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Altres ajuts: This study was funded by Novartis Pharmaceuticals Corporation (study design,collection, analysis, and interpretation of data, and medical editorial writing assistance). Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. registry number NCT01598077 (registered on 4 May, 2012). The online version of this article (10.1186/s12885-017-3641-6) contains supplementary material, which is available to authorized users.

Background: The RET receptor tyrosine kinase can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib, and vandetanib have demonstrated activity in RET dependent (RET+) malignancies. Recent development of selective RET inhibitors is poised to alter their treatment paradigm. However, the responsiveness of RET+ malignancies to immune checkpoint inhibition (ICI) is unknown. We compared the time to progression (TTP) on ICI with non-ICI therapy in patients with malignancies harboring activating RET mutations/fusions. Methods: A retrospective chart review of all RET+ patients who were referred to the phase 1 clinical trials program at MD Anderson Cancer Center between September 2014 and October 2018 was conducted. Patients who had not discontinued treatment or had discontinued treatment for reasons besides disease progression were censored. Time to progression was estimated using Kaplan-Meier analysis. Results: Out of 72 patients who had received systemic therapy for RET+ malignancies, 39 (54.2%) harbored RET mutations (RETm) and 33 (45.8%) harbored RET fusions (RETf). Nineteen patients (26.4%) received ICI and 53 (73.6%) received non-ICI therapy. Thirty four patients (47.2%) had medullary thyroid cancer, 29 (40.3%) had NSCLC and 9 (12.5%) had other types of cancer. PD-L1 expression was only available for 7 patients of which 5 (71.4%) were positive (≥ 1%). Patients had received a median of 1 (1-7) prior lines of therapy. Overall median TTP (mTTP) was 10.5 months (95% CI 6.7-30.1). Hazard ratio for ICI vs. non-ICI therapy was 1.73 (0.70, 4.26) p=0.25 in patients with RETf and 8.0 (2.27, 28.2) p=0.0025 in patients with RETm. Conclusions: In patients with RET+ malignancies, mTTP was shorter with ICI compared to non-ICI therapy. The effect of type of therapy was dependent on the type of RET pathway aberration, with a statistically significant higher risk of progression in RETm malignancies treated with ICI compared to non-ICI therapy. Time to ProgressionRETTherapyNmTTP (months)Freedom from Progression at 6 months (%)Freedom from Progression at 12 months (%)FusionNon-ICI218.36335FusionICI123.03624MutationNon-ICI3231.98273MutationICI75.6430 Citation Format: Aparna Hegde, Le Huang, Shuang Liu, Kenneth Hess, Maria Cabanillas, Mimi Hu, Naifa Busaidy, Steven Sherman, George Simon, George Blumenschein, Vassiliki A. Papadimitrakopoulou, David S. Hong, Funda Meric-Bernstam, John Heymach, Vivek Subbiah. Responsiveness to immune checkpoint inhibitors in RET dependent cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4997.

8504 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) induce major pathologic response (MPR) rates of 20 to 45% in resected NSCLCs. We report the results of NEOSTAR - a phase 2 trial of neoadjuvant N or NI for NSCLCs. Methods: Pts with stage I-IIIA (single N2) resectable NSCLC (AJCC 7th), PS 0-1, were randomized to N (3 mg/kg IV, D1, 15, 29) or N plus I (1 mg/kg IV, D1) followed by surgery (n = 44). Primary endpoint: MPR (≤10% viable tumor), hypothesized to be higher than MPR to induction chemotherapy historical controls. Tumor immune infiltrates and pre- & post-ICI tumor PD-L1 % were assessed by flow cytometry & IHC. Wilcoxon ranked sum test & Fisher’s exact test were used for comparisons. Results: 44 pts were randomized, 23 N, 21 NI: mean age 66, 64% males, 18% never smokers, 59% adenocarcinomas, stages: IA 8 (18%), IB 15 (34%), IIA 7 (16%) IIB 5 (11%); IIIA 9 (20%). Only 3 pts received < 3 doses due to TRAEs (7%). 34 pts had surgery post ICIs (7 not resected [7/41], 17%, [2 N, 5 NI], 3 pending). There were 10 MPRs in 41 pts overall (24%, 4 N, 6 NI), of which 6 were path CRs (15%, 2 N [9%], 4 NI [21%]). Among 34 resected pts, MPR rate was 29% (N 20%, NI 43%). Median % of viable tumor was lower post NI vs N (20% vs 65%, p = .097). ORR (RECIST v1.1) was 22% (8 PRs [5 N, 3 NI], 1 CR [NI]); 15% of pts had PD (3 N, 3 NI). The proportion of CR+PR in MPR+ was higher than in MPR- (6 [60%] vs 2 [7%], p < .001). Surgical complications included 2 bronchopleural fistulas (BPFs) in N & 8 air leaks (5 N, 3 NI). G3-G5 TRAEs included a death due to BPF post steroid-treated pneumonitis (G5, N); G3 pneumonia, hypoxia, hypermagnesemia (1 each, all N), G3 diarrhea (1 NI). CD3+ & CD103+ tissue resident memory CD8+ TILs were higher in NI- vs N-treated tumors (CD3+ 81.2% vs 54.4%, p = .028; CD8+ 56.2% vs 38.3%, p = .069). Median pre-treatment tumor PD-L1 was higher in responders (MPR+, CR+PR) vs non-responders (80% vs 1%, p = .024), and the % of viable tumor was lower in tumors with PD-L1 > 1% vs PD-L1 ≤1% (median 20% vs 80%, p = .046). Conclusions: Overall a 24% MPR rate to neoadjuvant ICIs was observed. NI induced a higher % of non-viable tumor and of tissue resident memory TILs vs N. Antitumor activity was associated with higher pre-treatment PD-L1 levels. Clinical trial information: NCT03158129.

Purpose: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program. Patients and Methods: Patients with previously treated non–small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS). Results: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04–3.58] and 8.48 months (95% CI, 5.78–10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-κB, and hypoxia pathways were identified potential drivers of sorafenib resistance. Conclusion: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials. Clin Cancer Res; 19(24); 6967–75. ©2013 AACR.

Purpose Increased hepatocyte growth factor/MET signaling is associated with poor prognosis and acquired resistance to epidermal growth factor receptor (EGFR) –targeted drugs in patients with non–small-cell lung cancer (NSCLC). We investigated whether dual inhibition of MET/EGFR results in clinical benefit in patients with NSCLC. Patients and Methods Patients with recurrent NSCLC were randomly assigned at a ratio of one to one to receive onartuzumab plus erlotinib or placebo plus erlotinib; crossover was allowed at progression. Tumor tissue was required to assess MET status by immunohistochemistry (IHC). Coprimary end points were progression-free survival (PFS) in the intent-to-treat (ITT) and MET-positive (MET IHC diagnostic positive) populations; additional end points included overall survival (OS), objective response rate, and safety. Results There was no improvement in PFS or OS in the ITT population (n = 137; PFS hazard ratio [HR], 1.09; P = .69; OS HR, 0.80; P = .34). MET-positive patients (n = 66) treated with erlotinib plus onartuzumab showed improvement in both PFS (HR, .53; P = .04) and OS (HR, .37; P = .002). Conversely, clinical outcomes were worse in MET-negative patients treated with onartuzumab plus erlotinib (n = 62; PFS HR, 1.82; P = .05; OS HR, 1.78; P = .16). MET-positive control patients had worse outcomes versus MET-negative control patients (n = 62; PFS HR, 1.71; P = .06; OS HR, 2.61; P = .004). Incidence of peripheral edema was increased in onartuzumab-treated patients. Conclusion Onartuzumab plus erlotinib was associated with improved PFS and OS in the MET-positive population. These results combined with the worse outcomes observed in MET-negative patients treated with onartuzumab highlight the importance of diagnostic testing in drug development.

Combined inhibition of vascular, platelet-derived, and epidermal growth factor receptor (EGFR) pathways may overcome refractoriness to single agents in platinum-pretreated non-small-cell lung cancer (NSCLC).This randomized, double-blind, multicenter, phase II trial evaluated sunitinib 37.5 mg/day plus erlotinib 150 mg/day versus placebo plus erlotinib continuously in 4-week cycles. Eligible patients had histologically confirmed stage IIIB or IV NSCLC previously treated with one or two chemotherapy regimens, including one platinum-based regimen. The primary end point was progression-free survival (PFS) by an independent central review.One hundred and thirty-two patients were randomly assigned, and the median duration of follow-up was 17.7 months. The median PFS was 2.8 versus 2.0 months for the combination versus erlotinib alone (HR 0.898, P = 0.321). The median overall survival (OS) was 8.2 versus 7.6 months (HR 1.066, P = 0.617). Objective response rates (ORRs) were 4.6% and 3.0%, respectively. Sunitinib plus erlotinib was fairly well tolerated although most treatment-related adverse events (AEs) were more frequent than with erlotinib alone: diarrhea (55% versus 33%), rash (41% versus 30%), fatigue (31% versus 25%), decreased appetite (30% versus 13%), nausea (28% versus 14%), and thrombocytopenia (13% versus 0%).The addition of sunitinib to erlotinib did not significantly improve PFS in patients with advanced, platinum-pretreated NSCLC.

BackgroundThe Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination trial1 prospectively obtained serum and tumor core biopsies and randomized 255 chemorefractory non–small-cell lung cancer (NSCLC) patients into four phase II trials: erlotinib, erlotinib-bexarotene, vandetanib, or sorafenib. Herein, we report the clinical and biomarker results of the phase II vandetanib trial.ResultsFifty-four patients received vandetanib. The 8-week disease control rate was 33%, median progression-free survival (PFS) 1.81 months, and median overall survival (OS) 6.5 months. No demographic subgroups had PFS or OS benefit. Eight patients with EGFR mutations had a trend for higher 8-week disease control rate (63% versus 31%; p = 0.12) but worse OS (5.9 months versus 9 months; p = 0.8). Patients with EGFR gene amplification (n = 6) had a worse OS (3.9 months versus 9.5 months; p = 0.04). KRAS mutation patients (3.9 months versus 9.5 months; p = 0.23) also had a worse OS. For the serum biomarker analysis, patients with below the median serum expression of interleukin 9c (p = 0.019) and eotaxin (p = 0.007) had a shorter PFS. A trend toward a shorter PFS was also seen in patients with higher than the median neutrophil gelatinase-associated lipocalin (p = 0.079) and lower than the median TNF-related apoptosis-inducing ligand (p = 0.087).ConclusionOur trial results are largely consistent with the literature in unselected pretreated NSCLC patients. Although vandetanib improved median PFS in EGFR mutation patients with epidermal growth factor receptor tyrosine kinase inhibitor–resistance compared with EGFR wild-type, there was no OS advantage. Although vandetanib is no longer in development in NSCLC, identification of a molecular phenotype that responds to dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition would contribute to the field.

Background As therapy for non–small-cell lung cancer (NSCLC) patients becomes more personalized, additional tissue in the form of core-needle biopsies (CNBs) for biomarker analysis is increasingly required for determining appropriate treatment and for enrollment into clinical trials. We report our experience with small-caliber percutaneous transthoracic (PT) CNBs for the evaluation of multiple molecular biomarkers in BATTLE (biomarker-integrated approaches of targeted therapy for lung cancer elimination), a personalized, targeted therapy NSCLC clinical trial. Methods The medical records of patients who underwent PTCNB for consideration of enrollment in BATTLE were reviewed for diagnostic yield of 11 predetermined molecular markers and procedural complications. Univariate and multivariate analyses of factors related to patient and lesion characteristics were performed to determine possible influences on diagnostic yield. Results One hundred and seventy PTCNBs were performed using 20-gauge biopsy needles in 151 NSCLC patients screened for the trial. The biopsy specimens of 82.9% of the patients were found to have adequate tumor tissue for analysis of the required biomarkers. On multivariate analysis, metastatic lesions were 5.4 times more likely to yield diagnostic tissue as compared with primary tumors ( p = 0.0079). Pneumothorax and chest tube insertion rates were 15.3% and 9.4%, respectively. Conclusions Image-guided 20-gauge PTCNB is safe and provides adequate tissue for analysis of multiple biomarkers in the majority of patients being considered for enrollment into a personalized, targeted therapy NSCLC clinical trial. Metastatic lesions are more likely to yield diagnostic tissue as compared with primary tumors.

Background We evaluated combined targeting with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in squamous cell carcinoma of the head and neck (SCCHN). Patients and methods The combination was studied in human endothelial cells and head and neck and lung cancer xenograft model systems. Patients with recurrent or metastatic SCCHN were treated with weekly cetuximab and bevacizumab, 15 mg/kg on day 1 given intravenously every 21 days, until disease progression. Analysis of tumor biomarkers and related serum cytokines was performed. Results Cetuximab plus bevacizumab enhanced growth inhibition both in vitro and in vivo, and resulted in potent reduction in tumor vascularization. In the clinical trial, 46 eligible patients were enrolled. The objective response rate was 16% and the disease control rate 73%. The median progression-free survival and overall survival were 2.8 and 7.5 months, respectively. Grade 3–4 adverse events were expected and occurred in less than 10% of patients. transforming growth factor alpha, placenta-derived growth factor, EGFR, VEGFR2 increased and VEGF decreased after treatment but did not correlate with treatment efficacy. Conclusions Cetuximab and bevacizumab are supported by preclinical observations and are well tolerated and active in previously treated patients with SCCHN.

© 2016 International Association for the Study of Lung Cancer Objectives This two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations. Methods Phase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens. Results The primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events—most commonly diarrhea, nausea, and fatigue—were manageable. Conclusions Trametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.

Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

Background: This randomized, double-blind, multicenter study evaluated sunitinib plus erlotinib versus placebo plus erlotinib. Subjects with advanced non-small-cell lung cancer had received prior treatment with a platinum-based regimen. Here, we report safety, pharmacokinetics, and antitumor activity of the combination of sunitinib and erlotinib.Methods: Lead-in subjects in this phase II study received sunitinib 37.5 mg/d and erlotinib 150 mg/d. Safety, including dose-limiting toxicities (DLTs, cohort 1 only), pharmacokinetic profiles, and antitumor activity were investigated (cohorts 1 and 2).Results: Thirty patients were evaluated. The combination of sunitinib and erlotinib was tolerable. Diarrhea (76.9%), fatigue (61.5%), and decreased appetite (53.8%) were the most frequent adverse events in cohort 1; and diarrhea (52.9%) and rash (41.2%) were the most frequent adverse events in cohort 2. DLTs were observed (fatigue, n = 2 and paronychial inflammation, n = 1) in three of 13 patients evaluated for DLTs. Geometric mean ratios for the maximum plasma concentration (C-max) and area under plasma concentration-time profile from time 0 to 24 hours of erlotinib with and without sunitinib were 1.05 and 1.03, respectively. Corresponding values for sunitinib with and without erlotinib were 0.62 and 0.62 for sunitinib, 2.13 and 2.07 for SU12662; and 0.81 and 0.79 for total drug. Three patients experienced partial response as per response evaluation criteria in solid tumor.Conclusion: A dosage of sunitinib 37.5 mg/d concurrently with erlotinib 150 mg/d was tolerable and established the recommended combinatorial dose in subjects with platinum-refractory non-small-cell lung cancer. Coadministration of sunitinib with erlotinib does not affect the pharmacokinetics of erlotinib, but may result in decreased exposure to sunitinib.

We investigated the relationship between plasma protein biomarker concentrations and clinical outcomes in 52 patients with relapsed/refractory advanced non-small cell lung cancer (NSCLC) treated with 400 mg bid sorafenib in a phase II trial. Blood samples were collected at baseline, on day 15 of cycle 1 (C1D15), and on day 1 of cycle 3 (C3D1), and plasma concentrations of total VEGF, VEGF-165, soluble (s) VEGFR-2, PDGF-BB, sPDGFR-β, sEGFR, sHER-2, uPA, PAI-1, uPAR, TIMP-1, and circulating Ras p21 were assayed by ELISA. Elevated baseline VEGF, VEGF-165, PDGF-BB, Ras p21, and TIMP- 1 concentrations were associated with poorer patient outcomes (shorter overall survival (OS) and/or progression-free survival (PFS)). During treatment, the mean concentrations of sVEGFR-2, PDGF-BB, sPDGFR-β, TIMP-1, uPAR, and PAI-1 decreased, while the mean sEGFR concentration increased. Increases in VEGF, VEGF-165, PDGF-BB, and TIMP-1 during treatment were associated with better outcomes (longer OS and/or PFS), whereas increases in plasma Ras p21 during treatment were associated with shorter PFS. The associations between baseline concentrations and/or pharmacodynamic changes in plasma proteins and clinical outcomes in NSCLC patients treated with sorafenib suggest that these biomarkers may have a prognostic role and/or predict the efficacy of sorafenib in patients with NSCLC.

While chemotherapy has been the standard of care for patients with advanced non-small cell lung cancer (NSCLC), efforts have shifted toward evaluating novel targeted agents in an attempt to improve outcome. These targeted agents are directed toward key components in several signalling pathways such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-IR). There is also increasing interest in using combinations of targeted agents to inhibit more than one pathway; for example, inhibition of VEGFR + EGFR and VEGFR + PDGFR + EGFR. Further investigation is needed to identify the most appropriate combinations of these targeted agents in select patient subgroups, and to define optimal treatment doses to thereby achieve the best therapeutic index. This review outlines the rationale for combining targeted agents for the treatment of advanced NSCLC.

Background Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting. Methods We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided. Results Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers. Conclusions Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.

Poster-Abstract

Purpose: Two phase II clinical trials in the aerodigestive tumors were undertaken to evaluate the efficacy of imatinib mesylate-docetaxel. We hypothesized that imatinib mesylate would inhibit platelet-derived growth factor receptor (PDGFR) on pericytes and increase docetaxel uptake into tumor cells for an additive antitumor effect. Baseline tumor specimens, serum, and perfusion computed tomography (CT) scans were obtained for supportive evaluation. Materials and Methods: Eligible patients with metastatic non-small cell lung cancer (NSCLC) treated with 1 prior therapy and chemonaive patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in separate trials, which administered both docetaxel (60 mg/m 2 every 3 weeks) and oral imatinib mesylate (400 mg daily). Both trials used interim analyses for efficacy and safety. Results: Twenty-two patients with NSCLC and seven patients with HNSCC were enrolled. Both trials were closed early due to lack of efficacy, significant toxicity, and a potential antagonistic effect. In the NSCLC study, the response rate was 4.5%, median progression-free survival (PFS) 7.9 weeks, and overall survival 35.6 weeks. The HNSCC trial yielded a response rate 0%, PFS 8.8 weeks, and overall survival 34.7 weeks. Baseline NSCLC tumor immunohistochemical biomarker analyses indicated that lower expression of stromal PDGFRβ correlated with a better PFS, whereas stromal PDGFRα and tumor cell PDGFRβ were associated with a worse clinical outcome when treated with imatinib mesylate-docetaxel. Conclusion: We do not recommend further investigation of this regimen in the aerodigestive tumors. Future investigations in PDGFR tyrosine kinase inhibitors should be used with caution in combination with taxanes and validation of the potential predictive or prognostic biomarkers stromal PDGFRα/β, and tumor cell PDGFRβ are needed.

Background We conducted a phase II clinical trial of induction chemotherapy followed by surgery ± radiotherapy for squamous cell carcinoma of the oral tongue (SCCOT) in young adults. Methods From September 2001 to October 2004, 23 patients aged 18 to 49 years with clinical T2–3 N0–2 M0 SCCOT and no prior radiotherapy, chemotherapy, or neck dissection underwent induction chemotherapy (paclitaxel, ifosfamide, and carboplatin) followed by glossectomy and neck dissection ± radiotherapy and chemotherapy. Results On final surgical pathology, 9 patients (39%) had a complete/major (2 complete) histologic response at the primary tumor site; 8 patients (35%) had no response or progression. Similarly, 9 patients (39%) had a complete response in the neck or remained node negative; 6 patients (26%) had an increase in nodal category. No treatment-associated deaths occurred, and toxicity was modest. At a median follow-up from the end of treatment of 52 months (minimum, 23 months), 10 patients (43%) developed recurrence, and all 10 died of cancer. Crude recurrence/cancer death rates were associated with ≤ a partial response at the tongue (p = .029), poor histologic differentiation (p = .012), and multiple adverse features on final surgical pathology (p = .040). Conclusion Response rates and overall survival with this induction chemotherapy regimen were limited, but complete/major response at the tongue was associated with excellent prognosis. Additionally, improved patient selection and predictive tumor biomarkers will be needed for induction chemotherapy to be routinely incorporated into the treatment of oral tongue cancer in young adults. © 2011 Wiley Periodicals, Inc. Head Neck, 2012

Standard therapy for advanced or metastatic non-small cell lung cancer (NSCLC) has primarily consisted of traditional cytotoxic chemotherapy, although use of targeted therapies has been approved in specific settings. Antiangiogenic agents represent a promising therapeutic strategy for treatment of advanced NSCLC. Bevacizumab is currently approved when given in combination with first-line platinum-based therapy in selected patients with nonsquamous NSCLC. Bevacizumab may also provide benefit in other clinical settings, as a part of a combination or maintenance strategy. Other antiangiogenic agents under development, including multi-targeted kinase inhibitors (MTKIs) and antibody-based agents, have exhibited mixed results in the NSCLC population. Published efficacy and safety data from clinical trials for antiangiogenic agents are reviewed, with an emphasis on novel agents and novel settings for established agents. Identification of biomarkers associated with improved efficacy may help select patients likely to receive the most benefit from these agents and may improve outcomes through development of personalized therapeutic strategies.

Introduction Non-small cell lung cancer (NSCLC) is often diagnosed in advanced stages and is associated with poor outcomes. Existing standards of care for NSCLC result in low overall cure rates, suggesting that novel treatment approaches are needed. In this review, we provide an updated look at the clinical data on immunotherapeutic interventions, which potentiate the immune system's response to lung tumor cells. Methods We searched articles on PubMed and abstracts from recent oncology meetings for publications on immunotherapies with clinical applicability to the treatment of NSCLC. Results Results from phase 2 trials show vaccine therapies, which target either tumor cells themselves or aberrantly expressed tumor markers (mucin 1, melanoma-associated antigen 3, or epidermal growth factor), may be promising immunotherapeutics for NSCLC. Antigen-independent immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibodies, talactoferrin alfa, and toll-like receptor 9 agonists, act on a stimulated immune system regardless of the tumor antigen and may be feasible interventions for metastatic NSCLC. Several immunotherapies are undergoing phase 3 studies to assess optimal treatment settings and to determine clinical benefit compared with current standard treatments for NSCLC. Conclusions A growing body of evidence suggests that immune responses to lung tumors are present. Immunotherapeutic interventions, including vaccine therapy and antigen-independent immunomodulatory strategies, may improve outcomes in NSCLC. Furthermore, treatments that enhance antitumor immune responses may prove to be synergistic with chemotherapy. Identification of biomarkers and further elucidation of immunotherapeutic mechanisms of action will be essential in determining which patients will experience the greatest benefit from immunotherapy.

Background Sorafenib, a small-molecule inhibitor of multiple kinases involved in tumor growth and progression, is approved for the treatment of advanced renal-cell carcinoma and advanced hepatocellular carcinoma. Encouraging activity and good tolerability of daily oral sorafenib, either as a single agent or in combination with gefitinib, have been demonstrated in phase I-II trials in patients with advanced non–small-cell lung cancer (NSCLC). Currently, minimal data are available describing the long-term safety and tolerability of sorafenib in patients with NSCLC. Materials and Methods We describe a series of 12 patients with advanced NSCLC (derived from 1 phase I and 2 phase II trials) who achieved long-term (ie, > 12 months) disease control and continued to receive sorafenib alone or in combination with gefitinib beyond the end of the study in which they were enrolled. Results The safety profile of sorafenib administered on a long-term basis did not differ significantly from that seen previously in the shorter term. The majority of adverse events (AEs) were Grade 1-2 in severity. Five of the 12 patients experienced no ≥ Grade 3 AEs. There was no evidence of increased frequency or severity of AEs over time, or of late AEs, and no patient in this series discontinued study treatment because of AEs. Conclusion In patients with advanced NSCLC who achieve a prolonged response or stable disease with sorafenib given as a single agent or as part of a combination regimen, sorafenib treatment could be continued until disease progression without major long-term safety or tolerability problems.

Purpose Non–small-cell lung cancer (NSCLC) commonly expresses the epidermal growth factor receptor (EGFR), which is associated with poor clinical outcome. Cetuximab is a chimerized monoclonal antibody that targets the EGFR and, in preclinical models, it demonstrates radiosensitization properties. We report a phase II trial testing the combination of cetuximab with chemoradiotherapy (CRT) in unresectable stage III NSCLC. Patients and Methods Eligibility criteria included unresectable stage III NSCLC, Zubrod performance status ≤ 1, weight loss ≤ 5%, forced expiratory volume in 1 second ≥ 1.2 L, and adequate organ function. Patients received an initial dose of cetuximab (400 mg/m2) on day 1 of week 1 and then weekly doses of cetuximab (250 mg/m2) until completion of therapy (weeks 2 through 17). During week 2, patients started CRT (63 Gy in 35 fractions) with weekly carboplatin at area under the [concentration-time] curve (AUC) 2 and six doses of paclitaxel at 45 mg/m2 followed by carboplatin (AUC 6) and two cycles of paclitaxel (200 mg/m2) during weeks 12 through 17. Primary end points included safety and compliance of concurrent cetuximab and CRT. Results In all, 93 patients were enrolled and 87 were evaluable. Median follow-up was 21.6 months. Response rate was 62% (n = 54), median survival was 22.7 months, and 24-month overall survival was 49.3%. Adverse events related to treatment included 20% grade 4 hematologic toxicities, 8% grade 3 esophagitis, and 7% grade 3 to 4 pneumonitis. There were five grade 5 events. Conclusion The combination of cetuximab with CRT is feasible and shows promising activity. The median and overall survival achieved with this regimen were longer than any previously reported by the Radiation Therapy Oncology Group.

To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175-200 mg/m(2)) plus carboplatin (AUC 6 mg min/ml) on day one of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed [grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, and grade 4 thrombocytopenia (n = 3)]. The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m(2) and carboplatin AUC 6 mg min/ml. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.

Aim: Nivo is the only immunotherapy to significantly improve overall survival (OS) in patients (pts) with R/M SCCHN who have progressed on or after platinum-based therapy. Here we report long-term data from the randomized, open-label, phase 3 CheckMate 141 study (NCT02105636). Patients: Pts with R/M SCCHN who progressed on or after platinum-based therapy were randomized 2:1 to nivo 3 mg/kg q2wk (n = 240) or IC (methotrexate, docetaxel, or cetuximab; n = 121). Endpoints: OS (primary), progression-free survival (PFS), safety. Minimum follow-up: 24.2 mo (data cut: Sep 2017). Results: Nivo improved OS significantly vs IC in the overall population (median [95% CI]: 7.7 [5.7, 8.8] mo vs 5.1 [4.0, 6.2] mo; HR [95% CI]: 0.68 [0.54, 0.86]). 2-yr OS rate (95% CI) was 16.9% (12.4, 22.0) with nivo vs 6.0% (2.7, 11.3) with IC. 8.3% of pts in the IC arm received subsequent immunotherapy. Outcomes by PD-L1 and HPV subgroups are shown in the Table. In pts with tumor PD-L1 Conclusion: With 2-yr follow-up, nivo continued to significantly improve OS and maintain a favorable safety profile vs IC. Nivo is the only immunotherapy to demonstrate OS benefit irrespective of PD-L1 expression in pts with SCCHN. Table: Outcomes by PD-L1 expression and HPV statusMedian OS (95% CI), monthsMedian PFS (95% CI), monthsNivoICHR (95% CI)NivoICHR (95% CI)PD-L1 < 1%6.5 (4.4, 11.7)5.5 (3.7, 8.5)0.73 (0.49, 1.09)2.0 (1.9, 2.1)2.7 (2.0, 4.6)1.13 (0.75, 1.71)PD-L1 ≥ 1%8.2 (6.7, 9.5)4.7 (3.8, 6.2)0.55 (0.39, 0.78)2.1 (2.0, 3.5)2.0 (1.9, 3.1)0.59 (0.41, 0.84)HPV+9.1 (6.5, 11.8)4.4 (3.0, 9.8)0.60 (0.37, 0.97)2.0 (1.9, 3.3)2.0 (1.6, 2.8)0.75 (0.46, 1.23)HPV−7.7 (4.8, 13.0)6.5 (3.9, 8.7)0.59 (0.38, 0.92)2.1 (1.9, 3.1)3.3 (1.9, 4.0)1.01 (0.65, 1.56) Citation Format: Robert L. Ferris, George R. Blumenschein, Jerome Fayette, Joel Guigay, A Dimitrios Colevas, Lisa Licitra, Kevin J. Harrington, Stefan Kasper, Everett E. Vokes, Caroline Even, Francis Worden, Nabil F. Saba, Lara Carmen Iglesias Docampo, Robert Haddad, Tamara Rordorf, Naomi Kiyota, Makoto Tahara, Mark Lynch, Vijayvel Jayaprakash, Li Li, Maura L. Gillison. Nivolumab (Nivo) vs investigator's choice (IC) in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): 2-yr outcomes in the overall population and PD-L1 subgroups of CheckMate 141 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT116.

3056Background: MAGE-A10 is expressed in 10-50% of urothelial, melanoma, head and neck (HNC), and non-small cell lung cancers (NSCLC). Affinity-enhanced autologous MAGE-A10c796T cells directed towa...

6028Background: Nivo is the only immunotherapy to significantly improve overall survival (OS) in pts with platinum (plt)–refractory R/M SCCHN. In the randomized, open-label, phase 3 CheckMate 141 t...

TPS3104Background: Melanoma-associated antigens 3 and 6 (MAGE-A3/A6) are among the most commonly expressed cancer testis antigens in a variety of tumors and are associated with poor disease prognos...

Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49

TPS78 Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy. T-cell receptor (TCR) engineered ACT approach has contributed to success in solid tumors. ACTengine IMA201 is a product based on autologous T cells engineered to express a naturally occurring TCR specific to a cancer-germline peptide. The target peptide has been characterized in depth by Immatics’ proprietary antigen discovery platform, XPRESIDENT showing exceptional specificity, copy number and expression homogeneity. XPRESIDENT has applied two independent methodologies to confirm the selectivity of tumor target: i) ultra-sensitive quantitative immunopeptidome analyses by mass spectrometry and ii) quantitative mRNA expression analyses by RNASeq. Immatics´ TCR discovery platform is optimized to identify TCRs with low micromolar affinity, specific recognition of tumor cell lines and lack of recognition of healthy normal cells. Methods: This study is an open-label first-in-human dose-escalating phase I trial investigating safety, tolerability and clinical activity in end-stage solid tumor patients. Key eligibility criteria include: recurrent or refractory squamous non-small cell lung cancer or head and neck squamous cell cancer, HLA-A*02:01 phenotype, qPCR biomarker positive from a tumor biopsy, prior established lines of therapy, RECIST v1.1 measurable lesions and ECOG score 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells (PBMC). The activated PBMC will be transduced with a lentiviral vector for manufacturing of IMA201. IMA201 is infused after a pre-conditioning (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and to identify the maximum tolerated dose. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objectives include: i) the persistence and functionality of IMA201 in vivo, ii) correlative biomarkers for clinical success, and iii) target expression levels in the tumor. Enrollment to the study is currently ongoing. Clinical trial information: NCT03247309 .

Purpose: Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti–epidermal growth factor receptor monoclonal antibody panitumumab in advanced non–small cell lung cancer (NSCLC). Experimental Design: Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line). Results: Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively. Conclusions: Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC. Clin Cancer Res; 16(1); 279–90

The promise of effective targeted therapy for lung cancer requires rigorous identification of potential targets combined with intensive discovery and development efforts aimed at developing effective “drugs” for these targets. We now recognize that getting the right drug to the right target in the right patient is more complicated than one could have imagined a decade ago. As knowledge of targets and development of agents have proliferated and advanced, so too have data demonstrating the biologic heterogeneity of tumors. The finding that lung cancers are genetically diverse and can exhibit several pathways of resistance in response to targeted agents makes the prospect for curative therapy more daunting. It is becoming increasingly clear that single-agent treatment will be the exception rather than the rule. This information raises important new questions about the development and assessment of novel agents in lung cancer treatment: (1) How do we identify the most important drug targets for tumor initiation and maintenance? (2) What is the best way to assess drug candidates that may only be relevant in a small fraction of patients? (3) What models do we use to predict clinical response and identify effective combinations? And (4) how do we bring combination regimens to the clinic, particularly when the agents are not yet approved individually and may be under development from different companies? The Fifth Cambridge Conference on Novel Agents in the Treatment of Lung Cancer was held in Cambridge, Massachusetts, on October 1–2, 2007, to discuss these questions by reviewing recent progress in the field and advancing recommendations for research and patient care. New information, conclusions, and recommendations considered significant for the field by the program faculty are summarized here and presented at greater length in the individual articles and accompanying discussions that comprise the full conference proceedings. A CME activity based on this summary is also available at www.informedicalcme.com/cme.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States. Angiogenesis, primarily mediated through vascular endothelial growth factor (VEGF), is one of the key steps in tumor growth and metastasis. VEGF is now a validated target for NSCLC based on the results of the Eastern Cooperative Oncology Group trial E4599 which showed that the addition of bevacizumab, a VEGF monoclonal antibody, to cytotoxic chemotherapy improves survival compared with chemotherapy alone in patients with metastatic NSCLC. As NSCLC has complex and integrated signaling pathways, a rational approach is to target more than one of these pathways concurrently. Sorafenib, which is approved for the treatment of renal cell carcinoma, is a multitargeted signal transduction inhibitor that inhibits raf-kinases, VEGF receptor-2, platelet derived growth factor receptor-B, and c-kit. In a phase II monotherapy trial in patients with previously treated NSCLC, sorafenib demonstrated activity with a disease control rate and survival rate comparable to other small molecules. Additionally, sorafenib has shown preliminary activity in combination with chemotherapy and with epidermal growth factor receptor inhibitors. Future directions will include the development of rational combinations either with cytotoxic compounds or biologically targeted compounds and the identification of subsets of patients that might benefit from the other targets of sorafenib.

Purpose The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m2/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted. Results A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss ≥ 5%, and had stage IV disease. The incidence and severity of most adverse events were similar between arms, although hyperlipidemia, neutropenia, fatigue, leukopenia, arthralgia, and diarrhea were more frequent in the bexarotene arm. Conclusion Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.

Purpose: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1–30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. Results: No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non–small cell lung cancer (n = 3). Conclusions: MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer. Clin Cancer Res; 21(11); 2462–70. ©2015 AACR.