Osimertinib Plus Savolitinib Exhibits Clinically Meaningful ORR vs Osimertinib in EGFR+ NSCLC

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The combination of osimertinib (Tagrisso) and savolitinib demonstrated a clinically meaningful improvement in objective response rate (ORR) compared with osimertinib monotherapy as first-line therapy in patients with de novo MET-aberrant, EGFR-mutant advanced non–small cell lung cancer (NSCLC), according to data from the phase 2 FLOWERS trial (NCT05163249) presented at the 2024 IASLC World Conference on Lung Cancer.¹

At a data cutoff date of May 28, 2024, with a median follow-up of 8.2 months, the ORR was 90.5% (95% CI, 69.6%-98.8%) in the combination arm (n = 21) vs 60.9% (95% CI, 38.5%-80.3%) in the osimertinib monotherapy arm (n = 23). In the combination arm 19 patients (90.5%) achieved partial response (PR), 1 (4.8%) achieved stable disease (SD), and 1 (4.8%) had progressive disease (PD). In the monotherapy arm 14 patients (60.9%) achieved PR, 6 (26.1%) achieved stable disease (SD), and 3 (13.0%) had progressive disease (PD). The disease control rate (DCR) was 95.2% (95% CI, 76.2%-99.9%) and 87.0% (95% CI, 66.4%-97.2%) in the osimertinib/savolitinib and osimertinib monotherapy arms, respectively.

“Patients on osimertinib plus savolitinib [were] showing deeper and more durable responses over the study for a while,” Jin-Ji Yang, MD, of Guangdong Lung Cancer Institute at the Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences) at the Southern Medical University in Guangzhou, China, said during the oral presentation.

Preclinical studies have shown that the coexistence of amplified or overexpressed MET and EGFR mutations reduce the sensitivity to EGFR TKIs, which are likely a significant mechanism in mediating primary resistance to first-line EGFR TKI monotherapy.

The phase 2 FLOWERS trial is a prospective, open-label, two-cohort, randomized, multicenter clinical trial based in China. In total, 44 patients were randomized 1:1 to receive 80 mg of osimertinib once daily or the same dose of osimertinib plus 300 mg of savolitinib twice daily. Patients were treated until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Of note, patients in the osimertinib monotherapy arm were allowed to cross over to the osimertinib/savolitinib arm if they experienced progression and were confirmed to have MET-aberrant/positive disease after first-line treatment. MET-aberrant/positive disease was defined by MET overexpression by immunohistochemistry 3+ in 75% or more of tumor cells and/or MET amplification by fluorescence in situ hybridization, with MET GCN of 5 or more or a MET/CEP7 ratio of 2 or more, or by tissue next-generation sequencing (NGS) MET CN of 5 or more.

Eligibility criteria required patients with histologically confirmed, locally advanced or metastatic NSCLC, who were treatment-naive for advanced disease, and had a documented EGFR sensitizing mutation, ECOG performance status of 0 or 1, and MET-aberrant/positive disease, as well as adequate organ function.

The primary end point was confirmed ORR assessed by investigators per RECIST v1.1; secondary end points included DCR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety and tolerability. Exploratory end points included the ORR of patients who crossed over from the osimertinib monotherapy arm to the osimertinib/savolitinib arm after progressive disease; resistance mechanisms; and the correlation of dynamic genetic variation and/or circulating tumor DNA (ctDNA) clearance with treatment response.

Additional results demonstrated that patients who were treated with osimertinib/savolitinib showed deeper and more durable responses throughout the study follow-up. Specifically, the median best reduction in tumor size was –47.7% (range, –65.9% to –38.7%) vs –42.2% (range, –58.0% to –27.9%) in the osimertinib/savolitinib and osimertinib monotherapy arms, respectively. The respective median follow-ups were 8.5 months (range, 5.5-11.4) and 7.8 months (range, 6.0-9.6); the median DOR was 18.6 months (95% CI, not reached [NR]-not estimable [NE]) and 8.4 months (95% CI, 6.6-NE), respectively.

Preliminary data for PFS demonstrated a trend favoring the osimertinib/savolitinib arm vs the osimertinib monotherapy arm. The median PFS was 53.4 months (95% CI, 10.2-NE) vs 9.5 months (95% CI, 7.4-NE) in the respective arms (HR, 0.80; 95% CI, 0.19-1.51).

Both treatment arms were tolerated and manageable, with grade 3 or higher treatment-related adverse effects (TRAEs) occurring in 57.1% and 8.7% of patients receiving osimertinib/savolitinib and osimertinib monotherapy, respectively. Treatment-emergent AEs (TEAEs) of any grade occurred in all patients in both arms; however, 15 (71.4%) and 6 (26.1%) patients experienced grade 3 or higher TEAEs in each respective arm. Of note, TEAEs leading to dose reduction only occurred in 5 patients (23.8%) in the combination arm; 5 patients (23.8%) experienced TEAEs leading to permanent discontinuation of treatment in the combination arm. No TEAEs led to death in any arm.

The most common TRAEs included rash (52.4%), thrombocytopenia (38.1%), peripheral edema (33.3%), and alanine aminotransferase increase (23.8%) in the combination arm vs diarrhea (56.5%), rash (52.2%), and pruritus (43.5%) in the osimertinib monotherapy arm.

“The FLOWERS/CTONG 2008 trial is the first phase 2 prospective, randomized study to report the efficacy and safety data of osimertinib with or without savolitinib as first-line treatment in de novo MET-aberrant, EGFR-mutant advanced NSCLC patients. The combination of osimertinib and savolitinib showed clinically meaningful improvements,” Yang concluded.

Reference

Yang JJ, Li A, Feng WN, et al. Osimertinib with or without savolitinib as 1L in de novo MET aberrant, EGFRm advanced NSCLC (CTONG 2008, FLOWERS): a phase II trial. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract PL04.10.