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Aberrant activation of CDK4/6 kinase is the most common somatic event in non-small cell lung cancer (NSCLC). Palbociclib is a highly specific CDK4/6 inhibitor shown to inhibit cell cycle progression and promote cellular senescence. We conducted a phase 2 clinical trial of palbociclib in 19 previously-treated patients with advanced NSCLC. Only patients with p16-null staining by immunohistochemistry and documented tumor progression were eligible. The primary endpoint was tumor response rate. Palbociclib therapy alone was well-tolerated. Of 16 evaluable patients who received > 1 month of therapy, there were no objective responses. However, 8 patients (50%) with previously progressive NSCLC had stable disease (SD) lasting a range of 4-10.5 months. Median overall survival (OS) for all cases was 5.1 months, and median overall survival for the subset of patients with SD was 16.6 months. We also performed preclinical testing of palbociclib in combination with 13 different targeted or cytotoxic chemotherapeutic agents using a cell viability assay. Only the combination of palbociclib and mTOR inhibitors resulted in synergistic growth inhibition, particularly in tumors carrying RAS mutations. Our findings warrant further clinical investigation of the combination of palbociclib and mTOR inhibitors, especially in patients carrying activated RAS mutations., Competing Interests: CONFLICTS OF INTEREST Dr. Pinder-Schenck has received income from Merck and GlaxoSmithKline. Dr. Chiappori has received income from Genentech, Boehringer Ingelheim, Merck, Takeda, Bristol-Myers Squibb, Celgene, Astra Zeneca and Novartis. Mr. Gordillo has received income from Sangamo Therapeutics. All other authors have declared that no conflicts of interest exist.

The GM.CD40L vaccine, which recruits and activates dendritic cells, migrates to lymph nodes, activating T cells and leading to systemic tumor cell killing. When combined with the CCL21 chemokine, which recruits T cells and enhances T-cell responses, additive effects have been demonstrated in non-small cell lung cancer mouse models. Here, we compared GM.CD40L versus GM.CD40L plus CCL21 (GM.CD40L.CCL21) in lung adenocarcinoma patients with ≥ 1 line of treatment. In this phase I/II randomized trial (NCT01433172), patients received intradermal vaccines every 14 days (3 doses) and then monthly (3 doses). A two-stage minimax design was used. During phase I, no dose-limiting toxicities were shown in three patients who received GM.CD40L.CCL21. During phase II, of evaluable patients, 5/33 patients (15.2%) randomized for GM.DCD40L (p = .023) and 3/32 patients (9.4%) randomized for GM.DCD40L.CCL21 (p = .20) showed 6-month progression-free survival. Median overall survival was 9.3 versus 9.5 months with GM.DCD40L versus GM.DCD40L.CCL21 (95% CI 0.70-2.25; p = .44). For GM.CD40L versus GM.CD40L.CCL21, the most common treatment-related adverse events (TRAEs) were grade 1/2 injection site reaction (51.4% versus 61.1%) and grade 1/2 fatigue (35.1% versus 47.2%). Grade 1 immune-mediated TRAEs were isolated to skin. No patients showed evidence of pseudo-progression or immune-related TRAEs of grade 1 or greater of pneumonitis, endocrinopathy, or colitis, and none discontinued treatment due to toxicity. Although we found no significant associations between vaccine immunogenicity and outcomes, in limited biopsies, one patient treated with GMCD40L.CCL21 displayed abundant tumor-infiltrating lymphocytes. This possible effectiveness warrants further investigation of GM.CD40L in combination approaches.

Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

Background: Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab., Methods and Materials: Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-"dry" IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR)., Results: From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board-approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications., Conclusions: Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chemoresistance is mediated, in part, by the inhibition of apoptosis in tumor cells. Survivin is an antiapoptotic protein that blocks chemotherapy-induced apoptosis. To investigate whether blocking survivin expression enhances docetaxel-induced apoptosis in patients with non-small-cell lung cancer (NSCLC), we compared the antitumor activity of the survivin inhibitor LY2181308 plus docetaxel with docetaxel alone. We used change in tumor size (CTS) as a primary endpoint to assess its use in early decision-making for this and future studies of novel agents in NSCLC. Patients (N = 162) eligible for second-line NSCLC treatment (stage IIIB/IV) with an Eastern Cooperative Oncology Group performance status of 0 to 1 were randomized 2:1 to receive LY2181308 (750 mg intravenously, weekly) and docetaxel (75 mg/m intravenously, day 1) or docetaxel alone every 21 days. CTS from baseline to the end of cycle 2 was compared between the two treatment arms. The mean (SD) tumor size ratio for LY2181308/docetaxel and docetaxel was 1.05 (0.21) and 1.00 (0.15) (p = 0.200), respectively, suggesting no significant improvement in antitumor activity between the arms. Because there was also no significant difference between the two arms for progression-free survival (PFS) (2.83 months with LY2181308/docetaxel and 3.35 months with docetaxel [p = 0.191]), both arms were combined. Using the combined arms, CTS correlated with PFS (PFS = 4.63 months in patients with decreased CTS compared with 2.66 months in patients with increased CTS), supporting its use in early decision-making in phase II studies.

Purpose: Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer., Experimental Design: Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed., Results: Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02)., Conclusions: We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role., (©2014 AACR.)

Background: Even with aggressive surgical treatment, relapse rates remain high for patients with resectable non-small-cell lung cancer (NSCLC). In an effort to improve survival in these patients, numerous clinical trials have evaluated neoadjuvant and adjuvant chemotherapy., Methods: The authors reviewed the results of the prospective randomized clinical trials that have established adjuvant chemotherapy as the standard of care for patients with surgically resected NSCLC. In addition, the authors summarize data on predictive and prognostic markers for patients with early-stage NSCLC and discuss novel therapies and clinical trials currently underway in early-stage NSCLC., Results: Three large randomized clinical trials and two meta-analyses have demonstrated a survival benefit for adjuvant cisplatin-based chemotherapy compared with surgery alone in patients with early-stage NSCLC. As a result, adjuvant cisplatin-based chemotherapy is recommended as the standard of care in these patients. Numerous promising biomarkers and agents have been developed in the metastatic setting and are currently being evaluated in the adjuvant setting., Conclusions: While adjuvant chemotherapy has improved survival for patients with early-stage NSCLC, the prognosis for early-stage lung cancer remains poor. Incorporation of molecular markers and targeted therapies into the management of patients with advanced NSCLC has improved outcomes. Development of these strategies in the adjuvant setting offers the potential to increase cure rates in patients with early-stage NSCLC.

Purpose: We assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Eligible patients were randomly assigned 2:1 to the trial's experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/carboplatin. The trial was powered for a 32% improvement in 6-month progression-free survival (PFS)., Results: Of 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P = .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months)., Conclusion: This demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.

Patients with stage IIIA non-small cell lung cancer, determined based on involvement of ipsilateral mediastinal lymph nodes, represent the most challenging management problem in this disease. Patients with this stage disease may have very different degrees of lymph node involvement. The pathologic confirmation of this involvement is a key step in the therapeutic decision. The difference in the degree of lymph node compromise has prognostic and treatment implications. Based on multiple considerations, patients can be treated with induction chemotherapy, chemoradiotherapy followed by surgery, or definitive chemoradiotherapy without surgery. Data derived from clinical trials have provided incomplete guidance for physicians and their patients. The best therapeutic plan is achieved through the multidisciplinary cooperation of a team specialized in lung cancer.

Even with aggressive surgical treatment, relapse rates remain high for patients with resectable non-small cell lung cancer (NSCLC). In an effort to improve survival in these patients, numerous clinical trials have evaluated neoadjuvant and adjuvant chemotherapy. Three large, randomized clinical trials and two meta-analyses have demonstrated a survival benefit for adjuvant cisplatin-based chemotherapy compared to surgery alone. Adjuvant chemotherapy has become the standard of care for patients with resected NSCLC. A neoadjuvant approach offers several potential advantages over adjuvant therapy, including earlier treatment of micrometastatic disease, improved compliance and pathologic confirmation of efficacy. Randomized trials have shown neoadjuvant therapy to be feasible and safe and some studies have yielded promising efficacy. The applicability of these results has been limited due to patient heterogeneity, imprecise staging and lack of standardization with respect to inclusion of radiation therapy. With novel agents, improved staging, better supportive care and relevant molecular markers, a neoadjuvant strategy is promising for future clinical trials in NSCLC.