Patient-reported outcomes with nivolumab in advanced solid cancers.

Patients with recurrent or metastatic cancer commonly suffer from debilitating toxicity associated with conventional treatment modalities, as well as disease-related symptoms, often with a concomitant negative impact on health-related quality of life (HRQoL). Patient-reported outcomes (PROs) provide important insights into the patient experience in clinical trials. Nivolumab is a programmed death-1 receptor inhibitor that extends survival in patients with recurrent or metastatic disease in multiple tumor types. In this review, we summarize published PRO analyses from eight phase II-IV clinical trials with nivolumab for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma (RCC), and squamous cell carcinoma of the head and neck (SCCHN). Symptom burden, physical functioning, and HRQoL were measured using generic, cancer-specific, and tumor type-specific validated PRO instruments. Nivolumab showed sustained stabilization across all tumor types and, in some cases, clinically meaningful improvement in HRQoL, whereas standard of care therapies often led to deteriorations. Exploratory analyses found a positive correlation between baseline HRQoL scores and overall survival in RCC, and between baseline HRQoL scores and healthcare resource utilization in SCCHN, suggesting that patient-reported symptoms at treatment initiation may have clinical value. In the era of value-based oncology care, stakeholders are increasingly interested in PRO findings to guide clinical, regulatory, and reimbursement decisions. However, missing data remain a significant challenge in PRO analyses, including in nivolumab trials. Future clinical trials in immuno-oncology should incorporate PRO data collection, including beyond treatment discontinuation or trial completion to assess the long-term effects of treatment on HRQoL

Case-Control Study of Fetal Microchimerism and Breast Cancer

Prior pregnancy is known to protect against development of breast cancer. Recent studies have demonstrated that pregnancy has the capacity to establish small numbers of immunologically active fetal-derived cells in the mother, a phenomenon known as fetal microchimerism (FMc). We asked whether presence of FMc, routinely acquired during pregnancy, is a protective factor for breast cancer.DNA extracts from peripheral blood specimens were obtained from a population-based case-control study of risk factors for breast cancer in women 21 to 45 years old. Specimens were tested with quantitative PCR for presence and concentrations of male DNA presumed to derive from prior pregnancies with a male fetus. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with consideration of multiple established reproductive and environmental risk factors for breast cancer. FMc results were generated on 99 parous women, 54 with primary invasive breast cancer and 45 general population controls. FMc prevalence was 56% (25/45) and 26% (14/54) in controls and cases, respectively. Women harboring FMc were less likely to have had breast cancer (OR = 0.29, 95% CI 0.11-0.83; p = 0.02, adjusting for age, number of children, birth of a son, history of miscarriage, and total DNA tested). In addition, FMc concentrations were higher in controls versus cases (p = 0.01). Median concentrations were 2 (0-78) and 0 (0-374) fetal genomes/10(6) maternal genomes in controls and cases, respectively.Results suggest that the enigma of why some parous women are not afforded protection from breast cancer by pregnancy might in part be explained by differences in FMc. Mechanistic studies of FMc-derived protection against breast cancer are warranted

Non-conventional sources of peptides presented by MHC class I

Effectiveness of immune surveillance of intracellular viruses and bacteria depends upon a functioning antigen presentation pathway that allows infected cells to reveal the presence of an intracellular pathogen. The antigen presentation pathway uses virtually all endogenous polypeptides as a source to produce antigenic peptides that are eventually chaperoned to the cell surface by MHC class I molecules. Intriguingly, MHC I molecules present peptides encoded not only in the primary open reading frames but also those encoded in alternate reading frames. Here, we review recent studies on the generation of cryptic pMHC I. We focus on the immunological significance of cryptic pMHC I, and the novel translational mechanisms that allow production of these antigenic peptides from unconventional sources

Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma.

PURPOSE: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types