Novello, Silvia

Abstract Background: Savo is an oral, potent and highly selective MET-TKI. In the Phase 2 SAVANNAH study (NCT03778229), savo + osi had a high rate of durable responses in pts with EGFRm advanced NSCLC and high MET OverExp and/or Amp levels. Early clearance of plasma EGFRm may predict outcomes. We report an exploratory analysis of plasma EGFRm clearance and its association with MET tissue biomarker status, ORR and PFS. Methods: Pts with EGFRm advanced NSCLC and MET OverExp and/or Amp with PD on 1L+ osi received savo 300 mg QD, 300 mg BID or 600 mg QD + osi 80 mg QD. MET OverExp/Amp was centrally confirmed (by IHC [Roche], 3+ intensity in ≥50% of tumor cells [MET IHC3+/≥50%]; by FISH [Abbott Molecular], MET gene copy number ≥5 or MET:CEP7 ratio ≥2 [FISH5+], or at higher thresholds of MET IHC3+/≥90% or FISH10+). Baseline (BL) and Wk 3 plasma EGFRm (Ex19del/L858R) were analyzed by ddPCR (Biodesix) as an estimate of tumor burden. MET Amp was not monitored in ctDNA due to low detection sensitivity. Clearance was defined as undetected EGFRm ctDNA at Wk 3, when detected at BL. PFS was investigator-assessed (RECIST 1.1). DCO: Aug 23, 2024. Results: Of 344 pts with evaluable BL ctDNA, 259 (75%) had detected EGFRm ctDNA. Of these, 225 had evaluable ctDNA at Wk 3 (82 [36%] had EGFRm clearance at Wk 3). Confirmed ORR was higher in pts with EGFRm Wk 3 clearance (56/82; 68%) vs non-clearance (38/143; 27%). PFS was longer in pts with vs without EGFRm clearance at Wk 3 (Table). Across all pts evaluable for ctDNA at Wk 3, clearance rates were higher in pts with vs without high MET (69/162 [43%] vs 13/63 [21%]; odds ratio [95% CI] 0.35 [0.16, 0.72]). Similar results were seen in the savo 300 mg QD + osi subgroup. Conclusions: In SAVANNAH, among pts with detected EGFRm ctDNA at BL, clearance at Wk 3 was associated with improved ORR and PFS. Plasma EGFRm clearance at Wk 3 is enriched in pts with MET IHC3+/≥90% or FISH10+ status, consistent with improved efficacy in this biomarker subgroup. Citation Format: Jonathan W. Riess, Filippo de Marinis, Benjamin Levy, Tae Min Kim, Laura Bonanno, Quincy Chu, Marcello Tiseo, Adrian Sacher, Silvia Novello, Christina Baik, Lyudmila Bazhenova, Jacques Cadranel, Giulio Metro, Cheng-Ta Yang, Tsung-Ying Yang, Gee-Chen Chang, Konstantinos Leventakos, Lorenzo Livi, James Chih-Hsin Yang, Lecia V. Sequist, John Argue, Wanning Xu, Aleksandra Markovets, Ryan Hartmaier, Myung-Ju Ahn. SAVANNAH: Clearance of plasma EGFRm in patients with EGFRm MET-overexpressed (OverExp) and/or -amplified (Amp) NSCLC post-osimertinib (osi) treated with savolitinib (savo) + osi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB416.

Purpose We conducted a phase II study of combination of the anti–insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non–small-cell lung cancer (NSCLC). Patients and Methods Patients were randomly assigned (2:1) to paclitaxel 200 mg/m2, carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI10, PCI20) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI10-20 patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI20 was enrolled on completion of the randomized study. Results A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI10 and 50 patients received PCI20 in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI20/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship. Conclusion These data suggest that PCI20 is safe and effective in patients with NSCLC.