SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%). Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC, whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patients, about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Therefore, pan RAS (expanded RAS) testing is now recommended.
STIVARGA® (Regorafenib), is an oral multi-kinase inhibitor approved by the FDA for the treatment of patients with metastatic CRC, who have progressed on 5FU, ELOXATIN® (Oxaliplatin), CAMPTOSAR® (Irinotecan), anti-VEGF and anti-EGFR therapies. STIVARGA® inhibits multiple kinases including VEGF1, VEGF2, VEGF3, PDGFR, FGFR involved in tumor angiogenesis and KIT, RET, RAF-1, BRAF involved in oncogenesis. The approval was based on a phase III trial in which patients receiving STIVARGA® had a statistically significant improvement in the Overall Survival and Progression Free Survival, compared to placebo.
Both STIVARGA® and ERBITUX® are approved for metastatic CRC. The optimal sequencing of these drugs however, has remained unclear. The current standard of care is to offer an ERBITUX® based regimen followed by STIVARGA®. STIVARGA® however has demonstrated activity in patients with metastatic CRC, when given earlier in the course of the disease. Further preclinical data suggests that downregulation of MAP kinase and Akt with STIVARGA® was shown to sensitize metastatic CRC cells to anti-EGFR therapies, such as ERBITUX®.
The REVERCE trial is a multicenter, randomized phase II trial which enrolled patients with KRAS wild-type metastatic CRC, after failure on combination chemotherapy with Fluoropyrimidine, Oxaliplatin, and Irinotecan. A total of 101 patients were randomized in a 1:1 ratio to receive sequential treatment with STIVARGA® followed by ERBITUX® with or without Irinotecan or reverse sequence of ERBITUX® with or without Irinotecan followed by STIVARGA®. Patients were stratified by prior use of AVASTIN® and intent to use ERBITUX® in combination with Irinotecan. Patients continued each sequence until disease progression or unacceptable toxicity, at which time patients switched to the alternative drug. The Primary endpoint was Overall Survival. Secondary endpoints included Progression Free Survival (PFS) with initial treatment (PFS1), PFS with second treatment (PFS2), Time to sequential Treatment Failure (TTF), Response Rate, Safety, and Quality of Life (QOL). The authors further investigated possible biomarkers including oncogenic mutations from circulating cell free DNA by liquid biopsy, with serial measurements.
It was noted that giving STIVARGA® before ERBITUX® resulted in a significantly longer median Overall Survival of 17.4 months, compared with 11.6 months with ERBITUX® followed by STIVARGA®. After a median follow up of 29 months, there was a 39% reduction in the risk of death with the STIVARGA®-ERBITUX® sequence (HR=0.61; P=0.029). The benefit with STIVARGA®-ERBITUX® sequence was consistently noted across all patient subgroups. In the subgroup of patients with left-sided primary tumors (N=81), patients who started treatment with STIVARGA® first followed by ERBITUX®, had a median Overall Survival of 20.5 months compared with 11.9 months for those receiving ERBITUX® first, and this meant a 49% reduction in mortality risk, which was statistically significant (P=0.01).
The first Progression Free Survival (PFS1) did not differ significantly according to the drug sequence, but the second PFS (PFS2) was more prolonged in those receiving ERBITUX® after STIVARGA®, with a 71% reduction in the risk of progression or death following the second treatment (HR=0.29; P<0.0001). The time to treatment failure was a median of 7.4 months with STIVARGA® followed by ERBITUX® and 6.1 months with ERBITUX® followed by STIVARGA® (HR=0.60; P=0.017). Safety and quality of life were comparable between the two treatment groups.
It was concluded that data from this study suggest that treatment with STIVARGA® first, followed by ERBITUX® resulted in longer survival than that of the current standard sequence and the longer Progression Free Survival following the second treatment period with ERBITUX® may have contributed to the improvement in Overall Survival with the STIVARGA®-ERBITUX® sequence. A biomarker analysis is still ongoing. Randomized phase II study of regorafenib followed by cetuximab versus reverse sequence for wild-type KRAS metastatic colorectal cancer previously treated with fluoropyrimidine, oxaliplatin, and irinotecan (REVERCE). Shitara K, Yamanaka T, Denda T, et al. DOI: 10.1200/JCO.2018.36.4_suppl.557 Journal of Clinical Oncology 36, no. 4_suppl (February 2018) 557-557.