Targeting tumor driver appears effective in half of NSCLC patients

Treatment with the investigative agent tepotinib — an oral MET inhibitor — appears to produce a response in about half of patients diagnosed with metastatic or relapsed non-small cell lung cancers, according to a presentation at the virtual annual meeting of the American Society of Clinical Oncology 2020 (ASCO), as well as reported in the New England Journal of Medicine .

Among 99 patients treated for 9 months with tepotinib, the response rate by independent review was 46%, with a median duration of response of 11.1 months in the combined-biopsy group of patients, reported Paul Paik, MD, clinical director of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center, New York.

“The VISION study showed that the selective MET inhibitor tepotinib had durable clinical activity in patients with non-small cell lung cancer with MET mutations associated with exon 14 skipping,” Dr. Paik reported. “These findings validate MET exon 14 skipping mutations as bona fide therapeutic targets and underscore the importance of routine testing for these MET alterations by means of liquid or tissue biopsy.”

In the study, the patients’ tumors were biopsied by both methods, he reported. The response rate was 48% among 66 patients in the liquid-biopsy group and 50% among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% and was similar regardless of the previous therapy received for advanced or metastatic disease, Dr. Paik and colleagues reported.

A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small cell lung cancer, the researchers noted. They explained that in the molecular cascade, the MET proto-oncogene encodes a receptor tyrosine kinase, and binding to its ligand induces downstream signaling through the RAS–RAF and phosphoinositide 3-kinase pathways. Aberrant MET signaling drives tumor growth through increased cell proliferation, survival, invasion, and metastasis. MET dysregulation through splice-site alterations that cause a loss of transcription of exon 14 in MET can result from point mutations, insertions or deletions, or large-scale whole-exon deletions. These alterations spatially disrupt distinct splicing sites at the acceptor or donor site flanking MET exon 14. As a result of MET exon 14 skipping mutations, the MET juxtamembrane domain, which contains a binding site for Y1003 CBL, is deleted; this leads to impaired MET ubiquitination, decreased MET turnover, and increased signaling.

Tepotinib is designed to inhibit the oncogenic MET receptor signaling caused by MET alterations, including both MET exon 14 skipping alterations and MET amplifications, or MET protein overexpression.

“The 50% response rate in this study is meaningful,” said Wasif Saif, MD, deputy physician-in-chief and medical director of the Northwell Health Cancer Institute, Lake Success, New York. “However, caution is required as this was an open-label, phase 2 study and not validated in a phase III study yet. The most assuring fact is that this 50% response rate is not short of the responses seen in other drugs tested for lung cancer in the recent years, such as pembrolizumab.”

Asked about the implications of the VISION trial findings, Dr. Saif said, “It is clear to us now that non-small cell lung cancer is not just 1 disease, but many types of disease with specific genetic differences. Certain people may have non-inherited gene mutations that can cause their cancer cells to grow and multiply.

“Hence, this agent, a selective MET inhibitor, offers a new treatment option with favorable safety profile and without the toxicities of chemotherapy agents. However, we know tumor is smart to develop resistance to agents, therefore, we are required to now focus on drug switching and/or combination therapy to overcome target resistance,” he said.

In the open-label, phase II study, Dr. Paik administered tepotinib at a dose of 500 mg once daily in patients with advanced or metastatic non-small cell lung cancer with a confirmed MET exon 14 skipping mutation. As of Jan. 1, the researchers had enrolled 152 patients into the study and had administered tepotinib.

The median age of the patients in the efficacy population was 74 years; 46% of the patients had a history of smoking, and almost all (97%) had metastatic disease at study entry.

Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients.

Dr. Saif said that the pursuit of a MET-targeted agent has had disappointing results when Phase III trials have been conducted. “One of the possible explanations for their failure is due to the inclusion of patients with MET aberrations that are dispensable for tumor growth and thus insensitive to MET inhibition,” he suggested.

“On the other hand, MET exon 14 mutations have been identified as primary oncogenic drivers, offering a potential target that will be sensitive to MET inhibitors,” he said. “In other words, if MET activity is a primary driver of MET exon 14 mutation-positive tumor growth, there is good reason to suppose that selective MET inhibitors have the potential to deliver better efficacy with a favorable safety profile. This study provided the proof of the hypothesis.

“This agent further strengthens ’precision oncology’ to treat the patient according to genetic makeup of the tumor,” Saif said.

  1. This phase II study appears to show benefit for the MET-inhibitor tepotinib in patients with advanced non-small cell lung cancer.
  2. This report describes a therapeutic drug, tepotinib, that is not FDA approved for NSCLC.

The study was supported by Merck of Darmstadt, Germany.

Dr. Paik reports personal fees from Boehringer Ingelheim, personal fees from Takeda, personal fees from Celgene, personal fees from EMD Serono, personal fees from Calithera, personal fees from AstraZeneca, personal fees from Abbvie, and personal fees from Lilly Oncology outside the submitted work.

Saif disclosed no relevant relationships with industry.

Edward Susman, Contributing Writer, BreakingMED™

Cat ID: 122

Topic ID: 78,122,730,122,24,935,192,195,65,172