Triple-drug chemotherapy regimens in combination with an anti-EGFR agent in metastatic colorectal cancer - prospects from phase II clinical trials

Introduction: The addition of monoclonal antibody (mAb) epidermal growth factor receptor (EGFR) inhibitors to classic chemotherapy doublet backbones has improved survival of metastatic colorectal cancer (mCRC). However, the role of triple-drug chemotherapy regimens in combination with an anti-EGFR mAb inhibitor is not yet clear.

Areas covered: The activity of triple-drug chemotherapy regimens when combined with an anti-EGFR mAb in mCRC patients is examined. We describe the overall safety and tolerability profiles based on a literature review of all published phase I and II clinical trials in this setting. Drug exposure, tumor mutational status, and metastases resectability are discussed. A review of PubMed and abstracts of major oncology congresses from 2009 to 2018, with MeSH and full-text search terms for clinical trials of anti-EGFR for ‘metastatic’ or ‘advanced’ ‘colorectal cancer/adenocarcinoma’ was implemented. Only English language publications were included.

Expert opinion: Efficacy data from phase II trials are promising, but the safety profiles are not as encouraging; the development of severe diarrhea and acneiform rash limit the drug exposure that is critical for improved outcomes. Phase II studies of these triplet chemotherapy/anti-EGFR mAb combinations have focused on conversion therapy in liver-limited disease or in the first-line setting in advanced disease. The identification of biomarkers of response and toxicity may support the use of personalized medicine and more precise design of phase III trials.     

Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.     

Mitogen‐activated protein kinase phosphatase‐2 deletion modifies ventral tegmental area function and connectivity and alters reward processing

Mitogen‐activated protein kinases (MAPKs) regulate normal brain functioning, and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen‐activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP‐2^?/? mice to assess whether MKP‐2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP‐2^?/? mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP‐2^?/? mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP‐2^?/? mice exhibited increased sucrose preference and impaired amphetamine‐induced hyperlocomotion. Overall, these data reveal that MKP‐2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present.