Tepotinib Plus Osimertinib Demonstrates Activity in EGFR+ NSCLC

Yi-Long Wu, MD

The combination of tepotinib (Tepmetko) and osimertinib (Tagrisso) provided clinical benefit and had a manageable toxicity profile in patients with EGFR-mutated non–small cell lung cancer (NSCLC) whose disease progressed on frontline osimertinib and had MET amplification, according to data from the phase 2 INSIGHT 2 study (NCT03940703) published in the Journal of Clinical Oncology.¹

The doublet (n = 98) elicited a confirmed objective response rate (ORR) of 50.0% (95% CI, 39.7%-60.3%), and this was comprised entirely of partial responses (PRs); 13% had stable disease for a minimum of 6 weeks and 23% experienced disease progression.

Notably, the ORR achieved with the combination was consistent across prespecified subsets. Those with a MET GCN of at least 10 (n = 53) experienced an ORR of 56.6% (95% CI, 42.3%-70.2%). Moreover, patients with a MET-to-CEP7 ratio of 2 or higher (n = 48) had an ORR of 56.3% (95% CI, 41.2%-70.5%) and those with a MET-to-CEP7 ratio of less than 2 (n = 50) achieved an ORR of 44.0% (95% CI, 30.0%-58.7%).

“Our findings suggest tepotinib plus osimertinib as a potential chemotherapy-sparing oral targeted therapy option for patients in this setting, who have a high unmet need,” lead study author and professor Yi-Long Wu, MD, at the Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, in Guangzhou, China, and co-authors, wrote in the paper.

The open-label, phase 2 INSIGHT 2 study enrolled patients with advanced or metastatic EGFR-mutated NSCLC who received frontline osimertinib, derived objective clinical benefit, and experienced disease progression. They were at least 18 years of age, had an ECOG performance status of 0 or 1, a minimum life expectancy of 12 weeks, measurable disease by RECIST 1.1 criteria, and confirmed MET amplification. Notably, those with asymptomatic brain metastases not requiring steroids, radiotherapy, surgery within 2 weeks prior to study treatment were permitted.

The trial had an initial safety run-in period to identify the recommended phase 2 dose (RP2D) of the doublet; this was followed by the main treatment period. After patients received the combination in the safety run-in, those with MET amplification were randomly assigned 2:1 to receive tepotinib plus osimertinib (n = 128) vs single-agent tepotinib (n = 12).

After 12 patients were enrolled in the monotherapy group, all were assigned to the combination group. Tepotinib was given at a dose of 500 mg and osimertinib was administered at a dose of 80 mg. Treatment continued until progressive disease, death, an adverse effect (AE) leading to discontinuation, or withdrawal.

The primary end point of the study was confirmed ORR by central independent review committee (IRC) assessment and RECIST 1.1 criteria. Secondary end points comprised duration of response (DOR), progression-free survival (PFS), overall survival (OS), health-related quality of life, and safety. Intracranial response, including confirmed ORR, disease control, DOR, and PFS served as an exploratory end points. Investigators also conducted exposure-response analyses.

The data cutoff date was March 28, 2023. The RP2D was determined to be 500 mg of tepotinib and 80 mg of osimertinib once daily.

The median patient age was 61 years (range, 52-67) and 58% of patients were female. Most patients were Asian (62%), never smokers (67%), and an ECOG performance status of 1 (73%). All patients had adenocarcinoma. Thirty-five percent of patients had brain metastases by RECIST 1.1 criteria and 23% had them by RANO-BM criteria. The median time on frontline osimertinib was 15.4 months.

Additional efficacy data showed that the median DOR was 8.5 months (95% CI, 6.1-not estimable [NE]) in the 49 patients who achieved a response in the primary activity population. Sixty-six percent (95% CI, 50%-77%) and 48% (95% CI, 33%-62%) were event free at 6 and 9 months, respectively.

At a median follow-up of 11.5 months (interquartile range, 9.0-13.8), the median PFS was 5.6 months (95% CI, 4.2-8.1); the event-free rates at 6 and 8 months were 48% (95% CI, 37%-58%) and 30% (95% CI, 20%-40%), respectively. At a median follow-up of 12.7 months (IQR, 9.9-20.3), the median OS was 17.8 months (95% CI, 11.1-NE); the event-free rates at 6 and 8 months were 81% (95% CI, 72%-88%) and 71% (95% CI, 60%-79%), respectively.

Fifty-four percent of patients who discontinued treatment (n = 76) went on to receive additional anticancer therapy.

A total of 24 patients had brain metastases at baseline that were evaluable by RANO-BM criteria. The doublet elicited an intracranial confirmed ORR of 29.2% (95% CI, 12.6%-51.1%) by IRC, comprised of a complete response rate of 25% and a PR rate of 4%; 50% had stable disease. The intracranial disease control rate was 79.2% (95% CI, 57.8%-92.9%). The median intracranial DOR was NE (95% CI, 3.6-NE) and the median intracranial PFS was 7.8 months (95% CI, 3.9-NE).

Grade 1 or 2 treatment-related adverse effects (TRAEs) were experienced by 54%; 29% experienced grade 3 events, 2% had grade 4 events, and 3% had grade 5 events. The most common TRAEs were diarrhea (grade 1/2, 48%; grade 3, 1%), peripheral edema (36%; 5%), paronychia (22%; 1%), nausea (19%; 2%), hypoalbuminemia (17%; 1%), reduced appetite (16%; 4%), increased aspartate aminotransferase (13%; 0%), increased blood creatinine (12%; 0%), vomiting (11%; 1%), rash (11%; 0%), anemia (10%; 2%), increased alanine aminotransferase (9%; 2%), increased lipase (9%; 2%), prolonged QT (5%; 4%), asthenia (5%; 2%), decreased platelet count (5%; 1%), decreased neutrophil count (4%; 1%), increased blood alkaline phosphatase (4%; 1%), generalized edema (3%; 2%), decreased white blood cell count (2%; 1%), pleural effusion (2%; 0%), dyspnea (2%; 0%), pneumonitis (2%; 2%), leukopenia (2%; 1%), neutropenia (2%; 1%), dehydration (1%; 1%), decreased lymphocyte count (1%; 1%), pneumonia (0%; 2%), acute kidney injury (0%; 1%), carbuncle (0%; 1%), dermatitis (0%; 1%), febrile neutropenia (0%; 1%), hepatic cytolysis (0%; 1%), malaise (0%; 1%), and myelosuppression (0%; 1%). Grade 4 events included decreased white blood count (2%), increased lipase (1%), decreased platelet count (1%), decreased neutrophil count (1%), and pleural effusion (1%).

Four deaths due to toxicities were determined to potentially be associated with a trial drug by investigator assessment: pneumonitis (2%), dyspnea (1%), decreased platelet count (1%), and respiratory failure (1%). One death was attributed to pneumonitis and dyspnea.

Serious TRAEs were experienced by 13% of patients. TRAEs resulted in dose reduction of at least 1 study drug for 20% of patients; they led to temporary discontinuation of at least one trial drug for 30% of patients and permanent discontinuation for 10% of patients.

Reference

1. Wu Y-L, Guarneri V, Voon PJ, et al. Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2024;25(8):989-1002. doi:10.1016/S1470-2045(24)00270-5