + osimertinib combination represents a promising therapy in patients with MET-amplified/overexpressed, EGFRm advanced NSCLC with disease progression on a prior EGFR-TKI. Acquired resistance mechanisms to this combination include those via MET, EGFR, and KRAS. On-treatment ctDNA dynamics can predict clinical outcomes and may provide an opportunity to inform earlier decision-making. This article is highlighted in the In This Issue feature, p. 1.

Figure 1.

A, Waterfall plot of best percentage change from baseline in target lesion size. B, Kaplan–Meier estimates of PFS for Part B subcohort B1 (evaluable response set).

Figure 2.

ctDNA clearance at C3 D1/C4 D1 in patients with baseline detectable ctDNA (Part B; n = 68). A, Kaplan–Meier estimates of PFS in patients with ctDNA clearance and nonclearance. B, Waterfall plot of best percentage change from baseline in ctDNA. mPFS, median progression-free survival.

Figure 3.

EGFRm allele frequency with and without detectable MET amplification via ctDNA NGS (A; n = 68); baseline genomics analysis (B); and an overview of baseline genomics in all patients with samples assessed in acquired resistance analysis (C), patients who had previously received third-generation EGFR-TKI (Part B1; D), and patients who had not previously received third-generation EGFR-TKI and were T790M-negative (Parts B2 and D combined; E). amp, amplification; BOR, best objective response; CNSR, censor; ex19del, exon 19 deletion; mut, mutant; sensit, sensitizing.F, Detailed breakdown of acquired resistance mutations in all patients. Patients who had not previously received third-generation EGFR-TKI and were T790M-positive (Part B3): no candidate resistance mechanism (n = 3), EGFR C797X, L718Q, G724S (n = 1). Due to small numbers, these data were not included as a figure. ^aTwo independent genotypes resulting in C797S.