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PARIS -- More than half of EGFR-positive lung cancers that progressed on osimertinib (Tagrisso) responded to the MET inhibitor tepotinib (Tepmetko) plus additional osimertinib, according to a prospective study reported here.

Among patients followed for 3 to 9 months, as many as 56% obtained objective responses with the combination. In contrast, only one of 12 patients treated with single-agent tepotinib responded. Among 48 evaluable patients, about 80% had some degree of tumor shrinkage with the combination therapy.

Most responses occurred within 6 weeks and lasted for 6 months or longer in half of cases, said Julien Mazieres, MD, of the University Cancer Institute of Toulouse in France, at the European Society for Medical Oncology (ESMO) annual congress.

"Tepotinib plus osimertinib is an active oral regimen, providing a potential chemotherapy-sparing targeted therapy option for patients with EGFR-mutant non-small cell lung cancer (NSCLC) with MET amplification after progression on first-line osimertinib, who have a high unmet need," Mazieres said in conclusion.

The ascendance of osimertinib to first-line treatment created a need for effective strategies to offer patients whose tumors progressed. As many as 30% of EGFR-mutant NSCLC patients treated with osimertinib develop resistance by means of MET amplification, which is associated with poor prognosis, said Mazieres.

In the phase Ib/II trial, the combination of tepotinib and gefitinib (Iressa) had clinical activity in EGFR-mutant NSCLC with MET amplification. Limited real-world evidence also suggested that tepotinib plus osimertinib is active, Mazieres continued.

The suggestive data led to the ongoing phase II trial to investigate the activity of tepotinib plus osimertinib in EGFR-mutant NSCLC with MET amplification. Eligible patients have acquired resistance to first-line osimertinib and MET amplification by fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS). Mazieres reported findings from an interim analysis, as the primary analysis will occur after all patients have at least 9 months of follow-up.

Thus far 100 patients have been treated, 88 with tepotinib plus osimertinib and 12 with single-agent tepotinib. Mazieres said 48 patients have been followed for at least 3 months, including 22 followed for at least 9 months.

Among 22 patients with MET amplification detected by FISH and followed for at least 9 months, 12 had partial responses and two others had stable disease. Sixteen of the patients also had MET amplification detected by NGS, and eight had partial responses.

For the 48 patients evaluated by FISH and followed for at least 3 months, 22 had partial responses, and three others had stable disease. Among 23 with MET amplification detected by NGS, 13 had partial responses and one patient had stable disease.

Among 88 evaluable patients, the most common treatment-related adverse events (TRAEs) were diarrhea (40.9%), peripheral edema (23.9%), and paronychia (17.0%). Grade ≥3 TRAEs consisted of peripheral edema in four patients, decreased appetite in two, and paronychia and vomiting in one patient each.

Six patients discontinued treatment because of adverse events (AEs). Two patients had fatal AEs that potentially were associated with the study drugs: one related to pneumonia/pneumonitis and the other related to pleural effusion.

The response rates of 50-55% for patients with mature follow-up are encouraging, but additional work is needed to identify optimal biomarkers to improve the activity, said ESMO invited discussant Helena Yu, MD, of Memorial Sloan Kettering Cancer Center in New York City. The limited activity with single-agent tepotinib indicates that the MET inhibitor should not be used without an EGFR-inhibitor partner, she added.

Multiple studies have established MET amplification as a driver of resistance to EGFR inhibitors and that the combination of MET and EGFR inhibition is a valid therapeutic strategy. Nonetheless, the studies have also shown a "clear ceiling" for efficacy, for reasons that remain unclear.

"What are the limits to treating resistance mechanisms?" Yu continued. "Acquired resistance alterations are always subclonal, so the degree of benefit will depend on the proportion of disease driven by the resistance mutation. I consider the variant allele frequency [VAF] as a biomarker for response, thinking about the resistance mutation with VAF on the numerator and the EGFR-sensitizing mutation on the denominator."

"Resistance is often heterogeneous, and when multiple resistance mechanisms are present, what do we target?" she added.

A final issue relates to the different methods for identifying MET biomarkers and determining the optimal cutoffs for those methods. All of the currently available techniques -- FISH, immunohistochemistry, NGS, and plasma detection of amplifications -- have drawbacks, said Yu.

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