First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced 1 Solid Tumors: Safety, Pharmacokinetics and Anti-Tumor Activity

Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is 33 implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability 34 and maximum tolerated dose (MTD) of the potent and selective MET inhibitor, savolitinib (AZD6094, 35 HMPL-504, volitinib). 36 Experimental design: This open-label, multi-center dose-escalation and -expansion study 37 evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3+3 design 38 assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose expansion phase 39 included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD and dose- 40 limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included 41 pharmacokinetics, biomarker research and anti-tumor activity. 42 Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib 43 (600 mg N =1, 800 mg N =1 and 1000 mg N =2); the MTD was 800 mg QD and not reached for BID 44 dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events 45 were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and 46 peripheral edema (15 patients, 31%). At 600 mg QD, C max was 2414.8 ng/mL, AUC was 47 17053.9 h·ng/mL and there was no apparent drug accumulation. Three patients with papillary renal 48 cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 49 weeks. 50 Conclusion: The tolerability profile of savolitinib was acceptable and the RP2D was 51 established as 600 mg QD. Preliminary anti-tumor activity was demonstrated supporting further 52 study in patients with PRCC. We present the results of the first-in-human phase I trial of savolitinib in patients with advanced solid tumors. The study was designed to evaluate the safety, tolerability and maximum tolerated dose (MTD) of savolitinib, with the additional exploratory objectives of evaluating biomarker research and anti-tumor activity. distribution by MET status biomarker, with 344 MET-driven status being defined as any of: MET copy number gain (either chromosome 7 gain or a 345 MET focal amplification of ≥6 copies), HGF gene amplification (≥6 copies), or MET kinase domain 346 mutations (allele frequency >5%) (23). The phase II study found savolitinib monotherapy at 600 mg QD to have an acceptable safety and tolerability profile in patients with PRCC with the most advantageous that anti-tumor activity in for


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MET (hepatocyte growth factor [HGF] receptor) is a key regulator of angiogenesis, cell 77 survival, invasion and proliferation and is expressed on the epithelial cells in numerous organs 78 including the kidney, bone marrow and liver (1). Dysregulation of the HGF/MET signaling pathway 79 has been implicated in the tumorigenesis of a variety of human cancers (2). Binding of the ligand 80 HGF to its receptor activates the MET tyrosine kinase, leading to the initiation of a cascade of 81 downstream signals including activation of the Ras/Raf/MEK/ERK and phosphatidylinositol-3-82 kinase/Akt pathways (1). Activating MET mutations and MET gene amplification have been reported 83 in various malignancies including gastric carcinomas, gliomas, and prostate cancer (3)(4)(5). MET 84 amplification is also a potential mechanism for the development of treatment resistance of 85 epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with the EGFR 86 inhibitors, erlotinib, gefitinib and osimertinib (3,6,7). Recent studies have also linked MET 87 dysregulation with papillary renal cell carcinoma (PRCC) (8-10). 88 Various strategies to inhibit the HGF/MET signaling pathway have been explored. 89 Monoclonal antibodies directed against HGF and MET, such as rilotumumab, onartuzumab and 90 emibetuzumab, have demonstrated anti-tumor activity in early phase clinical trials (11,12). Further 91 developments include the small-molecule tyrosine kinase inhibitors crizotinib, cabozantinib and 92 foretinib, multi-kinase inhibitors that inhibit a number of intracellular pathways, including . 94

Patients 126
Eligible patients had a histologically or cytologically documented, incurable, locally advanced 127 or metastatic solid tumor that had either progressed, failed to respond to standard systemic 128 therapy, or had no standard or effective existing therapy. Other important eligibility criteria 129 included: adults ≥18 years of age and an Eastern Cooperative Oncology Group (ECOG) performance 130 status of 0 or 1. Patients with poor hematologic status, who were pregnant, had received cancer 131 treatment within 4 weeks of the first dose of savolitinib, had a history of significant liver disease, had 132 previous or current exposure to a MET inhibitor, were excluded. Patients with poor liver or renal 133 function were also excluded. Poor liver function was defined as total bilirubin >1.5 x the upper limit 134 of normal (ULN) and AST and ALT >2.5 X ULN (patients with Gilbert disease and serum bilirubin levels 135 ≤3 x ULN and normal aspartate and alanine aminotransferase [AST, ALT] could be enrolled and 136 patients with documented liver metastases could have AST and/or ALT levels ≤5 x ULN at screening). 137 Poor renal function was defined as serum creatinine >1.5 x ULN (patients with a creatinine clearance 138 of ≥50 mL/min based on a documented 24-hour urine collection were eligible concentration-time profile was used to determine pharmacokinetic parameters for savolitinib and 178 the two major metabolites, M2 (active, with a potency 3-6-fold less than savolitinib for p-MET 179 inhibition and tumor cell growth inhibition in a variety of tumor cells with MET amplification) and 180 M3 (inactive), including area under the plasma concentration-time curve (AUC), maximum plasma 181 concentration (C max ), oral clearance (CL/F), apparent volume of distribution (Vd/F), time to reach 182 C max , accumulation ratio and elimination half-life (t1/2). 183

Anti-tumor activity 184
Tumor assessments were performed according to Response Evaluation Criteria in Solid 185

Patient population and drug exposure 211
A total of 48 patients were enrolled and 45 patients (94%) completed the study (first 212 treatment cycle; 21 days). Three patients (6%) did not complete the study due to withdrawal of 213 consent (N = 1), grade two fatigue (N = 1), and lost to follow-up (N = 1; Figure 1). The majority of 214 patients (85%) had metastatic disease and the most common primary tumor locations were the 215 kidney (N = 18; 38%) and large bowel (N = 9; 19%) ( Table 1). 216 After study completion, the primary subsequent reason for savolitinib discontinuation was 217 radiologically-confirmed disease progression (27 patients, 56%). Other reasons were withdrawal of 218 consent (six patients, 12.5%), investigator decision (five patients, 10.4%: three patients with 219 suspected disease progression, one patient with worsening liver function tests due to biliary 220 obstruction by the tumor, and one patient with a growing tumor and problematic nausea), AEs (four 221 patients, 8.3%), DLT (two patients 4.2%), lost to follow-up (one patient, 2.1%) and other (three 222 Research.
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Author Manuscript Published OnlineFirst on April 5, 2019; DOI: 10.1158/1078-0432. CCR-18-1189 patients, 6.3%: two patients with suspected disease progression and one patient due to sponsor 223 ending study). Patients with suspected disease progression were withdrawn on clinical grounds 224 before radiological progression. There appeared to be no relationship between the savolitinib dose 225 and frequency of study withdrawal or treatment discontinuation following study completion ( Figure  226 1). 227

Safety 228
No immediate DLTs were observed following a single dose of savolitinib of between 100 and 229 1000 mg (followed by a 7-day wash-out period). In the subsequent QD dosing cohorts that began 230 treatment 1 week after the single dose of savolitinib, five Grade 3 DLTs, all considered related to 231 treatment, were experienced by four patients (8%); fatigue (N = 1 at 800 mg QD, N = 2 at 1000 mg 232 QD), headache (N = 1 at 1000 mg QD), and abnormal liver function test (increased AST and ALT; 233 N = 1 at 600 mg QD) ( Figure 1). When considering any treatment-emergent AE (TEAE), whether or 234 not related to study treatment, QD dosing resulted in withdrawal of savolitinib in 10 patients (21%) 235 and dose interruption or reduction in 17 patients (35%). Treatment modification due to a Grade 3 236 TEAE occurred in nine patients who experienced 14 events, of which eight were considered possibly 237 or probably related to savolitinib. The MTD of savolitinib was determined to be 800 mg QD. For BID 238 four patients (57%) at 600 mg QD, 7 events in five patients (71%) at 800 mg QD and 18 events in 11 248 patients (92%) at 500 mg BID. In addition, there were 5 events of abnormal liver function test that 249 occurred in the 500 mg BID cohort outside of the DLT period. Consequently, the RP2D was 250 determined to be 600 mg QD. 251 AEs ≥Grade 3 considered related to savolitinib are shown by dose in Table 3  considered probably related to savolitinib: abnormal liver function test (two events) and individual 254 events of increased ALT, pyrexia and fatigue. Two further SAEs, small intestinal obstruction and 255 pyrexia, were considered possibly drug related. The frequency of SAEs did not appear to be clearly 256 related to the dose of study drug (Table 3). Seven patients each experienced one Grade 4 AE; five 257 events were considered probably not drug-related and two events, increased ALT and abnormal liver 258 function test, were considered probably drug-related. Three patients (6%) died during the study as a 259 result of disease progression. This first-in-human phase I study demonstrated that the selective MET tyrosine kinase 295 inhibitor, savolitinib, was generally well tolerated in patients with locally advanced or metastatic 296 Research.
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Author Manuscript Published OnlineFirst on April 5, 2019; DOI: 10.1158/1078-0432. CCR-18-1189 solid tumors. The MTD of savolitinib was determined to be 800 mg for QD dosing and the MTD for 297 BID dosing was not reached (maximum dose investigated was 500 mg BID). The RP2D was 298 determined as 600 mg QD based on toxicity, incidence of TEAEs ≥Grade 3 in severity, 299 pharmacokinetic data, and the indication of anti-tumor activity at this dose. Preclinical modelling 300 demonstrated phosphorylated-MET (pMET) inhibition at an effective concentration (EC)50 of 0.35 301 ng/mL and EC90 of 3.2 ng/mL; this is equivalent to an EC90 of 6.5 ng/mL in humans (19). At 600 mg 302 QD in humans, the minimal plasma concentration at steady-state exceeded this value (following 21-303 day continuous dosing, the median C min [pre-dose on day 1 of the 2 nd treatment cycle] was 25.4 304 ng/mL; range 18.0-54.6), providing the extensive and durable inhibition of pMET required to achieve 305 optimal efficacy. In practice this is considered to provide >90% pMET inhibition throughout the 306 treatment cycle. 307 The most frequent drug-related AEs reported (nausea, vomiting, fatigue, peripheral edema, 308 constipation and diarrhea) were similar to those reported by other MET inhibitors (crizotinib, 309 foretinib, cabozantinib) (13-15). The majority of fatigue and headache AEs were Grade 1-2, and the 310 few Grade ≥3 events reported were limited to high doses of savolitinib (800 mg QD and 1000 mg 311 QD). Most events of fatigue were considered possibly or probably related to savolitinib, however, 312 only events of Grade 3 led to study withdrawal (three patients with DLTs). As with other tyrosine 313 kinase inhibitors, there is the potential for hepatotoxicity such as raised AST and/or ALT (13-15). This 314 was seen in some patients following treatment with savolitinib, although such events generally 315 resolved after stopping treatment with savolitinib. However, AEs frequently reported (≥20% in phase 316 I, II and III trials) with other less selective MET inhibitors (foretinib, cabozantinib), such as 317 hypertension, hypophosphatemia and proteinuria, were rarely reported (≤2%) with savolitinib. This 318 is possibly due to the multi-kinase activity (including, VEGF, AXL, TIE-2 receptors) of foretinib and 319 cabozantinib (14,15,20). 320 Interestingly, three patients with PRCC obtained a PR in this study (two in the 600 mg QD 321 cohort and one in the 1000 mg QD cohort), therefore supporting the selection of the monotherapy 322 Research. Although the present study met its predetermined primary and secondary endpoints, it does 363 have some limitations. Firstly, as this study was primarily designed to evaluate the safety and 364 tolerability profile of savolitinib, care must be taken when interpreting initial anti-tumor results due 365 to the exploratory nature of these findings. Additionally, only a very small number of patients with monotherapy remains poor (23,27,28), the outcomes of a phase III study evaluating the efficacy and 374 safety of savolitinib compared with sunitinib in MET-driven PRCC (Clinicaltrials.gov identifier: 375 NCT03091192), will be of interest. 3 (6) 3 (6) 3 (6) 3 (6) 2 (4) Research.
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