Search

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with chemotherapy is a standard of care in the first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) and has demonstrated efficacy in later lines. Progressive disease (PD) occurs when tumours develop resistance to a therapy, although controversy remains about whether PD on a combination of chemotherapy and targeted agents implies resistance to both components. Here, we propose that some patients may gain additional clinical benefit from the reuse of cetuximab after having PD on regimens including cetuximab in an earlier treatment line. We conducted a non-systematic literature search in PubMed and reviewed published and ongoing clinical trials, focusing on later-line cetuximab reuse in patients with mCRC. Evidence from multiple studies suggests that cetuximab can be an efficacious and tolerable treatment when continued or when fit patients with mCRC are retreated with it after a break from anti-EGFR therapy. Furthermore, on the basis of available preclinical and clinical evidence, we propose that longitudinal monitoring of RAS status may identify patients suitable for such a strategy. Patients who experience progression on cetuximab plus chemotherapy but have maintained RAS wt tumour status may benefit from continuation of cetuximab with a chemotherapy backbone switch because they have probably developed resistance to the chemotherapeutic agents rather than the biologic component of the regimen. Conversely, patients whose disease progresses on cetuximab-based therapy due to drug-selected clonal expansion of RAS-mutant tumour cells may regain sensitivity to cetuximab following a defined break from anti-EGFR therapy. Looking to the future, we propose that RAS status determination at disease progression by liquid, needle or excisional biopsy may identify patients eligible for cetuximab continuation and rechallenge. With this approach, treatment benefit can be extended, adding to established continuum-of-care strategies in patients with mCRC.

Objective: To identify imaging markers predicting clinical outcomes to regorafenib in metastatic colorectal carcinoma (mCRC)., Methods: The RadioCORRECT study is a post hoc analysis of a cohort of patients with mCRC treated within the phase III placebo-controlled CORRECT trial of regorafenib. Baseline and week 8 contrast-enhanced CT were used to assess response by RECIST 1.1, changes in the sum of target lesion diameters (ΔSTL), lung metastases cavitation and liver metastases density. Primary and secondary objectives were to develop ex novo univariable and multivariable models to predict overall survival (OS) and progression-free survival (PFS), respectively., Results: 202 patients were enrolled, 134 (66.3%) treated with regorafenib and 68 (33.7%) with placebo. In the univariate analysis, PFS predictors were lung metastases cavitation at baseline (HR 0.50, 95% CI 0.27 to 0.92, p=0.03) and at week 8 (HR 0.58, 95% CI 0.36 to 0.93, p=0.02). Baseline cavitation (HR 0.23, 95% CI 0.08 to 0.66, p=0.007), RECIST 1.1 (HR 0.23, 95% CI 0.14 to 0.4, p <0.0001) and ΔSTL (HR 1.16, 95% CI 1.06 to 1.27, p=0.002) predicted OS. We found an increase of 9% of diameter as the best threshold for discriminating OS (HR 2.64, 95% CI 1.61 to 4.34, p <0.001). In the multivariate analysis, baseline and week 8 cavitation remained significant PFS predictors. Baseline cavitation, RECIST 1.1 and ΔSTL remained predictors of OS in exploratory multivariable models. Assessment of liver metastases density did not predict clinical outcome., Conclusions: RECIST 1.1 and ΔSTL predict favourable outcome to regorafenib. In contrast to liver metastases density that failed to be a predictor, lung metastases cavitation represents a novel radiological marker of favourable outcome that deserves consideration., Competing Interests: Competing interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are: RR reports grants from Bayer, during the conduct of the study, personal fees from Bayer (Consultancies, Speaker) outside the present work; AV reports grants from Bayer, during the conduct of the study; SG reports grants from Bayer, during the conduct of the study; AG reports grants and other from Bayer, during the conduct of the study; grants and other from Genentech, other from Taiho, outside the submitted work; AF reports grants and personal fees from Amgen, grants and personal fees from Merck, grants and personal fees from Roche, grants and personal fees from Bayer, personal fees from Lilly and personal fees from Sevier, outside the submitted work; MY reports personal fees from BAYER, personal fees from ROCHE, personal fees from AMGEN, outside the submitted work; CB reports personal fees from Bayer, outside the submitted work; OB reports personal fees from ROCHE, personal fees from MERCK SERENO, personal fees from NOVARTIS, personal fees from LILLY, personal fees from AMGEN, from null, outside the submitted work; MP reports grants from Bayer, during the conduct of the study, personal fees from Amgen, Sanofi, Servier outside the submitted work; YH reports other from Bayer Pharma, during the conduct of the study; LM reports honorarium charges displacement of Congress; JT reports other from Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda, outside the submitted work; TM reports grants from ROCHE, personal fees from SANOFI, personal fees and non-financial support from AMGEN, outside the submitted work; DR reports grants from Bayer, during the conduct of the study; KB reports grants from Bayer, during the conduct of the study; CF reports grants from Bayer, during the conduct of the study; AA reports personal fees from Amgen, personal fees from Bayer, personal fees from Lilly, outside the submitted work; AS-B participated at advisory boards for Amgen, Bayer and Lilly. AV reports grants from Bayer, during the conduct of the study; SS reports grants from Bayer, during the conduct of the study, participated at advisory boards for Amgen, Bayer, Lilly, Merck, Roche and Sanofi.