Chao H. Huang

Phase II Evaluation of Sorafenib in Advanced and Metastatic Squamous Cell Carcinoma of the Head and Neck: Southwest Oncology Group Study S0420

PURPOSEnWe conducted a phase II trial to evaluate the efficacy and safety of single-agent sorafenib in chemotherapy-naïve patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN). The primary end point was response probability (ie, confirmed complete and partial response [PR]).nnnPATIENTS AND METHODSnChemotherapy-naïve patients with metastatic, persistent, or recurrent SCCHN who received one induction or fewer or received an adjuvant chemotherapy regimen, who had adequate organ function, and who had a performance status <or= 1 were eligible. Sorafenib was administered orally at 400 mg twice daily on a continuous basis in 28-day cycles. Responses were evaluated according to RECIST (Response Evaluation Criteria in Solid Tumors).nnnRESULTSnSorafenib was generally well tolerated. Of the 41 eligible patients assessed for adverse events, one experienced a grade 4 adverse event as a result of an asymptomatic pulmonary embolus. The most common grades 2 to 3 adverse events were fatigue, anorexia, stomatitis/oral pain, abdominal pain, hand-foot syndrome, weight loss, and hypertension. There was one confirmed PR and two unconfirmed PRs. The estimated confirmed response probability was 2% (95% CI, 0% to 13%). The estimated median progression-free survival was 4 months (95% CI, 2 to 4 months), and the estimated median overall survival was 9 months (95% CI, 7 to 14 months).nnnCONCLUSIONnSorafenib was well tolerated. Although response was poor, progression-free and overall survival times compare favorably with previous Southwest Oncology Group, phase II, single-agent trials.

Potential Role of Platelet-Derived Growth Factor Receptor Inhibition Using Imatinib in Combination with Docetaxel in the Treatment of Recurrent Non-small Cell Lung Cancer

Introduction: Platelet-derived growth factor receptor (PDGFR) is expressed in lung cancer and is involved in angiogenesis. Preclinical models demonstrated that imatinib (Im) regulates angiogenesis through PDGFR inhibition and enhances efficacy of chemotherapy. Hypothesis: We hypothesized that Im plus docetaxel (D) would have a synergistic effect detectable by an increase in response rate in patients with recurrent non-small cell lung cancer (NSCLC). Methods: A phase II trial to evaluate Im in combination with D in patients with recurrent NSCLC was conducted. The primary end point was response rate, using a Simon two-stage design. Eligible patients had measurable disease and no more than two chemotherapy regimens. D was given at 30 mg/m2/wk intravenously ×3 every 4 weeks and oral Im at 600 mg daily for four cycles. Patients required two cycles to be evaluable for response. Nonprogressors after four cycles continued with Im maintenance until progression or for a total of 12 months. Results: Twenty-three patients were enrolled in the first stage. Toxicity was mainly nonhematologic. We observed one partial response (5.5%), four stable disease (22.2%), and 13 progressed (72.2%). Median time to progression was 1.9 months, and median overall survival was 6.1 months. Two patients who went on Im maintenance had time to progression of 7.78 months and 15.8 months. Conclusion: Im in combination with D did not achieve its primary objective of improving response rate in patients with recurrent NSCLC. An increased understanding of the complex PDGFR pathway in lung cancer and alternative strategies to inhibit it are needed.

Impact Study: MK-0646 (Dalotuzumab), Insulin Growth Factor 1 Receptor Antibody Combined with Pemetrexed and Cisplatin in Stage IV Metastatic Non-squamous Lung Cancer

Background Insulin-like growth factor 1 receptor (IGF-1R) regulates cell growth, proliferation, and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Dalotuzumab-MK0646 (D) is a humanized monoclonal antibody that targets IGF-1R. Pemetrexed (P) has higher activity in non-squamous lung cancer (NSQL). We initiated a randomized phase II trial to test the combination of P and Cisplatin (C)u2009±u2009D in NSQL. Methods Eligibility criteria were untreated NSQL stage IV, ECOG 0 or 1, measurable disease, adequate renal, hepatic and hematologic function, and no other intercurrent illness. P at 500u2009mg/m2 and C at 75u2009mg/m2 IV were given every 3u2009weeks. D was given at 10u2009mg/kg IV weekly on days 1, 8, and 15 of every 3-week cycle in the experimental group. The patients had a radiographic assessment after every two cycles and were treated for a maximum of six cycles if there was a response or stable disease. The primary objective of the study was to compare the clinical response rates of PC vs. PCu2009+u2009D. Results From 1/2009 to 2/2011, the study accrued 26 subjects: 16 male and 10 female, with a median age of 59; 14 were treated with PC and 12 were treated with PCu2009+u2009D. We observed two partial responses (PR), seven stable disease (SD), three progressive disease (PD), and two not evaluable (NE) in the PC arm. In comparison, for the PCu2009+u2009D arm, there were three PR, four SD, four PD, and one NE. The hematologic toxicity was similar in both groups. There was higher incidence of hyperglycemia in the experimental group; four cases with grade 3 and one case with grade 4. Conclusion PCu2009+u2009D had a similar response rate compared to PC, with a higher rate of hyperglycemia. Identification of responders using predictive markers would be key to continuing the study of D in NSQL. Trial Registration NCT00799240, clinicaltrials.gov

Impact of previous anti-angiogenesis treatment in nivolumab-treated advanced non-small cell lung cancer

Aim: To investigate how previous systemic therapy such as anti-angiogenesis can influence cancer immunotherapy for non-small cell lung cancer (NSCLC). Methods: A total of 134 patients with advanced NSCLC who were treated with nivolumab were retrospectively reviewed. Correlation between status of prior anti-angiogenesis treatment and clinical characteristics were determined. Impact of prior anti-angiogenesis on therapeutic outcome of nivolumab was investigated for tumor efficacy such as progressionfree survival (PFS). Results: Sixteen patients were treated with at least one anti-angiogenesis agent prior to nivolumab. The prior use of antiangiogenesis agent was associated with stage IV disease, non-squamous histology, and two or more lines of systemic therapy. Median PFS was significantly shorter in the prior anti-angiogenesis group than in no prior anti-angiogenesis group (8.3 vs. 11.3 weeks, log-rank P = 0.006). Multivariate analyses demonstrated that only prior anti-angiogenesis status was associated with worse PFS. There is also a slight trend for worse disease control rate (P = 0.101, Fisher’s exact test) and overall survival (P = 0.200, log-rank) in prior anti-angiogenesis group. Conclusion: This retrospective study suggests that prior anti-angiogenesis treatment negatively impacts the therapeutic outcome of immunotherapy in advanced NSCLC.

Updates in the Clinical Development of Epacadostat and Other Indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for Human Cancers

Recent application of immunotherapy in clinical oncology revolutionized our management of advanced human cancers. Check point inhibitors targeting CTLA4 and PD-1/PD-L1 axis are immunotherapeutic agents currently available to treat a variety of cancers. However, a novel therapeutic approach is needed to further improve patient outcome with these agents. Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme in the metabolism of essential amino acid tryptophan in the peripheral tissue. IDO1 is overexpressed in human cancer cells and suppresses effector T cell function and promotes regulatory T cells (Tregs). Overexpression of IDO1 is associated with poor patient survival in several types of human cancer. These findings indicate that IDO1 is a promising target that can improve the treatment outcome in the field of Immuno-oncology. Several orally available IDO1 inhibitors including Epacadostat have entered human clinical trials over the last few years without a major safety concern. Although there is no objective response in single-agent trials, combination regimens with PD-1 inhibitors appear to exceed the activity of PD-1 inhibitors alone. Recent phase III ECHO 301 trial testing the combination of Epacadostat with Pembrolizumab in melanoma did not show superior outcome compared to Pembrolizumab alone. This lead to halting of other phase III trials using IDO1 inhibitors. In this minireview, we will discuss the recent clinical development of Epacadostat and other IDO1 inhibitors.

PS01.33: Change in microRNA Profile in Lung Cancer Cell Treated with Chemotherapy Cisplatin (C), Pemetrexed (P) or PC with Bevacizumab (B): Topic: Medical Oncology

eliminate false positives, secondary negative screening was performed using H3118 cells that were stably transfected with CRE (CREB responsive element) containing the same luciferase vector backbone. The effects of potential NR4A2 promoter inhibitors were further validated using several lung cancer cell lines. Status of NR4A2 and a downstream gene, osteopontin (OPN) expression in these cell lines were determined by western blotting and RT-PCR. Since multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) were identified by the screening, inhibitors of downstream molecules such as RAF, MEK, PI3K, were then used to determine if they can influence NR4A2 signaling. Results: Among positive hits, 23 FDA and 43 Life chemicals had a known mechanism of action. Three EGFR-TKIs and one Src inhibitor were included and then further analyzed.. These drugs inhibited H3118 cell growth in vitro, and led to depression of phospho-ERK, NR4A2 and OPN protein levels, indicating these indirectly regulate NR4A2 by suppression of upstream pathway. Inhibitors of other EGFR downstream pathway such as RAF, PI3K, STAT3, did not affect cell proliferation or NR4A2/OPN protein expression. NR4A2 negative H2087 cells were not sensitive to EGFR/Src inhibitors as compared to H3118. Conclusion: Our HTS screening showed several EGFR and Src inhibitors can indirectly regulate NR4A2 by suppression of upstream signaling, suggesting a new mechanism where EGFR WT cancer cells can be addicted to EGFR-TKIs. Further research to confirm the findings are warranted. Positive hit compounds with unknown mechanism of action are also under investigation.

Abstract 2430: Treatment sequence and molecular biomarker in EGFR mutant lung cancer cells

Introduction Lung cancer is the leading cause of cancer related death in the US. A subset of patients with lung cancer has a mutation in the Epidermal Growth Factor Receptor (EGFR) which makes them extremely responsive to EGFR tyrosine kinase inhibitor (TKI) erlotinib. The emergence of EGFR TKI resistance is new challenge in the management of these patients. We conducted a study to determine the best treatment sequence after resistance to EGFR TKI, testing the use of chemotherapy Pemetrexed (P), Afatinib (A), Rociletinib (R) and the combination of these agents in lung cancer cell lines with EGFR mutation that were pretreated with erlotinib. Material and methods Lung cancer cell lines with EGFR mutation CRL-2868 (E746 - A750 deletion) and CRL-2871 (L747 - E749 deletion, A750P) mutation were treated with 5 nM erlotinib for 24h and 72 h. The erlotinib resistance cells were then treated with 10nM of A or 10nM of P, or 21.5 nM of R, or the combination AP or the combination of RP. As control, we used lung cancer HTB-177 which does not have EGFR mutation. MTT proliferation assay was performed after 24, 48, 72 and 144h after the treatment. microRNA profiling was done by real time PCR in all cells after erlotinib treatment to find potential biomarkers as hallmark of erlotinib resistance cells. Results Rociletinib induced the maximum inhibition of cell proliferation at 144h in both cell lines with EGFR mutation. The RP also induced decreased cell proliferation in both cell lines with EGFR mutation. RP combination was more effective then R alone in CRL 2871. The use of A alone, P alone or AP combination was not different in CRL2871 but P had antagonistic effect when combined with A or R in CRL 2868. microRNA 10b, 27a and 27b were upregulated in the erlotinib resistant cells. Conclusion. EGFR resistance arises after treatment with erlotinib in lung cancer cell lines with EGFR mutation. Treatment with R and the combination of RP induced greater inhibition of proliferation compared to A, P alone. The combination of AP was antagonistic. This may have implications in the management of patients resistant to EGFR TKI. microRNA analysis showed up-regulation of several microRNA that should be tested in clinical setting. Citation Format: Hannah Motes, Emma Borrego-Diaz Reyes, Jared Kevern, Chao H. Huang, Peter J. Van Veldhuizen. Treatment sequence and molecular biomarker in EGFR mutant lung cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2430. doi:10.1158/1538-7445.AM2015-2430