EP08.02-140 MET Biomarker-based Preliminary Efficacy Analysis in SAVANNAH: savolitinib+osimertinib in EGFRm NSCLC Post-Osimertinib

Ahn, M-j.; Marinis, F. De; Bonanno, L.; Cho, B.C.; Kim, T.-M.; Cheng, S.; Novello, S.; Proto, C.; Kim, S.-W.; Lee, J.S.; Metro, G.; Yang, J.C.; Xu, W.; Hartmaier, Ryan J.; Telaranta-Keerie, A.; Poole, L.; Sequist, Lecia V.

doi:10.1016/j.jtho.2022.07.823

Cited by 35 publications

(29 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Discussionsupporting

confidence: 72%

“…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 .…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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 ].…”

Section: Clinical Development Of Savolitinib: Phase II Trialsmentioning

confidence: 99%

See 3 more Smart Citations

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

Zhu

Lu²,

Lü

2022

Cancers

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Clinical Development Of Savolitinib: Phase II Trialsmentioning

confidence: 99%

See 2 more Smart Citations

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

Zhu

Lu²,

Lü

2022

Cancers

View full text Add to dashboard Cite

show abstract

“…Our data, along with preliminary findings from the phase II SAVANNAH study (NCT03778229; ref. 31 ), highlight the challenges and importance of monitoring MET amplification during treatment, particularly considering the observed association between tumor content and MET amplification detection and the degree of ctDNA decrease during treatment, resulting in a high level of false negatives. This affects the potential to distinguish between true loss of MET amplification versus ctDNA content just decreasing to an undetectable level.…”

Section: Discussionmentioning

confidence: 99%

Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor–Mutated, MET-Amplified Non–Small Cell Lung Cancer: TATTON

et al. 2022

View full text Add to dashboard Cite

MET-inhibitor and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) combination therapy could overcome acquired MET-mediated osimertinib resistance. We present the final PhIb TATTON (NCT02143466) analysis (Part B, n=138/Part D, n=42) assessing oral savolitinib 600 mg/300 mg once daily (QD) + osimertinib 80 mg QD in patients with MET amplified EGFR mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) and progression on prior EGFR-TKI. An acceptable safety profile was observed. In Parts B and D, respectively, objective response rates were 33–67% and 62%, and median progression-free survival (PFS) was 5.5–11.1 and 9.0 months. Increased antitumor activity may occur with MET copy-number ≥10. EGFRm circulating tumor DNA clearance on treatment predicted longer PFS in patients with detectable baseline ctDNA, while acquired resistance mechanisms to osimertinib+savolitinib were mediated by MET, EGFR, or KRAS alterations.

show abstract

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations

Okuma,

Kubota,

Shimokawa

et al. 2024

JAMA Oncol

View full text Add to dashboard Cite

ImportanceNon–small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations.ObjectiveTo determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations.Design, Setting, and ParticipantsThis multicenter, open-label, single-group, phase 2 nonrandomized clinical trial enrolled patients from April 10, 2020, to May 31, 2022, with a follow-up of 6 months from the date the last patient was enrolled. The study enrolled 42 patients with uncommon EGFR mutations, of whom 40 were eligible.InterventionOsimertinib, 80 mg once daily, was administered orally to patients.Main Outcomes and MeasuresThe primary end point was the overall response rate (ORR). The secondary end points were disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), duration of response (DoR), and safety of osimertinib. Patients were included in the study on an intention-to-treat basis.ResultsOf the 40 eligible patients, 22 were men (55.0%) and the median age was 72 years (range, 39.0-88.0 years). The most common mutations were G719X (20 [50.0%]), S768I (10 [25.0%]), and L861Q (8 [20.0%]). The ORR was 55.0% (90% CI, 40.9%-68.5%) and the DCR was 90.0% (95% CI, 76.3%-97.2%). The median PFS was 9.4 months (95% CI, 3.7-15.2 months) after a median follow-up of 12.7 months (range, 2.7-30.7 months). The median TTF was 9.5 months (95% CI, 5.6-30.3 months), median OS was not reached (NR; 95% CI, 19.3 months to NR), and median DoR was 22.7 months (95% CI, 9.5 months to NR). The ORR for patients with solitary or compound uncommon EGFR mutations was 45.5% (90% CI, 26.9%-65.3%) and 66.7% (90% CI, 43.7%-83.7%), respectively. Median PFS for patients with solitary or compound uncommon EGFR mutations was 5.4 months (95% CI, 3.6-22.7 months) and 9.8 months (95% CI, 5.1 months to NR), respectively. Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI, 12.3 months to NR) and NR, respectively. Median DoR for patients with solitary or compound uncommon EGFR mutations was 22.7 months (95% CI, 3.6-22.7 months) or NR (95% CI, 5.7 months to NR), respectively. Grade 3 or 4 adverse events were reported by 11 patients (27.5%), and 5 patients (12.5%) developed interstitial lung disease. All adverse events were manageable, and there were no treatment-related deaths.Conclusions and RelevanceOsimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations. The results support the use of osimertinib as a treatment option for this patient population.Trial RegistrationJapan Registry of Clinical Trials Identifier: jRCTs071200002

show abstract

EP08.02-140 MET Biomarker-based Preliminary Efficacy Analysis in SAVANNAH: savolitinib+osimertinib in EGFRm NSCLC Post-Osimertinib

Cited by 35 publications

References 0 publications

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

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

Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor–Mutated, MET-Amplified Non–Small Cell Lung Cancer: TATTON

First-Line Osimertinib for Previously Untreated Patients With NSCLC and Uncommon EGFR Mutations

Contact Info

Product

Resources

About