Panitumumab plus trifluridine/tipiracil as anti‐EGFR rechallenge therapy in patients with refractory <i>RAS</i> wild‐type metastatic colorectal cancer: Overall survival and subgroup analysis of the randomized phase II VELO trial

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Abstract

The randomized phase II VELO trial showed that the addition of panitumumab to trifluridine/tipiracil significantly improves progression‐free survival (PFS) as compared to trifluridine/tipiracil in third‐line therapy in patients with refractory RAS wild‐type (WT) metastatic colorectal cancer (mCRC). With longer follow‐up, final overall survival results and posttreatment subgroup analysis are presented. Sixty‐two patients with refractory RAS WT mCRC were randomly assigned to receive, as third‐line therapy, trifluridine/tipiracil alone (arm A) or in combination with panitumumab (arm B). Primary endpoint was PFS; secondary endpoints included overall survival (OS) and overall response rate (ORR). Median OS was 13.1 months (95% CI 9.5‐16.7) in arm A compared to 11.6 months (95% CI 6.3‐17.0) in arm B (HR: 0.96, 95% CI 0.54‐1.71, P = .9). To evaluate the impact of subsequent lines of treatment, subgroup analysis was performed for the 24/30 patients in arm A, that received fourth‐line therapy after disease progression. Median PFS was 4.1 months (95% CI 1.44‐6.83) for 17 patients treated with anti‐EGFR rechallenge as compared to 3.0 months (95% CI 1.61‐4.31) for seven patients that received other therapies (HR: 0.29, 95% CI 0.10‐0.85, P = .024). Median OS from the start of fourth‐line treatment was 13.6 months (95% CI 7.2‐20), and 5.1 months (95% CI 1.8‐8.3) for patients treated with anti‐EGFR rechallenge vs other therapies, respectively (HR: 0.30, 95% CI 0.11‐0.81, P = .019). Final results of the VELO trial support the role of anti‐EGFR rechallenge in the continuum of care of patients with RAS/BRAF WT mCRC.

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Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial

Axel Grothey, Eric Van Cutsem, Alberto Sobrero … (2013)

No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323. Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64-0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population. Bayer HealthCare Pharmaceuticals. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways

Ping Wee, Zhixiang Wang (2017)

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors.

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Randomized trial of TAS-102 for refractory metastatic colorectal cancer.

Robert Mayer, Eric Van Cutsem, Alfredo Falcone … (2015)

Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients.