Novel MET kinase inhibitor counteracts TKI resistance in NSCLC

Treatment with SCC244, a novel small molecule inhibitor of the enzyme MET kinase, appears to help overcome the resistance to tyrosine kinase inhibitors (TKI) mediated by MET amplification in nonsmall cell lung cancer (NSCLC), reports a new study presented at the recent 2022 European Society for Medical Oncology Asia Congress (ESMO Asia 2022).

“SCC244 plus osimertinib demonstrated clinical activity in EGFR-mutant NSCLC patients with MET amplification and with resistance to EGFR TKI,” said lead author Yongfeng Yu of the Shanghai Chest Hospital. “The safety profile was acceptable and manageable.”

The open-label phase Ib/II study included 30 patients (median age 64 years, 50 percent men) with locally advanced or metastatic disease. SCC244 was given at 200- or 300-mg doses once-daily, while osimertinib was dispensed at a fixed, once-daily dose of 80 mg. Patients were followed until disease progression or intolerable toxicity. In the Phase Ib portion, the primary outcome was safety, while the main metric of interest in phase II was overall response rate (ORR), as assessed by the instructor.

The ORR was 60.0 percent (95 percent confidence interval [CI], 40.6–77.3). Most of the responders (n=18; 60.0 percent) showed partial response to the combination treatment, while 30.0 percent (n=9) and 6.7 percent (n=2) reached stable disease and demonstrated progressive disease, respectively. [ESMO Asia 2022, abstract 305MO]

One patient had no available data for tumour assessment after treatment. None of the treated participants achieved complete response.

Overall, these findings led to a disease control rate of 90 percent (95 percent CI, 73.5–97.9). Over a median follow-up of 11.8 months, the median progression-free and overall survival was 6.9 and 16.9 months, respectively. The combination treatment had a median duration of response of 5.8 months.

As of study cutoff, three patients remained on treatment and were still showing signs of response.

Researchers then conducted subanalyses based on prior lines of treatment and genetic mutations. In the 19 patients who had progressed after first- or second-generation TKIs, and who were negative for the T790M EGFR mutation, the resulting ORR was 73.7 percent, with 14 patients reaching partial response.

Meanwhile, 11 patients had progressed after third-generation TKIs, of whom four achieved partial response, yielding an ORR of 36.4 percent.

Good safety profile

All patients developed treatment-emergent adverse events (TEAE). In 29 patients, the side effects were deemed to be related to the study intervention. Specifically, six cases were related only to SCC244, four to osimertinib alone, and 28 to the combination of the two agents.

Fifteen TEAEs were categorized as serious, almost all of which were due to the combination of SCC244 and osimertinib. Twenty toxicities were grade 3 or higher.

The most common TEAE was oedema, which had a prevalence rate of 63.3 percent. This was followed by leukopaenia (53.3 percent), anaemia (46.7 percent), thrombocytopaenia (46.7 percent), decreased appetite (43.3 percent), neutropaenia (43.3 percent), and aspartate aminotransferase elevations (43.3 percent).