Merck's MET inhibitor Tepmetko (tepotinib) has shown a promising possibility as a follow-up option to Tagrisso (osimertinib) in treating EGFR-mutant NSCLC, a disease with significant unmet need.

The August issue of the international journal The Lancet Oncology recently published the results of the phase 2 INSIGHT 2 study, in which Professor Kim Tae-min of the Department of Hematology/Oncology at Seoul National University Hospital participated as a corresponding author.

The INSIGHT 2 study evaluated the efficacy and safety of Tagrisso combined with Tepmetko in patients with advanced or metastatic EGFR-mutant NSCLC with MET gene amplification whose disease progressed after first-line treatment with Tagrisso.

Tagrisso, a third-generation EGFR TKI, is the global standard of care for the first-line treatment of advanced or metastatic EGFR-mutant NSCLC. However, there remains a significant unmet need in the field as chemotherapy is the only follow-up treatment option for patients who fail Tagrisso.

Various genetic alterations are observed in patients resistant to Tagrisso, with MET amplification being a major contributor to Tagrisso resistance. About 5-24 percent of disease progression with Tagrisso is due to MET amplification, which is more common when Tagrisso is used as first-line therapy.

The researchers tested whether patients with MET amplification who received Tagrisso as a first-line treatment and whose disease progressed could be further targeted with the combination of Tagrisso and Tepmetko.

The study was conducted at 179 centers in 17 countries, and patients had MET amplification confirmed by lung tissue FISH (MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy NGS (MET plasma gene copy number of ≥2-3) after first-line Tagrisso.

Patients then received Tepmetko 500 mg and Tagrisso 80 mg once daily, with the primary endpoint being objective response independently assessed in patients with MET amplification on FISH with at least nine months of follow-up, and safety analyzed in patients who received at least one dose of the drug

While 128 patients were enrolled between Feb. 13, 2020, and Nov. 4, 2022, the primary analysis included 98 patients with at least nine months of follow-up.

At a median follow-up of 12.7 months, the objective response rate (ORR) was 50.0 percent (49/98 patients), with an additional 13 patients (13 percent) maintaining stable disease for at least the first six weeks.

The median duration of response (mDoR) was 8.5 months, with 66 percent and 48 percent of patients maintaining a response at six and 12 months, respectively.

At a median follow-up of 11.5 months, median progression-free survival (mPFS) was 5.6 months, with progression-free survival rates at six and nine months of 48 percent and 30 percent.

The most common treatment-related Grade 3 or higher adverse events were peripheral edema (5 percent), decreased appetite (4 percent), electrocardiogram QT interval prolongation (4 percent), and pneumonia (3 percent). Serious treatment-related adverse events were reported in 16 patients (13 percent), and four patients (3 percent) died due to pneumonia (2 percent), platelet count decrease (1 percent), respiratory failure (1 percent), and dyspnea (1 percent).

One death was due to pneumonia and dyspnea, which were evaluated by the investigators as potentially related to the study drug.

"The combination of tepotinib and osimertinib showed promising activity and acceptable safety in patients with EGFR mutations and MET amplification as a mechanism of resistance to first-line osimertinib," the researchers concluded. “That showed potential as an oral targeted therapy option to defer chemotherapy, which warrants further study."