James Stevenson

Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study

BACKGROUND Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC. METHODS In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score (<1% vs ≥1%) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p<0·025 (one sided). Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned study treatment. This trial, which is closed for enrolment but continuing for follow-up, is registered with ClinicalTrials.gov, number NCT02039674. FINDINGS Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42-68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18-41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9-42%]; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia. INTERPRETATION Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study. FUNDING Merck & Co.

Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials

Background Programmed death 1 (PD‐1) programmed death‐ligand 1 (PD‐L1) inhibitors show significant clinical activity in non‐small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune‐mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD‐1 and PD‐L1 inhibitors. We sought to determine the overall incidence of pneumonitis and differences according to type of inhibitors and prior chemotherapy use. Methods MEDLINE, Embase, and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade ≥ 3 from all clinical trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian‐Laird random effects models. We compared incidences between PD‐1 and PD‐L1 inhibitors and between treatment naive and previously treated patients. Results Nineteen trials (12 with PD‐1 inhibitors [n = 3,232] and 7 with PD‐L1 inhibitors [n = 1,806]) were identified. PD‐1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis compared with PD‐L1 inhibitors (3.6%; 95% CI, 2.4%‐4.9% vs 1.3%; 95% CI, 0.8%‐1.9%, respectively; P = .001). PD‐1 inhibitors were also associated with higher incidence of grade 3 or 4 pneumonitis (1.1%; 95% CI, 0.6%‐1.7% vs 0.4%; 95% CI, 0%‐0.8%; P = .02). Treatment naive patients had higher incidence of grade 1 through 4 pneumonitis compared with previously treated patients (4.3%; 95% CI, 2.4%‐6.3% vs 2.8%; 95% CI, 1.7%‐ 4%; P = .03). Conclusions There was a higher incidence of pneumonitis with use of PD‐1 inhibitors compared with PD‐L1 inhibitors. Higher rate of pneumonitis was more common in treatment naive patients.

Incidence of pneumonitis with use of PD-1 and PD-L1 inhibitors in non-small cell lung cancer: A Systematic Review and Meta-analysis of trials

Background Programmed death 1 (PD‐1) programmed death‐ligand 1 (PD‐L1) inhibitors show significant clinical activity in non‐small cell lung carcinoma (NSCLC). However, they are often associated with potentially fatal immune‐mediated pneumonitis. Preliminary reports of trials suggest a difference in the rate of pneumonitis with PD‐1 and PD‐L1 inhibitors. We sought to determine the overall incidence of pneumonitis and differences according to type of inhibitors and prior chemotherapy use. Methods MEDLINE, Embase, and Scopus databases were searched up to November 2016. Rates of pneumonitis of any grade and grade ≥ 3 from all clinical trials investigating nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab as single agents in NSCLC were collected. The incidence of pneumonitis across trials was calculated using DerSimonian‐Laird random effects models. We compared incidences between PD‐1 and PD‐L1 inhibitors and between treatment naive and previously treated patients. Results Nineteen trials (12 with PD‐1 inhibitors [n = 3,232] and 7 with PD‐L1 inhibitors [n = 1,806]) were identified. PD‐1 inhibitors were found to have statistically significant higher incidence of any grade pneumonitis compared with PD‐L1 inhibitors (3.6%; 95% CI, 2.4%‐4.9% vs 1.3%; 95% CI, 0.8%‐1.9%, respectively; P = .001). PD‐1 inhibitors were also associated with higher incidence of grade 3 or 4 pneumonitis (1.1%; 95% CI, 0.6%‐1.7% vs 0.4%; 95% CI, 0%‐0.8%; P = .02). Treatment naive patients had higher incidence of grade 1 through 4 pneumonitis compared with previously treated patients (4.3%; 95% CI, 2.4%‐6.3% vs 2.8%; 95% CI, 1.7%‐ 4%; P = .03). Conclusions There was a higher incidence of pneumonitis with use of PD‐1 inhibitors compared with PD‐L1 inhibitors. Higher rate of pneumonitis was more common in treatment naive patients.

Current issues in malignant pleural mesothelioma evaluation and management.

Malignant pleural mesothelioma (MPM) is an uncommon disease most often associated with occupational asbestos exposure and is steadily increasing in worldwide incidence. Patients typically present at an older age, with advanced clinical stage and other medical comorbidities, making management quite challenging. Despite great efforts, the prognosis of MPM remains poor, especially at progression after initial treatment. Macroscopic complete resection of MPM can be achieved through extrapleural pneumonectomy (EPP) or extended (ie, radical) pleurectomy (e-P/D) in selected patients and can result in prolonged survival when incorporated into a multimodality approach. Given the morbidity associated with surgical resection of MPM, optimizing identification of appropriate patients is essential. Unfortunately, most patients are not candidates for EPP or e-P/D due to advanced stage, age, and/or medical comorbidity. Pemetrexed and platinum combination chemotherapy has become the cornerstone of therapy for patients with unresectable disease because the combination is associated with improved survival and quality of life in treated patients. However, MPM eventually becomes resistant to initial therapy, and benefit to further lines of therapy has not been substantiated in randomized clinical trials. Translational research has provided exciting insights into tumorigenesis, biomarkers, and immune response in MPM, leading to the development of multiple novel therapeutic agents that are currently in clinical trials. These advances hold the promise of a new era in the treatment of MPM and suggest that this disease will not be left behind in the war on cancer.

Reducing Unplanned Medical Oncology Readmissions by Improving Outpatient Care Transitions: A Process Improvement Project at the Cleveland Clinic

PURPOSE Reducing 30-day unplanned hospital readmissions is a national policy priority. We examined the impact of a quality improvement project focused on reducing oncology readmissions among patients with cancer who were admitted to palliative and general medical oncology services at the Cleveland Clinic. METHODS Baseline rates of readmissions were gathered during the period from January 2013 to April 2014. A quality improvement project designed to improve outpatient care transitions was initiated during the period leading to April 1, 2014, including: (1) provider education, (2) postdischarge nursing phone calls within 48 hours, and (3) postdischarge provider follow-up appointments within 5 business days. Nursing callback components included symptom management, education, medication review/compliance, and follow-up appointment reminder. RESULTS During the baseline period, there were 2,638 admissions and 722 unplanned 30-day readmissions for an overall readmission rate of 27.4%. Callbacks and 5-day follow-up appointment monitoring revealed a mean monthly compliance of 72% and 78%, respectively, improving over time during the study period. Readmission rates declined by 4.5% to 22.9% (P < .01; relative risk reduction, 18%) during the study period. The mean direct cost of one readmission was

Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC)

10,884, suggesting an annualized cost savings of

Safety and Efficacy of PD-1/PD-L1 Inhibitors in Treatment-Naive and Chemotherapy-Refractory Patients With Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis

1.04 million with the observed reduction in unplanned readmissions. CONCLUSION Modest readmission reductions can be achieved through better systematic transitions to outpatient care (including follow-up calls and early provider visits), thereby leading to a reduction in use of inpatient resources. These data suggest that efforts focused on improving outpatient care transition were effective in reducing unplanned oncology readmissions.

Phase II randomized trial of carboplatin, paclitaxel, bevacizumab with or without cixutumumab (IMC-A12) in patients with advanced non-squamous, non-small-cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E3508)

Objective: The aim of this study was to assess the efficacy of maintenance pembrolizumab in patients with extensive‐stage SCLC after treatment with platinum and etoposide. Methods: Patients with extensive‐stage SCLC with a response or stable disease after induction chemotherapy were eligible. Pembrolizumab at a dose of 200 mg administered intravenously every 3 weeks was initiated within 8 weeks of the last cycle of chemotherapy. The primary end point of the study was progression‐free survival (PFS) from study registration, with overall survival (OS) as a key secondary end point. Available tumor tissue was assessed for expression of programmed death ligand 1 (PD‐L1) both in the tumor cells and in the surrounding stroma. Blood for circulating tumor cells was collected before the first, second, and third cycles of pembrolizumab. Results: Of the 45 patients enrolled, 56% were male and 22% had treated brain metastases. The median PFS was 1.4 months (95% confidence interval [CI]: 1.3–2.8), with a 1‐year PFS of 13%. The median OS was 9.6 months (95% CI: 7.0–12), with a 1‐year OS of 37%. Of the 30 tumors that could be assessed, three had PD‐L1 expression (≥1%) in the tumor cells. A total of 20 tumors could be assessed for PD‐L1 expression in the stroma. The median PFS in the eight patients with tumors positive for expression of PD‐L1 at the stromal interface was 6.5 months (95% CI: 1.1–12.8) compared with 1.3 months (95% CI: 0.6–2.5) in 12 patients with tumors negative for this marker. No unexpected toxicities were observed. Conclusion: Maintenance pembrolizumab did not appear to improve median PFS compared with the historical data. However, the 1‐year PFS rate of 13% and OS rate of 37% suggest that a subset of patients did benefit from pembrolizumab.

Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non–small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study

Micro‐Abstract Programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors are a significant advance in the treatment of patients with non–small‐cell lung cancer. In this study we investigated the comparative safety and efficacy of these agents when used in patients who are chemotherapy‐naive vs. patients previously treated with chemotherapy. We found that PD‐1/PD‐L1 inhibitors have greater clinical efficacy in chemotherapy‐naive patients compared with patients who were previously treated with chemotherapy. Introduction Programmed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors show significant clinical activity in non–small‐cell lung carcinoma (NSCLC). However, there is a relative lack of data on comparative efficacy of these drugs in the first‐line setting versus chemotherapy‐treated patients. We compared the efficacy and toxicity of these drugs in these 2 distinct groups of patients. Materials and Methods Electronic databases (PubMed‐Medline, EMBASE, Scopus) and major conference proceedings were systematically searched for all phase I to III clinical trials in NSCLC using PD‐1/PD‐L1 inhibitors. Objective response rate (ORR) and progression‐free survival (PFS) data were collected and combined using DerSimonian and Laird random effects model meta‐analysis. The I2 statistic was used to assess heterogeneity. Results Seventeen distinct trials (8 with treatment‐naive patients [n = 937]; 14 with chemotherapy‐treated patients [n = 3620]; 5 with separate treatment‐naive and previously treated arms) were included. Treatment‐naive patients had a statistically significant higher ORR (30.2%; 95% confidence interval [CI], 22.70‐38.2) than patients previously treated with chemotherapy (ORR, 20.1%; 95% CI, 17.5‐22.9; P = .02). No significant differences in PFS were observed between the 2 groups. Treatment‐naive patients had statistically significant higher rates of all grade pneumonitis compared with previously treated patients (4.9%; 95% CI, 3.4‐6.7 vs. 3.0%; 95% CI, 2.0‐4.1; P = .04); however, no significant differences in any other immune‐related adverse events were observed. Conclusion PD‐1/PD‐L1 inhibitor therapy for advanced NSCLC has a significantly higher ORR and a higher rate of immune‐mediated pneumonitis when used in the first‐line setting compared with chemotherapy treated patients.

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer

Background Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. Methods Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). Results Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. Conclusions The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. ClinicalTrials.gov Identifier NCT00955305.