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.

In 2021, two drugs, amivantamab and mobocertinib each received FDA accelerated approval for second line use after platinum based therapy. The PAPILLON regimen received subsequent FDA approval. In this commentary, we review the details of PAPILLON and also discuss why the rival trial, EXCLAIM2, may have failed.

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

Inhibitors of protein export from the endoplasmic reticulum (ER), such as brefeldin A (BFA) and 2-methylcoprophilinamide (M-COPA), can suppress the activation of mutant RTKs in cancer cells, suggesting that RTK mutants cannot initiate signaling in the ER...Consistent with these results, in vitro pulldown assays showed that BFA/M-COPA blocked the function of ARF1, ARF4, and ARF5. Taken together, these results suggest that BFA/M-COPA targets at least ARF1, ARF4, and ARF5; in other words, RTKs require the simultaneous activation of ARF1, ARF4, and ARF5 for their ER export.

After platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

This pharmacovigilance study systematically explored the cardiovascular adverse events of amivantamab and provided new safety signals based on past safety information. Early and intensified monitoring is crucial, and attention should be directed towards high-risk signals.

P1/2, N=117, Recruiting, Janssen Research & Development, LLC

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

P3 | "Clinical Trial Registration Number: NCT05388669"

P3 | "Clinical Trial Registration Number: NCT04487080"

P2, N=300, Recruiting, Janssen Research & Development, LLC | N=180 --> 300

P2, N=74, Active, not recruiting, Janssen Research & Development, LLC | Recruiting --> Active, not recruiting

P1, N=110, Recruiting, Fusion Pharmaceuticals Inc. | Initiation date: Feb 2024 --> Jun 2024

The MARIPOSA trial was designed to study if the combination of amivantamab plus lazertinib in untreated epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients would provide improved progression-free survival. Here, we discuss the rationale for the study and the early results of MARIPOSA.

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.

Data provide new insights into the molecular mechanisms involved in CDPs cytotoxicity and antiproliferative effects, suggesting that the signal transduction mechanism may be related to the inhibition of the phosphorylation of the EGF/MET receptor at the level of substrate binding site by an inhibition mechanism similar to that of Gefitinib and foretinib anti-neoplastic drugs.

P1, N=0, Withdrawn, M.D. Anderson Cancer Center | N=60 --> 0 | Trial completion date: Dec 2025 --> Apr 2024 | Active, not recruiting --> Withdrawn | Trial primary completion date: Dec 2025 --> Apr 2024

NSCLC w/EGFRex19del & MET amp: durable intracranial + systemic response to amivantamab/osimertinib.

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.

Seventeen patients received immunotherapy, and 1 patient received targeted therapy with the MET inhibitor glumetinib. PSC has a higher incidence in the elderly, smokers, and males, is highly malignant and has a poor prognosis. Based on its molecular biological characteristics, PD-L1 expression and tumor molecular detection can be performed to guide treatment options.

Consequently, their detection allows for the selection of emerging treatment options to significantly improve patients' outcomes in these particular subgroups of EGFR-mutated advanced non-small cell lung cancer (NSCLC). Specifically, this commentary is focused on the notable progress of the Phase 3 PAPILLON study that showed primary efficacy results from amivantamab, a bispecific antibody with specific binding and affinity to extracellular domains of EGFR and MET, plus chemotherapy in the first-line setting for EGFR exon 20 insertion-mutated advanced or metastatic NSCLC patients, as compared with chemotherapy alone, thus becoming the new standard of care in this group of patients.

P2, N=88, Not yet recruiting, SWOG Cancer Research Network | Initiation date: Feb 2024 --> May 2024

Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.

P2, N=60, Recruiting, Beijing Scitech-Mq Pharmaceuticals Limited

P2, N=12, Terminated, Dana-Farber Cancer Institute | Trial completion date: Mar 2024 --> Oct 2023 | Active, not recruiting --> Terminated; Funding was pulled

P1/2, N=64, Recruiting, Beijing Scitech-Mq Pharmaceuticals Limited

No abstract available

The costly price of amivantamab is one of the major reasons for the high cost of this combined treatment strategy. Therefore, it is imperative to take into account the high cost of amivantamab in the subsequent clinical application and strive to attain a relative equilibrium between its significant clinical benefit and economic encumbrance.

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.

Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC.

P1, N=8, Not yet recruiting, AstraZeneca

P1/2, N=156, Recruiting, Avistone Biotechnology Co., Ltd.

P2, N=62, Terminated, Janssen Pharmaceutical K.K. | Completed --> Terminated; Due to reconsideration of development strategy

P1, N=60, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Phase classification: P1a/1b --> P1 | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

Recently, several TKIs, for instance regorafenib and cabozantinib, have showed clinical interest in treating osteosarcoma and target both vascular endothelial growth factor receptor (VEGFR) and mesenchymal epithelial transition factor (c-MET)...More importantly, BMS-794833 and anlotinib exerted synergistic therapeutic effects against osteosarcoma in vivo. Altogether, this study reveals a new (VEGFR)-targeting drug that can be combined with anlotinib for the treatment of osteosarcoma, which provides an important theoretical basis for overcoming anlotinib resistance.

P1/2, N=80, Recruiting, Janssen Research & Development, LLC | Trial completion date: Nov 2025 --> Aug 2026

P1, N=166, Recruiting, Janssen Research & Development, LLC | Trial primary completion date: Jan 2024 --> Oct 2024

P1, N=751, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2024 --> Jun 2025

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.

P1, N=216, Recruiting, Avistone Biotechnology Co., Ltd.

P1/2, N=22, Terminated, Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | N=192 --> 22 | Trial completion date: Dec 2024 --> Feb 2024 | Recruiting --> Terminated; sponsor adjusts its research and development strategy