Orpathys (savolitinib) / AstraZeneca, Hutchmed - LARVOL DELTA

SAVANNAH: Savolitinib (savo) + osimertinib (osi) in patients (pts) with EGFRm advanced NSCLC and METoverexpression (OverExp) and/or amplification (Amp) following progressive disease (PD) on osi (ELCC 2025) - P2, P3 | "After PD on 1L osi, savo 300 mg BID + osi was well tolerated and demonstrated clinically meaningful and durable response in pts with EGFRm advanced NSCLC with MET IHC 3+/≥90% and/or FISH10+ status. This combination offers a potential treatment option in this setting and is under further investigation in the ongoing Ph 3 SAFFRON study (NCT05261399)."

Clinical • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

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. (ASCO 2025) - P3 | "Eligible pts were randomly assigned (1:1) to receive savo 400 or 600 mg QD (for body weight of < 50, or ≥ 50 kg respectively) + osi 80 mg QD, or chemo (pemetrexed + carboplatin/cisplatin), stratified by brain metastases, prior use of 3G EGFR-TKI, and type of EGFR mutations... From 15 Oct 2021 to 30 Aug 2024 (DCO for IA), 211 pts were randomized to receive savo + osi or chemo (n=106 vs 105)... Savo + osi significantly improved PFS versus chemo in METamp NSCLC post EGFR-TKI, and the combination was safe and well tolerated. Savo + osi is a potential new treatment option for this genomically defined population. *52.4% of pts in chemo group were crossover to receive savo + osi or other MET Inhibitors."

Clinical • Late-breaking abstract • Metastases • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET

Savolitinib plus osimertinib versus chemotherapy for advanced, EGFR mutation-positive, MET-amplified non-small-cell lung cancer in China (SACHI): interim analysis of a multicentre, open-label, phase 3 randomised controlled trial. (PubMed, Lancet) - P3 | "The savolitinib-osimertinib combination improved PFS versus chemotherapy in patients with EGFR mutation-positive, MET-amplified NSCLC that had progressed on EGFR TKI therapy, while maintaining a favourable tolerability profile. This regimen offers a potential oral treatment option for this biomarker-selected population."

Journal • P3 data • P3 data: top line • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET

CALYPSO: A three-arm randomized phase II study of durvalumab alone or with savolitinib or tremelimumab in previously treated advanced clear cell renal cancer. (ASCO 2022) - P2 | "This randomised phase II study did not demonstrate significant efficacy for S alone or in combination with D in RCC. The addition of T to D did not demonstrate clearly superior efficacy to D in this setting."

Clinical • Late-breaking abstract • P2 data • Immune Modulation • Inflammation • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Final Overall Survival Analysis of S1500: A Randomized, Phase II Study Comparing Sunitinib With Cabozantinib, Crizotinib, and Savolitinib in Advanced Papillary Renal Cell Carcinoma. (PubMed, J Clin Oncol) - P2 | "In conclusion, we observed no significant difference in OS across treatment arms. Although cabozantinib represents a well-supported option for advanced PRCC, the lack of survival benefit underscores the need to develop novel therapies for this disease."

Journal • Metastases • P2 data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Pathologic concordance rate and outcomes by histologic subtype in advanced papillary renal cell (pRCC) carcinoma: An analysis from the SWOG S1500 (PAPMET) trial. (ASCO 2023) - P2 | " Patients with advanced pRCC who had received up to 1 line of therapy were randomized to receive either sunitinib, or cabozantinib, crizotinib or savolitinib stratified by pRCC subtype (type 1, type 2 or not otherwise specified [NOS])... Designation of pRCC subtype by central review did not identify a subset of patients with greater clinical benefit from cabozantinib. Further, classification of subtype was challenged by discordance in both local and central review. Supporting the removal of type 1 and 2 designations from the 2022 WHO guidelines, these findings highlight the limited clinical value and significant challenges associated with subtyping of pRCC."

Discordant • Metastases • Oncology • MET

Precision immuno-oncology for advanced non-small cell lung cancer (NSCLC) patients with PD-(L)1 inhibitors resistance (PIONeeR): A phase Ib/IIa clinical trial targeting identified resistance pathways (ESMO 2024) - P2 | "Pts were randomly allocated to Arm A: Durvalumab (Du) + Monalizumab, Arm B: Du + Oleclumab, Arm C: Du + Ceralasertib, Arm E: Du + Savolitinib or Arm D (control): Docetaxel. With its innovative and adaptive design, the PIONeeR trial was able to explore several options to overcome resistance to ICIs. Although no experimental arm performed better than outcomes observed with docetaxel, some pts had long DoR, suggesting durvalumab combinations can be highly effective. Biomarker work is ongoing to identify patients most likely to benefit from combination treatment."

Clinical • Immuno-oncology • IO biomarker • Late-breaking abstract • Metastases • P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Final efficacy data and biomarker analysis from the clear cell cohort of CALYPSO (ESMO 2025) - P2 | "Background CALYPSO is a phase II trial evaluating durvalumab (D), savolitinib (S) and tremelimumab (T) in previously treated advanced renal cell carcinoma (RCC). While response rates for DT were higher than D alone, the predefined requirements were not met. Other endpoints such as OS were not discriminatory compared to D monotherapy."

Biomarker • Clinical • IO biomarker • Tumor mutational burden • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • KIM1 • PD-L1 • TMB

Final overall survival and new ctDNA analysis in MET-driven advanced papillary renal cancer (CALYPSO). (ASCO-GU 2025) - P2, P3 | "Clinical Trial Registration Number: NCT02819596 Background: Phase II data from the CALYPSO study (NCT02819596) has shown activity for durvalumab (PD-L1 inhibitor) plus savolitinib (MET inhibitor) (D+S) in MET-driven advanced papillary renal cancer (aPRC), resulting in the ongoing randomised phase III study, SAMETA (NCT03091192). D+S continue to show impressive efficacy in MET driven tumors, supporting the ongoing SAMETA trial. ctDNA monitoring on therapy holds promise as a prognostic and potentially predictive tool in this setting."

Circulating tumor DNA • Clinical • IO biomarker • Metastases • Tumor mutational burden • Genito-urinary Cancer • Kidney Cancer • Oncology • Solid Tumor

A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. (PubMed, Lancet) - P2 | "Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC."

Clinical • Journal • Cardiovascular • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • MET

Pathological concordance rate and outcomes by subtype in advanced papillary renal cell carcinoma. (PubMed, BJU Int) - "The PRCC subtype assignment did not identify a subset of patients with greater clinical benefit from cabozantinib, with significant discordance between local and central review. Our findings confirm the limited clinical value of pathological subtyping of metastatic PRCC, in line with the recent World Health Organisation 2022 guidelines."

Discordant • Journal • Metastases • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

TATTON: AZD9291 in Combination With Ascending Doses of Novel Therapeutics (clinicaltrials.gov) - P1 | N=344 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer with MET overexpression and/or amplification following disease progression on osimertinib: primary results from the phase II SAVANNAH study. (PubMed, Ann Oncol) - P2 | "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."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • MET

SAVANNAH: Biomarker Concordance and Acquired Resistance in Patients with EGFRm MET-OverExp and / or Amp NSCLC (IASLC-WCLC 2025) - P2 | "MET ctDNA NGS had high specificity but modest sensitivity for MET FISH10+ detection, with further reduced sensitivity when IHC90+ was also considered. Acquired resistance mutation profiles to savolitinib ± osimertinib included known on-target and suspected bypass signalling resistance mechanisms."

Biomarker • Clinical • Discordant • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • BRAF • EGFR • ERBB3 • MET

Efficacy and CNS results from a randomized subset of the phase 2 SAVANNAH study comparing savolitinib (savo) + osimertinib (osi) combination with savo + placebo (PBO). (ASCO 2025) - P2 | "In EGFRm advanced NSCLC with MET IHC3+/≥90% and/or FISH10+ status after PD on 1L osi, efficacy of savo 300 mg BID + osi was numerically greater than savo + PBO and showed promising CNS activity. To date, this is one of the largest randomized data sets presented evaluating an oral MET-TKI in EGFRm NSCLC. Efficacy findings from SAVANNAH suggest that targeting both EGFR and MET is key and support further investigation of savo + osi and CNS activity in the Phase 3 SAFFRON study."

Clinical • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • MET

A tri-scale in silico framework integrating pharmacovigilance and mechanistic modeling suggests tepotinib-associated acute kidney injury risk. (PubMed, Ren Fail) - "Molecular docking revealed high-affinity binding between tepotiniband all six hub targets (Vina scores: -8.0 to -10.6 kcal/mol), providing a structural basis for the postulated mechanistic link to AKI. These findings not only highlight the necessity for enhanced renal monitoring in tepotinib-treated patients but, more broadly, establish the FAERS-NetDock Pipeline as a reusable, generalizable and hypothesis-generating framework for evaluating tyrosine kinase inhibitors (TKIs)-induced nephrotoxicity; this framework is immediately applicable to profiling the safety of other TKIs (e.g. crizotinib, capmatinib, savolitinib, afatinib and osimertinib) and is readily adaptable for de-risking a wider spectrum of targeted therapies."

Adverse events • Journal • Acute Kidney Injury • Lung Cancer • Nephrology • Non Small Cell Lung Cancer • Oncology • Renal Disease • Solid Tumor • AKT1 • CASP3 • CDC37 • EGFR • HSP90AA1

Targeting Mesenchymal-Epidermal Transition (MET) Aberrations in Non-Small Cell Lung Cancer: Current Challenges and Therapeutic Advances. (PubMed, Cancers (Basel)) - "Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC."

Journal • Review • Gastrointestinal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

SAVOIR: Savolitinib vs. Sunitinib in MET-driven PRCC. (clinicaltrials.gov) - P3 | N=60 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Genito-urinary Cancer • Kidney Cancer • Nephrology • Oncology • Papillary Renal Cell Carcinoma • Renal Cell Carcinoma • Renal Disease • Solid Tumor • Urethral Cancer • VHL

Ph2 Study of Savolitinib and Durvalumab (MEDI4736) Combination in Advanced MET Amplified Gastric Cancer(VIKTORY-2) (clinicaltrials.gov) - P2 | N=25 | Recruiting | Sponsor: Jeeyun Lee | Trial completion date: Dec 2026 ➔ Jun 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Gastric Cancer • Oncology • Solid Tumor • MET

Phase II Study Investigating the Safety and Efficacy of Savolitinib and Durvalumab in Metastatic Papillary Renal Cancer (CALYPSO). (PubMed, J Clin Oncol) - P2 | "The combination of savolitinib and durvalumab was tolerable and associated with high cRRs in the exploratory MET-driven subset."

IO biomarker • Journal • Metastases • P2 data • CNS Disorders • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

SAMETA: A Phase III study of savolitinib + durvalumab vs sunitinib and durvalumab monotherapy in patients with MET-driven, unresectable, locally advanced/metastatic papillary renal cell carcinoma (KCRS 2023) - No abstract available

Clinical • Metastases • Monotherapy • P3 data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

SOUND: Savolitinib Combine With Durvalumab in EGFR Wild-type Locally Advanced or Metastatic NSCLC (clinicaltrials.gov) - P2 | N=47 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Aug 2025 ➔ Jan 2027 | Trial primary completion date: Aug 2025 ➔ Jan 2027

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

Final OS results and subgroup analysis of savolitinib in patients with MET exon 14 skipping mutations (METex14+) NSCLC (ELCC 2022) - P2 | "Overall, with prolonged follow-up and exposure, the incidences of AE were similar to previously reported data, and consistent across subgroups. Conclusions The updated results further confirm the favorable benefit of savolitinib in pts with METex14+ NSCLC and each subgroup, and the acceptable safety profile."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

Efficacy of Savolitinib vs Sunitinib in Patients With MET-Driven Papillary Renal Cell Carcinoma: The SAVOIR Phase 3 Randomized Clinical Trial. (PubMed, JAMA Oncol) - P3 | "Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. ClinicalTrials.gov Identifier: NCT03091192."

Clinical • Journal • P3 data • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Long-Term Efficacy, Safety, and Subgroup Analysis of Savolitinib in Chinese Patients With NSCLCs Harboring MET Exon 14 Skipping Alterations. (PubMed, JTO Clin Res Rep) - P2 | "No new safety signals emerged with prolonged follow-up and exposure. The updated results further confirm the favorable benefit and acceptable safety of savolitinib in Chinese patients with METex14-positive NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • MET