Savolitinib Combo Prolongs PFS in Pretreated EGFR+ NSCLC

"Savolitinib in combination with osimertinib demonstrated a statistically significant and clinically meaningful improvement in median PFS [vs chemotherapy] in patients with MET-amplified NSCLC post first-line [treatment with an] EGFR TKI,” according to study author Shun Lu, MD, PhD.

A clinically meaningful and statistically significant progression-free survival (PFS) improvement occurred with savolitinib plus osimertinib (Tagrisso) vs chemotherapy among those with EGFR-mutant, MET-amplified advanced non–small cell lung cancer (NSCLC) after progressive disease on a prior EGFR tyrosine kinase inhibitor (TKI), according to a presentation on results from the phase 3 SACHI trial (NCT05015608) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

At a median follow-up of 16.5 months (95% CI, 9.7-24.9) in the intention-to-treat (ITT) population, the median investigator-assessed progression-free survival (PFS) in the combination arm (n = 106) was 8.2 months (95% CI, 6.9-11.2) compared with 4.5 months (95% CI, 3.0-5.4) in the chemotherapy arm (n = 105; stratified HR, 0.34; 95% CI, 0.23-0.49; P < .0001). At a median follow-up of 13.9 months (95% CI, 8.3-22.1), patients who received prior treatment with a first- or second-generation EGFR TKI achieved a median PFS of 9.8 months (95% CI, 6.9-12.5) in the combination arm (n = 69) vs 5.4 months (95% CI, 4.2-6.0) in the chemotherapy arm (n = 68; stratified HR, 0.34; 95% CI, 0.21-0.56; P < .0001). The study authors noted that the statistical significance thresholds for the primary end point of investigator-assessed PFS were met in both populations.

“Savolitinib in combination with osimertinib demonstrated a statistically significant and clinically meaningful improvement in median PFS [vs chemotherapy] in patients with MET-amplified NSCLC post first-line [treatment with an] EGFR TKI,” Shun Lu, MD, PhD, said during the presentation.

Lu is the chief of the Shanghai Lung Cancer Center, Shanghai Chest Hospital, School of Medicine, Shanghai Jiaotong University in China.

Exploring the Study Design and Baseline Characteristics

SACHI was an open-label, multicenter study that enrolled patients with unresectable or metastatic, EGFR-mutated NSCLC across 68 centers in China. Patients were required to have experienced disease progression following frontline treatment with an EGFR TKI; patients who received a prior first- or second-generation EGFR TKI had MET-amplified disease and did not have a T790M mutation and those treated with a third-generation EGFR TKI had MET-amplified disease only. All patients had an ECOG performance status of 0 or 1 and MET amplification status confirmed by a central lab.

Patients were randomly assigned 1:1 to receive savolitinib plus osimertinib or chemotherapy. Savolitinib was administered at a dose of 600 mg daily for patients weighing at least 50 kg or 400 mg daily for those weighing less than 50 kg. All patients in the investigational arm were treated with 80 mg of osimertinib daily. In the chemotherapy arm, patients received platinum plus pemetrexed for 4 to 6 cycles followed by pemetrexed maintenance.

Treatment in both arms continued until disease progression or intolerable toxicity. Conditional crossover from the chemotherapy arm to the investigational arm was allowed in the event of disease progression as determined by an independent review committee (IRC). Patients were stratified based on the presence of brain metastases (yes vs no), prior third-generation EGFR TKI treatment (yes vs no), and EGFR mutation type (exon 19 deletion vs L858R vs others).

The secondary end points included PFS by IRC, overall response rate (ORR), disease control rate (DCR), duration of response (DOR), time to response, overall survival (OS), and safety.

At baseline, the median ages in the combination and chemotherapy arms were 59.4 years (range, 34.1-75.8) and 61.9 years (range, 36.8-75.8), respectively. Most patients in both arms were females (58% vs 52%), had an ECOG performance status of 1 (74% vs 74%), had a pathological diagnosis of adenocarcinoma (99% vs 100%), and did not have brain metastases (63% vs 61%). Thirty-five percent of patients in both arms received prior treatment with a third-generation EGFR TKI in the frontline setting. EGFR mutation types in both arms consisted of exon 19 deletions (38% vs 38%), L858R mutations (52% vs 50%), and other mutations (10% vs 11%).

Additional Secondary End Point Data and Safety

Additional findings from SACHI showed that the median PFS per IRC in the ITT population was 7.2 months (95% CI, 5.7-11.1) in the combination arm compared with 4.2 months (95% CI, 4.0-5.7) in the chemotherapy arm (stratified HR, 0.40; 95% CI, 0.28-0.59; P < .0001). The median PFS values among patients who previously received first- or second-generation EGFR TKIs were 8.2 months (95% CI, 6.8-11.1) and 5.7 months (95% CI, 4.2-7.0), respectively (stratified HR, 0.47; 95% CI, 0.29-0.76; P = .0017).

Patients with a history of brain metastases in the combination arm (n = 38) achieved a median investigator-assessed PFS of 6.9 months (95% CI, 4.3-9.8) vs 4.7 months (95% CI, 2.8-5.6) in the chemotherapy arm (n = 39; unstratified HR, 0.40; 95% CI, 0.23-0.71; P = .0011). Those without a history of brain metastases in the combination (n = 68) and chemotherapy (n = 66) arms experienced a median PFS of 9.6 months (95% CI, 6.9-12.5) and 4.2 months (95% CI, 2.9-5.6), respectively (unstratified HR, 0.30; 95% CI, 0.18-0.48; P < .0001).

The investigator-assessed median PFS among patients who received a prior third-generation EGFR TKI was 6.9 months (95% CI, 4.2-9.7) in the combination arm (n = 37) vs 3.0 months (95% CI, 2.7-4.6) in the chemotherapy arm (n = 37; unstratified HR, 0.32; 95% CI, 0.18-0.57; P < .0001). The median PFS values per IRC were 6.9 months (95% CI, 4.3-11.1) and 3.0 months (95% CI, 2.7-4.1), respectively (unstratified HR, 0.32; 95% CI, 0.18-0.58; P < .0001).

The median OS in the ITT population was 22.9 months (95% CI, 16.8-not evaluable) in the combination arm vs 17.7 months (95% CI, 14.9-26.3) in the control arm (unstratified HR, 0.84; 95% CI, 0.55-1.29). The study authors noted that the OS data are still evolving, with an overall maturity of 40%.

The ORRs in the combination and chemotherapy arms were 58% (95% CI, 49%-68%) and 34% (95% CI, 25%-44%), respectively (stratified odds ratio [OR], 2.74; 95% CI, 1.50-4.98; P = .0004). The DCRs were 89% (95% CI, 81%-94%) and 67% (95% CI, 57%-76%), respectively (stratified OR, 3.98; 95% CI, 1.81-8.82; P = .0001). The respective median DOR values were 8.4 months (95% CI, 5.9-11.1) and 3.2 months (95% CI, 2.8-4.2).

In terms of safety, any-grade adverse effects (AEs) occurring in at least 20% of patients in the combination arm included decreased white blood cell count (49%), nausea (48%), and vomiting (44%). Common any-grade AEs in the chemotherapy arm (n = 96) included anemia (73%), decreased neutrophil count (59%), and decreased white blood cell count (53%). Grade 3 or higher AEs in the combination arm included decreased neutrophil count (14%), decreased white blood cell count (7%), and increased alanine aminotransferase levels (7%). In the control arm, grade 3 or higher AEs included decreased neutrophil count (26%) and anemia (23%).

The median durations of treatment in the investigational and control arms were 6.9 months (range, 0.03-29.04) and 4.1 months (range, 0.69-12.85), respectively. Any-grade treatment-emergent AEs (TEAEs) were reported at rates of 98% and 96%, respectively. Patients in both arms experienced grade 3 or higher TEAEs (57% vs 57%), TEAEs leading to dose modification (55% vs 53%), TEAEs leading to dose discontinuation (8% vs 8%), and serious TEAEs (38% vs 28%).

Any-grade treatment-related AEs (TRAEs) occurred in 97% of patients in the combination arm vs 95% of those in the chemotherapy arm. Grade 3 or higher TRAEs (45% vs 48%), TRAEs leading to dose modification (47% vs 40%), TRAEs leading to dose discontinuation (6% vs 8%), and serious TRAEs (27% vs 21%) were reported in both arms. Ten percent of patients in the investigational arm died within treatment cycles compared with 7% in the control arm.

Most patients in the investigational (63%) and control (73%) arms discontinued treatment. Reasons for discontinuation in both arms included disease progression (42% vs 61%), AEs (7% vs 2%), patient or guardian’s decision (7% vs 8%), or investigator’s decision (3% vs 2%). Five patients discontinued treatment due to death in the combination arm and 1 patient discontinued chemotherapy to receive a new antitumor therapy.

“Savolitinib [plus] osimertinib [represents] a new chemotherapy-free option for patients with EGFR-mutated NSCLC [with] a MET amplification after [disease] progression on [a] first-line EGFR TKI,” Lu said in his conclusion.

Disclosures: Lu holds leadership roles with Innovent Biologics, Inc, Shanghai Fosun, and Simcere Zaiming. He also has consulting or advisory roles with AstraZeneca, Boehringer Ingelheim, GenomiCare, Hutchison MediPharma, InventisBio Co Ltd, Menarini, Pfizer, Roche, Simcere, Yuhan, and Zai Lab. Lu is on the speakers’ bureau for AstraZeneca, Hansoh Pharma, Hengrui Therapeutics, and Roche. He received research funding from AstraZeneca, BeiGene, BMS, Hansoh, Hengrui Therapeutics, Hutchison MediPharma, Lilly Suzhou Pharmaceutical Co, and Roche.

Reference

Lu S, Wang J, Yang N, et al. Savolitinib (savo) combined with osimertinib (osi) versus chemotherapy (chemo) in EGFR-mutant (EGFRm) and MET-amplification (METamp) advanced NSCLC after disease progression (PD) on EGFR tyrosine kinase inhibitor (TKI): results from a randomized phase 3 SACHI study. J Clin Oncol. 2025;43(suppl 17):LBA8505. doi:10.1200/JCO.2025.43.17_suppl.LBA8505