Kristen A. Marrone

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

BACKGROUND Antibodies that block programmed death 1 (PD‐1) protein improve survival in patients with advanced non–small‐cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD‐1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD‐L1), mutational burden, and mutation‐associated, neoantigen‐specific T‐cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side‐effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD‐L1–positive and PD‐L1–negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T‐cell clones that were found in both the tumor and peripheral blood increased systemically after PD‐1 blockade in eight of nine patients who were evaluated. Mutation‐associated, neoantigen‐specific T‐cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD‐1 blockade. Treatment induced expansion of mutation‐associated, neoantigen‐specific T‐cell clones in peripheral blood. (Funded by Cancer Research Institute–Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621.)

Immune‐Related Adverse Events From Immune Checkpoint Inhibitors

Immunotherapy for cancer treatment has come of age, specifically with the use of immune checkpoint antibodies directed against molecules such as CTLA‐4, PD‐1, and PD‐L1. Single‐agent and combinatorial approaches utilizing these agents and other immunotherapies that may enhance antitumor effects are under investigation. With increasing clinical use of these agents, an appreciation for their toxicities comes to the fore. Adverse events that occur as a result of the immunologic effects of these therapies are termed “immune‐related adverse events” (irAEs), and range in both frequency and severity in reported single‐agent and combination studies. Improvements in our understanding of how and why irAEs develop and how to effectively manage them are needed. Herein we provide a state‐of‐the‐art synopsis of the incidence, clinical features, mechanisms, and management of selected irAEs with immune checkpoint inhibitors currently in use.

cancer Immunotherapy in Older Patients

Abstract Advancing age remains one of the most significant risk factors for cancer development. Changes in the immune system occur with aging, and likely play a role in the increased incidence of malignancy in older patients. With the advent of immune checkpoint inhibitors, and their use in a variety of malignancies, there has been an explosion of clinical trials evaluating their use. Unfortunately, these trials have not shown consistent results in elderly patients, nor have age-specific outcomes been consistently reported. Further evaluation of the efficacy and toxicity of these agents in the elderly is needed, as they are now in frequent clinical use. By investigating how age-related changes in the immune system occur and intersect with use of immune checkpoint inhibitors, their use can be optimized in a clear and safe manner. Further study of age-related changes in the immune system can also lead to effective combination immunotherapeutic approaches, maximizing the efficacy of immune checkpoint inhibitors across tumor types and across the age spectrum of cancer patients.

A Randomized Phase II Study of Metformin plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy‐Naïve Advanced or Metastatic Nonsquamous Non‐Small Cell Lung Cancer

Retrospective clinical data and laboratory studies point to metformin having a potential role in cancer treatment; however, the efficacy of this drug in cancer treatment therapy has not been validated in prospective trials. In particular, limited data evaluating the effects of metformin in lung cancer has been available. Responding to this need, a prospective phase II clinical trial was conducted, and this article evaluates response rate and progression‐free survival of platinum‐based doublet chemotherapy with or without metformin in chemotherapy‐naïive advanced or metastatic nonsquamous non‐small cell lung cancer.

Pneumonitis in Non–Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors

ABSTRACT Checkpoint inhibitor pneumonitis (CIP) is an immune‐related adverse event that can occur after initiation of anti–programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial‐enrolled and non–trial‐enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti–programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%–5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher‐grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life‐threatening complication of ICI therapy.

Neoadjuvant and consolidation immuno-oncology therapy in stage III non-small cell lung cancer

Lung cancer continues to be the leading cause of cancer death worldwide. Recently, immunotherapy for non-small cell lung cancer (NSCLC) has emerged as a powerful treatment option for advanced lung cancer. The relative success of programmed death 1 (PD-1) and/or programmed death ligand 1 (PD-L1) antibodies in metastatic disease have increased interest in expanding their use to earlier stage NSCLC. The complex and diverse nature of stage III disease also invites the incorporation of immunotherapy into treatment plans in both the neoadjuvant and consolidation settings. Currently available data of anti-PD-(L)1 therapies in stage III NSCLC are limited. However, interim results from two studies are encouraging: a phase II neoadjuvant nivolumab trial demonstrated early signals of efficacy, and the phase III PACIFIC trial of durvalumab recently showed significant improvement in progression-free survival (PFS). Preliminary results for the phase II DETERRED trial of durvalumab have also been reported. Many studies are testing anti-PD-(L)1 therapies in the neoadjuvant and consolidation settings for stage III NSCLC, and will be discussed. As these studies mature they may provide further treatment options in management of stage III NSCLC.

Single-Board Hematology Fellowship Track: A 10-Year Institutional Experience

TO THE EDITOR: In the United States, internal medicine subspecialty training is dictated primarily by the Accreditation Council for Graduate Medical Education (ACGME), which sets standards for clinical and education program requirements for recognized fellowships. For adult hematology and oncology

Nivolumab for refractory metastatic squamous non-small-cell lung cancer: fulfilling an unmet need.

Lung cancer is the leading cause of cancer death in the United States and worldwide (1,2). Approximately 85% of cases involve non-small-cell lung cancer (NSCLC), of which 30% will be squamous cell histology. Of those squamous cell lung cancers diagnosed yearly, it is estimated that more than 50% are metastatic at diagnosis. Until recently, the recommended treatment for good performance status patients with metastatic squamous lung cancer consisted of first-line platinum doublet chemotherapy followed, upon disease progression, by second-line single agent chemotherapy (1). Median overall survival from initial diagnosis of metastatic squamous lung cancer in patients who receive first-line platinum doublet chemotherapy ranges from 8-11 months (3,4). Therefore, effective new therapies are desperately needed. Building upon durable objective responses to the anti-programmed death-1 (anti-PD-1) antibody, nivolumab, reported in phase I studies, Rizvi et al. have recently published the results of a singlearm phase II trial of single-agent nivolumab in pretreated metastatic squamous lung cancer (5). In conjunction with headline results from a randomized phase III trial in secondline metastatic squamous lung cancer confirming improved OS for nivolumab compared with docetaxel, these data have led to the FDA approval of nivolumab for the treatment of metastatic squamous lung cancer after prior platinum-based chemotherapy (6).