Advanced nonsmall cell lung cancer

A new approach to the treatment of advanced nonsmall cell lung cancer (NSCLC) has reported showing clinically meaningful responses. The investigational drug savolitinib, a MET inhibitor; was used in combination with osimertinib in patients with advanced NSCLC who had resistance to prior epidermal growth factor receptor (EGFR); tyrosine kinase inhibitors (TKIs) and had acquired MET amplification.
The finding comes from the company-sponsored TATTON study (NCT02143466); presenting here at the American Association of Cancer Research (AACR); 2019 Annual Meeting (abstracts CT032, CT033). Data from the TATTON trial demonstrate for the first time the benefit of adding a MET inhibitor to an EGFR inhibitor in patients with EGFR-mutant NSCLC and with MET-driven acquired resistance,” presenter Lecia V. Sequist, MD, MPH, a thoracic medical oncologist at Massachusetts.

Combination targeted therapy

Therefore the study has shown the efficacy of combination targeted therapy in a patient population for whom chemotherapy is the current primary treatment option,” she added. Approached for comment, Alice T. Shaw, MD, Ph.D. That osimertinib and savolitinib “is a highly effective and tolerable combination for those patients who have MET amplification as their resistance mechanism to EGFR inhibitors.”
“They have been routinely screening for MET amplification for years; the results with the combination of osimertinib and savolitinib are very clinically relevant,” she said. Also approached for comment, Roy S. Herbst, MD, Ph.D., chief of medical oncology at the Yale Cancer Center, Connecticut, the results with savolitinib and osimertinib compelling and the combination is “ready for prime time.”
Therefore, patients enrolled to receive the combination of osimertinib and savolitinib required; to have locally advanced or metastatic EGFR-mutated NSCLC that was resistant to other EGFR-TKIs. So MET amplification status determined using next-generation sequencing; fluorescent in situ hybridization, or immunohistochemistry. But in cohort 1, patients enrolled who had progressed on prior first- or second-generation EGFR-TKIs (EGFR T790M-negative cohort).

Third-generation EGFR-TKIs

In cohort 2, patients enrolled who had progressed on prior third-generation EGFR-TKIs (EGFR T790M-positive cohort). The arm of TATTON that evaluated the combination of osimertinib and selumetinib enrolled patients with advanced EGFR-mutated NSCLC with disease progression on prior EGFR-TKIs; which included third-generation agents. Patients allowed to enroll regardless of T790M or KRAS status.

Part A was a dose-finding study that evaluated several continuous and intermittent dosing regimens of selumetinib; with osimertinib given once daily. Because of toxicities seen with the continuous-dosing regimen; patients enrolled into the dose expansion Part B cohort received selumetinib 75 mg given orally twice; daily on the intermittent dosing schedule 4/3 (4 days on therapy and 3 days off therapy).

Although ORR was 34% (all partial responses); there were very few responses in patients who negative for the EGFRT790M mutation, adding that this is an interesting option to evaluate in the front-line setting. “Continuous dosing of selumetinib is definitely toxic. The combo was better tolerated when selumetinib is dosed intermittently. There may a subset of patients for whom this combination may be effective, but the data are too early right now. In conclusion, Osimertinib and selumetinib will continue to evaluate in a Phase 2 study in treatment-naive patients with advanced NSCLC with EGFR mutations