Locally Advanced Non-small Cell Lung Cancer: The Past, Present, and Future

AbstractApproximately a third of patients with newly diagnosed non-small cell lung cancer (NSCLC) have locally or regionally advanced disease not amenable for surgical resection. Concurrent chemoradiation is the standard of therapy for patients with unresectable locally advanced NSCLC who have a good performance status and no significant weight loss. Prospective studies conducted over the past two decades have addressed several important questions regarding systemic therapy and thoracic radiation. They include the role of induction/consolidation chemotherapy, integration of newer chemotherapy agents with radiation and the impact of molecularly targeted agents. Improved radiation therapy techniques and precise targeting of the tumors have played a key role in this setting. Moreover, it has been shown that higher than conventional doses of thoracic radiation can be administered safely in combination with chemotherapy. This review will discuss these issues in detail and outline the strategies that need to be employed to improve the outcomes in patients with locally advanced NSCLC

Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL.

Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase and a molecule of adaptor that we have shown is important for non-small-cell lung cancer (NSCLC). We investigated if MET is a target of CBL and if enhanced in CBL-altered NSCLC. We showed that CBL wildtype cells have lower MET expression than CBL mutant cells. Ubiquitination of MET was also decreased in CBL mutant cells compared to wildtype cells. Mutant cells were also more sensitive to MET inhibitor SU11274 than wild-type cells. sh-RNA-mediated knockdown of CBL enhanced cell motility and colony formation in NSCLC cells, and these activities were inhibited by SU11274. Assessment of the phospho-kinome showed decreased phosphorylation of pathways involving MET, paxillin, EPHA2, and VEGFR. When CBL was knocked down in the mutant cell line H1975 (erlotinib-resistant), it became sensitive to MET inhibition. Our findings suggest that CBL status is a potential positive indicator for MET-targeted therapeutics in NSCLC

DNA repair biomarkers XPF and phospho-MAPKAP kinase 2 correlate with clinical outcome in advanced head and neck cancer.

BackgroundInduction chemotherapy is a common therapeutic option for patients with locoregionally-advanced head and neck cancer (HNC), but it remains unclear which patients will benefit. In this study, we searched for biomarkers predicting the response of patients with locoregionally-advanced HNC to induction chemotherapy by evaluating the expression pattern of DNA repair proteins.MethodsExpression of a panel of DNA-repair proteins in formalin-fixed paraffin embedded specimens from a cohort of 37 HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation were analyzed using quantitative immunohistochemistry.ResultsWe found that XPF (an ERCC1 binding partner) and phospho-MAPKAP Kinase 2 (pMK2) are novel biomarkers for HNSCC patients undergoing platinum-based induction chemotherapy. Low XPF expression in HNSCC patients is associated with better response to induction chemoradiotherapy, while high XPF expression correlates with a worse response (p = 0.02). Furthermore, low pMK2 expression was found to correlate significantly with overall survival after induction plus chemoradiation therapy (p = 0.01), suggesting that pMK2 may relate to chemoradiation therapy.ConclusionsWe identified XPF and pMK2 as novel DNA-repair biomarkers for locoregionally-advanced HNC patients undergoing platinum-based induction chemotherapy prior to definitive chemoradiation. Our study provides insights for the use of DNA repair biomarkers in personalized diagnostics strategies. Further validation in a larger cohort is indicated

Phase II Trial of Paclitaxel and Cisplatin in Patients with Extensive Stage Small Cell Lung Cancer: Cancer and Leukemia Group B Trial 9430

Cancer and Leukemia Group B (CALGB) trial 9430 was a randomized phase II trial which investigated the safety and activity of four novel doublets in untreated extensive stage small cell lung cancer (ES-SCLC). The results of the paclitaxel and cisplatin arm have not been reported

A randomized phase 2 network trial of tivantinib plus cetuximab versus cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154935/1/cncr32762.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154935/2/cncr32762_am.pd

Phase II Trial of Weekly Dose-Dense Paclitaxel in Extensive-Stage Small Cell Lung Cancer: Cancer and Leukemia Group B Study 39901

INTRODUCTION: Paclitaxel is an active agent in extensive-stage (ES) small cell lung cancer (SCLC). Nevertheless, the optimal schedule is uncertain. A dose-dense schedule was previously evaluated in a Cancer and Leukemia Group B study of patients with non-SCLC, resulting in a 42% response rate and median survival of 12.3 months. Because of these promising results, this dose and schedule of paclitaxel was evaluated in patients with ES-SCLC. METHODS: Patients were eligible for this phase II trial (Cancer and Leukemia Group B 39901) if they had documented ES-SCLC, no prior chemotherapy, and performance status of 0 to 2. Paclitaxel was administered as an intravenous infusion at 150 mg/m2 over 3 hours weekly for 6 consecutive weeks every 8 weeks. RESULTS: Thirty-six patients with median age of 65 were enrolled. Of them 25 were men and 33 with a performance status 0 to 1. A median of two 8-week cycles were delivered. The percent of patients with grade 3/4 toxicity included neutropenia 22%, anemia 9%, febrile neutropenia 6%, fatigue 20%, sensory neuropathy 26%, motor neuropathy 11%, and dyspnea 17%. There were two treatment-related deaths, both from pneumonitis. The overall response rate was 33% (3% complete response and 30% partial response). Median progression-free and overall survivals were 3.7 and 9.2 months, respectively. One-year progression-free and overall survivals were 17% and 36%, respectively. CONCLUSIONS: For patients with ES-SCLC, dose-dense weekly paclitaxel was associated with fairly mild hematologic toxicity. Nevertheless, nonhematologic toxicities, including neuropathy, fatigue, and dyspnea required frequent dose delays and reductions. The overall response rate is disappointing and much lower than that seen with standard platinum-based combinations. Paclitaxel in this dose and schedule should not be used as front-line therapy for patients with ES-SCLC

Randomized Phase II Study of Pemetrexed, Carboplatin, and Thoracic Radiation With or Without Cetuximab in Patients With Locally Advanced Unresectable Non–Small-Cell Lung Cancer: Cancer and Leukemia Group B Trial 30407

Cancer and Leukemia Group B conducted a randomized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy (TRT)

Alliance Foundation Trial 09: A randomized, multicenter, phase 2 trial evaluating two sequences of pembrolizumab and standard platinum-based chemotherapy in patients with metastatic NSCLC

INTRODUCTION: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. METHODS: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a pick a winner design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. RESULTS: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively ( CONCLUSIONS: Additional evaluation of either sequence in a phase 3 trial is not warranted

A randomized phase 2 study of temsirolimus and cetuximab versus temsirolimus alone in recurrent/metastatic, cetuximab‐resistant head and neck cancer: The MAESTRO study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155947/1/cncr32929_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155947/2/cncr32929.pd