Summary Background Metastatic DNA mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) colorectal cancer (mCRC) has a poor prognosis following conventional chemotherapy and exhibits high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators, all features that correspond with response to programmed cell death receptor-1 (PD-1) blockade in other tumour types. Thus, nivolumab, a PD-1 immune checkpoint inhibitor, was evaluated in this population. Methods In this is ongoing, multicentre, open-label, nonrandomised, phase 2 trial, adult patients (aged ≥18 years) with histologically confirmed recurrent or mCRC locally assessed as dMMR/MSI-H who had progressed on/after or been intolerant of at least one prior line of treatment, including a fluoropyrimidine and oxaliplatin or irinotecan, were enrolled. Patients were given nivolumab 3 mg/kg every 2 weeks until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors v1·1. All patients who received at least one dose of study drug were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02060188. Findings Among the 74 patients who were enrolled between March 12, 2014, and March 16, 2016, most (54·1%) had received ≥3 prior therapies. At a median follow-up of 12·0 months (interquartile range 8·57–18·00 months), 23 of 74 patients (31·1% [95% CI 20·8%–42·9%]) achieved an investigator-assessed objective response; 68·9% (95% CI 57·1%–79·2%) of patients had disease control for ≥12 weeks. Median duration of response was not yet reached; all responders were alive, and 8 (34·8%) had responses of ≥12 months. The most common (≥10% of patients) drug-related adverse events was fatigue (n=16 [21·6%]), diarrhoea (n=15 [20·3%]), pruritus (n=10 [13·5%]) and rash (n=8 [10·8%]). The most common grade 3 or 4 drug-related adverse events were increased lipase (n=6 [8·1%]) and amylase (n=2 [2·7%]) levels. Five patients (6·8%) discontinued treatment because of increased alanine aminotransferase, colitis, duodenal ulcer, acute kidney injury, and stomatitis (n=1 each). Twenty-three patients (31·1%) died during the study; none of these deaths was considered to be treatment related by the investigator. Interpretation Nivolumab provided durable responses and disease control, as well as long-term survival in pre-treated patients with dMMR/MSI-H mCRC, and is a new treatment option for these patients.

The data and regulatory considerations leading to the U.S. Food and Drug Administration (FDA) January 30, 2012 approval of Erivedge (vismodegib) capsules for the treatment of patients with recurrent, locally advanced, or metastatic basal cell carcinoma (BCC) are described. The FDA's approval decision was based primarily on the results observed in a single-arm, parallel cohort, international trial of vismodegib, administered orally at 150 mg daily until disease progression, in patients with pathologically confirmed, recurrent, locally advanced basal cell carcinoma (laBCC) or metastatic basal cell carcinoma (mBCC). An independent review committee confirmed an overall response rate (ORR) of 30.3% [95% confidence interval (CI): 15.6-48.2] in 33 patients with mBCC and an ORR of 42.9% (95% CI: 30.5-56.0) in 63 patients with laBCC; median response durations were 7.6 months and 7.6 months for patients with mBCC and laBCC, respectively. The most common adverse reactions were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, cough, arthralgias, vomiting, headache, ageusia, insomnia, and upper respiratory tract infection. Animal toxicology studies confirmed that vismodegib is a potent teratogenic agent. Approval was based on durable objective tumor responses supported by knowledge of the pathologic role of Hedgehog signaling in BCC and acceptable toxicity in a population without effective alternative therapies.

No abstract

No abstract