Celebrating the 10th Anniversary
A decade of discoveries in Cancer Discovery. For the community. By the Community.
Turning the Tide against Non–Small Cell Lung Cancer
Mortality from non–small cell lung cancer (NSCLC) has sharply declined in recent years, a decrease that has coincided with a spate of FDA approvals for targeted therapies in patients whose tumors harbor various genetic alterations. In 2015, two papers in Cancer Discovery showed that MET exon 14 splice site mutations were recurrent and actionable in patients with NSCLC. Frampton and colleagues performed genomic profiling on more than 38,000 tumors and identified more than 200 distinct alterations in MET that affected splicing of exon 14. Such mutations were most common in NSCLC, occurring in approximately 3% of all cases, but also were identified in other tumor types. Loss of MET exon 14 was shown to activate MET and transform cells, consistent with earlier studies. MET exon 14 loss also conferred in vitro sensitivity to the MET inhibitor capmatinib, and two patients with NSCLC with MET exon 14 alterations who were treated with capmatinib experienced partial responses. Paik and colleagues presented a case series of 4 patients with MET exon 14 splice site alterations who were treated with either crizotinib or cabozantinib, tyrosine kinase inhibitors with activity against MET: 3 patients experienced a partial response, and 1 patient experienced a complete metabolic response of a metastatic lesion. In 2018, Subbiah, Gainor, Evans, and colleagues presented the preclinical characterization and early demonstration of clinical activity for BLU-667, a next-generation small-molecule inhibitor of RET, which is activated by gene rearrangement in 1% to 2% of NSCLCs (RET fusions or missense mutations are also common in thyroid cancers and found in other tumor types). BLU-667 potently inhibited RET-dependent cell growth and induced regression of RET-altered tumor models, and 2 patients with RET fusion–positive NSCLC treated with BLU-667 experienced partial responses. These findings paved the way for clinical trials in patients with NSCLC whose tumors harbored MET exon 14 mutations or RET fusions, and ultimately a number of FDA approvals in less than 5 years. In 2020, the FDA granted accelerated approval to capmatinib in patients with metastatic NSCLC with MET exon 14 skipping mutations as detected by an FDA-approved companion diagnostic. An accelerated approval for the MET inhibitor tepotinib soon followed in 2021. In 2020, BLU-667 (now known as pralsetinib) was granted accelerated approval by the FDA for patients with metastatic RET fusion–positive NSCLC as detected by an FDA-approved test.