Promising Targeted Therapies for Hard-to-Treat Molecularly Driven NSCLC

Targeted therapy is currently the preferred treatment approach for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR, ALK, ROS1, BRAF, and NTRK alterations, while immune checkpoint inhibitors with or without chemotherapy are the standard of care for patients without these mutations. In recent years, new actionable targets in NSCLC have been uncovered and have led to the development of promising targeted therapies for these hard-to-treat NSCLC patients, including those with MET mutations, RET fusions, EGFR exon 20 insertions, and KRAS G12C mutations. In this update, we will highlight several phase I and II trials of these novel targeted therapies presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting.

New Treatment Options for NSCLC With MET Exon 14 Skipping Mutations

Approximately 3% to 4% of patients with NSCLC have MET alterations that result in exon 14 skipping. These alterations lead to aberrant regulation of MET kinase and are associated with poor prognosis. While immunotherapy is relatively ineffective in patients with MET alterations, MET inhibitors, including the tyrosine kinase inhibitors (TKIs) tepotinib and capmatinib, have demonstrated clinical activity against MET exon 14 alterations in patients with NSCLC. New data presented at the 2019 ASCO meeting provided further evidence of the efficacy of these MET inhibitors.

In the single-arm, phase II VISION trial (Abstract 9005), the safety and efficacy of tepotinib (500 mg daily) was evaluated in 87 patients with advanced NSCLC with MET exon 14 mutations, as determined by either plasma or tissue biopsy. The objective response rate (ORR) as assessed by independent review committee was 50.0% among patients who were MET-positive by liquid biopsy and 45.1% among patients who were MET-positive by tissue biopsy. The median duration of response (DoR) was 12.4 months and 15.7 months for liquid and tissue biopsy, respectively. Although best responses were seen in patients receiving tepotinib as first-line therapy (ORR: 58.8% and 44.4%), response rates were still high in patients who had received two or more prior lines of therapy (37.5% and 40.0%). Patients with brain metastases at baseline benefitted equally from tepotinib treatment. Median progression-free survival (PFS) was 9.5 months in liquid biopsy-positive patients and 10.8 months in tissue biopsy-positive patients. The adverse event (AE) profile of tepotinib was mild and easily managed. There were no grade 4 or 5 AEs. Four patients discontinued treatment due to AEs. Follow-up of the VISION trial is ongoing and results from a second cohort of patients with any MET aberration are awaited.

The phase II GEOMETRY mono-1 trial (Abstract 9004) evaluated a second MET inhibitor, capmatinib (400 mg twice daily), in patients with NSCLC with MET exon 14 mutations, including those who had progressed on 1 to 2 prior lines of treatment (cohort 4; n = 69) and patients who were treatment naïve (cohort 5b; n = 28). The ORR was 40.6% in cohort 4 and 67.9% in cohort 5b by blinded independent review committee. Responses to capmatinib were durable, with a median DoR of 9.72 months and 11.14 months in cohorts 4 and 5b, respectively. The median PFS was 5.42 months for the previously treated patients in cohort 4 and 9.69 months for the treatment-naive patients in cohort 5b. Capmatinib also demonstrated intracranial activity, with an intracranial response rate of 54% among the 13 patients with brain lesions. The AE profile of capmatinib was mild and primarily comprised grade 1 and 2 events. A total of 11.1% of patients discontinued treatment due to AEs.

Selective RET Inhibitor Promising for RET-Fusion+ NSCLC

While RET fusions are found frequently in thyroid cancer, they are rare in NSCLC, occurring in only 1% to 2% of patients. Unfortunately, available treatment options for the few patients who carry this aberration are limited and these patients commonly receive chemotherapy and/or immune checkpoint inhibitors despite the limited efficacy of these agents in this population. At the 2019 ASCO meeting, results from the expansion cohort of the phase I/II ARROW trial evaluating the safety and efficacy of selective RET inhibitor BLU-667 (400 mg daily) in 120 patients with advanced NSCLC with RET alterations were presented (Abstract 9008). BLU-667 was highly active in RET fusion-positive patients, with an ORR of 58% and a disease control rate of 96%. Responses were durable, and the median DoR has not yet been reached. Prior therapy, including previous treatment with a checkpoint inhibitor or platinum chemotherapy, did not impact response to BLU-667. Among patients with brain metastases, 78% experienced shrinkage of measurable brain lesions. BLU-667 was associated with primarily low-grade, reversible AEs, with neutropenia and hypertension as the most common treatment-related AEs of grade 3 or higher. About 7% of patients discontinued treatment due to treatment-related toxicity.

Targeting Exon 20 Insertion Mutations in NSCLC

EGFR exon 20 insertion mutations occur in approximately 6% of patients with NSCLC, and there are currently no approved targeted therapies available to treat these patients. Approved EGFR inhibitors are mostly ineffective against these mutations, and are associated with a median PFS of only 2 months. TAK-788 is an oral EGFR/HER2 inhibitor with potent and selective activity against exon 20 insertions, which is currently being evaluated for patients with NSCLC with EGFR exon 20 insertions in a phase I/II clinical trial. Results from 28 patients treated with a dose of 160 mg daily (Abstract 9007), showed meaningful clinical activity, including a confirmed ORR of 43% and a median PFS of 7.3 months. Furthermore, 3 of 12 patients (25%) with brain metastases at baseline achieved a confirmed ORR. At the time of data cut-off, 50% of patients remained on study, with a median time on treatment of 7.9 months. TAK-788 was well tolerated, and most treatment-related AEs were of grade 1 or 2 and were reversible with dose modifications.

Novel KRAS Inhibitor Active in KRASG12C-mutant NSCLC

Finally, a small phase I study (Abstract 3003) evaluated the safety and efficacy of AMG510, a first-in-class inhibitor of KRAS G12C in patients with advanced solid tumors carrying this mutation, including 14 patients with NSCLC and 19 patients with colorectal cancer. KRAS G12C is found in 13% of lung cancers and there are currently no treatments targeting this mutation. The ORR was 50% in the entire trial population, including 5 partial responses from the 10 evaluable patients with NSCLC. The agent was well tolerated, with a mild AE profile.

J Clin Oncol. 2019;37(suppl 15): Abstract 9005.

J Clin Oncol. 2019;37(suppl 15): Abstract 9004.

J Clin Oncol. 2019;37(suppl 15): Abstract 9008.

J Clin Oncol. 2019;37(suppl 15): Abstract 9007.

J Clin Oncol. 2019;37(suppl 15): Abstract 3003.
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