Acquired Resistance to Osimertinib Plus Savolitinib Is Mediated by MET-D1228 and MET-Y1230 Mutations in EGFR-Mutated MET-Amplified Lung Cancer

Introduction

MET gene amplification is an established mechanism of acquired resistance to all classes of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated lung cancer. Novel strategies to target EGFR-mutated MET-amplified tumors in clinical trials have reported promising results, with a clear activity of the combination of osimertinib and savolitinib reported from the TATTON trial (NCT02143466) in 2020.¹ Savolitinib is a type IB–selective MET kinase inhibitor in the same class as capmatinib and tepotinib (Table 1).^2,3 There is a paucity of data on the mechanisms of acquired resistance to combination therapy with osimertinib and savolitinib. Here, we report a case of EGFR-mutated and MET-amplified lung adenocarcinoma that developed resistance to a combination therapy of osimertinib and savolitinib owing to MET-dependent mechanisms. The clinical, genomic, radiographic, and retrospective outcome data used for this case report have been compiled under an ongoing institutional review board–approved protocol at our institution with an appropriate waiver of consent.

Table 1.

MET TKI Activity Against MET Wild-Type and Activating Loop Mutations

Type	Name	MET Wild-Type	MET-D1228H	MET-D1228N	MET-D1228V	MET-Y1230C	MET-D1230H
Ia	Crizotinib	Sensitive	Resistant	Resistant	Resistant	Resistant	Resistant
Ib	Savolitinib	Sensitive	Resistant	Resistant	Resistant	Resistant	Resistant
Ib	Capmatinib	Sensitive	Resistant	Resistant	—	Resistant	Resistant
II	Cabozantinib	Sensitive	—	Sensitive	Sensitive	—	Sensitive
II	Glesatinib	Sensitive	Sensitive	Sensitive	—	Sensitive	Sensitive

Note: References numbers 2 to 6 were used to generate the modified heat map. Green indicates sensitivity whereas red indicates resistance, with the intensity of color indicating higher or lower preclinical inhibitory patterns. —, indicates data not available.

TKI, tyrosine kinase inhibitors.

Case Presentation

A 61-year-old Asian man with a previous 5-pack-year history of smoking initially presented with early stage node-positive lung adenocarcinoma. After initial management with lobectomy and adjuvant platinum doublet chemotherapy, within 1 year he developed widespread metastatic recurrence harboring EGFR delL747_T751 mutation. He was treated with oral erlotinib daily for 14 months before developing disease progression in his liver. Targeted biopsy revealed metastatic lung adenocarcinoma with EGFR-delL747_T751 (exon 19 deletion) and MET amplification (FoundationOne, Foundation Medicine). The MET:centrome_probe_SE7 ratio was 7.73 (cMET FISH Kreatech assay, Integrated Genetics, LabCorp), confirming high-level amplification.

Suspecting MET amplification as the mechanism of resistance to the EGFR TKI, he was transitioned to oral osimertinib 80 mg daily in combination with oral savolitinib 300 mg daily under the clinical trial TATTON;¹ he achieved partial response for 18 months before developing progressive disease (Fig. 1). Tissue biopsy confirmed adenocarcinoma, and next-generation sequencing of circulating tumor DNA (FoundationOne Liquid, Foundation Medicine) revealed EGFR-delL747_T751 mutation (allele frequency [AF] 3.3%), lack of EGFR-T790M and EGFR-C797S, MET amplification, and MET mutations (D1228H AF 15.6%, D1228N AF 1.8%, D1228Y AF 1.6%, and Y1230C AF 0.98%). Off-label oral cabozantinib 60 mg daily was added to oral osimertinib 80 mg daily in an effort to target these MET mutations (Table 1). Although he achieved stable disease (Fig. 1), he developed considerable fatigue, gastrointestinal toxicity, and cytopenias on dual-inhibitor therapy, thus requiring cessation of cabozantinib. A repeat liquid biopsy revealed the original truncal EGFR mutation, MET amplification, and the known MET-D1228X mutations (Fig. 1). He was continued on osimertinib but died after 3 months.

Figure 1.

The clinical, radiographic, and genomic course of EGFR-mutant NSCLC with MET-mediated resistance before, during, and after osimertinib plus savolitinib therapy. Graphical representation of RECIST target lesion measurements in percentage (baseline set at 100% at the time before the commencement of osimertinib plus savolitinib) over the course of therapy. Noted are different types of kinase inhibitors targeting EGFR (erlotinib and osimertinib) or targeting MET (savolitinib and cabozantinib). The results of tissue-based and liquid biopsy–based comprehensive genomic profiling results are highlighted in accordance with the course of therapy. The tissue-based comprehensive genomic profiling test (FoundationOne) at the time of erlotinib resistance also revealed additional genomic aberrations, including TP53 N239I, FGF14 amplification, and IRS2 amplification. The liquid biopsy–based (FoundationOne Liquid) tests after osimertinib and savolitinib also identified the TP53 N239I mutation. EGFR-del19 indicates EGFR exon 19 deletion (delL747_T751). The left white arrow indicates previous periods of erlotinib use; ∗ indicates the time of death. A note is made that this occurred during the COVID-19 pandemic in Massachusetts and no autopsy or SARS-CoV-2 testing was performed. COVID-19, coronavirus disease 2019; RECIST, Response Evaluation Criteria in Solid Tumor; SARS-CoV-2, severe acute respiratory syndrome-coronavirus-2.

Discussion

MET amplification is a frequently observed (5%–20% of cases) mechanism of resistance to EGFR TKIs. The EGFR plus MET coinhibition strategy of osimertinib plus savolitinib is undergoing final regulatory approval for EGFR-mutated plus MET-amplified advanced lung cancer in the SAVANNAH trial (NCT03778229). Resistance to combined EGFR and MET inhibition is poorly understood but can be expected to occur should this strategy gain wide appeal. Our report highlights MET-dependent resistance mechanisms (rather than EGFR-dependent mechanisms) mediated by MET kinase mutations in a pattern similar to the one seen in a previous case report.⁴ Single-agent savolitinib has been associated with MET-D1228X and Y1230X resistance mutations in other MET-amplified tumor types.⁵ Cabozantinib is a multikinase type II MET kinase inhibitor with putative preclinical activity against type I MET inhibitor resistance mutations, including MET-D1228X and Y1230X activation loop mutations (Table 1)^4,6 and offers a potential treatment strategy as seen in a previous case treated with oral erlotinib 100 mg daily plus oral cabozantinib 60 mg daily⁴ but has significant toxicity that may limit widespread combinatory use as seen in our case report. Understanding the true frequency of MET mutations as a mechanism of resistance to osimertinib plus savolitinib will help define the need to develop novel MET inhibitors with broader activity against MET mutations and additional therapies to delay or prevent the heterogeneity of on-target and off-target resistance to EGFR TKIs.