Akhil Chopra

Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

BACKGROUND For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. METHODS We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. FINDINGS Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. INTERPRETATION Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. FUNDING Bristol-Myers Squibb.

Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040.

LBA101 Background: Overexpression of PD-L1 in HCC has a poor prognosis. Safety and preliminary antitumor efficacy of nivolumab, a fully human IgG4 monoclonal antibody PD-1 inhibitor, was evaluated in a multiple ascending-dose, phase I/II study in patients (pts) with HCC. METHODS Pts with histologically confirmed advanced HCC with Child-Pugh (CP) score ≤ B7 and progressive disease (PD) on, intolerant of, or refusing sorafenib were enrolled. Dose escalation occurred in parallel cohorts based on etiology: no active hepatitis virus infection or virus-infected HCC pts. Pts received nivolumab 0.1 - 10 mg/kg intravenously for up to two years. The primary endpoint was safety. Secondary endpoints included antitumor activity using mRECIST criteria, pharmacokinetics, and immunogenicity. RESULTS The study has enrolled 41 pts with a CP score of 5 (n = 35) or 6 (n = 6), ECOG score of 0 (n = 26) or 1 (n = 15), 73% with extrahepatic metastasis and/or portal vein invasion, and 77% with prior sorafenib use. Eighteen pts remain on study, and 23 discontinued treatment due to PD (n = 17), complete response (CR; n = 2), drug-related adverse events (AEs; n = 2) and non-drug-related AEs (n = 2). Drug-related AEs of any grade occurred in 29 pts (71%; 17% grade 3/4), with ≥ 10% of pts experiencing aspartate aminotransferase (AST) increase and rash (each 17%), alanine aminotransferase(ALT) and lipase increase (each 15%), and amylase increase (12%). Grade 3 and 4 AEs ≥ 5% were AST increase (12%), ALT increase (10%) and lipase increase (5%). A dose-limiting toxicity occurred in an uninfected pt at 10 mg/kg; no maximum tolerated dose was defined in any cohort. Response was evaluable in 39 pts: 2 CR (5%) and 7 partial responses (PR; 18%). Response duration was 14-17+ months for CR, < 1-8+ months for PR, and 1.5-17+ months for stable disease (SD). Overall survival (OS) rate at 6 months is 72%. CONCLUSIONS Nivolumab has a manageable AE profile and produced durable responses across all dose levels and HCC cohorts, with a favorable 6-month OS rate. Updated safety, antitumor activity, and biomarker data will be presented. CLINICAL TRIAL INFORMATION NCT01658878. [Table: see text].

Timeliness of diagnosing lung cancer: Number of procedures and time needed to establish diagnosis

Abstract To study number of procedures and time to diagnose lung cancer and factors affecting the timeliness of clinching this diagnosis. Retrospective cohort study of lung cancer patients who consecutively underwent diagnostic bronchoscopy in 1 year (October 2013 to September 2014). Out of 101 patients diagnosed with lung cancer from bronchoscopy, average time interval between first abnormal computed tomogram (CT) scan-to-1st procedure, 1st procedure-to-diagnosis, and 1st abnormal CT scan-to-diagnosis was 16 ± 26, 11 ± 19, and 27 ± 33 days, respectively. These intervals were significantly longer in those requiring repeat procedures. Multivariate analysis revealed inconclusive 1st procedure to be the predictor of prolonged (>30 days) CT scan to diagnosis time (P = 0.04). Twenty-nine patients (28.7%) required repeat procedures (n = 63). Reasons behind repeating the procedures were inadequate procedure (n = 14), inaccessibility of lesion (n = 9), inappropriate procedure (n = 5), mutation analysis (n = 2), and others (n = 2). Fifty had visible endo-bronchial lesion, 20 had positive bronchus sign, and 83 had enlarged mediastinal/hilar lymph-nodes or central masses adjacent to the airways. Fewer procedures, and shorter procedure to diagnosis time, were observed in those undergoing convex probe endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) (P = 0.04). Most patients exhibit enlarged mediastinal lymph node or mass adjacent to the central airway accessible by convex probe EBUS-TBNA. Hence, combining it with conventional bronchoscopic techniques such as bronchoalveolar lavage, brush, and forceps biopsy increases detection rate, and reduces number of procedures and time to establish diagnosis. This may translate into cost and resource savings, timeliness of diagnosis, greater patient satisfaction, and conceivably better outcomes.

Antitumor activity of nivolumab in recurrent and metastatic nasopharyngeal carcinoma: An international, multicenter study of the mayo clinic phase 2 consortium (NCI-9742)

Purpose This multinational study evaluated the antitumor activity of nivolumab in nasopharyngeal carcinoma (NPC). Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Patients and Methods Patients with multiply pretreated recurrent or metastatic NPC were treated with nivolumab until disease progression. The primary end point was objective response rate (ORR) and secondary end points included survival and toxicity. The expression of programmed death-ligand 1 (PD-L1) and human leukocyte antigens A and B in archived tumors and plasma clearance of Epstein-Barr virus DNA were correlated with ORR and survival. Results A total of 44 patients were evaluated and the overall ORR was 20.5% (complete response, n = 1; partial response, n = 8). Nine patients received nivolumab for > 12 months (20%). The 1-year overall survival rate was 59% (95% CI, 44.3% to 78.5%) and 1-year progression-free survival (PFS) rate was 19.3% (95% CI, 10.1% to 37.2%). There was no statistical correlation between ORR and the biomarkers; however, a descriptive analysis showed that the proportion of patients who responded was higher among those with PD-L1 positive tumors (> 1% expression) than those with PD-L1-negative tumors. The loss of expression of one or both human leukocyte antigen class 1 proteins was associated with better PFS than when both proteins were expressed (1-year PFS, 30.9% v 5.6%; log-rank P = .01). There was no association between survival and PD-L1 expression or plasma Epstein-Barr virus DNA clearance. There was no unexpected toxicity to nivolumab. Conclusion Nivolumab has promising activity in NPC and the 1-year overall survival rate compares favorably with historic data in similar populations. Additional evaluation in a randomized setting is warranted. The biomarker results were hypothesis generating and validation in larger cohorts is needed.

Abiraterone or Enzalutamide in Advanced Castration‐Resistant Prostate Cancer: An Indirect Comparison

To perform a comparative effectiveness analyses between enzalutamide and abiraterone acetate in both the pre‐docetaxel and post‐docetaxel settings based on published phase III randomized trials.

Comparative effectiveness of approved first-line anti-angiogenic and molecularly targeted therapeutic agents in the treatment of good and intermediate risk metastatic clear cell renal cell carcinoma

BackgroundBased on improved clinical outcomes in randomized controlled clinical trials (RCTs) the FDA and EMA have approved bevacizumab with interferon, sunitinib, and pazopanib in the first-line treatment of low to intermediate risk metastatic clear cell renal cell carcinoma (mRCC). However, there is little comparative data to help in choosing the most effective drug among these agents.MethodsWe performed an indirect comparative effectiveness analysis of the pivotal RCTs of bevacizumab with interferon, sunitinib, or pazopanib compared to one another or interferon alone in first-line treatment of metastatic or advanced RCC. Endpoints of interest were overall survival (OS), progression free survival (PFS), and response rate (RR). Adverse events were also examined.ResultsThe meta-estimate of the hazard ratio (95% confidence interval) for OS for bevacizumab with interferon vs. interferon alone was 0.86 (0.76-0.97), for sunitinib vs. interferon alone was 0.82 (0.67-1.00), for pazopanib vs. interferon alone was 0.74 (0.57-0.97), for sunitinib vs. bevacizumab with interferon was 0.95 (0.75-1.20), for pazopanib vs. bevacizumab with interferon was 0.86 (0.64-1.16), and for pazopanib vs. sunitinib was 0.91 (0.76-1.08). Similarly, bevacizumab with interferon, sunitinib, or pazopanib had better PFS and RR than interferon alone. Sunitinib and pazopanib had better RR than bevacizumab with interferon and there was suggestive evidence pazopanib may outperform sunitinib in terms of RR.ConclusionsBevacizumab with interferon, sunitinib, and pazopanib are adequate first-line options in treatment of mRCC. Interferon alone should not be considered an optimal first-line treatment.

Comparative effective analysis between enzalutamide and abiraterone in the treatment of metastatic castration-resistant prostate cancer.

217 Background: Recently Abiraterone (A) and Enzalutamide (E), new drugs with different novel mechanisms of action, have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC) based on the COU-AA-301 and AFFIRM phase III trials, after docetaxel failure. The lack of direct comparative trials has introduced a new treatment dilemma for the practicing oncologist: is one drug more effective than the other? METHODS We performed an indirect comparative effectiveness analysis between E and A using the results of the AFFIRM and COU-AA-301 pivotal trials. Due to the lack of study-to-study replication of comparisons, these indirect comparisons are subject to the assumption that the relative effects of each drug relative to placebo are the same across studies. RESULTS 1) Overall survival (OS)- the respective hazard ratios (95% confidence intervals {CI}) in the AFFIRM and COU-AA-301 trials for OS for E vs. placebo and A vs. placebo were 0.63 (0.53-0.75) and 0.66 (0.56-0.79). The indirect estimate of the hazard ratio (HR) (95% CI; p-value) for E vs. A was 0.96 (0.75-1.22; 0.72) 2) Time to PSA progression- the respective HR(95% CI) in the AFFIRM and COU-AA-301 trials for time to PSA progression for E vs. placebo and A vs. placebo were 0.25 (0.20-0.30) and 0.58 (0.46-0.73). The indirect estimate of the HR (95% CI; p-value) for E vs. A was 0.43 (0.32-0.58; 4.3 × 10-8). 3) Radiographic progression Free Survival (rPFS)- The respective HR (95% CI) in the AFFIRM and COU-AA-301 trials for time to PSA progression for E vs. placebo and A vs. placebo were 0.40 (0.35-0.47) and 0.67 (0.59-0.78). The indirect estimate of the HR (95% CI; p-value) for E vs. A was 0.60 (0.49-0.74; 7.1 × 10-7). 4) PSA response- the respective odds ratios (95% CI) in the AFFIRM and COU-AA-301 trials for time to PSA progression for E vs. placebo and A vs. placebo were 77.08 (34.02-174.70) and 5.49 (3.84-7.84). The indirect estimate of the odds ratio (95% CI; p-value) for E vs. A was 14.04 (5.75-34.28; 6.6 × 10-9). CONCLUSIONS In this indirect comparative effectiveness analysis, E appears to be more effective than A in terms of time to PSA progression, rPFS and PSA response. OS was not different.

Non-invasive detection of actionable mutations in advanced non-small-cell lung cancer using targeted sequencing of circulating tumor DNA

OBJECTIVE To evaluate the feasibility of detecting actionable gene mutations in circulating tumor DNA (ctDNA) in patients with advanced non-small-cell lung cancer (NSCLC) using targeted next-generation sequencing (NGS). MATERIALS AND METHODS In total 50 plasma samples from patients newly diagnosed with advanced NSCLC or resistant to first-line tyrosine kinase inhibitors (TKIs) were subjected to deep sequencing on a seven-gene panel (BRAF, EGFR, ERBB2, KRAS, NRAS, PIK3CA, PTEN) incorporated with molecular barcodes to improve accuracy in variant detection. When possible, results were compared with those from matched tissue samples. RESULTS At least one alteration in the ctDNA was detected in 44 out of 50 patients (88%); EGFR was the most frequently mutated gene. Half the total number of patients (50%, 25 of 50) had at least one actionable genetic alteration with targeted therapies available for treatment. Our results showed a high concordance rate of 81% in detection of EGFR mutation between 26 matched tissue and plasma samples. For progressive patients, from whom tissue is mostly unavailable, the resistant EGFR T790 M mutation was validated using the droplet digital polymerase chain reaction (ddPCR), yielding a concordance of 92% between alternative platforms. CONCLUSION Our study demonstrated that therapeutically actionable mutations can be detected with high accuracy in ctDNA using NGS. This promising approach offers alternative and non-invasive diagnostic methods for treatment guidance and clinical monitoring.

Subglottic Extramedullary Plasmacytoma With Light Chain Multiple Myeloma Masquerading as Adult-Onset Asthma

Extramedullary plasmacytoma (EMP) arises outside the bone marrow and can be associated with multiple myeloma (MM). A 55-year-old gentleman, who presented with dyspnea and expiratory wheeze, was diagnosed and treated for asthma. A subsequent relapse 6 months later prompted an Otolaryngology consult. Preliminary findings showed a benign-looking nodular lesion at the subglottis. Work-up at our institution revealed an Fludeoxyglucose (FDG) avid left subglottic lesion with multiple bone metastases on a Positron Emission Tomography / Computed Tomography (PET/CT). The patient underwent a panendoscopy and laser excision of the subglottic lesion with subglottic jet ventilation. Histology showed an EMP. Further work-up revealed the presence of kappa light chain MM with adverse cytogenetics. Patient was treated systemically with lenalidomide, bortezomib, and dexamethasone for four cycles with rapid improvement in his symptoms. We review the literature about EMP of the subglottis with MM. We present the first case of subglottic laryngeal EMP with MM managed via CO2 laser excision.