Results of a Phase II Placebo-controlled Randomized Discontinuation Trial of Cabozantinib in Patients with Non–small-cell Lung Carcinoma

Abstract

Cabozantinib is an inhibitor of receptor tyrosine kinases, including MET, vascular endothelial growth factor receptors, AXL, RET, and ROS1. We assessed cabozantinib in 60 patients with nonesmall-cell lung carcinoma enrolled in a phase II randomized discontinuation trial. Tumor regression was observed in most patients, including patients with KRAS and epidermal growth factor receptor mutations. The safety profile was consistent with that reported for cabozantinib in other solid tumors. Introduction: Cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against MET, vascular endothelial growth factor receptor 2, AXL, ROS1, and RET was assessed in patients with nonesmall-cell lung carcinoma (NSCLC) as part of a phase II randomized discontinuation trial with cohorts from 9 tumor types. Patients and Methods: Patients received cabozantinib 100 mg/day during a 12-week open-label lead-in stage. Those with stable disease per Response Evaluation Criteria in Solid Tumors version 1.0 at week 12 were randomized to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and progression-free survival (PFS) after randomization. Results: Sixty patients with NSCLC who had received a median of 2 prior lines of therapy were enrolled. ORR at week 12 was 10%; 6 patients had a confirmed partial response, and no patients had a complete response. Overall disease-control rate (ORR þ stable disease) at week 12 was 38%. Tumor regression was observed in 30 (64%) of 47 patients with post-baseline radiographic tumor assessments, including 3 or 4 patients with KRAS or epidermal growth factor receptor mutations, respectively. Median PFS after randomization was 2.4 months for both the cabozantinib and placebo arms. Median PFS from first dose for the entire cohort was 4.2 months. The most common grade 3/4 adverse events were fatigue (13%), palmar-plantar erythrodysesthesia (10%), diarrhea (7%), hypertension (7%), and asthenia (5%); 1 treatment-related grade 5 adverse event (hemorrhage) was reported during the lead-in stage. Conclusion: Cabozantinib exhibited clinical activity based on ORR and regression of tumor lesions in pretreated patients with NSCLC, including in patients with KRAS mutations.

AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

“…The capsule form of cabozantinib, Cometriq®, has been approved by the FDA for the treatment of advanced RCC and metastatic medullary thyroid carcinoma [215]. Numerous phase I/II trials have been conducted in patients with melanoma, metastatic breast cancer, NSCLC, AML, castration-resistant prostate cancer and HCC with promising preliminary activities [148–150, 216–220]. However, a randomized phase II study of 60 mg p.o.…”

“…AXL small molecule inhibitors have pronounced therapeutic effects; nonetheless, their inherent limitations, the off-target effects, might give rise to the inhibition of additional kinases and subsequent unexpected toxicities, limiting their clinical use. A variety of side effects have been reported for molecular targeted therapies, especially for multi-targeted AXL TKIs [148, 151–153, 210, 220, 235–237].…”

Clinical Impact of the Epithelial-Mesenchymal Transition in Lung Cancer as a Biomarker Assisting in Therapeutic Decisions

“…Additionally, the redundancy of EMT activation pathways (Fig. 2) also constitutes a clear challenge in targeting EMTs [Zoni et al, 2015;Yin et al, 2019] and pleads in favor of multitarget TKI approaches that are being examined [de Jonge et al, 2019;Hellerstedt et al, 2019;Wheatley-Price et al, 2019]. Multiple therapeutics against EMT-activating pathways (e.g., TGFβ, FAK, FGFR, or PDGFR) have been tested with no convincing effects [Giaccone et al, 2015;Paik et al, 2017;Han et al, 2018;Gerber et al, 2020], although research is still ongoing with FGFR [SenthilKumar et al, 2020] or FAK inhibitors [Mak et al, 2019].…”

The Role of MET Inhibitor Therapies in the Treatment of Advanced Non-Small Cell Lung Cancer

“…In general, cabozantinib improved OS and PFS, but not all results were statistically significant. In this context, cabozantinib seems to be a suitable treatment option, but, once again, more studies are needed to evaluate with more certainty which treatment is the best option to extend patients' lifetime and improve the quality of life, considering all benefits and limitations of each treatment [22][23][24][25].…”

“…There was no statistically significant difference in the median PFS values between the two groups (from 4.2 months at week 0 to 2.4 months at week 12 in the cabozantinib and placebo groups). The most common adverse effects were fatigue (13%), palmar-plantar erythrodysesthesia (10%), diarrhea (7%), hypertension (7%), and asthenia (5%) [25].…”