New approaches to treating drug-resistant non-small cell lung cancer

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About 80% of lung cancers are non-small cell lung cancers (NSCLC / NSCLC) and about 15 to 20% of these cells carry epidermal growth factor receptor (EGFR) activating mutations.

The treatment of EGFR mutant CPNPC has improved considerably with the introduction of EGFR tyrosine kinase inhibitors (TKIs). Several TKIs targeting this receptor have been developed, including the first generation EGFR TKI, gefitinib (Iressa) and erlotinib (Tarceva).

Although EGFR-mutated NSCLC patients derive substantial benefits from EGFR TKI, their disease tends to evolve within a year because tumors eventually develop resistance to treatment.

Second-generation TKI EGFR includes afatinib (Gilotrif) and dacomitinib (Vizimpro), as well as third-generation neratinib and EGFR TKIs, including osimertinib (Tagrisso), and experimental therapeutics. like olmutinib and nazartinib.

The most common activating EGFR mutations in NSCLC include the deletion of exon 19 and L858R. Patients whose tumors harbor these EGFR-activating mutations are treated with first-generation EGFR TKIs. Although most patients initially responded to these treatments, more than 60% of them develop resistance by acquiring the "gatekeeper" point mutation, T790M.

Third-generation inhibitors, such as osimertinib, have been developed to target T790M mutations and to be active against the suppression of the original exon 19 and L858R. However, patients also develop resistance to this treatment, through alternative bridging mechanisms, as described in the table below.

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The targeted treatment of lung cancer patients with EGFR mutations consisted solely of monotherapy with various EGFR tyrosine kinase inhibitors, although we have known for more than 10 years that cancers resistant to EGFR TKIs result from activation of the MET bypass pathway.

Resistance acquired by amplification of MET as a derivation pathway is observed in approximately 5 to 10% of patients whose disease progresses after treatment with first- or second-generation EGFR-TKI and in approximately 25% of those whose disease progresses after TKI treatment of third-generation EGFR. The resistance induced by the MET confers a more aggressive behavior to cancers with EGFR mutants.

Combination of osimertinib and savolitinib

A combination of osimertinib and savolitinib, a MET inhibitor, was tested in a first cohort of patients with EGFR mutant lung cancer with acquired resistance induced by MET amplification after ITK therapy. first or second generation EGFR. Patient tumors were also negative for the T790M mutation.

In the second cohort, the same combination was tested in patients with EGFR-mutant lung cancer with acquired resistance induced by MET metabolism enhancement following treatment with osimertinib or another third-generation experimental TKI. EGFR.

The goal sought through the study of patients who received previous first-generation and second-generation EGFR-TKIs and those who had previously received previous third generation EGFR-TKIs in two separate cohorts was to provide more accurate assessments of combined treatment in these two distinct groups of patients.

For the cohort of patients who have previously received first- or second-generation EGFR-TKI, treatment with the osimertinib-savolitinib combination covers both the current dominant resistance mutation (based on MET amplification) and a likely future mutation resistance (based on T790m). "In this branch, we hypothesized that the response rate would be high," Sequist said in an interview.

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On the other hand, in the cohort of patients who have already received third-generation EGFR-TKIs (osimertinib or one of the other third-generation EGFR experimental TKIs), their cancer probably acquired resistance via T790M after treatment with TKI EGFR generation, and following treatment with a third-generation EGFR TFR covering T790M, a second mutation driven by MET amplification appeared, distinguishing their disease from that of the first cohort.

In the cohort of 46 patients who had previously received a first- or second-generation EGFR TKA, savolitinib-treated osimertinib treatment yielded an objective response rate (ORR) of 52%, with 24 partial responses (PR). ). The median duration of response (DOR) was 7.1 months.

In the cohort of 48 patients who received a third-generation EGFR TKI, savolitinib-treated osimertinib treatment resulted in a ROP of 28%, with 12 RPs. The median DOR was 9.7 months.

"This discovery illustrates the value of careful patient selection in targeted therapy studies," said Sequist, adding, "These clinically significant responses also demonstrate that, as different heterogeneous mutation resistance appear, they can their turn to be controlled by adapting the therapy. "