Immuno-oncology-the new paradigm of lung cancer treatment.

Systemic therapy is an essential part of treatment for all patients with small-cell lung cancer (sclc) and for most patients with non-small-cell lung cancer (nsclc). Standards of care have evolved dramatically since 2009, especially in the setting of incurable or advanced nsclc. Part of that evolution has been the incorporation of immuno-oncology drugs, especially immune checkpoint inhibitors (icis) into multiple therapeutic scenarios. In the present review, we discuss the role of the immune system in lung cancer and the previous failures of immunotherapy for patients with lung cancer. We then provide an overview of the existing evidence for the use of icis in patients with advanced nsclc that is either treatment-naïve or pretreated, for consolidative treatment after chemoradiotherapy in stage iii nsclc, and for palliative therapy in patients with sclc. Finally, we discuss duration of treatment, special populations, and the future of immuno-oncology for patients with lung cancer. Overall, we provide an evidence-based snapshot of immuno-oncology agents in the treatment of lung cancer up to early 2019.

A Canadian cancer trials group phase IB study of durvalumab (anti-PD-L1) plus tremelimumab (anti-CTLA-4) given concurrently or sequentially in patients with advanced, incurable solid malignancies.

Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration.

Resource use in the last three months of life by lung cancer patients in southern Ontario.

Background: End-of-life cancer care involves multidisciplinary teams working in various settings. Evaluating the quality of care and the feedback from such processes is an important aspect of health care quality improvement. Our retrospective cohort study reviewed health care use by lung cancer patients at end of life, their reasons for visiting the emergency department (ed), and feedback from regional health care professionals. Methods: We assessed 162 Ontario patients with small-cell and relapsed or advanced non-small-cell lung cancer. Demographics, disease characteristics, and resource use were collected, and the consenting caregivers for patients with ed visits were interviewed. Study results were disseminated, and feedback about barriers to care was sought. Results: Median patient age was 69 years; 73% of the group had non-small-cell lung cancer; and 39% and 69% had received chemotherapy and radiation therapy respectively. Median overall survival was 5.6 months. In the last 3 months of life, 93% of the study patients had visited an oncologist, 67% had telephoned their oncology team, 86% had received homecare, and 73% had visited the ed. Death occurred for 55% of the patients in hospital; 23%, at home; and 22%, in hospice. Goals of care had been documented for 68% of the patients. Homecare for longer than 3 months was associated with fewer ed visits (80.3% vs. 62.1%, p = 0.022). Key themes from stakeholders included the need for more resources and for effective communication between care teams. Conclusions: Use of acute-care services and rates of death in an acute-care facility are both high for lung cancer patients approaching end of life. In our study, interprofessional and patient-provider communication, earlier connection to homecare services, and improved access to community care were highlighted as having the potential to lower the need for acute-care resources.

Breaking the biomarker code: PD-L1 expression and checkpoint inhibition in advanced NSCLC.

BACKGROUND: Lung cancer is the most common cause of cancer-related death among males and the second leading cause among females globally. Checkpoint inhibitors re-engage the immune system to fight cancer. This review evaluates phase III data on the use of checkpoint inhibitors in the treatment of advanced NSCLC and addresses PD-L1 expression in predicting efficacy. METHODS: Six phase III clinical trials investigating checkpoint inhibitors for NSCLC were identified through a search of PubMed (to November 15, 2016) and conference databases, with findings updated from a directed search of eligible studies conducted in January 2018. RESULTS: Significant reductions in the risk of death ranging from 27% to 41% and were observed second-line and beyond. A relationship between PD-L1 expression and survival was apparent in most trials with optimal benefit for the highest expression levels (≥50%). Benefit was also observed at low or no PD-L1 expression levels and in third-line in some studies. Significantly improved PFS was observed for pembrolizumab at high PD-L1 expression levels (≥50%) first-line. Immune-related adverse events associated with checkpoint inhibitors are tolerable and rates of pneumonitis may be lower among PD-L1 inhibitors. Use of checkpoint inhibitors for tumors with driver mutations should only be considered after all appropriate targeted therapy and chemotherapy have been exhausted. PD-L1 testing presents a valuable tool to guide treatment sequencing and we recommend use of agent-specific PD-L1 tests and respective scoring systems until a standardized, convenient and broadly applicable test is identified. CONCLUSIONS: Checkpoint inhibitors represent a major advance in the treatment of advanced NSCLC and PD-L1 status can inform treatment decisions.

Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.

Background: Nivolumab was the first immuno-oncology agent available for the treatment of lung cancer in Canada. In the present study, we evaluated the real-world benefit of nivolumab in Canadian patients with lung cancer. Methods: Patients included in the cohort were identified from a registry of patients treated through expanded access to nivolumab before and after Health Canada approval. Demographics were collected from the application forms. Outcome data for the duration of treatment and survival were collected retrospectively. Results: In contrast to the randomized clinical trial populations, our study cohort included patients who were older (median age: 66 years; range: 36-92 years) and who had an Eastern Cooperative Oncology Group performance status of 2 (8.9%). Despite the poorer-prognosis cohort, median overall survival was 12.0 months, which is comparable to the survival demonstrated in the randomized phase iii trials of nivolumab in lung cancer. Median time to treatment discontinuation was 3.45 months and was similar for all patient subgroups, including poorer-prognosis groups such as those with a performance status of 2, those 75 years of age and older, and those with brain metastases. Conclusions: Nivolumab given in a real-world clinical setting was associated with results similar to those reported in the phase iii clinical trial setting.

Management of EGFR-mutated non-small-cell lung cancer: practical implications from a clinical and pathology perspective.

Starting in the early 2000s, non-small-cell lung cancer (nsclc) subtypes have evolved from being histologically described to molecularly defined. Management of lung adenocarcinomas now generally requires multiple molecular tests at baseline to define the optimal treatment strategy. More recently, second biopsies performed at progression in patients treated with tyrosine kinase inhibitors (tkis) have further defined the continued use of molecularly targeted therapy. In the present article, we focus on one molecular subtype: EGFR-mutated nsclc. For that patient population, multiple lines of tki therapy are now available either clinically or in clinical trials. Each line of treatment is guided by the specific mutations (for example, L858R, T790M, C797S) identified in EGFR. We first describe the various mechanisms of acquired resistance to EGFR tki treatment. We then focus on strategies that clinicians and pathologists can both use during tissue acquisition and handling to optimize patient results. We also discuss future directions for the molecular characterization of lung cancers with driver mutations, including liquid biopsies. Finally, we provide an algorithm to guide treating physicians managing patients with EGFR-mutated nsclc. The same framework can also be applied to other molecularly defined nsclc subgroups as resistance patterns are elucidated and additional lines of treatment are developed.