Merck KGaA Advancing Tepotinib in MET-Altered Cancer Subpopulations

NEW YORK (GenomeWeb) – Early clinical trial data on Merck KGaA's c-Met inhibitor tepotinib suggests the drug may be efficacious against lung and liver tumors driven by alterations in the MET oncogene.

The development program for the drug in a molecularly defined non-small cell lung cancer subpopulation includes a companion diagnostic strategy involving tests that can gauge MET exon-14-skipping mutations in tumor tissue and blood.

At the American Society of Clinical Oncology's meeting earlier this month, the German drugmaker presented preliminary data from the single-arm, Phase II VISION study involving advanced NSCLC patients who had tumors characterized by MET exon-14-skipping mutations as established by Thermo Fisher Scientific's next-generation sequencing multimarker Oncomine Focus Assay and Guardant Health's circulating tumor DNA blood test Guardant360. 

Based on the preliminary evaluation of 28 patients, 43 percent saw their tumors shrink, and 21 percent had stable disease lasting at least three months.

"In a population that's not responding, as far as I can tell, to available therapies, [this] is quite remarkable," Tim Demuth, head of global clinical development oncology at Merck KGaA, told GenomeWeb. Approximately 3 percent of NSCLC patients harbor MET exon-14-skipping mutations, and the clinical evidence to date suggests that this subset of patients don't respond well to the class of immunotherapeutics called checkpoint inhibitors. 

At the time of the interim analysis in the VISION trial, 23 patients harbored MET exon-14-skipping mutations by ctDNA analysis, 31 patients were mutation positive by tumor tissue testing, and 17 patients were mutation positive by both methods. Out of 16 patients in included in the efficacy analysis who had mutation status determined by liquid biopsy, nine had a partial response, two had stable disease, three had progression, and two were not evaluable. Of the 26 treated who were included in the efficacy analysis and who had mutation status determined by tissue-based NGS testing, 11 had a partial response to the drug, six had stable disease, five had progression, and four were not evaluable.

Merck's development strategy for tepotinib in NSCLC includes simultaneous advancement of liquid biopsy- and tissue-based companion diagnostics. "We plan to get these tests approved in parallel with any tepotinib filing process," he said. "They will be used as companion diagnostics for the treatment of NSCLC patients with MET exon-14-skipping alterations identified in their tumors or peripheral blood."

In the VISION trial, mutation status in tumor tissue was determined using Thermo Fisher's multimarker Oncomine Focus assay, though it's worth noting that the US Food and Drug Administration has already approved a 23-gene NSCLC panel, called Oncomine Dx Target Test, which can analyze MET (though it's not one of the genes with an FDA-approved CDx indication). Guardant is also preparing to submit a regulatory filing with the FDA for its liquid biopsy assay, which was used in the VISION trial.

Merck sees the value of using tests that can gauge a variety of mutations in lung cancer and guide treatment to multiple drugs. "The system we are currently planning to implement is an NGS-based panel approach to obtain all relevant information from one assay in the most convenient way for patients and physicians," Demuth said. "The approach will not only include assays for our focal interest of MET exon-14-skipping mutations and MET gene amplification, but also assays to assess the genetic and genomic status of other known lung cancer biomarkers."

Using this approach, he said Merck will be able to better adapt as research elucidates new molecular insights. Demuth highlighted that Merck also has a collaboration with Illumina from 2015 around its universal NGS panel test. 

The VISION trial is continuing and will enroll 120 patients, half of whom will have their mutation status determined by Guardant's test and the other half by Oncomine. The study is slated for completion this month, at which point Merck will decide its regulatory strategy in the US. Meanwhile, the Japanese Ministry of Health, Labor, and Welfare has already granted fast track review status to tepotinib as a treatment for NSCLC patients with MET exon-14-skipping mutations.

Better than Xalkori?

"Tepotinib clearly hits the target," Ross Camidge from the University of Colorado, Aurora, said at the ASCO meeting in reviewing the data from the VISION trial. "But it's not particularly clear yet whether this is any better [in terms of efficacy] or better tolerated than crizotinib," which is marketed by Pfizer as Xalkori.

Xalkori is a first-generation c-Met and ALK inhibitor though the drug is currently only approved for NSCLC patients with ALK and ROS1 rearrangements, and not for those with MET alterations. Based on early data for VISION, tepotinib seems to have comparable response rates with Xalkori in this molecularly defined subpopulation, and while the median duration of response seems longer for tepotinib (at around 12 months), Camidge noted that these are still early data from a small number of patients.

Common adverse events seen with tepotinib in the VISION study were grade 1 or 2 peripheral edema and diarrhea, and 13 percent of participants in the trial discontinued the study based on treatment-related adverse events. Tepotinib may have fewer adverse events compared to Xalkori, such as vision impairments and nausea, though Camidge noted that these side effects are also manageable.

At ASCO, Camidge presented data from a study in which 37 NSCLC patients with low, medium, and high MET amplification were treated with Xalkori. Of these patients, eight out of 20 patients with high MET amplification, two out of 14 patients with medium amplification, and one out of three patients with low amplification saw their tumors shrink. Two patients with high MET amplification had complete responses, while patients in the other biomarker groups had partial responses. The median progression-free survival was 6.7 months, 1.9 months, and 1.8 months in the high, medium, and low MET-amplified subgroups, respectively.

"Patients with NSCLC with high MET amplification showed clinically meaningful antitumor activity with rapid and durable responses," Camidge and colleagues concluded in an abstract. The researchers are exploring how MET amplification coincides with MET exon 14 alterations in Xalkori-treated patients.

One of Xalkori's downsides is that although lung cancer patients on the drug initially respond well to treatment, their disease eventually returns and often spreads to the brain. Next-generation drugs in the same class are trying to overcome this limitation. For example, Genetech's Alecensa (alectinib), which the FDA approved last year in ALK-positive NSCLC, has shown it can significantly reduce the risk of brain metastases in patients compared to patients receiving Xalkori. 

"Crizotinib has a clear liability in terms of its [central nervous system] activity," Camidge said. A few patients with small CNS tumors were included in the VISION trial, though he noted the need to further explore tepotinib's activity against brain metastases. Based on the data presented on tepotinib at ASCO, Camidge said it also remains unclear if the drug has activity against any of the known resistance mechanisms to MET tyrosine kinase inhibitors.

'Met-altered' tumors

Merck is exploring how different types of Met activating alterations impact response to tepotinib in tumor types beyond NSCLC.

Earlier this month, Merck announced that two studies investigating tepotinib in MET-positive, advanced liver cancer had met their primary endpoints. The first Phase Ib/II trial compared tepotinib against Bayer's Nexavar (sorafenib) as a front-line option in 90 Asian patients, and a second, single-arm trial investigated the c-Met inhibitor as a second-line option for 49 patients who have failed to respond to Nexavar.

Patients in the liver cancer trials had to have MET-positive tumors as determined by central lab testing, although Merck hasn't publicly disclosed how it's defining MET positivity. The company plans to present detailed data from these trials at an upcoming medical conference.

"These results [in the liver cancer studies], together with the interim data seen in patients with advanced non-small cell lung cancer harboring MET exon-14-skipping mutations presented at ASCO, provide further evidence of the potential of tepotinib as an innovative precision medicine," Luciano Rossetti, Merck's global head of research and development, said in a statement.