Abstract CT251: Savolitinib (savo) + osimertinib (osi) vs savo + placebo (PBO) in patients (pts) with EGFR-mutated (EGFRm), MET-amplified advanced NSCLC with progression on osi
Authors: Yang James Chih-Hsin , Chen Yuh-Min , Batra Ullas , Do Kien , Sitthideatphaiboon Piyada , Danchaivijitr Pongwut , Lee Kang-Yun , Chindaprasirt Jarin , Yang Cheng-Ta , Chang Gee-Chen , Charoentum Chaiyut , Ungtrakul Teerapat , Moran Juan Ignacio Hernandez , Hartmaier Ryan , Haskins Matthew , Xu Wanning , Riess Jonathan W. 
Published: April 2024

Abstract
Background Osi, an EGFR-TKI, is the preferred 1L treatment (tx) for EGFRm aNSCLC; however, resistance eventually develops in most pts. MET amplification is the most common known resistance mechanism to osi. Combining osi with savo, a MET-TKI, has shown antitumor activity in EGFRm, MET-amplified aNSCLC. We conducted a Phase II, double-blind, randomized study (NCT04606771) to assess the individual contribution of savo to the combination.
Methods Pts with EGFRm (Ex19del, L858R), MET-amplified (MET gene copy ≥5 or MET/CEP7 ratio ≥2; central confirmation by FISH), aNSCLC with progression on ≥1 tx, including osi, were randomized (1:1) to savo 300 mg QD + osi 80 mg QD or savo 300 mg QD + PBO. Tx continued until PD, unacceptable AEs, or other discontinuation criterion. Primary endpoint: ORR per RECIST 1.1 (investigator-assessed). Efficacy was also assessed by exploratory, higher MET cutoffs (determined retrospectively): 3+ staining ≥90% tumor cells (IHC90+) and/or MET gene copy ≥10 (FISH10+). Plasma was collected for exploratory analyses.
Results 30 pts were randomized (savo + osi n=14; savo + PBO n=16). Table shows efficacy data. Grade ≥3 AEs and sAEs occurred in: 3 (21%) and 4 (29%) pts receiving savo + osi; 5 (31%) and 3 (19%) pts receiving savo + PBO, respectively. Most common any-grade AEs with savo + osi vs savo + PBO were nausea (50% vs 19%), peripheral edema (36% vs 25%) and vomiting (21% vs 31%).
Conclusion Savo + osi demonstrated clinical activity, with savo + PBO showing lower clinical activity. Clinical activity was observed in pts with higher MET cutoffs (FISH10+ and/or IHC90+). Due to small sample sizes, these data need to be interpreted with caution. Safety was consistent with known AE profiles of each tx. This study was terminated early as the contribution of savo to the savo + osi combination is being further assessed in SAVANNAH (NCT03778229), which uses a different savo dosing regimen and higher MET-amplification cutoffs.

TABLE 1. NAND Savolitinib + osimertinib Savolitinib + placebo FISH10+ and/or IHC90+a (n=8) All patients(n=14) FISH10+ and/or IHC90+ a (n=7) All patients (n=16) ORR, % (95% CI)b 63 (24, 91) 57 (29, 82) 29 (4, 71) 13 (2, 38) Complete response, n (%)b 0 0 0 0 Partial response, n (%)b 5 (63) 8 (57) 2 (29) 2 (13) Median duration of response, weeks (95% CI) 30.6 (23.0, NC) 30.6 (18.9, NC) NR (12.4, NC) NR (12.4, NC) PFS events, n (%)c 4 (50) 9 (64) 5 (71) 13 (81) Median PFS, months (95% CI) 8.2 (4.1, NC) 7.4 (5.6, NC) 4.0 (1.3, NC) 1.6 (1.3, 4.1) aAs IHC was not used to determine pt eligibility, this subgroup does not comprise all randomized pts due to limited sample availability; bResponses included unconfirmed responses; cOnly included events that occurred within 2 missed visits of the last evaluable assessment. CI, confidence interval; FISH10+, FISH (MET copy number ≥10); IHC90+, immunohistochemistry overexpression (3+ staining intensity) in ≥90% of tumor cells; NC, not calculable; NR, not reached; ORR, objective response rate; PFS, progression-free survival.
Citation Format: James Chih-Hsin Yang, Yuh-Min Chen, Ullas Batra, Kien Do, Piyada Sitthideatphaiboon, Pongwut Danchaivijitr, Kang-Yun Lee, Jarin Chindaprasirt, Cheng-Ta Yang, Gee-Chen Chang, Chaiyut Charoentum, Teerapat Ungtrakul, Juan Ignacio Hernandez Moran, Ryan Hartmaier, Matthew Haskins, Wanning Xu, Jonathan W. Riess. Savolitinib (savo) + osimertinib (osi) vs savo + placebo (PBO) in patients (pts) with EGFR-mutated (EGFRm), MET-amplified advanced NSCLC with progression on osi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT251.