Eligibility of real-world patients with chemo-refractory, K-RAS wild-type, metastatic colorectal cancer for palliative intent regorafenib monotherapy

Abstract

The CORRECT trial demonstrated survival benefits with regorafenib monotherapy in patients with treatment-refractory, metastatic colorectal cancer (mCRC). However, the trial's stringent eligibility criteria for regorafenib may limit its external validity. We aimed to examine treatment attrition rates and eligibility for regorafenib in routine practice. We identified patients at the British Columbia Cancer Agency diagnosed with mCRC who demonstrated disease progression or intolerable toxicity on 2 or more lines of systemic therapy. During the study timeframe, panitumumab and cetuximab were only used in the chemo-refractory setting. Data on clinicopathologic variables and patient outcomes were ascertained and analyzed. Eligibility was determined using the CORRECT trial criteria. A total of 391 patients were identified, among whom only 39% were eligible for regorafenib: 35% in the panitumumab group and 51% in the cetuximab group. The main reasons for ineligibility in all patients were Eastern Cooperative Oncology Group Performance Status (ECOG PS) > 1 (69%), an elevated total bilirubin (21%), and thromboembolic events in the past 6 months (10%). No difference in eligibility for regorafenib was observed between patients previously receiving panitumumab or cetuximab (P = 0.914; 95% CI 0.550-1.951). Kaplan-Meier analyses showed that regorafenib-eligible compared to regorafenib-ineligible patients had an increased median overall survival of 5.3 versus 2.1 months, respectively (P < 0.001). However, Cox proportional hazard analyses showed that only ECOG PS rather than trial eligibility was correlated with outcomes. The strict eligibility criteria disqualify most patients with treatment-refractory mCRC for regorafenib therapy. Future trials should broaden the eligibility criteria to improve external validity.

Efficacy of Regorafenib in Metastatic Colorectal Cancer: A Multi-institutional Retrospective Study

“…This compares favorably with similar reported studies. 13,15 Our subgroup analysis confirmed that performance status is one of the most important factors in regorafenib efficacy. All prior pivotal studies included only patients with PS 0 to 1, while one-third of our patients had PS more than one with a significant difference in PFS and OS (P = .0002 and .01, respectively) on both univariate analysis and multivariate analysis (P = .0097 and .0065, respectively).…”

“…This result is in concordance with the result of the REBACCA study where 10.6% of patients had PS more than 1 and the difference in OS between the groups with PS 0 to 1 compared to >1 was statistically significant ( P < .001). 16 In addition, performance status was reported to correlate with outcome in the study reported by Angeles et al 15…”

“…This result is in concordance with the result of the REBACCA study where 10.6% of patients had PS more than 1 and the difference in OS between the groups with PS 0 to 1 compared to >1 was statistically significant (P < .001). 16 In addition, performance status was reported to correlate with outcome in the study reported by Angeles et al 15 Despite dose reduction showed prognostic significance on univariate analysis in PFS, this did not translate to benefit on multivariate analysis. Moreover, dose reduction is usually an event that occurs after starting therapy and accordingly cannot be used as a prognostic factor for response to therapy.…”

Chemotherapeutic Effectiveness of Combining Cetuximab for Metastatic Colorectal Cancer Treatment: A System Review and Meta-Analysis

“…The main indication described in its drug insert (Merck, Germany) is mCRC which is resistant to chemotherapy with irinotecan-based drugs. Previous studies have found that mCRC is often accompanied with genetic mutations, such as K-Ras mutations, and the mutated mCRC is no longer regulated by EGFR (14,15). At this point, the drugs that target EGFR will become ineffective.…”

“…Ye et al (26). Additionally, Qin et al(22) and Angeles et al(14) obtained a positive result through RCT, suggesting that the use of cetuximab can be benefit to mCRC patients, while RCT conducted by Yu et al(19), Sirotnak et al(11) came to a contrary conclusion. Therefore, there is no consensus on the effective therapeutic significance of cetuximab in mCRC patients with ITT.…”