Targeted Therapy Options for MET-Dependent Lung Cancer

At the virtual 2020 Personalized Therapies in Thoracic Oncology meeting, Alexander Drilon MD, PhD, Memorial Sloan Kettering Cancer Center, New York, shared insight on targeted therapies for the treatment of patients with MET-dependent lung cancer.

Dr Drilon discussed the different states of MET dependency in the setting of lung cancers, pointing out that lung cancers can be dependent on MET as a primary or secondary driver. Of note, as a primary driver MET takes the form of MET amplification or MET exon 14 operations.

“Essentially it's a primary oncogene that drives cancer growth, and as you’ll see this can either take the form of MET amplification or MET exon 14 operations are the most popular to speak about,” Dr Drilon explained.

In looking at patients with MET exon 14-altered non–small-cell lung cancer (NSCLC), 40% have high expression of PD-L1, but the tumor mutation burden is still lower than compared with other lung cancers.

According to Dr Drilon, patients can respond to immunotherapy, but those with high PD-L1 expression may favor a combination of chemotherapy and immunotherapy over single-agent pembrolizumab.

Dr Drilon went on to mention the different ways to inhibit MET in cancer cells, starting with the type 1 tyrosine kinase inhibitors (TKIs), which are ATP-competitive and bind to the active conformation, using crizotinib (a type 1a drug), or capmatinib, tepotinib, and savolitinib (type 1b drugs).

In a study published by the New England Journal of Medicine on type 1 TKIs doe MET exon 14-altered NSCLC, capmatinib yielded objective response rates (ORRs) 68% (28) amongst treatment-naïve patients and 41% (69) among patients receiving capmatinib as second-line therapy. Treatment-naive patients also had a longer median progression-free survival (PFS) than second-line patients (9.7 months vs 8.1 months, respectively).

Meanwhile, savolitinib has been shown to yield the highest percentage of ORR for patients receiving second-line therapy (59%), but also had the highest drug discontinuation rate (15%), Dr Drilon told attendees.

Alternatively, tepotinib has had the most steady results with an overall ORR of 46% (44% treatment-naive; 46% second-line therapy) and a median overall PFS of 8.6 months. It also had the lowest drug discontinuation rate amongst all 3 treatment options.

In terms of resistance, MET inhibitor acquired resistance occurs on- and off-target, but patients have responded to TKI type switching, and more strategies to address resistance are still being explored.

MET TKI activity increases with increasing MET amplification, Dr Drilon noted.

“It’s something we’ve seen across a variety of clinical trials, that the activity of a TKI does seem to be dependent on increasing levels of amplification, meaning a cancer with high level amplification is more likely to be dependent on MET,” he said.

“Thankfully, MET inhibitors are active in MET-dependent cancers, and we have the FDA approval of capmatinib for MET exon 14,” Dr Drilon concluded.—Alexandra Graziano