Cabozantinib and Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer

Abstract

Lessons Learned Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long‐term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted. Background The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild‐type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c‐MET, and may delay or reverse anti‐EGFR resistance. Methods In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. Results Twenty‐five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3–7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5–14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib. Conclusion The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.

Cabozantinib combination therapy for the treatment of solid tumors: a systematic review

“…Five studies reported outcomes in patients with gastrointestinal cancers, including three that showed encouraging clinical activity with: cabozantinib in combination with either nivolumab or durvalumab in patients with HCC; cabozantinib plus durvalumab in patients with advanced GEA and CRC; and cabozantinib plus panitumumab in patients with mCRC. 32 , 67 , 69 , 71 , 73 , 74 …”

“…In a phase Ib study of 25 patients with chemotherapy refractory KRAS wild-type mCRC, outcomes were measured after treatment with cabozantinib (60 mg/day) and panitumumab. 32 , 69 Median (95% CI) OS and PFS were 12.1 (7.5–14.3) months and 3.7 (2.3–7.1) months, respectively. Of the 25 patients treated, 13 had received prior anti-epidermal growth factor receptor (anti-EGFR) therapy, and four patients (16%) had a confirmed PR.…”

“…Of the 25 patients treated, 13 had received prior anti-epidermal growth factor receptor (anti-EGFR) therapy, and four patients (16%) had a confirmed PR. 32 …”

“… 3 , 29 , 30 There is also evidence that the activity of androgen deprivation therapy is likely to be enhanced by concomitant inhibition of angiogenesis with cabozantinib. 31 Furthermore, combination treatment with cabozantinib may serve to block the development of MET-driven resistance observed with some therapies, such as endothelial growth factor receptor (EGFR) inhibitors, 32 – 35 and the resistance to VEGFR inhibition with other TKIs driven by additional targets of cabozantinib, such as AXL and fibroblast growth factor receptor. 36 …”

Epithelial-Mesenchymal Transition in Metastatic Colorectal Cancer

“…Cabozantinib interferes with AXL signaling, downregulates EMT-TFs, and increases E-cadherin expression. However, in a combined treatment with the EGFR inhibitor panitumumab for KRAS wild-type CRC patients, cabozantinib showed a 16% response in terms of clinical parameters (84). Methotrexate successfully increased Ecadherin expression levels 10-fold in CRC cell lines, and it has been shown to be ineffective in clinical settings (85).…”