Association of the prognostic model iSEND with PD-1/L1 monotherapy outcome in non-small-cell lung cancer.

BACKGROUND: Accessible biomarkers are needed for immunotherapy in advanced non-small-cell lung cancer (NSCLC). We previously described a multivariate risk prediction model, the iSEND, which categorises advanced NSCLC patients treated with nivolumab into Good, Intermediate or Poor groups. This model was developed by using only clinical and analytical variables (sex, ECOG-performance status, neutrophil-to-lymphocyte ratio [NLR] and post-treatment delta NLR). METHODS: An international database of 439 patients who received post-platinum PD-1/L1 monotherapies was collected for validation. Performance of the iSEND to different PD-L1 groups was compared by using time-dependent positive predictive value (PPV) for their mortality events. RESULTS: Median follow-up was 18.2 months (95% CI: 15.9-19.6). The overall survival of the iSEND Good (HR = 0.31, 95% CI: 0.22-0.43, p < 0.0001) was superior to the iSEND Poor. Time-dependent PPV for mortality of iSEND Poor was superior to PD-L1 = 0% group at 12 (75 vs. 53%, p = 0.01) and 18 months (85 vs. 46%, p = 0.03). However, female gender did not independently associate with better outcome in the validation cohort. CONCLUSION: The iSEND model is associated with the outcome of post-platinum PD-1/L1 monotherapy in advanced NSCLC patients. The iSEND Poor demonstrated a superior performance to PD-L1 = 0% in negative prognostication. Prospective investigation and modelling with other significant parameters in a larger cohort are warranted.

Brigatinib for ALK-positive metastatic non-small-cell lung cancer: design, development and place in therapy.

Despite the benefits of first and second generation anaplastic lymphoma kinase (ALK) inhibitors in the management of ALK-rearranged advanced non-small-cell lung cancer (NSCLC), the development of acquired resistance poses an ongoing dilemma. Brigatinib has demonstrated a wider spectrum of preclinical activity against crizotinib-resistant ALK mutant advanced NSCLC. The current review narrates a brief history of tyrosine kinases, the development and clinical background of brigatinib (including its pharmacology and molecular structure) and its use in ALK-positive NSCLC.

EGFR Mutation Testing: Changing Patterns of Molecular Testing in Brazil.

BACKGROUND: In Brazil, cancer is the second most common cause of death. Most patients in resource-limited countries are diagnosed in advanced stages. Current guidelines advocate for EGFR mutation testing in all patients with metastatic adenocarcinoma. Tyrosine kinase inhibitors are recommended in patients with advanced or metastatic disease harboring sensitizing mutations. In Brazil, there are limited data regarding the frequency of EGFR testing and the changes in patterns of testing overtime. MATERIALS AND METHODS: This was an observational, retrospective study. We obtained deidentified data from a commercial database, which included 11,684 patients with non-small cell lung cancer treated between 2011 and 2016 in both public and private settings. We analyzed the frequency of EGFR mutation testing over time. We also directly studied 3,664 tumor samples, which were analyzed between 2011 and 2013. These samples were tested for EGFR mutations through an access program to tyrosine kinase inhibitors in Brazil. RESULTS: Overall, 38% of patients were tested for EGFR mutations; 76% of them were seen in the private sector, and 24% were seen in the public center. The frequency of testing for EGFR mutations increased significantly over time: 13% (287/2,228 patients) in 2011, 34% (738/2,142) in 2012, 39% (822/2,092) in 2013, 44% (866/1,972) in 2014, 53% (1,165/2,184) in 2015, and 42% (1,359/3,226) in 2016. EGFR mutations were detected in 25.5% of analyzed samples (857/3,364). Deletions in Exon 19 were the most frequent mutations, detected in 54% of patients (463/857). CONCLUSION: Our findings suggest that the frequency of EGFR mutation in this cohort was lower than that found in Asia but higher than in North American and Western European populations. The most commonly found mutations were in Exon 19 and Exon 21. Our study shows that fewer than half of patients are being tested and that the disparity is greater in the public sector. IMPLICATIONS FOR PRACTICE: These data not only indicate the shortage of testing but also show that the rates of positivity in those tested seem to be higher than in other cohorts for which data have been published. This study further supports the idea that awareness and access to testing should be improved in order to improve survival rates in lung cancer in Brazil.

Complete response to ipilimumab and nivolumab therapy in a patient with extensive extrapulmonary high-grade small cell carcinoma of the pancreas and HIV infection.

BACKGROUND: Immune checkpoint inhibitors (CPIs) have shown promising results in many solid tumors. There are limited data on the safety and efficacy of these drugs in HIV infected patients as they have traditionally been excluded from CPIs clinical trials. CASE PRESENTATION: We present a case of an HIV-positive patient with extensive extrapulmonary high-grade small cell carcinoma who was treated with dual CPIs (nivolumab and ipilimumab) with a complete response to therapy and with a manageable safety profile. We performed a comprehensive literature review identifying 62 total HIV positive cases treated with CPIs showing this to be a potentially safe option in HIV-positive patients. CONCLUSION: HIV infection is not an absolute contraindication to CPI therapy. Our case and others provide justification for ongoing trials of CPI therapy in patients with HIV infection, a group that has traditionally been excluded from clinical trials.

Autoimmune haemolytic anaemia in a patient with advanced lung adenocarcinoma and chronic lymphocytic leukaemia receiving nivolumab and intravenous immunoglobulin.

We describe a rare case of severe autoimmune haemolytic anaemia (AIHA) in the setting of underlying chronic lymphocytic leukaemia receiving intravenous immunoglobulin, history of warm IgG autoantibody and treatment with nivolumab for advanced non-small cell lung cancer. In this report, we describe AIHA as a potential serious immune-related adverse event from immune checkpoint inhibitors, discuss other potential contributing factors and review previously described cases of AIHA in patients receiving programmed death 1 (PD-1) inhibitors. In the era of immunotherapy, we hope to add literature to raise awareness of potential immune-related sequelae such as AIHA. We aim to highlight the importance of close monitoring for prompt identification and management of potentially fatal AIHA and immune-related adverse events of PD-1 inhibitors by holding immunotherapy and treating with high-dose steroids, particularly in subgroups which may be at increased risk.

Developing a Predictive Model for Clinical Outcomes of Advanced Non-Small Cell Lung Cancer Patients Treated With Nivolumab.

INTRODUCTION: Despite significant improvement of clinical outcomes of advanced non-small-cell lung cancer (NSCLC) patients treated with immunotherapy, our knowledge of optimal biomarkers is still limited. PATIENTS AND METHODS: We retrospectively evaluated 159 advanced NSCLC patients in our institution treated with nivolumab after disease progression during platinum-based chemotherapy. We correlated several variables with progression-free survival (PFS) to develop the immunotherapy, Sex, Eastern Cooperative Oncology Group performance status, Neutrophil-to-lymphocyte ratio (NLR), and Delta NLR (iSEND) model. We categorized patients into iSEND good, intermediate, and poor risk groups and evaluated their clinical outcomes. Performance of iSEND at 3, 6, 9, and 12 months was evaluated according to receiver operating characteristic (ROC) curves and internally validated using bootstrapping. The association of iSEND risk groups with clinical benefit was evaluated using logistic regression. RESULTS: Median follow-up was 11.5 months (95% confidence interval [CI], 9.4-13.1). There were 50 deaths and 43 with disease progression without death. PFS rates at 3, 6, 9, and 12 months were 78.4%, 63.7%, 55.3%, and 52.2% in iSEND good; 79.4%, 44.3%, 25.9%, and 19.2% in iSEND intermediate; and 65%, 25.9%, 22.8%, and 17.8% in iSEND poor. Time-dependent area under ROC curves of iSEND for PFS at 3, 6, 9, and 12 months were 0.718, 0.74, 0.746, and 0.774. The iSEND poor group was significantly associated with progressive disease at 12 ± 2 weeks (odds ratio, 9.59; 95% CI, 3.8-26.9; P < .0001). CONCLUSION: The iSEND model is an algorithmic model that can characterize clinical outcomes of advanced NSCLC patients receiving nivolumab into good, intermediate, or poor risk groups and might be useful as a predictive model if validated independently.

The Concept of Biosimilars: From Characterization to Evolution-A Narrative Review.

Biologic agents are currently the fastest emerging segment of drug expenditure. Unlike chemically synthesized small-molecule drugs, biologics are more complex, medicinal products produced by a living organism. They have become part of the standard of care in the treatment of a large variety of diseases, such as growth disorders, autoimmune diseases, cancer, cardiovascular illnesses, hemophilia, and rare genetic conditions, to name a few. Biosimilars, which are copies of biologics that are highly similar, were introduced in the market with an aim to offer efficacy that is not clinically different from the originator or reference product, at lower prices. We aim to clarify the concept of biosimilar, from definitions, history, market entry, challenges faced, and future evolution. For that purpose, we performed a literature search on the sites of the medicines regulatory agencies and PubMed from 1990 to 2014 with the keywords "biosimilars," "market," and "regulatory." In 2006, the first biosimilar, somatropin [rDNA origin], was marketed and led the way for biosimilar drug manufacturing. As a result, manufacturers have entered a diversified competition, facing challenges in manufacturing these complex agents, such as immunogenicity and efficiency. Biosimilars are set to evolve differently in various markets, namely the U.S., Japan, the European Union, and the "pharmerging" economies. IMPLICATIONS FOR PRACTICE: This article highlights the importance of biosimilars, as a cost-cutting strategy, in the delivery of state-of-the-art health care in developing countries, at a fraction of what a reference biological agent would cost.

Comparative effectiveness and safety of nab-paclitaxel plus carboplatin vs gemcitabine plus carboplatin in first-line treatment of advanced squamous cell non-small cell lung cancer in a US community oncology setting.

INTRODUCTION: Real-world comparative effectiveness, safety, and supportive care use of nab-paclitaxel plus carboplatin vs gemcitabine plus platinum were analyzed in patients with advanced or metastatic squamous cell non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients who received ≥ 1 cycle of first-line nab-paclitaxel plus carboplatin or gemcitabine plus platinum were identified from the Navigating Cancer database. Clinical effectiveness endpoints included overall survival (OS) and time to treatment discontinuation (TTD). Other endpoints included safety and utilization of supportive care. Cox proportional hazards models were used to control for potential confounding effects of baseline characteristics. RESULTS: In total, 193 patients were included (nab-paclitaxel plus carboplatin, n = 61; gemcitabine plus platinum, n = 132). Baseline characteristics were generally similar between the cohorts. Patients receiving nab-paclitaxel plus carboplatin had a significantly longer OS than those receiving gemcitabine plus carboplatin (median, 12.8 vs 9.0 months; P = 0.03). However, the adjusted difference was not statistically significant (adjusted HR 1.55; 95% CI, 0.99-2.42; P = 0.06). nab-Paclitaxel plus carboplatin-treated patients had significantly longer TTD than gemcitabine plus carboplatin-treated patients (median, 4.3 vs 3.5 months; P = 0.03; adjusted HR 1.39; 95% CI, 1.01-1.90; P = 0.04). Grade 3 or 4 anemia and neutropenia were significantly lower in patients treated with nab-paclitaxel plus carboplatin vs gemcitabine plus carboplatin. Nausea and neuropathy (grade not specified) were significantly higher in the nab-paclitaxel plus carboplatin than the gemcitabine plus carboplatin group. No differences in supportive care use were observed between the cohorts. CONCLUSION: These real-world data support the effectiveness and safety of nab-paclitaxel plus carboplatin for first-line treatment of advanced squamous cell NSCLC.

Longitudinal monitoring of ctDNA EGFR mutation burden from urine correlates with patient response to EGFR TKIs: A case series.

Targetable, somatic EGFR mutations are highly prevalent in patients with non-small cell lung cancer (NSCLC), making them eligible for tyrosine kinase inhibitor (TKI) therapy. Circulating tumor DNA (ctDNA), isolated from blood or urine, has been demonstrated to reliably identify somatic tumor associated EGFR mutations, specifically in patients with inconclusive biopsy. When conventional imaging modalities are inconclusive, quantitative assessment of systemic ctDNA burden has the potential to assess therapeutic response. We report on the clinical use of non-invasive, urinary ctDNA liquid biopsies for the ultrasensitive detection and longitudinal monitoring of ctDNA EGFR systemic mutation burden in five patients with NSCLC treated with EGFR TKIs. Urinary ctDNA-based quantitative assessment of systemic EGFR mutant allele burden is a non-invasive molecular diagnostic testing modality that has the potential to be utilized as an ancillary tool to assess disease burden and response to therapy.

Clinical trials targeting lung cancer with active immunotherapy: the scope of vaccines.

Successful active immunotherapy is expected to be specific and nontoxic. Until now, the success of immunotherapy in cancer has been sporadic and unpredictable. This has been attributable in part to the lack of a full understanding of the mechanistic underpinnings of immune regulation. Furthermore, the lack of systematic success of immunotherapy, as argued in this review, stems from failing to effectively target tumors such as non-small cell lung cancer. In this review, the rationale and design for induction of immunity to non-small cell lung cancer and clinical trials of the most important lung cancer vaccines in development are discussed.

Interferon-alpha-induced focal segmental glomerulosclerosis in chronic myelogenous leukemia: a case report and review of the literature.

Chronic myelogenous leukemia (CML), hepatitis C, and interferon alpha (IFNalpha) have all been associated with renal dysfunction. In this paper we present a patient with the diagnosis of nephrotic syndrome and a known history of hepatitis C who received IFNalpha therapy for newly diagnosed CML. The renal biopsy showed focal segmental glomerulosclerosis, which has only been previously reported in two cases of CML treated with IFNalpha. There have also been two cases of patients with hepatitis C associated with focal segmental glomerulosclerosis. Despite the underlying hepatitis C, this case represents renal abnormalities consistent with IFNalpha therapy for CML.

Concomitant weekly docetaxel, cisplatin and radiation therapy in locally advanced non-small cell lung cancer: a dose finding study.

The optimal dose of weekly docetaxel in combination with cisplatin and concomitant thoracic radiation therapy (XRT) in patients with locally advanced non-small cell lung cancer (NSCLC) is not well defined. The purpose of this study was to define the maximal tolerated dose (MTD) of docetaxel in this combination. Eligible patients had unresectable stage IIIA or IIIB NSCLC without pleural effusion. Treatment consisted of cisplatin 25 mg/m(2) plus docetaxel weekly and concomitant standard XRT for a total of 60 Gy at 200 cGy/fraction/day 5 times weekly for 6 weeks. The starting dose of docetaxel in the first cohort was 15 mg/m(2)/week. This dose was escalated by 5 mg/m(2) per cohort of 3 patients. No intrapatient dose escalation was allowed. The doses of cisplatin and XRT were not escalated. A total of 23 patients were enrolled, and 19 patients were evaluable for analysis. The first cohort (docetaxel 15 mg/m(2)/week) completed treatment without any Grade 3 or 4 toxicities. The second cohort (docetaxel 20 mg/m(2)/week) was expanded to 6 patients because of Grade 3 cough observed in 1 patient. One of 5 patients experienced Grade 3 esophagitis at the docetaxel 25 mg/m(2)/week dose level. Dose limiting toxicity consisting of Grade 3 esophagitis was reached in 4 of 5 patients receiving docetaxel at 30 mg/m(2)/week. This study determined the MTD of weekly docetaxel to be 25 mg/m(2) when combined with cisplatin 25 mg/m(2) and radiation therapy for locally advanced NSCLC. Further evaluation of this regimen in a phase II trial is underway.

Pulmonary toxicity secondary to procarbazine.

Procarbazine is a chemotherapy methylating agent that has been used in combination with other drugs, perhaps most successfully in the treatment of Hodgkin's disease. There are several side effects that it is commonly associated with; however, it has only rarely been reported to cause lung injury. The resulting pneumonitis may be severe and irreversible. There are eight reported cases in the literature. Here, we report another such case.