Just weeks after seeing one late-stage candidate hit a wall in a subtype of non-small-cell lung cancer (NSCLC), Merck KGaA's EMD Serono has won accelerated approval from the FDA for another important NSCLC therapy, Tepmetko (tepotinib). The new oral drug, for adults with metastatic disease harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations, became the first of its kind to win a global regulatory go-ahead in March 2020 with approval from Japan’s MHLW. Now it will join Novartis AG's Tabrecta (capmatinib), FDA-approved in May 2020, in expanding the options for patients who until last year had few good choices.

On the road to approval, the FDA granted Tepmetko both breakthrough therapy and orphan status.

Until recently, METex14 patients have primarily been treated with either Keytruda (pembrolizumab, Merck & Co. Inc.) monotherapy or combined with chemotherapy. But, as they tend to be elderly, that combination is rarely well-tolerated or highly effective. Tepmetko "offers a much more tailored, targeted treatment option" for those patients, Klaus Edvardsen, global head of oncology development at Merck Group, told BioWorld. As a once-daily pill, it also provides greater ease and convenience vs. Tabrecta's twice-daily regimen, especially for patients taking their medicine primarily at home.

Klaus Edvardsen, global head of oncology development, Merck Group

METex14 skipping occurs in about 3% to 4% of advanced NSCLC cases, representing a fairly small population in the broader occurrence of lung cancer, the second most common cancer globally after breast cancer. But Merck has its eye on a much bigger picture.

"The broader picture for where Tepmetko is going to be an important player is as a rescue medicine for EGFR-mutation-driven non-small-cell lung cancer," Edvardsen said.

Astrazeneca plc's Tagrisso (osimertinib) has seen strong overall uptake in NSCLC given its demonstrated survival advantage. "But, as with any other TKI, sooner or later those patients will be in need of another treatment," he said. One of the resistance mechanisms that can lead to that point is MET amplification, with maybe a third of patients who relapse after taking the drug. Preliminary data suggest that Tepmetko could be a very effective medicine in that respect, he said, something that's being evaluated now in Merck's ongoing Insight-2 trial. The phase II study combines tepotinib with Tagrisso for patients with relapsed MET factor amplification NSCLC.

From the earlier Insight trial, Merck has even more data showing that Tepmetko, a reversible ATP-competitive c-Met inhibitor, works as a rescue therapy for those NSCLC patients who develop resistance to the earlier Astrazeneca medicine Iressa (gefitinib).

The company is also exploring tepotinib's potential applications in other tumors with MET amplification where those drivers may play a bigger role than in NSCLC, such as metastatic colorectal cancer. To evaluate that theory, the company has planned a phase II trial that will combine the drug with Erbitux (cetuximab). The trial is not yet recruiting.

Small trial, big need

For Thursday's FDA approval, efficacy of Tepmetko was demonstrated in the Vision trial, a non-randomized, open-label, multicohort study that enrolled 152 patients with advanced or metastatic NSCLC with MET exon 14 skipping alterations. Participants received 450 mg of tepotinib once daily until their disease progressed or they hit unacceptable toxicity.

On its primary endpoint, objective response rate (ORR), in the 69 treatment-naïve patients, the ORR was 43%, with a median response duration of 10.8 months. The 83 previously treated patients saw an ORR of 43%, with a median response duration of 11.1 months. The outcome was superficially similar to those that helped Tabrecta win approval, though the trials can’t truly be compared head-to-head.

The most common adverse reactions in the Vision study were edema, fatigue, nausea, diarrhea, musculoskeletal pain and dyspnea. As is the case with all of the FDA's accelerated approvals, continued approval for Tepmetko may be contingent upon verification and description of clinical benefit in confirmatory trials.

Though there are avenues available for identifying patients whose tumors have METex14 skipping alterations, an FDA-approved test for doing so in NSCLC to select patients for treatment with Tepmetko is not available, the agency said Thursday. That has been in part because research hasn’t focused in the area due to there being so few treatments, Edvardsen said. To address that issue, Merck has been exploring the potential use of a liquid biopsy to test for circulating tumor DNA and has a parallel effort underway to get such a test acknowledged by the FDA. Tabrecta is used with companion diagnostic Foundationone Cdx from Cambridge, Mass.-based Foundation Medicine Inc.

Though big news for patients, near-term the FDA approval of Tepmetko is likely to play a small part in fulfilling Merck's ambition of generating $2 billion in revenue from its pipeline by 2022. That goal will be largely driven by its multiple sclerosis drug, Mavenclad (cladribine), and the cancer drug Bavencio (avelumab). But Tepmetko clearly has an ongoing and potentially expansive role to play in the company’s future. A marketing authorization application for tepotinib for an indication similar to that green-lit by the FDA was validated by the EMA in November 2020. Applications have also been submitted in Australia, Switzerland and Canada under the FDA's Project Orbis initiative.