Cabozantinib
Cabozantib is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2, and RET. It is already FDA approved for the treatment of patients with progressive, metastatic medullary thyroid cancer, and patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy.3
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In a phase 2 study of 115 patients with EGFR wild-type NSCLC, researchers compared the efficacy and safety of everolimus to that of cabozantinib and everolimus plus cabozantinib. Participants were randomly assigned 1:1:1 to receive everolimus 150 mg orally once daily, cabozantinib 60 mg orally once daily, or everolimus plus cabozantinib 40 mg daily.
Results showed that at a median follow-up of 8.5 months, median progression-free survival was 3.9 months (hazard ratio 0.33; 80% CI, 0.22-0.49; P = .0002) with cabozantinib and 4.1 months (hazard ratio 0.31; 80% CI, 0.21-0.46; P = .0002) compared with 1.9 months with everolimus. Median overall survival was significantly longer with cabozantinib and the combination in contrast with everolimus alone (P = .02).
Grade 3 to 4 treatment-related hypertension and mucositis were more frequently reported with cabozantinib and grade 3 to 4 diarrhea was more common with the drug combination. Overall worst grade toxicities were significantly more common with cabozantinib alone and everolimus plus cabozantinib.
“The RET gene arrangement occurs in only 1% to 2% of all NSCLC cases, but cabozantinib appears to have some activity in that group and looks quite promising in this small subset of patients,” Dr Masters said. “It fits in with our desire to understand each individual cancer and to give the most appropriate treatment for the individual driving mutations.”
Brigatinib
Crizotinib is indicated for the treatment of patients with metastatic NSCLC whose tumors are ALK-positive, and ceritinib and alectinib were each granted accelerated approval for patients who have progressed on or are intolerant to crizotinib.4
Now, brigatinib, an investigational kinase inhibitor, exhibited dual inhibitory activity against ALK and EGFR. An updated analysis from a phase 1/2 study in 79 patients with ALK-positive NSCLC demonstrated a 1-year overall survival rate of 100% among 8 evaluable crizotinib-naïve patients and 81% among 71 evaluable patients who received prior crizotinib therapy.
Further, brigatinib conferred a median progression-free survival of 13.4 months among patients with prior crizoinib therapy, while median progression-free survival has not yet been reached in crizotinib-naive patients. The most common treatment-emergent adverse events were nausea, fatigue, diarrhea, headache, and cough.
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The efficacy and safety of brigatinib are also being evaluated in the pivotal phase 2 ALTA trial and the phase 3 ALTA 1L trial, to assess the drug’s use in the frontline treatment setting.
“Although brigatinib is similar to ceritinib and alectinib, having multiple options for patients who do not tolerate 1 option is always great for patients,” Dr Masters noted.
