Rachel E. Sanborn

Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer

PURPOSE To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). METHODS A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1. RESULTS A total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks). CONCLUSION Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.

Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study

BACKGROUND PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC). METHODS We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naive patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947. FINDINGS Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18·8 weeks (IQR 11-33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9-44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3-60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8-58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12-74] of ten patients). INTERPRETATION Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as the dose for phase 3 studies, which are ongoing. FUNDING MedImmune.

Neoadjuvant Therapy for Resectable Non–Small Cell Lung Cancer with Mediastinal Lymph Node Involvement

The optimal treatment for stage IIIA (N2) NSCLC remains controversial. Numerous studies with induction chemotherapy or chemoradiotherapy show that both approaches in the neoadjuvant setting are feasible. Outcomes following induction therapy have been associated with mediastinal nodal response, with residual mediastinal involvement a negative predictor of survival. Appropriate selection of patients to undergo resection following induction therapy is critical. Lobectomy may be safely performed following induction therapy while pneumonectomy may carry a high and possibly unacceptable rate of perioperative mortality. Combined modality therapy has increased the overall survival of patients with stage III NSCLC. Future trials looking at different induction regimens with or without radiotherapy and with or without surgery may help identify the ideal treatment for this heterogeneous disease stage. The SAKK-16/00 study is an ongoing phase III European trial randomizing patients with stage IIIA NSCLC to receive neoadjuvant chemotherapy with three cycles of docetaxel and cisplatin followed by radiation and then surgical resection, or to chemotherapy with the same regimen followed by surgery alone. Other ongoing trials include investigations of novel chemotherapeutic combinations, such as cisplatin with pemetrexed, in the phase II setting. The RTOG 0229 phase II study is evaluating neoadjuvant paclitaxel and carboplatin concurrently with radiation therapy, followed by surgery and consolidation chemotherapy with paclitaxel and carboplatin for stage III NSCLC. The combination of neoadjuvant docetaxel, carboplatin, and radiation therapy followed by surgical resection for stage III NSCLC is also currently being investigated in a phase II trial. The future of treatment for stage III NSCLC may lie in the outcome of trials investigating molecularly targeted agents, such as EGFR inhibitors, anti-angiogenic agents, or multitargeted agents. Optimal incorporation into the multimodality approach required of locally advanced N2 NSCLC will require careful investigation. The results from these trials are eagerly awaited.

Cisplatin Versus Carboplatin in NSCLC: Is There One “Best” Answer?

Opinion statementPlatinum-based chemotherapeutic doublets have produced significant survival benefits for patients with non-small cell lung cancer of all disease stages. The optimal combination of chemotherapy has been the subject of much investigation, and the ideal platinum agent the subject of ongoing and heated debate. For patients with resected disease, all evidence of survival advantage rests with cisplatin, and the only clinical trial to evaluate carboplatin-based therapy failed to show a survival benefit. In the setting of locally advanced lung cancer, no comparative data exist, and even randomized phase III trials are largely lacking. Cisplatin-based doublets provide the most consistent evidence of superior survival when coupled with definitive thoracic radiation. Meta-analyses of palliative chemotherapy indicate consistent survival advantages with cisplatin-based therapy over carboplatin; however, the relative advantage is small. Cisplatin carries a higher toxicity profile, including nausea, vomiting, neuropathy, renal insufficiency, and alopecia in comparison to carboplatin. When the goal of therapy is curative, the survival benefits with cisplatin are in most circumstances worth the increased toxicities. When the goal of therapy is palliation, the relative price of toxicity needs to be weighed on the basis of the individual patient in an effort to maximize quality of life.

Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of the Efficacy and Safety of Apricoxib in Combination With Either Docetaxel or Pemetrexed in Patients With Biomarker-Selected Non–Small-Cell Lung Cancer

PURPOSE Overexpression of COX-2 correlates with advanced stage and worse outcomes in non-small-cell lung cancer (NSCLC), possibly as a result of elevated levels of COX-2-dependent prostaglandin E2 (PGE2). Exploratory analyses of studies that used COX-2 inhibitors have demonstrated potentially superior outcome in patients in whom the urinary metabolite of PGE2 (PGE-M) is suppressed. We hypothesized that patients with disease defined by PGE-M suppression would benefit from the addition of apricoxib to second-line docetaxel or pemetrexed. PATIENTS AND METHODS Patients with NSCLC who had disease progression after one line of platinum-based therapy, performance status of 0 to 2, and normal organ function were potentially eligible. Only patients with a ≥ 50% decrease in urinary PGE-M after 5 days of treatment with apricoxib could enroll. Docetaxel 75 mg/m(2) or pemetrexed 500 mg/m(2) once every 21 days per the investigator was administered with apricoxib or placebo 400 mg once per day. The primary end point was progression-free survival (PFS). Exploratory analysis was performed regarding baseline urinary PGE-M and outcomes. RESULTS In all, 101 patients completed screening, and 72 of the 80 who demonstrated ≥ 50% suppression were randomly assigned to apricoxib or placebo. Toxicity was similar between the arms. No improvement in PFS was seen with apricoxib versus placebo. The median PFS for the control arm was 97 days (95% CI, 52 to 193 days) versus 85 days (95% CI, 67 to 142 days) for the experimental arm (P = .91). CONCLUSION Apricoxib did not improve PFS, despite biomarker-driven patient selection.

A phase II study of enzastaurin in combination with erlotinib in patients with previously treated advanced non-small cell lung cancer

INTRODUCTION Regardless of epidermal growth factor receptor (EGFR) mutation status, erlotinib improves survival for patients with advanced non-small cell lung cancer (NSCLC) after one or more chemotherapy regimens. Enzastaurin is an oral serine/threonine kinase inhibitor. This phase II study was designed to evaluate the efficacy and safety of erlotinib and enzastaurin in NSCLC, a combination with promise to overcome EGFR resistance based on preclinical models. METHODS Eligible patients with advanced NSCLC (IIIB or IV) who had failed one or two prior systemic treatment regimen(s) were enrolled and received erlotinib 150 mg/day and enzastaurin 500 mg/day (after a 1125-mg loading dose on day 1, cycle 1), both orally in 28-day cycles. The primary endpoint was progression-free survival (PFS). RESULTS From January 2008 to July 2009, 49 patients were enrolled: 29 (59%) men and 20 (41%) women; 8 (16%) were non-smokers. The median PFS was 1.7 months (one-sided 90% CI: 1.5-NA) and median overall survival (OS) was 8.3 months (95% CI: 5.3-14.3). Five patients had partial response, for an overall response rate of 10.2%; the disease control rate was 30.6% (responders+10 patients with stable disease). Grade 3-4 drug-related adverse events in ≥5% of patients were diarrhea, acne, and nausea. One possibly drug-related death due to interstitial lung disease occurred during the study. CONCLUSIONS In previously treated, unselected, advanced NSCLC patients, the addition of enzastaurin to erlotinib did not improve PFS, response, or OS compared with historical data of single-agent erlotinib, but was well tolerated.

Definitive Chemoradiotherapy for Non-Small Cell Lung Cancer with N2 Disease

The treatment of NSCLC continues to evolve over time. Newer therapies and techniques help achieve success in this difficult disease. Since the 1970s, one can observe trends in median survival and notice that they have improved from 9 to 10 months to now 15 to 24 months with concurrent chemoradiation. Unfortunately, despite the advances made, most patients still die from their disease. Chemoradiation without induction or consolidation therapy continues to remain the standard of care in this country for unresectable locally advanced NSCLC. Evaluation of epidermal growth factor receptor tyrosine kinase inhibitors and other biologics continue to be investigated but are not considered standard of care yet. Technologies continue to expand including the use of four-dimensional CT scans and PET scans to more accurately plan patients. Future application of molecular profiling to predict patients most likely to benefit from tailored chemotherapeutic approaches is awaited following validation in early- and advanced-stage disease. With continued diligence to testing new ideas in NSCLC, it is hoped that outcomes will continue to improve the lives of patients with this devastating disease.

Tumor response from durvalumab (MEDI4736) + tremelimumab treatment in patients with advanced non-small cell lung cancer (NSCLC) is observed regardless of PD-L1 status

Meeting abstracts As single agents, durvalumab (MEDI4736), a human IgG1 anti-PD-L1 antibody, and tremelimumab, a human IgG2 anti-CTLA-4 antibody, have shown acceptable safety profiles and antitumor activity. Similar to other anti-PD-L1/anti-PD-1 monotherapies, durvalumab has shown greater objective

Ensartinib (X-396) in ALK-Positive Non–Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non–small cell lung cancer (NSCLC). Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible. Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%. Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771–9. ©2018 AACR.

Adjuvant Therapy for Non–Small Cell Lung Cancer with Mediastinal Nodal Involvement

Since the publication of the meta-analysis in 1995 indicating a potential survival benefit with adjuvant cisplatin-based chemotherapy for patients with resected NSCLC, the management of patients with resected NSCLC and N2 disease involvement has evolved dramatically. The delivery of systemic therapy in the postoperative setting remains difficult, however, because tolerance for the toxicities of chemotherapy is reduced by recovery from surgery itself. Even with a proven survival benefit with adjuvant chemotherapy, cure is not guaranteed, and most patients die from relapse of their cancer. Optimization of treatment through the administration of neoadjuvant therapy, application of more modern radiotherapy techniques, and combined-modality therapy with chemoradiation or molecularly targeted agents are areas currently under active investigation. Ideally, the improvement of prediction of which patients harbor micrometastatic disease before undergoing surgical resection and the prediction of which patients would benefit from different systemic therapies may help to improve further the chance of cure for NSCLC while at the same time reducing toxicity.