By Laura Cowen, Senior medwireNews Reporter
medwireNews: Combination therapy with tepotinib and osimertinib shows promising activity in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) with MET amplification after progression on first-line osimertinib, suggest initial data from the phase II INSIGHT 2 trial.
Speaking at the ESMO Congress 2022 in Paris, France, Julien Mazieres, from Université Paul Sabatier in Toulouse, France, said the data show that “tepotinib plus osimertinib is an active oral regimen providing a potential chemotherapy-sparing targeted therapy option for [these] patients.”
For the study, 425 people with advanced EGFR-mutated NSCLC were screened for MET amplification following progression on the tyrosine kinase inhibitor (TKI) osimertinib. Of these, 25% carried the resistance mechanism according to fluorescent in situ hybridisation (FISH) in tissue biopsy samples, 3% were positive by next-generation sequencing of liquid biopsy, and 8% had MET amplification with both methods.
At the time of the analysis, 100 patients had received treatment; 88 were given the MET–TKI tepotinib 500 mg/day (450 mg active moiety) in combination with osimertinib 80 mg/day and 12 were given tepotinib monotherapy.
Paul Sabatier reported that the primary end point of confirmed objective response rate (ORR) in patients with MET amplification detected by FISH who had at least 9 months of follow-up (n=22) was 54.5% with the combination therapy. For the 48 patients with at least 3 months of follow-up the confirmed ORR was 45.8%.
In the group that had MET amplification detected by liquid biopsy, 50.0% of 16 participants with at least 9 months of follow-up had a complete or partial response, as did 56.5% of 23 with at least 3 months of follow-up.
Responses mostly occurred within 6 weeks and half of responders remained on treatment for at least 6 months. The median response duration had not yet been reached at the time of the analysis.
By comparison, the ORR was 8.3%, consisting of one partial response, among the 12 patients treated with tepotinib monotherapy who had at least 6 months of follow-up and had MET amplification detected by FISH.
This finding “strongly suggests that for these patients, the combination should be the standard of care not the monotherapy”, the presenter remarked. He added that the full primary analysis will be carried out when all participants have at least 9 months of follow-up
Paul Sabatier also noted that the safety profile of the combination “was consistent with the known safety profile of each drug.”
Overall, 73.9% of participants experienced a treatment-related adverse event (TRAE) of any grade and 23.9% had a TRAE of grade 3 or worse. At this grade, the most common TRAEs were peripheral oedema (4.5%), decreased appetite (2.3%), vomiting (1.1%) and paronychia (1.1%). Six (6.8%) patients discontinued treatment as a result of AEs and two patients died, one from pneumonia/pneumonitis and one from pleural effusion, with both events possibly related to treatment.
A second study – ELIOS – presented in the same session by Zofia Piotrowska from Massachusetts General Hospital in Boston, USA, showed that MET amplification was the main acquired resistance mechanism to osimertinib in patients given the drug for EGFR–TKI naïve advanced NSCLC.
In all, 46 (39%) of 119 treated patients had pretreatment and post-progressive disease tissue samples analysed for tumour and proteomic markers by next-generation sequencing and mass spectrometry.
Of these, 17% acquired MET amplifications, while CDKN2A, CDKN2B and MTAP deletions, as well as EGFR C797S mutations, each occurred in 15% of the group during treatment.
In terms of protein expression, AXL and MET increased in 67% and 50% of participants, respectively, while HER2 and HER3 decreased in a respective 33% and 50%.
In her conclusion, Zofia Piotrowska pointed out that the study highlights “the challenges of obtaining post-progressive tissue biopsies and the need for more comprehensive non-invasive testing methods.”
Summarizing the two studies, session discussant Helena Yu from Memorial Sloan Kettering Cancer Center in New York, USA, said that “addressing resistance mechanisms can improve patient outcomes [but] further efforts are needed to define unknown resistance mechanisms.”
She continued: “MET amplification can be effectively targeted using MET and EGFR combination therapy”, adding that “further work is needed to define appropriate MET biomarkers.”
LBA55 - Mazieres J, Kim TM, Lim BK, et al. Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study. Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089
LBA53 - Piotrowska. Z, Ahn M, Pang YK, et al. ELIOS: A multicentre, molecular profiling study of patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib. Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089
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