Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+).

Abstract

9519 Background: There are unmet medical needs for pts with METex14+ NSCLC. PSC is a rare type of NSCLC with high incidence of MET exon 14 mutations and poor prognosis. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective oral MET tyrosine kinase inhibitor, and its anti-tumor activity has been shown in combination with osimertinib in pts with EGFR-mutant, MET-amplified NSCLC (Yu H, et al. 2019 AACR, Abstract CT032). Methods: This was a multicenter, multi-cohort, single-arm phase II study (NCT02897479) to evaluate the efficacy, safety, and pharmacokinetics of savolitinib in pts with unresectable or metastatic METex14+ PSC and other NSCLC. MET mutation was tested or retrospectively confirmed by central laboratory. Savolitinib was taken orally, once daily (QD) (600mg for weight ≥50kg or 400mg weight < 50kg) until disease progression or intolerable toxicity. Tumor was evaluated every 6 weeks during the 1st year and every 12 weeks thereafter. The primary endpoint was independent review committee (IRC) assessed objective response rate (ORR) (RECIST version 1.1). Here we report the results of one cohort of prior MET-treatment naïve patients. Results: As of October 31, 2019, 593 pts were pre-screened/screened, 87 identified with METex14+ and 70 treated. Among treated pts, median age was 68.7 years (range 51.7-85.0), 58.6% pts were male, 92.9% stage IV, 60.0% previously treated, 57.1% with adenocarcinoma, 35.7% with PSC and the rest with other pathological types. Sixty-one pts were efficacy evaluable by IRC assessment (N = 61) (including pts who had at least one measurable lesion at baseline and had ≥1 scheduled post-baseline tumor assessment or evidence of any post-baseline radiological disease progression): ORR was 47.5% (95% CI: 34.6%, 60.7%), disease control rate 93.4% (95% CI: 84.1%, 98.2%) and median duration of response not reached yet. The median progression-free survival was 6.8 months (95% CI 4.2, 13.8) among all treated pts. Efficacy results were consistent with investigators’assessments. The most common (≥20%) treatment-related adverse events (TRAEs) were peripheral edema, nausea, increased AST/ALT, vomiting and hypoalbuminemia. The incidence of ≥ grade 3 TRAEs was 41.4%. TRAEs leading to treatment discontinuation occurred in 14.3% pts, among which liver injury and hypersensitivity were most common (each 2.9%). Conclusions: Savolitinib demonstrated promising anti-tumor activity and acceptable tolerability in METex14+ NSCLC pts. Clinical trial information: NCT02897479 .

New Verse for a Familiar Song: Small Molecule Inhibitors for MET exon 14 Skipping Non-Small Cell Lung Cancer

“…Most recently, savolitinib demonstrated similar efficacy in a phase II trial conducted in China for patients with METex14 NSCLC. The reported ORR was 47.5% (95% CI, 34.6–60.7), the DCR was 93.4%, and the median PFS was 6.8 months ( n = 61) [10]. These results together unequivocally demonstrated that METex14 is an actionable driver oncogene in NSCLC with valid targeted‐therapy options.…”

Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors

“…If the preliminary clinical efficacy seen for type-I inhibitors such as savolitinib in settings where cMET plays a key role as a tumor driver 17 or resistance driver 10,11 is confirmed in further clinical studies, then the molecular understanding of clinically acquired resistance mechanisms such as that described here for D1228V cMET will become important areas of future clinical research.…”

“…Savolitinib is an exquisitely selective cMET inhibitor, 14 which has recently shown promising safety and antitumor activity in the clinic. 10,11,17 However, as found with all therapies in the advanced NSCLC setting, patients ultimately develop therapeutic resistance. Resistance mechanisms can be described as on-target, preventing drug binding, or bypass, where the tumor cell has established an alternative proliferative drive that overcomes target inhibition.…”

The METeoric rise of MET in lung cancer

“…Toxicity was in keeping with that of other MET inhibitors. 37 Numerous MET-targeting agents currently are in early-phase trials, including TKIs, antibodies, bispecific antibodies, and drug-antibody conjugates (Table 1). 32,34,36,[38][39][40][41][42][43] Attempts have been made to combine TKIs with ICIs for the treatment of NSCLC.…”

“…The ORR was 47.5% (95% CI, 34.6%‐60.7%), with a median DOR that had not yet been reached at the time of last follow‐up and a median PFS of 6.8 months (95% CI, 4.2‐13.8 months). Toxicity was in keeping with that of other MET inhibitors 37 . Numerous MET‐targeting agents currently are in early‐phase trials, including TKIs, antibodies, bispecific antibodies, and drug‐antibody conjugates (Table 1).…”