Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration—A Narrative Review

Simple Summary In this article, we outline updates on the clinical development of savolitinib, a novel, reversible c-MET kinase inhibitor conditionally approved in China for treatment of advanced non-small cell lung cancer (NSCLC) patients harboring MET exon 14 skipping mutation (METex14). Savolitinib was developed as a monotherapy for NSCLC with MET alterations, and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who developed resistance to EGFR–TKIs because of MET alterations. Savolitinib showed anti-tumor activity in preclinical models. The early phase I trial established the recommended phase II dose to be 600 mg once-daily. Savolitinib plus osimertinib showed beneficial efficacy and safety in EGFR mutant patients with acquired resistance due to MET amplification and/or c-MET overexpression. Benefits were noted with savolitinib in Chinese patients with pulmonary sarcomatoid carcinoma and other NSCLC subtypes positive for METex14 mutation. Results from phase III trials are awaited to further confirm the beneficial effects from early phase trials. Abstract Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys®) is highly selective mesenchymal epithelial transition (MET)–tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (METex14). This article summarizes the clinical development of savolitinib, as a monotherapy in NSCLC with METex14 mutation and in combination with epidermal growth factor receptor (EGFR) inhibitor in post EGFR–TKI resistance NSCLC due to MET-based acquired resistance. Preclinical models demonstrated anti-tumor activities in MET-driven cancer cell line and xenograft tumor models. The Phase Ia/Ib study established an optimized, recommended phase II dose in Chinese NSCLC patients, while TATTON study of savolitinib plus osimertinib in patients with EGFR mutant, MET-amplified and TKI-progressed NSCLC showed beneficial efficacy with acceptable safety profile. In a pivotal phase II study, Chinese patients with pulmonary sarcomatoid carcinoma, brain metastasis and other NSCLC subtype positive for METex14 mutation showed notable responses and acceptable safety profile with savolitinib. Currently, results from ongoing clinical trials are eagerly anticipated to confirm the efficacious and safety benefits of savolitinib as monotherapy and in combination with EGFR–TKI in acquired resistance setting in advanced NSCLC and its subtypes with MET alterations.


Introduction
Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers with a low 5-year survival rate of about 22% [1,2]. Most NSCLC are usually diagnosed at an advanced stage with traditional chemotherapy and radiotherapy showing  1 Based on overall NSCLC population. 2 Based on treatment-naïve NSCLC population. 3 Based on EGFR-positive treatment-naïve NSCLC population.

2-11
Li XM et al. [23] Lai GGY et al. [24] 1 Based on overall NSCLC population. 2 Based on treatment-naïve NSCLC population. 3  Currently the FDA approved MET-TKIs are capmatinib and tepotinib with crizotinib granted as breakthrough therapy designation, while savolitinib is conditionally approved in China [26][27][28]. Further, for EGFR-mutated NSCLC with MET amplification treatment, efficacy of combination of MET-TKIs with EGFR-TKIs has been preliminarily approved by several clinical trials [29,30]. The clinical development strategy for savolitinib is centered both as monotherapy for advanced METex14-altered NSCLC and in combination with EGFR-TKI for correction of MET-driven acquired resistance to EGFR-TKIs [31]. In this review, we briefly describe the major milestones achieved in the clinical development of savolitinib as standard of care for NSCLC with METex14 mutation and potential treatment for NSCLC with other MET alterations.

Savolitinib, in Brief
Savolitinib (Orpathys ® ) is an orally bioavailable and highly selective small molecule MET-TKI that has demonstrated profound efficacy in preclinical and clinical studies of various cancers, including NSCLC, papillary renal cell carcinoma (PRCC) and gastric carcinoma [32][33][34]. Figure 2 demonstrates the chemical structure of savolitinib.
of savolitinib as standard of care for NSCLC with METex14 mutation and potential treatment for NSCLC with other MET alterations.

Savolitinib, in Brief
Savolitinib (Orpathys ® ) is an orally bioavailable and highly selective small molecule MET-TKI that has demonstrated profound efficacy in preclinical and clinical studies of various cancers, including NSCLC, papillary renal cell carcinoma (PRCC) and gastric carcinoma [32][33][34]. Figure 2 demonstrates the chemical structure of savolitinib. Early on, in vitro studies have established inhibitory effect of savolitinib on growth of gastric cells lines, while in vivo studies observed anti-tumor activity in human xenograft tumor models of MET-amplified gastric cancer and PRCC [33][34][35]. Another study by Jones and colleagues related to pharmacokinetic-pharmacodynamic (PK-PD) model observed inhibition of phosphorylated-MET by savolitinib at an effective concentration (EC)50 of 0.35 ng/mL and EC90 of 3.2 ng/mL in a cell line-derived xenograft (CDX) mice model using human lung cancer (EBC-1) and gastric cancer (MKN-45) cells [36]. Furthermore, PK studies in healthy male Chinese volunteers administered with single oral savolitinib doses of 200, 400 and 600 mg following an overnight fast or a high-fat and highcalorie breakfast prior to dosing showed no clinically relevant impact on PK and bioavailability of savolitinib [37].
In NSCLC with MET aberrations, several clinical trials have shown the potential benefit of savolitinib as a monotherapy and in combination with EGFR-TKI [30]. Savolitinib received its first approval by The National Medical Products Administration (NMPA), China for patients with METex14-altered locally advanced or metastatic NSCLC with disease-progression following systemic treatment or unable to receive chemotherapy [28]. The approval was based on a phase II trial conducted in China in patients with METex14altered NSCLC, including patients with the more aggressive PSC subtype [38]. The key milestones in the development of savolitinib for NSCLC treatment are demonstrated in Figure 3. Early on, in vitro studies have established inhibitory effect of savolitinib on growth of gastric cells lines, while in vivo studies observed anti-tumor activity in human xenograft tumor models of MET-amplified gastric cancer and PRCC [33][34][35]. Another study by Jones and colleagues related to pharmacokinetic-pharmacodynamic (PK-PD) model observed inhibition of phosphorylated-MET by savolitinib at an effective concentration (EC)50 of 0.35 ng/mL and EC90 of 3.2 ng/mL in a cell line-derived xenograft (CDX) mice model using human lung cancer (EBC-1) and gastric cancer (MKN-45) cells [36]. Furthermore, PK studies in healthy male Chinese volunteers administered with single oral savolitinib doses of 200, 400 and 600 mg following an overnight fast or a high-fat and high-calorie breakfast prior to dosing showed no clinically relevant impact on PK and bioavailability of savolitinib [37].
In NSCLC with MET aberrations, several clinical trials have shown the potential benefit of savolitinib as a monotherapy and in combination with EGFR-TKI [30]. Savolitinib received its first approval by The National Medical Products Administration (NMPA), China for patients with METex14-altered locally advanced or metastatic NSCLC with disease-progression following systemic treatment or unable to receive chemotherapy [28]. The approval was based on a phase II trial conducted in China in patients with METex14altered NSCLC, including patients with the more aggressive PSC subtype [38]. The key milestones in the development of savolitinib for NSCLC treatment are demonstrated in Figure 3.

First Steps towards the Development of Savolitinib as Mono and Combination Therapies
The availability of substantial evidence of anti-tumor activity and acceptable safety profile led to the development of savolitinib as a treatment for advanced NSCLC with MET aberrations. The high selectivity of savolitinib for MET was confirmed using a screening platform of more than 900 cell lines of which 111 represented NSCLC [39]. In vitro study by Henry and colleagues demonstrated the ability of savolitinib as a single agent to inhibit MET activity and reduce NSCLC cell viability in a dose dependent manner [39]. Further, anti-tumor efficacy was observed with savolitinib in vivo, in lung cancer PDX model with METex14 mutation. Savolitinib showed tumor regression (tumor volume reduction: 62%) with a dose of 25 mg/kg in all mice on treatment (n = 9) as well as 98% inhibition in tumor growth (TGI) with 5 mg/kg dose in 4 out of 9 mice of PDX model (Data

First Steps towards the Development of Savolitinib as Mono and Combination Therapies
The availability of substantial evidence of anti-tumor activity and acceptable safety profile led to the development of savolitinib as a treatment for advanced NSCLC with MET aberrations. The high selectivity of savolitinib for MET was confirmed using a screening platform of more than 900 cell lines of which 111 represented NSCLC [39]. In vitro study by Henry and colleagues demonstrated the ability of savolitinib as a single agent to inhibit MET activity and reduce NSCLC cell viability in a dose dependent manner [39]. Further, anti-tumor efficacy was observed with savolitinib in vivo, in lung cancer PDX model with METex14 mutation. Savolitinib showed tumor regression (tumor volume reduction: 62%) with a dose of 25 mg/kg in all mice on treatment (n = 9) as well as 98% inhibition in tumor growth (TGI) with 5 mg/kg dose in 4 out of 9 mice of PDX model (Data on file). In addition, in vivo study using H1993 and EBC-1 tumor xenografts showed considerable decrease in tumor growth, with savolitinib achieving an optimal response at doses as low as 0.3 mg/kg and 2.5 mg/kg in H1993 and EBC-1 tumors, respectively [39]. Interestingly, the same group (Henry and colleagues) concurred that savolitinib resistance in NSCLC is partially driven by MYC overexpression in H1993 cells, suggesting potential mechanism and treatment strategies for future acquired resistance to MEK-TKI.
Savolitinib, in combination with erlotinib, a first-generation EGFR-TKI inhibitor, showed substantial tumor inhibition in H441, an EGFR wild type model with MET amplification [40,41]. In addition, savolitinib treatment exhibited substantial anti-tumor activity in vivo (tumor regression: 35%) in the NSCLC cancer cell line NCI-H820 harboring an activating EGFR mutation (Ex19del), a gefitinib/erlotinib resistant mutation (T790M) as well as hyperactivated MET (data on file). Osimertinib, a third-generation, irreversible EGFR-TKI, at either 25 mg/kg daily or 12.5 mg/kg daily exhibited minimal anti-tumor activity, with TGI of 24% and 4%, respectively. However, when treated in combination with savolitinib, 25 mg/kg of savolitinib plus osimertinib at either 25 mg/kg or 12.5 mg/kg daily resulted in 94% and 90% TGI, respectively. These preclinical results highlight the beneficial anti-tumor effect of osimertinib plus savolitinib combination at optimal doses of 0.3~1.5 mg/kg savolitinib combined with 10 mg/kg osimertinib. Further, another study analyzed different doses of savolitinib, ranging from 0.02 mg/kg to 15 mg/kg (15 mg/kg equivalent to 600 mg clinical dose), in combination with a fixed dose of 10 mg/kg osimertinib (equivalent to 80 mg clinical dose). Pan-CYP inhibitor 1-aminobenzotriazole was dosed along with savolitinib and osimertinib to prolong PK half-life by reducing elimination rate so that plasma concentration time profile matches clinical exposure of the drugs (data on file). The combination of osimertinib and savolitinib demonstrated strong anti-tumor activity leading to tumor regressions. The benefit of combination treatment was observed with as low as 0.3 mg/kg dose of savolitinib. Thus, these encouraging preclinical results led to the evaluation of savolitinib's efficacy and safety in clinical trials for NSCLC with MET aberrations.

Clinical Development of Savolitinib: Phase I Trials
A first in-human phase I clinical study (NCT01773018) was conducted in patients (n = 48) with locally advanced solid tumors from Australia [42]. The doses administered were 100-1000 mg once daily (OD) and 300-500 mg twice-daily (BID), and the maximum tolerated dose was 800 mg. Savolitinib showed preliminary efficacy in patients with papillary renal cell carcinoma with MET gene copy number changes. The most frequent adverse events (AE) were nausea (62.5%), vomiting (41.7%), fatigue (35.4%) and peripheral edema (27.1%). The tolerability profile of savolitinib was acceptable, and the recommended phase II dose (RP2D) was established as 600 mg OD [42]. In another open-label, multi-center, phase Ia/Ib study (NCT0198555) conducted in China in patients (n = 85) with advanced tumors bearing MET aberrations, savolitinib demonstrated a manageable safety profile and promising anti-tumor activity in NSCLC with METex14 mutation, apparent tumor shrinkage (55% and 27%) in target lesions was observed, although partial response (PR) was not achieved. The most common treatment-related AEs were nausea (29.4%), vomiting (27.1%) and peripheral edema (21.2%). The RP2D of savolitinib was established at 600 mg OD or 500 mg BID and was consistent with phase I first-in human study conducted in Australia [43]. There was certain comparability between the patients with NSCLC enrolled in the phase I study conducted in Australia and the phase I study conducted in China, and thus the results could be analyzed accordingly [42,43].
Savolitinib demonstrated the ability to overcome MET-mediated resistance in patients with EGFR-mutant, MET-amplified or c-MET overexpressed NSCLC when combined with osimertinib, and these benefits extended to those with disease that had previously progressed on a prior EGFR-TKI [29,44]. Part A of the multi-arm phase Ib TATTON study (NCT02143466) demonstrated the safety and tolerability of osimertinib plus savolitinib (n = 18) in patients with advanced NSCLC disease progression on a prior EGFR-TKI [44]. Doses of savolitinib applied were escalated from 600 to 800 mg OD with a fixed dose of osimertinib 80 mg. The most common AEs reported were nausea (67%), rash (56%) and vomiting (50%). The objective response rate (ORR) was 44% [44]. Furthermore, in the expansion cohorts of TATTON trial, investigators evaluated the safety and efficacy of osimertinib plus savolitinib in locally advanced or metastatic, MET-amplified, EGFR mutation-positive NSCLC patients who had progressed on EGFR-TKIs [29]. Part B (n = 138) was substratified into three cohorts: B1 included those who had previously received a third-generation EGFR-TKI; patients without prior third-generation EGFR-TKI treatment were separated into B2 with Thr790Met negative and B3 with Thr790Met positive, at the time of enrolment. These patients received 600 mg QD, although the protocol was later amended, causing patients who weighed lesser than 55 kg to receive a 300-mg dose of savolitinib. The Part D expansion cohort was comprised of patients (n = 42) who had not previously received a third-generation EGFR-TKI and were T790M negative, and these patients received osimertinib 80 mg plus savolitinib 300 mg OD. Objective partial responses (PR) were observed (by 4 March 2020) in 68 (49%) patients in total of part B, with 23 (33%) patients, 33 (65%) patients and 12 (67%) patients in B1, B2 and B3, respectively, while in 26 (62%) patients in part D [45]. Regarding safety, the 4 expanded cohorts had similar safety profiles with 28% in part B and 19% in part D experiencing AEs possibly related to savolitinib. Serious AEs of grade 3 or 4 were associated with 49% patients in part B and 38% patients in part D. The most common AEs of grade 1-2 in expanded cohorts included nausea (48%), peripheral edema (34%), decreased appetite (32%), vomiting (30%) and fatigue (28%). In part B cohorts, the most common grade 3 or higher AEs related to savolitinib were decreased neutrophil count (6%) and aminotransferase elevations (4%), while in part D, hypersensitivity (5%), diarrhea (5%) and myalgia (5%) are more frequent [45]. Generally, in the dose expansion cohorts of TATTON trial, savolitinib plus osimertinib showed promising anti-tumor activity in MET-amplified EGFR positive advanced NSCLC patients who received a prior third-generation EGFR-TKI. These results have now been further investigated in the phase II SAVANNAH trial.
In another phase Ib study (NCT02374645), the clinical evaluation of savolitinib plus gefitinib (a first-generation EGFR-TKI) demonstrated promising anti-tumor activity with acceptable safety profile in EGFRm, MET-amplified advanced NSCLC patients from China who had disease progression on EGFR-TKIs. Patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally OD for which no dose-limiting toxicities were reported in safety run-in. The most commonly reported AEs were vomiting (46%), nausea (40%) and increased aspartate aminotransferase (39%) [30]. ORR in EGFR T790M-negative and -positive patients were 52% and 9%, respectively, suggesting beneficial anti-tumor activity [30].

Clinical Development of Savolitinib: Phase II Trials
A pivotal open-label phase II clinical study (NCT02897479) conducted in China demonstrated encouraging efficacy and tolerable safety profile of savolitinib in overall and patient subsets stratified according to tumor type (PSC and other NSCLC), brain metastasis status and prior anti-tumor treatment (pretreated and treatment naïve) [38]. Unresectable or metastatic NSCLC patients (n = 70) harboring METex14 mutation were administered savolitinib monotherapy at recommended starting dose of 600 mg orally once daily (OD) for patients weighing ≥50 kg, or 400 mg OD for patients weighing <50 kg, until disease progression or unacceptable toxicity. The majority of patients were elderly with advanced NSCLC on prior systemic therapy. In both the full analysis set (FAS) and the tumor response evaluable set (TRES), independent review committee (IRC) assessments were the main analyses, while investigators' (INV) assessments were supportive analyses. The IRC-assessed tumor response evaluable set (TRES) was comprised of 62 patients. The ECOG performance status of full analysis set (FAS) for majority of patients (81%) was 1 and in pre-specified subsets (PSC vs. other NSCLC subtypes, treatment naïve vs. previously treated), 78% to 88% patients had ECOG status of 1. Of the total PSC population (n = 25), pre-treated and treatment-naïve subsets were comprised of 29% and 46%, while brain metastasis and non-brain metastasis groups were comprised of 13% and 42% of PSC patients, respectively [38,46,47]. The primary efficacy end point was ORR (as assessed by IRC in TRES) defined as the proportion of patients with a confirmed complete response or partial response according to RECIST version 1.1. Secondary outcomes included duration of response (DoR), time to response (TTR), progression free survival (PFS), overall survival (OS) and safety. The latest results of the trial were presented at the 2022 ELCC conference and published in JTO Clinical and Research Reports [46,48]. The baseline characteristics are provided in Table 2.  [38,48].
In subgroup analyses (assessed in TRES set by INV, median follow-up of 28.4 months), for PSC (n = 20), 10 patients had partial response (ORR 50%) with a median duration of response of 12.4 months. In other NSCLC subtypes (n = 42), 23 patients had partial response (ORR 54.8%) with a median duration of response of 5.6 months and DCR of 92.9%. In pre-treated (n = 38) patients, partial response was observed in 20 patients (52.6%), while in treatment-naïve (n = 24) subgroup, partial response was observed in 13 patients (54.2%). Extracranial ORR for brain metastasis group was 64.3%. For survival outcomes, the PSC group showed a mPFS of 5.5 months, while with brain metastasis (n = 15), it was 7.0 months and without brain metastasis was 6.2 months. Similar values of mPFS were observed with pre-treated (6.9 months) and treatment-naïve (6.9 months) subgroups, respectively. The mOS for PSC and other NSCLC patients was 10.6 months and 17.3 months, respectively, with corresponding 24-month OS rates of 26% and 35%. Among brain metastases patients, the mOS was 17.7 months with the 24-month OS rate being 36%. The mOS for pre-treated and treatment-naïve patients was 19.4 months and 10.9 months, respectively, with corresponding 24-month OS rates of 38% and 22% [48]. However, this large difference in OS can be attributed to the higher proportion of patients with PSC in treatment-naïve population (46% vs. 29% in pre-treated patients) and a higher median age (74.5 vs. 67.7 in pre-treated patients). Patients with PSC had a short mOS vs other NSCLC patient (10.6 months vs. 17.3 months), likely due to the poor prognosis associated with PSC. These results confirmed savolitinib having beneficial efficacy towards NSCLC with METex14 mutation and its PSC subtype [32,38,48]. The PFS and OS results have been illustrated graphically in Table 3. An earlier study reported mOS of 6.7 months in patients with METex14 mutation NSCLC on chemotherapy treatment who did not receive prior targeted therapy [49]. In addition, mOS of PSC subset in NSCLC patients treated with chemotherapy has been reported to be 4 to 8 months [32,[49][50][51][52][53]. With savolitinib, mOS of NSCLC patients reaches 12.5 months with 70% maturity. In PSC subset, higher OS is seen with savolitinib treatment compared to chemotherapy, with OS reaching 10.6 months. So far, literature related to MET inhibitor treatment with PSC population is available only for savolitinib [51][52][53][54].
P-glycoprotein (gp) and breast cancer resistance protein (BRCP) are efflux proteins located in the luminal membrane of brain capillary endothelium, preventing drugs from entering the central nervous system. Most MET inhibitors, such as crizotinib and tepotinib, are known substrates of the P-gp and BRCP efflux transport system [55][56][57]. Steady concentrations of savolitnib are readily maintained in an intracerebral area which may be attributed to it not being a substrate of P-gp and BRCP efflux transport system. Promising efficacy of savolitinib was observed in brain metastasis subgroup, with ORR at 64.3%, DCR at 100% and significant survival benefit (PFS, 7.0 months; OS, 17.7 months). These encouraging results provide a treatment option for this subgroup of patients with poor prognosis and few treatment options [38,47,48].

Safety Evidence
Savolitinib demonstrated tolerable safety profile consistent with previous trials; most AEs were grades 1-2 and resolved with dose adjustment and discontinuation. Adverse events that presented at rates of ≥30% are listed below (Table 4, median follow-up of 28.4 months). The incidence of grade3 or more AEs was 65.7%, while 50% of patients reported treatment-related serious adverse events (SAE). The top ≥ grade 3 AE was elevated AST (12.9%). The most common treatment-related AEs (TRAEs) (≥30%) are peripheral edema (55.7%), nausea (45.7%) and elevated aminotransferase (38.6% and 37.1%). The top ≥ grade 3 treatment related AE was elevated AST (12.9%) [48,58]. The common SAEs reported were abnormal liver function (4.3%, 3 patients), drug hypersensitivity reaction (2.9%, 2 patients) and fever (2.9%, 2 patients). Treatment related fatal SAE, tumor lysis syndrome was reported in one patient. Ten patients discontinued treatment due to AEs, of which drug-induced liver damage and drug hypersensitivity reactions were seen in 2.9% of patients (2 patients), respectively [38]. No occurrence of pulmonary interstitial pneumonia and interstitial lung disease (ILD) was observed with savolitinib, while ILD is seen with tepotinib (n = 2) and capmatinib (n = 1) [4,59]. Data in n (%). Derived from latest safety analysis of phase II trial (NCT02897479) [48]. The updated results further confirm that savolitinib can benefit METex14-mutated NSCLC patients and each subgroup with acceptable safety profile [38,[46][47][48]. Savolitinib thus displays promising efficacy and tolerability in PSC associated with METex14 mutation and holds potential to become the first approved treatment in this setting. In addition, the study showed that savolitinib can penetrate the blood-brain barrier and is effective in patients with brain metastases.

Brief Introduction of Other Phase II Trials
Other ongoing phase II trials include SAVANNAH, SOUND and FLOWERS trials. SA-VANNAH trial (NCT03778229) continues to explore the sequence of savolitinib plus osimertinib with previous osimertinib monotherapy resistance. It is a phase II, single-arm study evaluating the efficacy of osimertinib in combination with savolitinib in 259 patients with EGFRm and MET amplified and/or c-MET overexpressed locally advanced or metastatic NSCLC who have progressed on osimertinib. Patients were treated with osimertinib (80 mg OD) and savolitinib (300 mg QD, 300 mg BID or 600 mg OD) until objective disease progression. Efficacy endpoints-such as ORR (primary endpoint), PFS, OS, DoR, HRQoL, pharmacokinetics, safety points such as AEs and patient related outcomes (PROs)-were studied. This is the first phase II clinical study of the third-generation EGFR-TKI osimertinib resistance in patients with advanced NSCLC with MET amplification and/or c-MET overexpression. MET detection was performed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods. The detection criteria were set to FISH, MET GCN ≥ 5 and/or MET/CEP7 ≥ 2; IHC, ≥50% tumor cells 3+. Sixty-two percent of osimertinib resistant patients was at low threshold [IHC50+ and/or FISH5+] as well as 34%-at the high threshold [IHC90+ and/or FISH10+] subgroups. Figure S1 provides the proportion of patient population with MET amplified and/or c-MET overexpressed in this study suggesting amplification and/or overexpression is the most common osimertinib resistance mechanism. The baseline characteristics are provided in Table S1. The overall median age of patients is 63 years, 62% were female, 54% were Asian and 34% were with brain metastases at baseline. On savolitinib 300 mg OD plus osimertinib 80 mg OD treatment, advanced NSCLC patients (n = 193) with high MET amplification and/or high threshold c-MET overexpression level show a trend toward better efficacy benefit, emphasizing the necessity of patients' selection according to appropriate MET detection criteria in this population. Among the overall population, ORR was 32%; median DoR was 8.3 months; and median PFS was 5.3 months, while among 108 patients who met the threshold for high MET amplification and/or high threshold c-MET overexpression level (IHC90+ and/or FISH10+), ORR was 49%; median DoR was 9.3 months; and median PFS was 7.1 months (Table S2). The safety results showed that the incidence of treatment-related AEs was 84%; treatment-related ≥grade 3 AEs at 20%; and treatment-related SAEs at 7% (Table S3). The incidence of hypersensitivity, ILD and pneumonia were 2% (4/196), and QT interval prolongation at 5% (10/196) [60].
In addition, the FLOWERS trial (NCT05163249) explores the efficacy and safety of osimertinib with or without savolitinib in patients with de novo MET amplified and/or c-MET overexpressed, EGFR-mutant advanced NSCLC. In SOUND trial (NCT05374603), an open-label, interventional, multi-center, exploratory trial, savolitinib combined with durvalumab will be evaluated in Chinese EGFR wild-type locally advanced or metastatic NSCLC patients with MET alterations. NSCLC patients from China with MET amplification (n = 30) and METex14 mutation (n = 30) will be treated with 1500 mg durvalumab and 300 to 600 mg savolitinib (OD) for 28-day/cycle till disease progression, death or toxicity. Efficacy endpoints will be PFS, ORR, DoR, DCR, 12 m OS rate and safety endpoints will be AEs and AEs of special interest (AESI) [61]. Further, phase III SAFFRON trial (NCT05261399) is investigating savolitinib plus osimertinib versus platinum-based doublet chemotherapy in participants with NSCLC (EGFR mutated, c-MET overexpressed and/or MET gene amplified) who have progressed on osimertinib treatment.

Ongoing Phase III Trials
Currently, four phase III trials evaluating savolitinib as a monotherapy and in combination with EGFR-TKIs are underway. The confirmatory phase IIIb clinical study (CTR20211151) is evaluating efficacy and safety of savolitinib in two cohorts from patients with locally advanced or metastatic NSCLC with METex14 mutation in China; patients of one cohort are with disease progression or toxicity intolerance after previous platinum-based chemotherapy regimens, and patients of another cohort are with no prior systemic antineoplastic therapy for advanced disease. The patients were treated until disease progression or intolerable toxicity. Phase III SACHI trial (CTR20211441) is a randomized, two-arm, open-label, multi-center study evaluating the efficacy and safety of savolitinib plus osimertinib versus chemotherapy in NSCLC patients from China with MET amplification who has progressed after first-to third-generation EGFR-TKI therapy and has already begun its recruitment in multiple centers. Another similar phase III trial SAFFRON is designed to evaluate the efficacy and safety of the same combined therapy as SACHI versus chemotherapy, but focus on global advanced NSCLC patients with MET amplification/c-MET overexpression that progressed after osimertinib treatment. SANOVO Phase III study is evaluating the efficacy and safety of savolitinib in combination with osimertinib in treatment-naïve patients with EGFR mutant positive and c-MET overexpression advanced NSCLC (NCT05009836).

Discussion
Savolitinib, an investigational MET highly selective agent, has shown pronounced efficacy in preclinical and clinical studies. Savolitinib demonstrated preclinical anti-tumor activity against MET-dependent cancer cell line growth and MET-driven tumor growth in xenograft models. Following which, data from a phase I clinical trial established recommended phase II dose in patients with METex14-mutated NSCLC. Further, the TAT-TON study established utility of savolitinib with osimertinib in advanced NSCLC with MET-mediated acquired resistance to EGFR-TKIs. Final results of the phase II study (NCT02897479) further confirmed the benefit of savolitinib in patients with METex14mutated NSCLC across all predefined subgroups. In addition, phase IIIb clinical study CTR20211151 is confirming the result of phase II study on METex14-mutated NSCLC, while three ongoing phase II trials, SAVANNAH, SOUND and FLOWERS, as well as three phase IIIB trials, SAFFRON, SACHI and SANOVO, are actively exploring solutions for different types of savolitinib combination regimens against EGFR resistance mechanisms. Preliminary results of the SAVANNAH trial have demonstrated the beneficial efficacy of osimertinib plus savolitinib in EGFRm NSCLC patients with MET amplified and/or c-MET overexpressed, supporting the results of TATTON study and paving the way for phase III SACHI and SAFFRON study.
In the hallmark phase II registry trial, savolitinib displayed promising efficacy and tolerability in patients with METex14-altered advanced NSCLC, with mOS reaching 12.5 months. The effect of savolitinib was rapid, substantiated by time to response (TTR) of 1.4 months. Promising results with PFS of 5.5 months and OS of 10.6 months were also seen in the PSC subtype, which does not respond well to chemotherapy and has limited effective treatments. By now, savolitinib is the only MET inhibitor with data related to PSC associated with METex14 mutation and is becoming the first approved agent in this setting. For patients of treatment naïve population, the PFS and OS of savolitinib were 6.9 months and 10.9 months, respectively, while PFS and OS of prior treatment patients reached 6.9 months and 19.4 months, respectively. In the current scenario, the reported ORR of savolitinib is the highest in the prior treatment population compared to other treatments (52.6% vs. 44.0% of capmatinib, 49.5% of tepotinib and 21% of amivantamab) [48,[62][63][64]. Savolitinib is also currently the only MET inhibitor that has recorded beneficial OS data in brain metastases, with PFS of 7.0 months and OS of 17.7 months. In addition, savolitinib has the best tumor response in brain metastasis population with ORR at 64.3% and DCR at 100% [38,48]. Based on these promising results, savolitinib received its first conditional approval by NMPA, China in June 2021, for patients with METex14-altered NSCLC after systemic treatment resistance or unable to receive chemotherapy. Post-marketing phase IIIb trial is now undergoing (HutchMed) in larger population of NSCLC patients and is expected to provide more clinical evidences for savolitinib in first-line therapy. Furthermore, latest post hoc analysis based on ctDNA detection suggests undetectable baseline METex14 or post-treatment clearance in ctDNA being relevant to favourable clinical outcomes, including better PFS and OS results, while secondary MET mutations and other acquired gene alterations after treatment (e.g., RTK-RASP-I3K pathway) may explain resistance mechanism to savolitinib [65]. Table 5 summarizes the data for MET-TKIs developed for METex14-altered advanced NSCLC population as well as subtypes [4,38,47,48,58,59,[62][63][64][66][67][68][69][70][71][72][73]. Patient population of Chinese Phase II registry trial were from China. In other global trials, east Asian population varied from 15.9 to 50.9%. Proportion of NSCLC patients with brain metastases was higher (28.9%) in Chinese Phase II registry trial compared to other trials [48]. Tumor response of different types of MET-TKIs shows ORR (54.8%) and DCR (92.9%) to be highest with savolitinib. Among AEs, most commonly, elevated transaminases were seen with savolitinib, tepotinib and crizotinib; peripheral edema with savolitnib, capmatinib and tepotinib; ILD with capmitnib, tepotinib and crizotinib; difficulty in breathing in tepotinib, crizotinib and amivantamab [38,48,58,59,[62][63][64][67][68][69][70][71][72][73]. The number of patients and the proportion of patients with brain metastases are based on other types of NSCLC in general, and the ORR, DCR and median PFS data are derived from data from other types of NSCLC in the efficacy-evaluable set [48]; safety data is analyzed based on the overall patient (n = 70) [38,48]. 2 Data derived from the latest analysis of four different cohorts from GEOMETRY mono-1 study: cohort 4, expansion cohort 6, cohort 5b and expansion cohort 7. Number of patients, proportion of brain metastases, ORR and DCR represent four cohorts in total; proportion of population based on cohort 4, 5b and 7; mPFS reflect results of four cohorts, respectively [62,71]. 3 Data based on VISION study cohort A + cohort C latest overall analysis [63]. 4 Patient population, number of patients, ORR, DCR and median PFS data are derived from two different studies of AcSé [72] and PROFILE-1001 [73]; safety data is based on combination of these two trials. 5 Data from latest analysis of CHRYSALIS study [64]. Bypass activation mediated by the MET signaling pathway is one of the important mechanisms leading to EGFR-TKI resistance. MET-driven resistance can be manifested as gene-level amplification or protein-level overexpression with previous treatment regimens such as chemotherapy, immunotherapy and targeted therapies including EGFR, BRAF and MEK [74,75]. The efficacy of tepotinib on NSCLC with T790M-negative MET amplification and/or c-MET overexpression after first/second-generation EGFR-TKI resistance is limited, with a mPFS of only 4.9 months [76,77]. The current immunotherapy efficacy for advanced NSCLC after EGFR-TKI resistance needs further improvement, and there is a lack of MET amplification and/or c-MET overexpression subgroup data. Nivolumab monotherapy has limited efficacy after EGFR-TKI resistance, with a mPFS of only 1.5-1.7 months [78,79]. In IMpower 150 and ORIENT-31 studies, EGFR-TKI resistance, followed by immunotherapy combined with bevacizumab and chemotherapy, showed a mPFS of 6.9-9.7 months but no subgroup data on MET amplification and/or c-MET overexpression was reported; meanwhile, safety of the combination therapy regimen needs attention [80,81]. MET-amplified and/or c-MET overexpressed advanced NSCLC patients with EGFR-TKI resistance have limited therapeutic effect with MET inhibitor monotherapy. Only 1 of 12 evaluable patients on inhibitor monotherapy reported an objective response [82]. Dual-target inhibition of EGFR and MET pathways may bring synergistic therapeutic benefit in MET-driven EGFR-TKI-resistant advanced NSCLC patients [83]. Meanwhile, efficacy of savolitinib combined with durvalumab in EGFR wild-type NSCLC with MET alterations is also under exploration in SOUND trial, as previously described.
The combination of EGFR inhibitor and MET-highly selective TKI possesses the potential to prevent or overcome MET-driven resistance to EGFR-TKIs. Acquired resistance to first-and second-generation EGFR-TKIs is often caused by the acquisition of the T790M mutation, which accounts for approximately 60% of resistant cases and has been overcome by third-generation EGFR-TKIs such as osimertinib. For first-and second-generation EGFR-TKIs, acquired resistance for MET-amplification is at least 5% (for example, gefitinib), while up to 25% of acquired resistance is observed with third generation EGFR-TKI (for example, osimertinib) [84]. TATTON study, set up in the back drop of acquired MET amplification associated with EGFR-TKI resistance offered explicit benefit with savolitinib in NSCLC patients without prior third-generation EGFR-TKI, while those who were administered with a prior third-generation EGFR-TKI had a relatively lower rate of response regardless of T790 status, possibly related to larger proportion of patients with ≥3 lines of treatment comprising the prior third-generation EGFR-TKI group (56.5% vs. 22.6% in partB2 + partD). Nonetheless, TATTON program demonstrated beneficial efficacy of savolitinib plus osimertinib combination in the MET-amplified, EGFR mutation-positive setting with acceptable safety profile which is a first in this setting [44]. Further, SAVANNAH phase II trial validates TATTON results with advanced NSCLC patients with MET amplification or c-MET overexpression due to osimertinib-acquired resistance. Initial results from the SAVANNAH trial show a trend toward improved response rates, with increasing level of MET amplified and/or c-MET overexpressed. Across all patients in this analysis, ORR was 32%; mDoR was 8.3 months; and mPFS was 5.3 months, while in high level MET amplification and/or c-MET overexpression subgroup, ORR was 49%; mDoR was 9.3 months; and mPFS was 7.1 months [60]. A summary of key data after EGFR-TKI resistance with secondary MET alterations treated with combination therapies available so far is provided in Table 6. MET amplification can be detected by using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). With MET amplification, MET/CEP7 ratio is as follows: low: ≥1.8 to ≤2.2; intermediate: >2.2 to <5; or high: ≥5 will be applied in clinical settings when treating patients with MET inhibitors [90]. The frequency of MET amplification in NSCLC ranges from 3% to 10% depending on the cut-off of MET copies per cell [91]. c-MET overexpression score of 2+ or 3+ as determined by IHC is considered as MET positive [60]. The TATTON study conducted an exploratory analysis of the relationship between the MET detection method and the dual-target efficacy after third-generation EGFR-TKI resistance: Based on FISH detection, the ORR value of MET local amplification was higher than that of MET polysomy patients although polysomy patients benefited from the treatment. In the MET-amplified population, patients with higher gene copy numbers detected by FISH had a better treatment benefit [44]. Further in SAVANNAH trial, promising clinical efficacy in a population with high MET amplification and/or high threshold c-MET overexpression level (IHC 90+ and/or FISH 10+) with an ORR 49%, mDoR of 9.3 months, and mPFS of 7.1 months was observed. The safety profile was acceptable, similar to that of TATTON study [60]. Further results of the SAVANNAH trial are awaited. However, the sample sizes of these studies are limited. Hence the need to interpret the results with caution is warranted, and further verification is required with larger clinical trials. Further phase III confirmatory trials, SAFFRON and SACHI have been initiated in patients whose disease progressed following treatment with any EGFR-TKI.

Conclusions
The conditional approval of savolitinib for the treatment of metastatic METex14mutated NSCLC is based on encouraging results from phase 2 trial conducted in China including patients with the more aggressive PSC subtype and brain metastasis. Savolitinib is a potent, highly selective MET inhibitor with robust response in advanced NSCLC. Preclinical and clinical data have shown savolitinib as effective and tolerable treatment in advanced NSCLC patients with METex14 skipping mutations. When used in combination with EGFR-TKIs, savolitinib has the potential to overcome resistance to these treatments driven through MET amplifications and/or c-MET overexpression, with future clinical trials verification needed. In conclusion, savolitinib offer another promising targeted treatment in the paradigm of metastatic NSCLC.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/cancers14246122/s1, Figure S1: Proportion of MET-altered NSCLC patients using different detection methods in SAVANNAH trail; Table S1: Baseline characteristics and clinical demographics of SAVANNAH study; Table S2: Efficacy parameters of SAVANNAH study; Table S3: Safety results of SAVANNAH trial.