Drugs Xagena
The European Commission has approved Tepmetko ( Tepotinib ) for use as a single agent in adult patients with advanced non-small cell lung cancer ( NSCLC ) harboring METex14 skipping alterations who require systemic therapy after prior treatment with immunotherapy and/or Platinum-based chemotherapy.
The approval is supported by findings from the phase 2 VISION trial, which has shown that the agent elicited an objective response rate ( ORR ) of 46% ( 95% CI, 36-57% ) by independent review among 99 patients evaluable for efficacy.
All responders experienced partial responses ( PRs ) to treatment.
The multicenter, multicohort, single-arm, open-label trial enrolled patients with histologically or cytologically confirmed, locally advanced or metastatic NSCLC with MET exon 14 skipping mutations, who are at least 18 years of age, had measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.
Patients were able to have received up to 2 courses of prior treatment for advanced or metastatic disease.
Patients with stable central nervous system metastases whose glucocorticoid dose was being tapered, were able to participate.
The trial is comprised of 3 cohorts; those in cohort A had MET exon 14 skipping mutations and those in cohort B had MET-amplified disease without METex14 skipping mutations.
Cohort C is enrolling patients with MET exon 14 skipping mutations for a confirmatory analysis of cohort A.
Participants received oral Tepotinib at a once-daily dose of 500 mg until disease progression, withdrawn consent, or toxicities leading to treatment discontinuation.
The primary end point of the trial was confirmed objective response rate per RECIST v1.1 criteria, and key secondary end points included investigator-assessed objective response, duration of response ( DoR ), progression-free survival ( PFS ), and overall survival ( OS ).
Among those in cohort A who were determined to be evaluable for efficacy, the median age was 74 years, 46% had a history of smoking, and 97% had metastatic disease at the time of study entry. Three patients were noted to have tumors that had sarcomatoid features.
56 of the 99 evaluable patients previously received treatment; 29 of these patients had received prior immunotherapy.
Patients received Tepotinib for a median of 6.9 months ( range, less than 0.1 to 36.7 ). The median follow-up in the efficacy population was 17.4 months.
Additional data have shown that the investigator-assessed response rate with Tepotinib was 56% ( 95% CI, 45-66% ). Per this assessment, 2 patients were noted to have achieved a complete response [ CR ], and 53 experienced a partial response [ PR ].
Per independent review, 89% of patients experienced tumor shrinkage; per investigator assessment, this rate was 88%.
The median duration of response with Tepotinib was 11.1 months ( 95% CI, 7.2–not estimable [ NE ] ) per independent review in the 99 patients with a combined biopsy.
The median duration of response was 9.9 months ( 95% CI, 7.2-NE ) in the group who only had a liquid biopsy ( n = 66 ); in those who only had a tissue biopsy ( n = 60 ), the median duration of response was 15.7 months ( 95% CI, 9.7-NE ).
In the combined-biopsy group, the median duration of progression-free survival per independent review was 8.5 months ( 95% CI, 6.7-11.0 ); this was 8.5 months ( 95% CI, 5.1-11.0 ) in the liquid-biopsy group and 8.5 months ( 95% CI, 5.7-17.1 ) in the tissue-biopsy group.
Similar findings were observed per investigator assessment. Although the data were not yet mature, the median duration of overall survival was 17.1 months ( 95% CI, 12.0-26.8 ).
Among 11 patients with brain metastases, Tepotinib resulted in a response rate of 55% ( 95% CI, 23-83% ) per independent review, and the median duration of response was 9.5 months ( 95% CI, 6.6-NE ) and the median progression-free survival was 10.9 months ( 95% CI, 8.0-NE ).
In the safety population ( n = 152 ), 98% were reported to have experienced a toxicity of any cause, with 89% experiencing events that were determined by investigators to be associated with Tepotinib.
Grade 3 or higher toxicities occurred in 28% of patients, with the most common being peripheral edema ( 7% ).
Although increased levels of amylase were frequently observed, these cases were noted to range from mild to moderate in severity.
Fifteen percent of patients experienced serious toxicities determined to be related to Tepotinib. Treatment-related adverse effects ( TRAEs ) that resulted in dose reduction was observed in 33% of patients; 11% of patients discontinued treatment permanently because of TRAEs.
Reductions and discontinuations were mostly associated with peripheral edema, pleural effusion, or dyspnea.
Peripheral edema was the most frequently reported TRAE and resulted in a dose reduction or interruption for 16% and 18% of patients, respectively.
Only 5% of patients discontinued treatment with Tepotinib because of this toxicity.
Twenty-one patients experienced adverse effects that resulted in death, with 1 death considered by investigators to be associated with the study drug. ( Xagena )
Source: Merck Group, 2022
XagenaMedicine_2022
