Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.

BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).

Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically on the based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present 5-year outcomes from the phase 3 KEYNOTE-189 study (ClinicalTrials.gov identifier: NCT02578680). Eligible patients with previously untreated metastatic nonsquamous non-small-cell lung cancer without EGFR/ALK alterations were randomly assigned 2:1 to pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles with pemetrexed and investigator's choice of carboplatin/cisplatin for four cycles, followed by maintenance pemetrexed until disease progression or unacceptable toxicity. Primary end points were overall survival (OS) and progression-free survival (PFS). Among 616 randomly assigned patients (n = 410, pembrolizumab plus pemetrexed-platinum; n = 206, placebo plus pemetrexed-platinum), median time from random assignment to data cutoff (March 8, 2022) was 64.6 (range, 60.1-72.4) months. Hazard ratio (95% CI) for OS was 0.60 (0.50 to 0.72) and PFS was 0.50 (0.42 to 0.60) for pembrolizumab plus platinum-pemetrexed versus placebo plus platinum-pemetrexed. 5-year OS rates were 19.4% versus 11.3%. Toxicity was manageable. Among 57 patients who completed 35 cycles of pembrolizumab, objective response rate was 86.0% and 3-year OS rate after completing 35 cycles (approximately 5 years after random assignment) was 71.9%. Pembrolizumab plus pemetrexed-platinum maintained OS and PFS benefits versus placebo plus pemetrexed-platinum, regardless of programmed cell death ligand-1 expression. These data continue to support pembrolizumab plus pemetrexed-platinum as a standard of care in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations.

Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors.

BACKGROUND: Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors. METHODS: Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed. RESULTS: No DLTs occurred in parts A (n=18) or B (n=85). Grade 3-5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35). CONCLUSIONS: Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02043665.

Standard-Dose Osimertinib in EGFR-Mutated Non-Small-Cell Lung Adenocarcinoma With Leptomeningeal Disease.

PURPOSE: Leptomeningeal disease (LMD) in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma is associated with a poor prognosis and limited treatment options. Osimertinib is a potent third-generation EGFR tyrosine kinase inhibitor with confirmed CNS penetration. This study reports on outcomes of patients with EGFR-mutated non-small-cell lung cancer who developed LMD and were subsequently treated with osimertinib. METHODS: We identified patients treated with osimertinib 80 mg PO daily under a compassionate access scheme across nine tertiary Australian institutes between July 2017 and July 2020. Patient demographics, tumor characteristics, and treatment history were collected. Median overall survival, median progression-free survival, disease control rates (DCR), and overall response rates (ORR) were assessed. Kaplan-Meier analysis was performed and descriptive statistics were used. RESULTS: Thirty-nine patients were analyzed of which 74% were female. Exon 19 deletions (49%) and L858R point mutations (41%) were the most common EGFR mutations. Forty-nine percentage of patients were Eastern Cooperative Oncology Group 1. The median duration of osimertinib therapy was 6 months. The extracranial DCR and ORR were 60% and 54%, and the intracranial DCR and ORR were 68% and 53%, respectively. Median overall survival was 10.5 months (95% CI, 8.17 to 15.05 months). CONCLUSION: There are limited treatment options for LMD in EGFR-positive lung cancer, and osimertinib at a dose of 80 mg daily is an active therapeutic option for these patients.

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer.

PURPOSE: In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680). METHODS: Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS: As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION: First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

Differences of opinion: a survey of knowledge and bias among clinicians regarding the role of chemotherapy in metastatic non-small cell lung cancer.

STUDY OBJECTIVES: To quantify clinician knowledge and bias regarding the role of chemotherapy for stage IV non-small cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS: A 16-question, multiple-choice questionnaire was sent to all Australian general internists, pulmonary and palliative care physicians, medical and radiation oncologists, and thoracic surgeons to assess beliefs concerning the role of chemotherapy in metastatic NSCLC. An overall assessment of "pessimism" and "optimism" regarding the role of chemotherapy in metastatic NSCLC was made, and knowledge of specific outcome measures was evaluated. MEASUREMENTS AND RESULTS: A total of 1,325 questionnaires were mailed, with 679 replies (51%) received and 544 replies (41%) assessable. Overall, 60% of respondents were deemed to have good knowledge. There was a wide variation in knowledge between specialist groups (p < 0.0001), with more medical oncologists (76%) but fewer thoracic surgeons (35%) and general internists (50%) with good knowledge. Fewer medical oncologists (6%) were classified as pessimistic compared with palliative care physicians (31%), radiation oncologists (28%), or pulmonary physicians (22%). Sixty-eight percent of respondents agreed that most patients receiving chemotherapy have symptomatic improvement. More medical oncologists (77%) and pulmonary physicians (73%), but fewer general internists (55%) and palliative care physicians (57%) agreed with this. Medical oncologists were far more likely to agree that chemotherapy was of benefit in patients aged > or = 70 years compared with any of the other specialist groups. CONCLUSIONS: There were significant differences regarding the perceived role of chemotherapy in metastatic disease between the various specialty groups involved in the treatment of NSCLC. Many clinicians had a poor understanding of contemporary data regarding the use of chemotherapy in metastatic NSCLC. This study raises substantial issues regarding the beliefs of clinicians treating NSCLC and emphasizes the importance of multidisciplinary assessment.

Outcome of patients admitted to the intensive care unit with newly diagnosed small cell lung cancer.

Patients with newly diagnosed small cell lung cancer (SCLC) may be considered for admission to an intensive care unit (ICU). Even though SCLC is highly responsive to chemotherapy, it is not clear whether patient outcomes justify the resource use of an ICU. This paper reports the results of a retrospective review of 20 newly diagnosed cases of SCLC who were admitted to one of three ICUs in Melbourne, Australia. Patients who had more than one negative prognostic factor did uniformly poorly, with no survivors beyond 4 months. Five patients were treated with chemotherapy whilst intubated and receiving mechanical ventilatory support. Two of these patients responded to chemotherapy and were extubated 4 days later. Both of these patients were alive and free of tumour recurrence 7 months later. In contrast, patients not treated with chemotherapy died early (within 40 days). We conclude that some patients with SCLC achieve a medium to long-term survival following treatment with chemotherapy instituted during or around the time of their admission to an ICU. The admission to an ICU of selected patients with SCLC may be justified, and prognostic indicators may be of benefit in making these difficult treatment decisions.

Complete radiological and metabolic response of metastatic renal cell carcinoma to SU5416 (semaxanib) in a patient with probable von Hippel-Lindau syndrome.

We report a case of a patient with probable von Hippel-Lindau (VHL) syndrome and metastatic renal cell cancer (RCC) who had a complete radiological and metabolic response to SU5416 (semaxanib). The patient was enrolled on a clinical study examining the efficacy of SU5416 in patients with metastatic cancer. Treatment with SU5416 was given at a dose of 145 mg/m2 intravenously twice-weekly for 11 doses. The patient achieved an early metabolic response on an F-18 fluorodeoxyglucose (FDG) Positron Emission Tomographic (PET) scan within 2 weeks of therapy. Subsequent computerized tomography (CT) and PET scans (9 and 12 months after treatment, respectively) confirmed ongoing complete radiological and metabolic response. He remains tumor-free 18 months after treatment. This is the first documented report of metastatic RCC in the setting of presumed VHL syndrome responding to treatment with SU5416. While vascular endothelial growth factor (VEGF) inhibitors have been shown to produce a modest response in sporadic metastatic RCC, further studies utilizing VEGF inhibitors in patients with VHL syndrome and RCC warrants exploration.

Metastatic myoepithelioma of the breast.

Myoepitheliomas are typically benign tumours arising from exocrine glands. There have only been five reports of malignant myoepitheliomas from breast origin previously published in the English literature. This report describes a patient with myoepithelioma arising in the breast which later metastasized despite the primary tumour having benign histological features. Impaired immune function due to end-stage renal failure and haemodialysis may have contributed to the malignant potential of her tumour. The literature regarding myoepithelial tumours is reviewed. All breast myoepitheliomas should be managed as potentially malignant tumours with appropriate surgical clearance and staging.