Rathi N. Pillai

Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial

BACKGROUND Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. METHODS The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. FINDINGS Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. INTERPRETATION Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. FUNDING Bristol-Myers Squibb.

Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial

Summary Background There are few effective treatments for advanced urothelial carcinoma after progression following platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma who progressed after prior platinum-based therapy. Methods This phase 1/2 multicentre open-label study enrolled patients aged ≥18 years with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra unselected by programmed death ligand-1 (PD-L1). Tumour PD-L1 membrane expression was assessed. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or study treatment discontinuation, whichever occurred later. The primary endpoint was objective response rate by investigator assessment. All patients who received at least one dose of any study medication were analysed. Here we report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394. Findings Between June 2014 and April 2015, 86 patients with metastatic urothelial carcinoma were enrolled and 78 were treated with nivolumab monotherapy. At data cutoff (March 24, 2016), minimum follow-up was 9 months. A confirmed investigator-assessed objective response was achieved in 19 (24·4%) of 78 patients (95% CI 15·3–35·4). Grade 3/4 treatment-related adverse events occurred in 17 (21·8%) of 78 patients, the most common being laboratory abnormalities: asymptomatic elevated lipase in four (5·1%) and asymptomatic elevated amylase three (3·8%) patients. Serious adverse events were reported in 36 (46·2%) of 78 patients. Two (2·6%) of 78 patients discontinued due to treatment-related adverse events (pneumonitis and thrombocytopenia) and subsequently died. Interpretation Nivolumab monotherapy was associated with significant and durable clinical responses and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data indicate a favourable benefit:risk profile for nivolumab and support further investigation of nivolumab monotherapy in advanced urothelial carcinoma.

Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent

Immunotherapeutic PD-1–targeted therapies require CD28 to promote cancer cell killing. CD28 is a critical target for PD-1 blockade PD-1–targeted therapies have been a breakthrough for treating certain tumors and can rejuvenate T cells to unleash the anticancer immune response (see the Perspective by Clouthier and Ohashi). It is widely believed that PD-1 suppresses signaling through the T cell receptor (TCR). However, Hui et al. find instead that the TCR costimulatory receptor, CD28, is the primary target of PD-1 signaling. Independently, Kamphorst et al. show that CD28 is required for PD-1 therapies to kill cancer cells efficiently and eliminate chronic viral infections in mice. Lung cancer patients that responded to PD-1 therapy had more CD28+ T cells, which suggests that CD28 may predict treatment response. Science, this issue p. 1428, p. 1423; see also p. 1373 Programmed cell death–1 (PD-1)–targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.

Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients.

Significance Therapies that harness the immune system have recently been approved for cancer treatment. Identification of biomarkers to monitor or predict patients’ responses to immunotherapies would help guide treatment decisions. Herein we analyzed changes in peripheral blood T cells from lung cancer patients receiving immunotherapy blocking the PD-1 inhibitory pathway. We detected CD8 T-cell responses following treatment in most patients. In addition, our data suggest that an increase in proliferation of PD-1+ CD8 T cells in the blood within 4 wk of treatment initiation may be associated with positive clinical outcome. Our analysis provides valuable insights into cancer patients’ responses to PD-1–targeted therapies and warrant further studies on peripheral blood biomarkers. Exhausted T cells in chronic infections and cancer have sustained expression of the inhibitory receptor programmed cell death 1 (PD-1). Therapies that block the PD-1 pathway have shown promising clinical results in a significant number of advanced-stage cancer patients. Nonetheless, a better understanding of the immunological responses induced by PD-1 blockade in cancer patients is lacking. Identification of predictive biomarkers is a priority in the field, but whether peripheral blood analysis can provide biomarkers to monitor or predict patients’ responses to treatment remains to be resolved. In this study, we analyzed longitudinal blood samples from advanced stage non–small cell lung cancer (NSCLC) patients (n = 29) receiving PD-1–targeted therapies. We detected an increase in Ki-67+ PD-1+ CD8 T cells following therapy in ∼70% of patients, and most responses were induced after the first or second treatment cycle. This T-cell activation was not indiscriminate because we observed only minimal effects on EBV-specific CD8 T cells, suggesting that responding cells may be tumor specific. These proliferating CD8 T cells had an effector-like phenotype (HLA-DR+, CD38+, Bcl-2lo), expressed costimulatory molecules (CD28, CD27, ICOS), and had high levels of PD-1 and coexpression of CTLA-4. We found that 70% of patients with disease progression had either a delayed or absent PD-1+ CD8 T-cell response, whereas 80% of patients with clinical benefit exhibited PD-1+ CD8 T-cell responses within 4 wk of treatment initiation. Our results suggest that peripheral blood analysis may provide valuable insights into NSCLC patients’ responses to PD-1–targeted therapies.

Small Cell Lung Cancer: Therapies and Targets

Small cell lung cancer (SCLC) remains a fatal disease due to limited therapeutic options. Systemic chemotherapy is the bedrock of treatment for both the limited and extensive stages of the disease. However, the established management paradigm of platinum-based chemotherapy has reached an efficacy plateau. A modest survival improvement, approximately 5%, was witnessed with the addition of cranial or thoracic radiation to systemic chemotherapy. Other strategies to improve outcome of platinum-based chemotherapy in the last two decades have met with minimal success. The substitution of irinotecan for etoposide in the frontline treatment of SCLC achieved significant efficacy benefit in Japanese patients, but similar benefit could not be reproduced in other patient populations. Salvage treatment for recurrent or progressive SCLC is particularly challenging, where topotecan remains the only agent with regulatory approval to date. Ongoing evaluation of biologic agents targeting angiogenesis, sonic hedgehog pathway, DNA repair pathway, and immune checkpoint modulators hold some promise for improved outcome in SCLC. It is hoped that the coming decade will witness the application of new molecular biology and genomic research techniques to improve our understanding of SCLC biology and identification of molecular subsets that can be targeted appropriately using established and emerging biological agents similar to the accomplishments of the last decade with non-small cell lung cancer (NSCLC).

Postoperative Radiotherapy is Associated with Better Survival in Non–Small Cell Lung Cancer with Involved N2 Lymph Nodes: Results of an Analysis of the National Cancer Data Base

Introduction: Use of postoperative radiotherapy (PORT) in non–small-cell lung cancer remains controversial. Limited data indicate that PORT may benefit patients with involved N2 nodes. This study evaluates this hypothesis in a large retrospective cohort treated with chemotherapy and contemporary radiation techniques. Methods: The National Cancer Data Base was queried for patients diagnosed 2004–2006 with resected non–small-cell lung cancer and pathologically involved N2 (pN2) nodes also treated with chemotherapy. Multivariable Cox proportional hazards model was used to assess factors associated with overall survival (OS). Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce selection bias. OS was compared between patients treated with versus without PORT using the adjusted Kaplan–Meier estimator and weighted log-rank test based on IPTW. Results: Two thousand and one hundred and fifteen patients were eligible for analysis. 918 (43.4%) received PORT, 1197 (56.6%) did not. PORT was associated with better OS (median survival time 42 months with PORT versus 38 months without, p = 0.048). This effect was significant in multivariable and IPTW Cox models (hazard ratio: 0.87, 95% confidence interval: 0.78–0.98, p = 0.026, and hazard ratio: 0.89, 95% confidence interval: 0.79–1.00, p = 0.046, respectively). No interaction was seen between the effects of PORT and number of involved lymph nodes (p = 0.615). Conclusions: PORT was associated with better survival for patients with pN2 nodes also treated with chemotherapy. No interaction was seen between benefit of PORT and number of involved nodes. These findings reinforce the benefit of PORT for N2 disease in modern practice using the largest, most recent cohort of chemotherapy-treated pN2 patients to date.

Clinical Validation and Implementation of a Targeted Next-Generation Sequencing Assay to Detect Somatic Variants in Non-Small Cell Lung, Melanoma, and Gastrointestinal Malignancies

We tested and clinically validated a targeted next-generation sequencing (NGS) mutation panel using 80 formalin-fixed, paraffin-embedded (FFPE) tumor samples. Forty non-small cell lung carcinoma (NSCLC), 30 melanoma, and 30 gastrointestinal (12 colonic, 10 gastric, and 8 pancreatic adenocarcinoma) FFPE samples were selected from laboratory archives. After appropriate specimen and nucleic acid quality control, 80 NGS libraries were prepared using the Illumina TruSight tumor (TST) kit and sequenced on the Illumina MiSeq. Sequence alignment, variant calling, and sequencing quality control were performed using vendor software and laboratory-developed analysis workflows. TST generated ≥500× coverage for 98.4% of the 13,952 targeted bases. Reproducible and accurate variant calling was achieved at ≥5% variant allele frequency with 8 to 12 multiplexed samples per MiSeq flow cell. TST detected 112 variants overall, and confirmed all known single-nucleotide variants (n = 27), deletions (n = 5), insertions (n = 3), and multinucleotide variants (n = 3). TST detected at least one variant in 85.0% (68/80), and two or more variants in 36.2% (29/80), of samples. TP53 was the most frequently mutated gene in NSCLC (13 variants; 13/32 samples), gastrointestinal malignancies (15 variants; 13/25 samples), and overall (30 variants; 28/80 samples). BRAF mutations were most common in melanoma (nine variants; 9/23 samples). Clinically relevant NGS data can be obtained from routine clinical FFPE solid tumor specimens using TST, benchtop instruments, and vendor-supplied bioinformatics pipelines.

Heat shock protein 90 inhibitors in non-small-cell lung cancer.

Purpose of review Heat shock protein 90 (Hsp90) protects cellular proteins from degradation by the ubiquitin-proteasome system in conditions of stress. Many cancers have increased expression of Hsp90 to ensure their malignant phenotype of increased proliferation, decreased apoptosis, and metastatic potential by conservation of proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homologue B1, AKT, B-cell lymphoma 2, and cell cycle proteins. This review discusses recent developments in the strategy of Hsp90 inhibition as a targeted therapy in non-small-cell lung cancer (NSCLC). Recent findings Hsp90 inhibitors result in growth inhibition and tumor regression in NSCLC cell lines and tumor xenograft models, both as monotherapy and in combination with other drugs. Hsp90 inhibition has particular efficacy in molecular subtypes of NSCLC, such as EGFR-mutated and ALK-rearranged NSCLC. IPI-504 and ganetespib have activity in NSCLC both as monotherapy and in combination with docetaxel. Summary Preclinical studies and early clinical trials have confirmed the efficacy of Hsp90 inhibition as a targeted therapy in NSCLC. Ongoing trials will further define the utility of Hsp90 inhibitors in NSCLC.

Atypical Carcinoid Tumor of the Lung: A Surveillance, Epidemiology, and End Results Database Analysis

Background: Atypical carcinoid (AC) of the lung is a rare form of thoracic malignancy. The limited knowledge of its biology and outcome stems largely from small, single institution experiences. We analyzed the Surveillance, Epidemiology, and End Results database (SEER) to better understand the clinical characteristics of this disease. Methods: Demographic, treatment, and outcome data on all patients with pulmonary AC were obtained from the SEER database with 18 reporting sites from 1973 to 2010 using SEER*Stat 8.1.2. Statistical analysis was performed using SAS 9.3 (SAS Institute, Inc., Cary, NC). Results: There were 947,463 patients diagnosed with lung and bronchus tumors in the SEER database, of which 441 had AC (0.05%). Median age of AC patients was 65 years; 69% were women and 87% of white ethnicity. Metastatic disease was present in 20% of patients at diagnosis. In terms of treatment, 78% of patients underwent resection and 12.5% received radiation. The overall 1-year and 3-year survival rates were 86% and 67%, respectively. The 3-year survival rates for distant (M1), regional (lymph node involvement), and localized (lung only) disease were 26% (13 of 50), 69% (50 of 72), and 85% (99 of 116), respectively. On univariate analysis, patients treated with surgery had reduced risk of death (hazard ratio, HR 0.19; p < 0.001), whereas radiation treatment was associated with increased risk of death (HR 2.45; p < 0.001). Conclusions: AC accounted for less than 1% of all lung cancers diagnosed and was more frequent in women. The best outcomes were observed with surgical resection for localized disease.

Advances in the Diagnosis and Treatment of Non–Small Cell Lung Cancer

The diagnostic and therapeutic landscape of non–small cell lung cancer (NSCLC) has changed dramatically in the past 50 years since the Surgeon Generals report on smoking and lung cancer. Early detection is now a reality for lung cancer. The use of low-dose computed tomography scans for early detection decreases mortality and is beginning to be used in routine clinical practice. Technological advances such as positron emission tomography and endobronchial ultrasound have improved the accuracy of NSCLC staging. The cure rate for early-stage NSCLC has improved as a result of multimodality treatment approaches. The role of systemic therapy has also expanded to earlier stages of the disease. In recent years, the initial steps toward personalized medicine by utilization of targeted treatments based on tumor genotype have been undertaken. Emerging technological advances and greater insights into tumor biology are poised to greatly reduce the burden of lung cancer in the years to come. Mol Cancer Ther; 13(3); 557–64. ©2014 AACR.