de Marinis F, Kim T M, Bonanno L, Cheng S, Kim S-W, Tiseo M, Chu Q, Proto C, Sacher A, Luo Y-H, Novello S, Hao D, Baik C, Bazhenova L, Lee J S, Cho B C, Cadranel J, Diep T B, Metro G, Narayanan P, Yoneshima Y, de Castro Carpeño J, Baldotto C, Nyhus C, Yang J C-H, Sequist L V, Levy B, Hartmaier R, Igwegbe I, Poole L, Xu W, Ahn M-J
Thoracic Oncology Division, European Institute of Oncology (IEO), IRCCS, Milan, Italy.
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
Ann Oncol. 2025 Aug;36(8):920-933. doi: 10.1016/j.annonc.2025.04.003. Epub 2025 Jun 2.
MET-based resistance following osimertinib treatment for epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) is common. We report the primary analysis of the phase II SAVANNAH study (NCT03778229) evaluating savolitinib plus osimertinib in this setting.
Patients had EGFR-mutated, advanced NSCLC with MET overexpression and/or amplification. MET cut-offs were initially MET immunohistochemistry (IHC)3+/≥50% (3+ intensity in ≥50% of tumor cells) and/or FISH5+ (≥5 MET gene copies or MET/chromosome 7 centromere ratio ≥2), and increased to MET IHC3+/≥90% and/or FISH10+ after a preliminary analysis. Patients received oral savolitinib [300 mg twice daily (b.i.d.) or once daily (o.d.), or 600 mg o.d.] plus osimertinib 80 mg o.d., or savolitinib 300 mg b.i.d. plus placebo. A primary endpoint was investigator-assessed objective response rate (ORR) in patients with progression on first-line osimertinib and MET IHC3+/≥90% and/or FISH10+ status receiving savolitinib 300 mg b.i.d. plus osimertinib (primary efficacy population). Safety was analyzed in all patients receiving savolitinib plus osimertinib.
Of the 365 patients treated, 341 received savolitinib plus osimertinib, with 80 of these included in the primary efficacy population. Investigator-assessed confirmed ORR in the primary efficacy population was 56.3% [95% confidence interval (CI) 44.7% to 67.3%]; the median duration of response (mDoR) was 7.1 months (95% CI 5.6-9.6 months); the median progression-free survival (PFS) was 7.4 months (95% CI 5.5-7.6 months). Blinded independent central review was consistent: confirmed ORR 55.0% (95% CI 43.5% to 66.2%); mDoR 9.9 months (95% CI 6.0-13.7 months); median PFS 7.5 months (95% CI 6.4-11.3 months). The most common any grade adverse events in patients receiving savolitinib plus osimertinib were peripheral edema (46.0%), nausea (40.5%), and diarrhea (23.2%).
Savolitinib 300 mg b.i.d. plus osimertinib demonstrated high, clinically meaningful and durable responses in patients with EGFR-mutated, advanced NSCLC with MET IHC3+/≥90% and/or FISH10+ status following progression on first-line osimertinib. The combination was well tolerated and may provide a new oral targeted treatment approach in this setting.
奥希替尼治疗表皮生长因子受体（EGFR）突变的晚期非小细胞肺癌（NSCLC）后出现的MET 相关耐药很常见。我们报告了II期SAVANNAH研究（NCT03778229）的初步分析，该研究评估了在这种情况下赛沃替尼联合奥希替尼的疗效。
患者为EGFR突变的晚期NSCLC，伴有MET过表达和/或扩增。MET的截断值最初为MET免疫组化（IHC）3+/≥50%（≥50%的肿瘤细胞中强度为3+）和/或FISH 5+（≥5个MET基因拷贝或MET/7号染色体着丝粒比率≥2），在初步分析后增加到MET IHC 3+/≥90%和/或FISH 10+。患者接受口服赛沃替尼[300 mg每日两次（b.i.d.）或每日一次（o.d.），或600 mg o.d.]联合奥希替尼80 mg o.d.，或赛沃替尼300 mg b.i.d.联合安慰剂。主要终点是在一线奥希替尼治疗进展且MET IHC 3+/≥90%和/或FISH 10+状态的患者中，接受赛沃替尼300 mg b.i.d.联合奥希替尼治疗的研究者评估的客观缓解率（ORR）（主要疗效人群）。对所有接受赛沃替尼联合奥希替尼治疗患者的安全性进行分析。
在接受治疗的365例患者中，341例接受了赛沃替尼联合奥希替尼治疗，其中80例纳入主要疗效人群。主要疗效人群中研究者评估确认的ORR为56.3%[95%置信区间（CI）44.7%至67.3%]；中位缓解持续时间（mDoR）为7.1个月（95% CI 5.6 - 9.6个月）；中位无进展生存期（PFS）为7.4个月（95% CI 5.5 - 7.6个月）。盲法独立中央审查结果一致：确认的ORR为55.0%（95% CI 43.5%至66.2%）；mDoR为9.9个月（95% CI 6.0 - 13.7个月）；中位PFS为7.5个月（95% CI 6.4 - 11.3个月）。接受赛沃替尼联合奥希替尼治疗的患者中最常见的任何级别不良事件为外周水肿（46.0%）、恶心（40.5%）和腹泻（23.2%）。
对于一线奥希替尼治疗进展且具有MET IHC 3+/≥90%和/或FISH 10+状态的EGFR突变晚期NSCLC患者，赛沃替尼300 mg b.i.d.联合奥希替尼显示出高的、具有临床意义且持久的缓解。该联合方案耐受性良好，可能为这种情况下提供一种新的口服靶向治疗方法。
