Kalyan Mantripragada

Paclitaxel poliglumex, temozolomide, and radiation for newly diagnosed high-grade glioma: a Brown University Oncology Group Study.

Objectives:Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m2/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas. Methods:Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m2/wk) combined with standard daily temozolomide (75 mg/m2) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy). Results:Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months. Conclusions:PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.

Targeting genomic alterations in squamous cell lung cancer.

Squamous cell lung cancer causes approximately 400,000 deaths worldwide per year. Identification of specific molecular alterations, such as activating mutations in the epidermal growth factor receptor kinase and echinoderm microtubule-associated protein-like 4/anaplastic lymphoma kinase fusions have led to significant therapeutic gains in patients with adenocarcinoma. However, meaningful therapeutic gains based on the molecular pathobiology of squamous cell lung cancer have not yet been realized. A comprehensive genomic characterization of 178 cases of squamous cell lung cancer has recently been reported. Squamous cell lung cancer appears to be characterized by a broader and more complex group of genomic alterations than adenocarcinoma. In this review, potentially targetable genes or pathways in squamous cell lung cancer are emphasized in relation to available therapeutic agents in development or active clinical trials. This organization of data will provide a framework for development for clinical investigation. Squamous cell lung cancer appears to be characterized by not only driver mutations in candidate genes but also gene copy number alterations resulting in tumor proliferation and survival. Better understanding of these genetic alterations and their use as therapeutic targets will require broad collaboration between industry, government, the cooperative groups, and academic institutions with the ultimate goal of rapid translation of scientific advancement to patient benefit.

Adjuvant Therapy for Resected Gallbladder Cancer: Analysis of the National Cancer Data Base

Background: Management of resected gallbladder cancer relies on single‐arm trials and retrospective observations. Our objective was to evaluate adjuvant therapy in a nationwide data set using causal inference methods to address sources of bias. Methods: We studied patients with T2‐3 or node‐positive, nonmetastatic gallbladder cancer, resected with grossly negative margins and reported to the National Cancer Data Base between 2004 and 2011. We defined adjuvant therapy as any chemotherapy within 90 days of surgery, and upfront concurrent chemoradiation as radiation within 14 days of first chemotherapy. After adjusting for missing data and guarantee‐time bias, and using propensity score analysis to minimize indication bias, we compared overall survival of patients receiving adjuvant therapies with untreated case subjects. Results: Adjuvant chemotherapy was administered to 28.8% of 4775 patients, and upfront chemoradiation to 13.5%. Treatment was less frequent among patients who were older, patients with comorbidities, and among white Hispanic women. T3 or node‐positive disease, microscopically positive margins, or extended resection increased the likelihood of adjuvant therapy. Overall survival at three years was 39.9% (95% confidence interval [CI] = 38.4% to 41.4%) and was unaffected by adjuvant therapy after adjusting for multiple confounders (hazard ratio = 1.01, 95% CI = 0.92 to 1.10). Patients with T3 or node‐positive tumors treated with upfront adjuvant chemoradiation had a modest early survival advantage (absolute difference at two years = 6.8%, 95% CI = 1.1% to 12.6%), but survival curves converged after five years of follow‐up. Conclusions: The curative potential of current adjuvant therapy in gallbladder cancer is questionable, justifying placebo‐controlled investigation of novel chemotherapy combinations or alternative approaches. Chemoradiation may provide a short‐term benefit in locally advanced tumors.

A Phase I Study of Dasatinib with Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer

Objectives: Src family kinases (SFKs) are expressed in non-small cell lung cancer (NSCLC) and may be involved in tumor growth and metastases. Inhibition of SFK may also enhance radiation. The purpose of this study was to evaluate if a maximum dose of 100 mg of dasatinib could be safely administered with concurrent chemoradiation and then continued as maintenance for patients with newly diagnosed stage III NSCLC. Methods: Patients with stage III locally advanced NSCLC received paclitaxel, 50 mg/m2/week, with carboplatin area under the curve (AUC) = 2, weekly for 7 weeks, and concurrent radiotherapy, 64.8 Gy. Three dose levels of dasatinib 50, 70, and 100 mg/day were planned. Results: 11 patients with locally advanced NSCLC were entered. At the 70 mg dose level 1 patient had grade 5 pneumonitis not responsive to therapy, and one patient had reversible grade 3 pneumonitis and grade 3 pericardial effusion. Due to these toxicities the Brown University Oncology Group Data Safety Monitoring Board terminated the study. Conclusion: Dasatinib could not be safely combined with concurrent chemoradiation for stage 3 lung cancer due to pneumonitis.

Response to Anti-PD-1 Therapy in Metastatic Merkel Cell Carcinoma Metastatic to the Heart and Pancreas

Metastatic Merkel cell carcinoma (MCC) is a lethal, Merkel cell polyomavirus (MCPyV) cancer with no currently available effective therapy. Harnessing the immune system through an immune checkpoint blockade is an attractive option because the immune system appears to be dysfunctional in the Merkel cell tumor microenvironment. Although MCPyV is expressed in 80% of MCCs and serves as a powerful antigen for stimulating host immune response, intratumoral CD8+ T-cell infiltration is seen only in 18% of MCCs. In contrast, about 50% of MCPyV-positive MCCs express the programmed death-ligand 1 (PD-L1) on multiple cell types in the tumor microenvironment. We present a case of a young patient with MCC involving the heart and pancreas that showed an impressive response after treatment with four cycles of the anti-PD-1 monoclonal antibody, nivolumab.

Clinical Trial Accrual Targeting Genomic Alterations After Next-Generation Sequencing at a Non-National Cancer Institute–Designated Cancer Program

PURPOSE Successful clinical trial accrual targeting uncommon genomic alterations will require broad national participation from both National Cancer Institute (NCI)-designated comprehensive cancer centers and community cancer programs. This report describes the initial experience with clinical trial accrual after next-generation sequencing (NGS) from three affiliated non-NCI-designated cancer programs. MATERIALS AND METHODS Clinical trial participation was reviewed after enrollment of the first 200 patients undergoing comprehensive genomic profiling by NGS as part of an institutional intuitional review board-approved protocol at three affiliated hospitals in Rhode Island and was compared with published experience from NCI-designated cancer centers. RESULTS Patient characteristics included a median age of 64 years, a median of two lines of prior therapy, and a predominance of GI carcinomas (58%). One hundred sixty-four of 200 patients (82%) had adequate tumor for NGS, 95% had genomic alterations identified, and 100% had variants of unknown significance. Fifteen of 164 patients (9.2%) enrolled in genotype-directed clinical trials, and three patients (1.8%) received commercially available targeted agents off clinical trials. The reasons for nonreceipt of NGS-directed therapy were no locally available matching trial (48.6%), ineligibility (33.6%) because of comorbidities or interim clinical deterioration, physicians choice of a different therapy (6.8%), or stable disease (11%). CONCLUSION This experience demonstrates that a program enrolling patients in specific targeted agent clinical trials after NGS can be implemented successfully outside of the NCI-designated cancer program network, with comparable accrual rates. This is important because targetable genes have rare mutation rates and clinical trial accrual after NGS is low.

FOLFOX+Nab-Paclitaxel (FOLFOX-A) for Advanced Pancreatic Cancer: A Brown University Oncology Research Group Phase I Study.

Background:The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel. Methods:Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-fluorouracil 2400 mg/m2 with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m2) every 2 weeks. Dose-limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity. Results:Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m2 every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX-A. Following an amendment to reduce oxaliplatin to 65 mg/m2 if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months. Conclusions:The maximum tolerated dose of nab-paclitaxel is 150 mg/m2 every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer.

Optimizing initial chemotherapy for metastatic pancreatic cancer.

The two combination chemotherapy regimens FOLFIRINOX and gemcitabine plus nab-paclitaxel represent major breakthroughs in the management of metastatic pancreatic cancer. Both regimens showed unprecedented survival advantage in the setting of front-line therapy. However, their application for treatment of patients in the community is challenging because of significant toxicities, thus limiting potential benefits to a narrow population of patients. Modifications to the dose intensity or schedule of those regimens improve their tolerability, while likely retaining survival advantage over single-agent chemotherapy. Newer strategies to optimize these two active regimens in advanced pancreatic cancer are being explored that can help personalize treatment to individual patients.

PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study: BrUOG 244.

Purpose: Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O6-methylguanine-DNA methyltransferase (MGMT) methylation. Materials and Methods: Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m2/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS). Results: Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation. Conclusions: PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.