China’s NMPA Accepts sNDA for Savolitinib in Locally Advanced/Metastatic MET Exon 14+ NSCLC

China’s National Medical Products Administration has accepted for review a supplemental new drug application (sNDA) seeking the approval of the selective MET TKI savolitinib (Orpathys) for the treatment of patients with treatment-naive or previously treated locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations.¹ If the sNDA is approved, the new label indication for savolitinib will expand to include previously untreated patients in China.

The sNDA is supported by findings from a confirmatory phase 3b trial (NCT04923945). Preliminary findings from the frontline cohort were presented during the 2023 IASLC World Conference on Lung Cancer, and final data from the trial were presented during the 2024 European Lung Cancer Congress.

The single-arm, multicenter phase 3 trial enrolled patients at least 18 years of age with histologically diagnosed locally advanced or metastatic NSCLC harboring MET exon 14 mutations.² Cohort 1 included patients with intolerable toxicity or disease progression following prior platinum-based chemotherapy. Cohort 2 included patients who had received no prior antitumor therapy for advanced diseases. Patients needed to have measurable lesions per RECIST v1.1 criteria; an ECOG performance status of 0 or 1 or a Karnofsky performance status of at least 80; a life expectancy of over 12 weeks; and adequate liver, bone marrow, and kidney function.

Key exclusion criteria included the presence of gene mutations sensitive to targeted drugs for ALK, EGFR, or ROS1; the presence of other malignant tumors or a history of other infiltrating malignant tumors in the past 5 years; prior exposure to antitumor therapy within 3 weeks prior to the initiation of the study treatment, or prior exposure to small molecule TKIs within 2 weeks prior to initiating the study treatment.

Patients with a baseline weight of at least 50 kg received oral savolitinib at 600 mg once daily on a continuous dosing schedule. Patients with a baseline weight of less than 50 kg received the agent at 400 mg orally once daily. Treatment continued in 21-day cycles until disease progression, intolerable toxicity, death, or other protocol-specified termination criteria, whichever occurred first.

The primary end point was objective response rate (ORR) per RECIST v1.1 criteria. Progression-free survival (PFS) per RECIST v1.1 criteria and the incidence of adverse effects (AEs) served as secondary end points.

In previously untreated patients, the ORR was 62.1% (95% CI, 51.0%-72.3%), the disease control rate (DCR) was 92.0% (95% CI, 84.1%-96.7%), and the median duration of response (DOR) was 12.5 months (95% CI, 8.3-15.2) per independent review committee assessment.¹ The median PFS was 13.7 months (95% CI, 8.5-16.6), and the median overall survival (OS) was not reached (NR) at a median follow-up of 20.8 months.

Among previously treated patients, the ORR was 39.2% (95% CI, 28.4%-50.9%), the DCR was 92.4% (95% CI, 84.2%-97.2%), and the median DOR was 11.1 months (95% CI, 6.6-NR) per independent review committee assessment. The median PFS was 11.0 months (95% CI, 8.3-16.6). At a median follow-up of 12.5 months, the median OS was not mature.

The range of time to response was between 1.4 months and 1.6 months in both the treatment-naive and previously treated patient cohorts.

The safety profile of savolitinib was tolerable, and investigators observed no new safety signals. The most common drug-related, treatment-emergent AEs of grade 3 or higher included abnormal hepatic function (16.9%), increased alanine aminotransferase (14.5%), increased aspartate aminotransferase (12.0%), increased gamma-glutamyltransferase (6.0%), and peripheral edema (6.0%).

In 2021, savolitinib became the first selective MET inhibitor to gain conditional approval in China for patients with NSCLC harboring MET exon 14 skipping alterations who have progressed after prior systemic therapy or are ineligible for chemotherapy.

References

1. HUTCHMED announces savolitinib sNDA accepted in China for treatment-naïve or previously treated patients with locally advanced or metastatic MET exon 14 NSCLC. News release. HUTCHMED. March 28, 2024. Accessed March 28, 2024. https://www.hutch-med.com/savolitinib-china-snda-accepted-ex14-nsclc/
2. Savolitinib for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) patients. ClinicalTrials.gov. Updated September 2, 2021. Accessed March 28, 2024. https://clinicaltrials.gov/study/NCT04923945