Tabrecta (capmatinib)

The majority of these AEs were observed within the initial months of initiating treatment with MET-selective TKIs and persistently thereafter. Notably, our investigation unveiled a significant correlation between the usage of capmatinib and the incidence of hearing loss and difficulty in swallowing. Diligent monitoring and the implementation of supportive care strategies are essential in managing the toxicities associated with MET-selective TKIs, particularly those related to gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and ototoxicity.

P4, N=50, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2024 --> Jun 2025 | Trial primary completion date: Jul 2024 --> Jun 2025

P1/2 | "Clinical Trial Registration Number: NCT05488314"

Further, patients receiving CT (HR: 4.43; 95% CI: 1.54-12.75; p = 0.006) and IO + CT (HR: 3.53, 95% CI: 1.41-8.85; p = 0.007) had higher rates of mortality than patients receiving capmatinib. The study showed better clinical outcomes with capmatinib than other standard therapies in 1L setting for aNSCLC harboring METex14.

Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation...Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1...Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.

A T-cell mediated killing sensitivity gene-based prognostic score TTKPI showed good accuracy in predicting survival in AML. TTKPI corresponded to functional and immunological features of the tumor microenvironment including checkpoint expression patterns and should be investigated for precision medicine approaches.

Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.

There are three currently active sub-studies and one soon to be activated sub-study studying amivantamab-vmjw in MET amplification positive NSCLC (S1900J). Current sub-studies: S1900E (KRAS) activated on April 2, 2021 and is studying sotorasib (AMG 510) in non-squamous NSCLC...S1900G (EGFR and MET) activated on April 3, 2023 and is studying capmatinib and osimertinib with or without ramucirumab in NSCLC. S1900K (MET exon 14 skipping) activated on December 18, 2023 and is studying tepotinib with or without ramucirumab in NSCLC...One hundred seventy (7%) were submitted with the classification of "Other". The most common reasons included: no sub studies available, patient chose hospice, and patient transferred to different hospital.

Here, we present a case of a 72-year-old woman with NEC of the gallbladder with multiple liver and lymph node metastases, who was resistant to conventional chemotherapy including carboplatin plus etoposide as first-line treatment and irinotecan as second-line treatment, but she responded to capmatinib. After 6 weeks of treatment, CT scan showed a partial response (80% reduction in size), but after 13 weeks, regrowth of liver metastasis was observed. Herein, we report a meaningful efficacy of capmatinib to the patient of NEC of the gallbladder origin with MET amplification.

A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.

P2, N=373, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.

While c-MET inhibitors such as crizotinib, capmatinib, tepotinib and cabozantinib have garnered FDA approval for non-small cell lung cancer (NSCLC), their potential within breast cancer therapy is still undetermined...Furthermore, we highlight the pivotal role of c-MET-targeted therapies in breast cancer, offering a clinical perspective on this promising avenue of intervention. In this pursuit, we strive to unravel the potential of c-MET as a beacon of hope in the fight against breast cancer, unveiling new horizons for therapeutic innovation.

In addition, the fold changes in ctDNA dynamics during treatment significantly correlated with changes in tumor size and CEA levels, as well as with droplet digital PCR copy number fold changes. In a patient with MET amplification, ctDNA NGS identified MET Y1230H as a potential acquired resistance mutation after crizotinib treatment, which responded to cabozantinib but not to capmatinib.Conclusions Initial tumor profiling using ctDNA NGS yielded outcomes comparable to those of tumor tissue NGS in guiding treatment for patients with newly diagnosed mCRC, thereby suggesting its utility as an initial profiling method in mCRC.

In a transwell assay, the A. lactiflora diethyl ether extract (32 μg/ml) and dihydroactinidiolide (250 μg/ml) markedly inhibited the migration and invasion of non-small cell lung cancer (NSCLC) cells, similar to the standard anti-metastatic drug (capmatinib). Western blot analysis revealed that mesenchymal N-cadherin is downregulated in NSCLC cells under the treatment conditions. The potential anti-metastatic property of dihydroactinidiolide is promising as a new candidate anti-metastatic agent for lung cancer treatment.

One patient received Capmatinib and one patient Pembrolizumab. This study showed that NSCLC with METex14 are poorly differenciated tumors with necrotic background,multinucleation,atypical mitoses,and pleomorphic/sarcomatoid features. Larger studies are needed to confirm our preliminary findings. Routine NGS testing on cytological specimens is feasible and essential for METex14 testing and select patients with advanced lung NSCLC for targeted therapies.

Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added...The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.

Promising preliminary results from trials enrolling patients with EGFR-mutated, METamp advanced NSCLC progressing on an EGFR-tyrosine kinase inhibitor (TKI) were observed with MET-TKIs (i.e., tepotinib, savolitinib, and capmatinib) in combination with EGFR-TKIs (i.e., gefitinib and osimertinib). For metastatic NSCLC and high-level METamp, monotherapy with capmatinib, crizotinib, and tepotinib are recommended in the 2022 published NSCLC NCCN Guidelines...Several treatments are promising in treating METamp NSCLC. Additional studies evaluating the clinical, economic, and humanistic burdens are needed.

CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.

Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC ranging from IC 0.60 to 2.32 µM...Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis. These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.

P2, N=37, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | Trial completion date: Jan 2025 --> Dec 2025 | Trial primary completion date: Jan 2025 --> Dec 2025

P3, N=22, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed

Inhibition of MET with capmatinib enhanced the effect of radiation in both MET exon 14-mutated and MET-amplified NSCLC models.

P1/2, N=161, Recruiting, Janssen Research & Development, LLC | Trial completion date: Sep 2025 --> Aug 2026

P2, N=3, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2028 --> Aug 2026 | Trial primary completion date: Sep 2023 --> Aug 2026

MET exon 14 (METex14) skipping mutation is noted in approximately 4% of NSCLC cases and is targetable with the recently approved tyrosine kinase inhibitors capmatinib and tepotinib. We highlight some ongoing capmatinib clinical trials that expand their role to other subsets of patients, especially those with EGFR mutations, who develop MET alterations as a resistance pathway. We further provide our perspective on the management of METex14 NSCLC, strategies for sequencing agents, and toxicity management.

P2; Not yet recruiting --> Recruiting

We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance.

P=N/A, N=100, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2025 --> Oct 2024 | Trial primary completion date: Mar 2025 --> Oct 2024

An interim analysis is planned for when 26 progression-free survival events have been reported. Summary Statement As of June 30, 2023, three LUNGMAP participants have been assigned and two have registered to S1900G.

An interim analysis is planned for when 26 progression-free survival events have been reported. Summary Statement As of June 30, 2023, three LUNGMAP participants have been assigned and two have registered to S1900G.

The best five candidates, namely tucatinib, capmatinib, moxidectin, rifampicin, and acetyldigoxin, were evaluated further in vitro. Together, our results suggest that two known drugs currently being used to treat specific cancer types may have a dual effect and target more than one enzyme that facilitates the development of these types of cancers. Furthermore, the results of this study could be used as a new starting point for identifying more potent and specific LDH-B inhibitors.

Improvements with tepotinib vs comparators were also seen in VISION pts overall and pts in Asia, regardless of T+ status. Conclusions Based on available evidence (with limited capmatinib subgroup size), the MAICs show no clinically relevant differences in ORR and trends for longer PFS and/or OS with tepotinib vs savolitinib, gumarontinib, or capmatinib in pts in Asia in 1L and 2L+.

The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine appears elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.

The use of hepatoprotective drugs, in addition to oral ursodeoxycholic acid, resulted in liver blood tests normalization...Only two cases of DILI out of 105 reports were found for tepotinib. Our data support a potential association between capmatinib and DILI in patients who have also been previously exposed to immunotherapy. Considering the potential implications for sequence strategy and timing of ICI and MET inhibitor, further investigation is warranted.

P1, N=65, Completed, SCRI Development Innovations, LLC | Active, not recruiting --> Completed

48 patients received subsequent METi (crizotinib, n=20; capmatinib, n=15; bozitinib, n=4; tepotinib, n=3; amivantamab, n=3; cabozantinib, n=3; other, n=4; different METi in subsequent lines, n=4)... Robust and durable efficacy, particularly in the 1L setting, support early use of tepotinib in the treatment sequence. Almost half of this elderly population received subsequent treatment, higher than the 20%–30% reported for 1L CT/IO IPSOS trial in elderly patients (median age 75). METi treatment sequencing analyses are ongoing.

Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Dual EGFR and MET inhibition yielded high clinical response rate after progression on OSI. Resistance mechanisms to EGFR-MET double TKI inhibition include MET secondary mutation, EGFR secondary mutation, or loss of MET amplification.

Patients with METex14 skipping are more likely to have certain characteristics, but no patient subgroup can be ruled out; thus, it is crucial to test all patients with NSCLC to identify suitable candidates for MET inhibitor therapy. MET TKIs appeared to result in higher efficacy outcomes, although no direct comparison with chemotherapy or immunotherapy regimens was found.

No abstract available

P2; Trial completion date: May 2028 --> Sep 2028 | Initiation date: May 2023 --> Sep 2023 | Trial primary completion date: May 2026 --> Sep 2026

FDA-approved MET-TKIs currently represent the best option for treating exon 14 skipped advanced NSCLC patients, thanks to their excellent efficacy profile, alongside their manageable safety and tolerability. However, we currently lack specific agents to treat patients progressing on capmatinib or tepotinib, due to a limited understanding of the mechanisms underlying both on- and off-target resistance. In this respect, on-target mutations presently constitute the most explored ones from a mechanistic point of view, and type II MET-TKIs are currently under investigation as the most promising agents capable of overcoming the acquired resistance.