Trials In Non-small Cell Lung Cancer Research Articles

OA 01.06 Radiation Therapy is Associated with an Increased Incidence of Cardiac Events in Small Cell Lung Cancer Patients

Radiation (RT) dose to the heart was a predictor of inferior overall survival (OS) in the non-small cell lung cancer trial RTOG 0617, but little data quantifies cardiac morbidity for small cell lung cancer (SCLC) patients treated with RT.

MS 13.04 The Role of Chemotherapy in the Management of CNS Metastasis

The optimal management of patients with CNS metastases from lung cancer should be a multidisciplinary approach which encompasses supportive therapy, local CNS-directed therapies including surgery, stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT), and most importantly systemic therapy. In the case of patients with small cell lung cancer (SCLC), both the primary tumor and systemic metastases are generally chemosensitive, at least initially. Most studies suggested that brain metastases are as sensitive to systemic chemotherapy as extracranial disease. The concept of the brain as a pharmacologic sanctuary site for established metastases is in contrast with clinical observations of frequent responses in brain metastases to systemic chemotherapy. Response rates (RRs) of brain metastases from SCLC to systemic chemotherapy in treatment naive patients have been reported to range from 27% to 85%. RRs in previously treated patients with brain metastases range from 22% to 50% and are comparable to the RRs with second-line chemotherapy observed in extracranial disease. A meta-analysis of five studies with a single chemotherapy for pretreated patients showed RRs ranging from 33% to 43%.1 Adding WBRT to chemotherapy increases the RR of the brain metastases, but does not appear to improve survival as shown in a phase III trial by the European Organization for Research and Treatment of Cancer.2 For patients with advanced non-small cell lung cancer (NSCLC) without molecular drivers, chemotherapy is the mainstay of treatment. Although NSCLC is less responsive to systemic chemotherapy than SCLC, results of combining platinum compounds and third generation agents are substantially better than with earlier regimens. Platinum-based doublets are the cornerstone treatment in the first-line setting for metastatic NSCLC.3 There is a presumed lack of effectiveness of systemic chemotherapy in CNS metastases from NSCLC because of the belief that chemotherapeutic drugs cannot cross the blood-brain barrier (BBB).4 However, there is increasing evidence that the integrity of the BBB is impaired and disrupted in the presence of macroscopic CNS metastases. Despite a low penetration of the CNS, chemotherapy drugs have demonstrated encouraging activity against CNS metastases from NSCLC. A number of phase II studies reported RRs to cisplatin-based combination chemotherapy regimens ranging from 35% to 50%. Several clinical trials with upfront platinum-based chemotherapy have shown intracranial RRs ranging from 23% to 50% which correlated with and almost comparable to systemic RRs.5 These data suggest that the intrinsic sensitivity of the tumor to the cytotoxic drug is more important in predicting response to the chemotherapeutic drug than the theoretical expected ability of the drug to penetrate the BBB. There are few randomized phase III trials of advanced or metastatic NSCLC evaluating different kinds of treatment in patients with brain metastases because generally, such patients have been excluded from clinical trials because of poor prognosis. Despite a penetration of CNS of less than 5%, pemetrexed demonstrated a consistent activity against brain metastases from NSCLC. One of the first evidence of pemetrexed activity against brain metastases came from a retrospective Italian study by Bearz and colleagues on 39 NSCLC patients with CNS metastases treated with pemetrexed as second or third line.6 Although the patients were unselected for histology, the study reported an intracranial RR of 30.8%, with clinical benefit obtained in 69% of patients. All patients who had an overall response (i.e., partial response and stable disease) to pemetrexed had a benefit over cerebral metastases as well with partial response in 11 patients (28.2%) and stable disease in 21 (53.8%), with a clinical benefit rate of 82% for CNS metastases and an overall survival (OS) of 10 months. The addition of platinum compounds to pemetrexed slightly improved the outcome as shown in subsequent studies. In a phase II trial on 43 chemotherapy naïve NSCLC with brain metastases (93% with non-squamous histology) treated with pemetrexed and cisplatin for six cycles, the intracranial RR was 41.9%.7 A comparable intracranial RR of 40% was observed when pemetrexed was combined with carboplatin in an observational study on 30 patients with adenocarcinoma and brain metastases.8 These clinical trials showed that platinum-based regimens are active against brain metastases from NSCLC and high RRs can be achieved with pemetrexed-containing regimens in patients with non-squamous NSCLC. A post-hoc analysis of a large prospective observational European study on 1,564 patients with newly diagnosed advanced NSCLC receiving first-line platinum-based regimens showed that in the subgroup of 263 patients with brain metastases the median OS was 7.2 months which ranged from 5.6 months for patients treated with cisplatin/gemcitabine up to 9.3 months for those treated with platinum/pemetrexed.9 In conclusion, systemic chemotherapy is an important part of the multidisciplinary management of CNS metastases. Patients with small asymptomatic brain metastases from SCLC and NSCLC should be treated with the most active platinum-based combination chemotherapy upfront. Radiation therapy and other CNS-directed treatment may be deferred until the effects of the systemic chemotherapy on the CNS metastases can be determined.

Estimated Benefit of Dose Reduction to Highly Ventilated Lung Regions for Stage III Non–small Cell Lung Cancer Patients Using Normal Tissue Complication Probability Models

We hypothesize that preferential and intentional dose reduction to regions of lung that are highly ventilated at baseline in radiation treatment plan optimization for stage III non-small cell lung cancer (NSCLC) patients will preserve lung ventilation and ultimately limit radiation-induced toxicities. To test this hypothesis, this study develops a novel treatment planning formulism combining anatomical and functional imaging and estimates the normal tissue complication probability (NTCP) improvement with this formulism. Fifty-eight stage III NSCLC patients from 2 institutions were retrospectively studied. In 21 patients from institution A, in-silico planning comparisons (ISPC) were conducted between PlanDV, using dose-volume (DV) constraints of organs-at-risk (OAR), and PlanDFV, using dose-function-volume (DFV) constraints derived from fractional regional ventilation (FRV) images. A multivariable logistic regression NTCP model was then developed using a cohort of 37 patients from institution B from whom clinical data on radiation fibrosis (RF) was available. Two hallmark characteristics of RF were recorded: volume loss and airway dilation. The NTCP model specifically incorporated the volume of functional lung exposed to irradiation. Other candidate variables included in the model were demographics (age, sex, etc.) and clinical treatment parameters (TNM stage, histology, etc.). We estimated the potential benefit of PlanDFV over PlanDV in reducing RF by integrating the results of the ISPC into the NTCP models. ISPC showed that with same target coverage, PlanDFV met OAR constraints such that all conventional DV metrics were indistinguishable (P>0.05). When DFV metrics were compared, 5-10% reductions of function-weighted V20 (P = 0.04) and function-weighted mean lung dose (P<0.01) were achieved with PlanDFV. The most predictive variables for volume loss were sV20 (lung voxels with relative function values above 60% receiving 20 Gy), smoking history and age (AUC = 0.95). NTCP modeling showed that lowering sV20 by 5% using PlanDFV, a 21% toxicity reduction could be achieved for 55 year-old non-smoker patients. Similarly, the most predictive variables for airway dilation were sV20, T stage and histology (AUC = 0.93). For squamous cell carcinoma, lowering sV20 by 5% using PlanDFV, toxicity could be reduced by 22% and 11% for T2 and T4 patients, respectively. This study showed that the inclusion of lung ventilation (in addition to lung volume), when optimizing radiation therapy plans for NSCLC patients, may allow for a clinically meaningful benefit for individual patients. A prospective trial is planned to validate these findings to determine if treatment-related morbidity and mortality can be reduced that might guide potential future dose escalation trials in NSCLC.

1325P - Generalization and representativeness of phase III immune checkpoint inhibitor trials in NSCLC

Background: Immune checkpoint inhibitors (ICBs) have become standard treatment in platinum-failed non-small cell lung cancer (NSCLC) based on several phase III studies. Recent randomized phase III trials have led to the approval of ICB. However, strict criteria for patient enrollment of phase III trials raise questions regarding generalization in the real world. The aim of this study was to evaluate whether pivotal phase III trials using ICB represent the real world NSCLC patients. Methods: We reviewed the inclusion/exclusion criteria of 3 practice changing phase III trials (CheckMate057, CheckMate017, KEYNOTE-010). Availability of tumor tissue and other exclusion criteria for KEYNOTE-010 were additionally checked. We retrospectively analyzed the database of stage IIIB or IV NSCLC patients diagnosed from 2011 to 2013 at Seoul National University Hospital (cohort 1). We also analyzed the criteria in 53 NSCLC patients who have treated with nivolumab or pembrolizumab as a routine practice (cohort 2). Results: Among the 715 NSCLC patients in cohort 1, 499 (69.9%) were ineligible for 3 trials. Reasons for ineligibility were as follows: no platinum doublet 23.6%, lack of tissue 22.7%, the Eastern Cooperative Oncology Group performance status > 1 14.1%, steroid use 18.2%, active central nervous system metastasis 8.3%, hepatitis B or C virus/human immunodeficiency virus 8.0% and no measurable lesion 7.3%. EGFR mutation was more common in ineligible group than eligible group (44.7% vs 19.7%, P < 0.001) In cohort 2 which comprise 53 patients who received ICB as a routine practice, 67.9% were classified as ineligible group. Treatment outcomes of ICB in cohort 2 seems to be inferior than those of 3 trials: response rate of 11.3%, disease control rate of 26.4%, and median progression-free survival of 1.67 months. Conclusions: Only 30.2% of NSCLC patients were eligible for ICB phase III trial. Although ICB have approved for all platinum-failed NSCLC, the real world efficacy of 60% ineligible patients were still unknown. These findings suggest that a huge gap between the practice changing phase III trials and real world NSCLC patients. Legal entity responsible for the study: Bhumsuk Keam Funding: None Disclosure: All authors have declared no conflicts of interest.

102P - Analytic validation of a next generation sequencing assay to identify tumor mutational burden from blood (bTMB) to support investigation of an anti-PD-L1 agent, atezolizumab, in a first line non-small cell lung cancer trial (BFAST)

102P - Analytic validation of a next generation sequencing assay to identify tumor mutational burden from blood (bTMB) to support investigation of an anti-PD-L1 agent, atezolizumab, in a first line non-small cell lung cancer trial (BFAST)

Targeting Hypoxia to Improve Non-Small Cell Lung Cancer Outcome.

Oxygen deprivation (hypoxia) in non-small cell lung cancer (NSCLC) is an important factor in treatment resistance and poor survival. Hypoxia is an attractive therapeutic target, particularly in the context of radiotherapy, which is delivered to more than half of NSCLC patients. However, NSCLC hypoxia-targeted therapy trials have not yet translated into patient benefit. Recently, early termination of promising evofosfamide and tarloxotinib bromide studies due to futility highlighted the need for a paradigm shift in our approach to avoid disappointments in future trials. Radiotherapy dose painting strategies based on hypoxia imaging require careful refinement prior to clinical investigation. This review will summarize the role of hypoxia, highlight the potential of hypoxia as a therapeutic target, and outline past and ongoing hypoxia-targeted therapy trials in NSCLC. Evidence supporting radiotherapy dose painting based on hypoxia imaging will be critically appraised. Carefully selected hypoxia biomarkers suitable for integration within future NSCLC hypoxia-targeted therapy trials will be examined. Research gaps will be identified to guide future investigation. Although this review will focus on NSCLC hypoxia, more general discussions (eg, obstacles of hypoxia biomarker research and developing a framework for future hypoxia trials) are applicable to other tumor sites.

Liposomal honokiol induced lysosomal degradation of Hsp90 client proteins and protective autophagy in both gefitinib-sensitive and gefitinib-resistant NSCLC cells.

Honokiol (HK), a natural chemical isolated from Mangnolia officinalis, has shown antitumorigenic activities when used to treat a variety of tumor cell lines. The mechanism of honokiol activity when used to treat gefitinib-sensitive and gefitinib-resistant non-small cell lung cancer (NSCLC) requires elucidation. Here, the presence of liposomal honokiol (LHK) induced apoptotic and antitumor activities in four xenograft models generated using NSCLC cell lines such as HCC827 (gefitinib-sensitive) and H1975 (gefitinib-resistant). Mechanistic studies revealed that LHK inhibited the Akt and Erk1/2, both EGFR signaling cascades effectors, by promoting degradation of HSP90 client proteins (HCP), including wild-type or mutant EGFR, Akt and C-Raf. Molecular biology assays showed that LHK induced HCP degradation through a lysosomal pathway, rather than the canonical proteasome protein degradation pathway. As a result of misfolded protein accumulation, LHK induced endoplasmic reticulum (ER) stress and autophagy. Inhibition of ER stress (with 4-phenylbutyrate) or autophagy (with small interfering RNA) reduced LHK-induced HCP degradations. Additionally, LHK induced autophagy showed a protective role for cancer cell as inhibition of autophagy invitro and invivo by autophagosome degradation inhibitors could promote the anticancer activity of LHK. LHK has been approved by the China Food and Drug Administration for first-in-human clinical trials in NSCLC. The current study will guide the design of future LHK clinical trials.

Abstract CT070: A open-label phase 3b/4 safety trial of flat-dose nivolumab in combination with ipilimumab in patients with advanced non-small cell lung cancer (NSCLC)

Abstract Background: Nivolumab and ipilimumab are immune checkpoint inhibitor antibodies with distinct but complementary mechanisms of action, and their combination may improve clinical outcomes compared with single-agent therapy. Nivolumab plus ipilimumab is approved for the first-line treatment of metastatic melanoma and has shown encouraging clinical activity in other tumor types, including NSCLC. In CheckMate 012, a multi-cohort phase 1 trial that evaluated nivolumab as monotherapy or in combination with other agents in chemotherapy-naïve patients with NSCLC, weight-based administration of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) yielded objective response rates (ORR) of up to 47%, depending on the dosing schedule. The discontinuation rates attributable to treatment-related adverse events (AEs) in patients treated with nivolumab plus ipilimumab were similar to nivolumab monotherapy, and AEs were consistent with the known safety profiles of the individual agents. Pharmacokinetic, safety, and efficacy data indicate comparable safety and efficacy profiles for 240 mg flat-dose nivolumab and 3 mg/kg nivolumab. This open-label phase 3b/4 study (ClinicalTrials.gov identifier: NCT02869789) will characterize the safety of flat-dose nivolumab combined with ipilimumab in patients with advanced NSCLC. Moreover, this study will evaluate this combination in special patient populations that are typically excluded from NSCLC trials. Methods: Adult patients with stage IV/recurrent NSCLC and no prior systemic anticancer therapy, including epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors (cohort A), or with stage IIIb/IV NSCLC and recurrence or progression during or after one prior platinum doublet chemotherapy regimen (cohort B) will be enrolled, with a planned sample size of 400 patients per cohort. Patients are required to have assessment of programmed death-1 ligand 1 expression, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, and no untreated brain metastases, carcinomatous meningitis, autoimmune disease, or active malignancy requiring concurrent intervention. A third cohort (A1) of approximately 200 patients with no prior systemic therapy will have either ECOG PS 2 or one or more of the following: asymptomatic untreated brain metastases, renal or hepatic dysfunction, and/or HIV. All patients will receive flat-dose nivolumab (240 mg every 2 weeks) combined with weight-based ipilimumab (1 mg/kg every 6 weeks). The primary endpoint is a descriptive assessment of the number and percentage of patients with high-grade treatment-related select and immune-mediated AEs in cohorts A and B. Secondary efficacy endpoints include progression-free survival, ORR, duration of response, and patient-reported outcomes based on the Functional Assessment of Cancer Therapy-Lung (FACT-L). Citation Format: Rathi N. Pillai, Bradley Lash, Istvan Albert, Gabrielle Gagnon, Carl Chakmakjian, Neal Ready, Wenhua Hu, Lee Krug, Sutapa Mukhopadhyay, Luis Paz-Ares. A open-label phase 3b/4 safety trial of flat-dose nivolumab in combination with ipilimumab in patients with advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT070. doi:10.1158/1538-7445.AM2017-CT070

Abstract CT143: Pooled analysis of PD-L1 expression across 6 tumor types in the nivolumab clinical program

Abstract Introduction: Programmed death ligand 1 (PD-L1) is a key biomarker for PD-1 checkpoint inhibitors; PD-L1 evaluation is incorporated across the nivolumab clinical trial program. Understanding relative expression of PD-L1 for a specific tumor type is important in evaluating its predictive and prognostic value. In this analysis, we present prevalence data from 13 050 patients across 6 tumor types from 23 nivolumab clinical trials. Methods: PD-L1 expression on tumor cells was evaluated with the Dako PD-L1 IHC 28-8 pharmDx assay in select clinical studies: melanoma (MEL), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), small-cell lung cancer (SCLC), urothelial cancer (UC), and squamous cell carcinoma of the head and neck (SCCHN). All tumor types included previously treated patients; MEL, NSCLC, and RCC trials also included treatment-naive. PD-L1 IHC staining and interpretation was conducted by reference laboratories. Interpretation was based on a scoring guideline developed for each tumor type, consistent with Dako development standards. Cut-off for data collection was November 23, 2016. Results: Across all tumor types, 93% of samples were evaluable for PD-L1 (Table). PD-L1 expression was evaluated in individual tumor types; proportion of samples with PD-L1 expression ≥1% varied by type (9.0% [SCLC] to 62.8% [MEL]). Proportion of samples at other expression levels also varied, with the highest proportion of ≥50% PD-L1 expression in NSCLC (28.4%). Evaluating the 3 largest nivolumab programs (MEL, NSCLC, and RCC), the profile of PD-L1 expression was significantly different between tumor types (P&amp;lt;0.0001). Conclusion: Prevalence of PD-L1 expression ≥1% and expression levels for screened patients vary significantly by tumor type with minor differences between treatment-naive and overall population. PD-L1 prevalence in nivolumab NSCLC trials is consistent with previously published results, including those with other PD-L1 assays (Aggarwal et al, Ann Oncol 2016;27[s6]). Table 1.PD-L1 expression by tumor type in 23 nivolumab clinical trials evaluated for PD-L1 expressionTumor typeMELNSCLCSCCHNUCRCCSCLCTotal, nNumber of trials, n67133323Patients with PD-L1 tests, n40525241309685204571813 050Treatment-naive3424372600109808248Previously treated62815153096859477184802Total in all trials, %Evaluable PD-L1 tests, % (n)96.6 (3915)91.1 (4777)88.7 (273)92.3 (632)96.0 (1964)79.0 (568)93.0Quantifiable PD-L1 in total population analyzed, %Mean, %≥1% expression62.861.956.942.724.49.043.0&amp;lt;1% expression37.238.143.157.375.691.057.1Total in all trials, %Non-evaluable PD-L1 tests, % (n)3.4 (137)8.9 (464)11.3 (35)7.7 (53)4.0 (81)20.9 (150)7.0Indeterminate PD-L1 tests, % (n)6.3 (247)0.1 (6)0000.4 (2)2.1 Citation Format: Gabriel Krigsfeld, James Novotny, Emin Oroudjev, Josette Carnahan, Songlan Zuo, Steven D. Averbuch, Virginia Burns. Pooled analysis of PD-L1 expression across 6 tumor types in the nivolumab clinical program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT143. doi:10.1158/1538-7445.AM2017-CT143

In vitro and in vivo anti-tumor activity of alectinib in tumor cells with NCOA4-RET.

Rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) accounts for approximately 1–2% of all NSCLCs. To date, RET fusions that involve at least six fusion partners in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1, and ERC1, have been identified. Recent clinical trials for RET fusion-positive NSCLC using vandetanib or cabozantinib demonstrated positive clinical response and considerable differential activities for RET inhibitors among fusion partners. Alectinib, an approved ALK inhibitor, is reported to inhibit KIF5B-RET and CCDC6-RET. However, the activity of alectinib with respect to RET with other fusion partners is unknown. In the present study, we investigated the effects of alectinib on NCOA4-RET fusion-positive tumor cells in vitro and in vivo. Alectinib inhibited the viability of NCOA4-RET-positive EHMES-10 cells, as well as CCDC6-RET-positive LC-2/ad and TPC-1 cells. This was achieved via inhibition of the phosphorylation of RET and induction of apoptosis. Moreover, alectinib suppressed the production of thoracic tumors and pleural effusions in an orthotopic intrathoracic inoculation model of EHMES-10 cells. In vivo imaging of an orthotopically inoculated EHMES-10 cell model also revealed that alectinib could rescue pleural carcinomatosis. These results suggest that alectinib may be a promising RET inhibitor against tumors positive for not only KIF5B-RET and CCDC6-RET, but also NCOA4-RET.

Bayesian Two-Stage Design for Phase II Clinical Trials with Switching Hypothesis Tests

Conventional phase II clinical trials use either a single-arm or a double-arm scheme to examine the treatment effect of an investigational drug. The hypotheses tests under these two schemes are different, as a single-arm study usually tests the response rate of the new drug against a set of fixed reference rates and a double-arm randomized trial compares the new drug with the standard treatment or placebo. To bridge the single- and double-arm schemes in one phase II clinical trial, we propose a Bayesian two-stage design with changing hypothesis tests. Stage 1 enrolls patients solely to the experimental arm to make a comparison with the reference rates, and stage 2 imposes a double-arm comparison of the experimental arm with the control arm. The design is calibrated with respect to error rates from both the frequentist and Bayesian perspectives. Moreover, we control the “type III error rate”, defined as the probability of prematurely stopping the trial at stage 1 when the trial is supposed to move on to stage 2. We conduct extensive simulations on the calculations of these error rates to examine the operational characteristics of our proposed method, and illustrate it with a non-small cell lung cancer trial.

Efficacité des inhibiteurs du checkpoint immunitaire PD-1/PD-L1 et testing PD-L1 dans les cancers thoraciques

Tumoral immune environment is a major component of cancer. Its composition and its organization represent a reproducible characteristic of tumors and a validated prognostic factor. In non-small cell lung cancer (NSCLC), cytotoxic T CD8+ lymphocyte density, associated with a Th1environment and tertiary lymphoid structures impacts survival. Tumor cell-immune cell interaction is targeted by PD1/PD-L1inhibitors. In advanced NSCLC, PD1/PD-L1inhibitors are more effective than second-line chemotherapy. Pembrolizumab outperforms first-line chemotherapy in NSCLC strongly positive for PD-L1. PD1/PD-L1inhibitors are currently tested in mesothelioma and thymic tumors. PD-L1expression evaluated with immunochemistry is the most studied predictive biomarker of PD1/PD-L1inhibitor efficacy. Tumor and immune cell expression of PD-L1is still difficult to evaluate because of intra-tumoral heterogeneity and expression modulation by the microenvironment. Four commercial diagnostic antibodies are in development, with differences concerning recognized epitopes, methodology of evaluation of PD-L1expression, positivity threshold, kit and platforms used. Clinical trials in NSCLC have shown that patients with tumors strongly positive for PD-L1derived the best clinical benefit with PD1/PD-L1inhibitors whereas clinical benefit is less common in tumors negative for PD-L1. PD-L1expression is not a perfect biomarker since some PD-L1negative NSCLC respond to PD1/PD-L1inhibitors and some PD-L1positive NSCLC do not. PD-L1testing is likely to be implemented in daily practice for selection of advanced NSCLC that will be treated with pembrolizumab, underscoring the relevance of ongoing harmonization studies of the use of the different antibodies available for PD-L1testing.

Abstract A14: A randomized trial of exemestane +/- seribantumab (MM-121) in postmenopausal women with locally advanced or metastatic ER/PR+ HER2- breast cancer: Final analysis and extended subgroup analysis

Abstract Heregulin (HRG) is the cognate ligand of the human epidermal growth factor receptor 3 (ErbB3) and has been identified as a potent driver of a distinct tumor cell phenotype characterized by enhanced survival that appears to be inherently more resistant to standard of care therapies. Preclinical studies indicate that not only can HRG induce proliferation of cellular cancer models but also that it can mediate insensitivity to numerous classes of anticancer agents including chemotherapies and targeted therapeutics. Furthermore, we and others have found that HRG-ErbB3 signaling is adept at mediating insensitivity to several classes of anti-hormonal agents that currently represent the mainstay of treatment options for hormone receptor (HR+), HER2 negative advanced breast cancer. This finding, coupled with the fact that HRG is expressed in almost half of all HR+, HER2 negative advanced breast cancers, indicates that HRG-ErbB3 signal transduction may be contributing to loss of sensitivity to endocrine based therapies in this disease. Mechanistically, anti-hormonal drugs including, fulvestrant have been implicated in increasing ErbB3 expression levels, resulting in a compensatory mechanism where cells become resistant to endocrine treatments due to estrogen independent proliferation. Seribantumab is a fully human monoclonal antibody designed to block HRG from binding to ErbB3 and prevent the establishment of HRG-driven cancer cell survival in response to standard of care therapies, including chemotherapies and anti-endocrine therapies. Clinical results from a randomized, Phase 2 study in women with metastatic breast cancer who received seribantumab plus exemestane or placebo plus exemestane highlighted the ability to sensitize HRG-positive tumors to exemestane by co-administration with seribantumab. Overall, data indicated that there was a positive trend in prolonging progression-free survival (PFS) and a statistically significant difference in overall survival (OS) in this randomized and unselected or “all-comers” patient population for those patients who had seribantumab added to their exemestane therapy rather than placebo. Safety analysis indicated that seribantumab plus exemestane was well tolerated, with manageable diarrhea being the most frequent adverse event observed. A preplanned biomarker analysis using archived tissue samples showed that women who have HRG-positive tumors were less sensitive to exemestane alone and derived substantial clinical benefit when receiving the combination of seribantumab plus exemestane, illustrated by a statistically significant improvement in PFS in this HRG-positive population. Further clinical subgroup analysis suggested that patients who received prior chemotherapy and patients whose disease had progressed in the metastatic setting may be more likely to benefit from the addition of seribantumab to their exemestane. To identify patients with HRG-driven cancers, an RNA in situ hybridization (ISH) diagnostic assay has been developed and is currently being utilized to select patients in a Phase 2 non-small cell lung cancer trial. We will present updates on clinical outcomes based on recent patient subgroup analyses along with a clinical development plan for seribantumab in HR+, HER2- advanced breast cancer. Citation Format: Greg Finn, Hong Zhang, Anna Blois, sara Mathews, Art Kudla, Jason Baum, Mike Cieslewicz, gavin macbeath, Bambang Adiwijaya, Akos Czibere. A randomized trial of exemestane +/- seribantumab (MM-121) in postmenopausal women with locally advanced or metastatic ER/PR+ HER2- breast cancer: Final analysis and extended subgroup analysis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A14.

P3.02c-056 Interim Results From the Phase I Study of Nivolumab + nab-Paclitaxel + Carboplatin in Non-Small Cell Lung Cancer (NSCLC): Topic: IT

Chemotherapy, including nab-paclitaxel, plus an immune checkpoint inhibitor has demonstrated antitumor activity in patients with metastatic breast cancer (mBC) and NSCLC. Here, results from the 2 lung cohorts of the phase I nivolumab + nab-paclitaxel in pancreatic cancer (± gemcitabine), NSCLC (+ carboplatin), and mBC safety trial are presented. Enrollment in the lung cohorts (C and D) was initiated in two sequential parts: Dose-limiting toxicity (DLT) evaluation was done in Part 1 prior to treatment arm expansion in Part 2. Chemotherapy-naive patients with stage IIIB/IV NSCLC received 4 cycles of nab-paclitaxel 100 mg/m2 D 1, 8, 15 + carboplatin area under the curve (AUC) 6 D 1 + nivolumab 5 mg/kg D 15 (starting in cycle 1 [Arm C] or cycle 3 [Arm D]) of each 21-day cycle; nivolumab continued as monotherapy from cycle 5. Primary endpoints were DLTs (Part 1), and grade 3/4 treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation (Parts 1 and 2). Patients who received ≥ 2 nivolumab cycles and remained on study for 14 days after the last nivolumab dose or discontinued due to DLT prior to completing 2 nivolumab cycles were considered DLT-evaluable. Key secondary endpoints include safety, PFS, OS, and ORR. As of May 25, 2016, 21 patients have enrolled in Arm C (18 nivolumab-treated); most were aged ≥ 65 years (57.1%) and female (71.4%), 33.3% had ECOG PS 0, 42.9% and 33.3% had adenocarcinoma and squamous cell carcinoma, respectively. No DLTs were reported (5 DLT-evaluable patients). The most common grade 3/4 AEs in Arm C (all patients) were neutropenia (28.6%), anemia (19.0%), and hypokalemia (14.3%); gastrointestinal disorders (11.1%) were the most frequent grade 3/4 immune-related AE in nivolumab-treated pts. Seven patients (5 nivolumab-treated) discontinued treatment (majority due to progressive disease [PD]). Of the 18 nivolumab-treated patients, 9 had a PR, 8 had stable disease, and data is pending in 1 patient; tumor shrinkage (baseline to nadir) ranged from 3% to 83%. The median PFS (n = 4 with PD or death; nivolumab-treated) was 7.3 months (treatment duration, 0.7 - 9.4 months). Eight patients have enrolled in Arm D (4 nivolumab-treated); 1 DLT (pneumonitis) was reported in 4 DLT-evaluable patients. These results demonstrate that the combination of nivolumab with nab-paclitaxel/carboplatin is tolerable and has promising antitumor activity in patients with NSCLC. Updated results will be presented at the meeting. (NCT02309177).

Abstract A092: Comprehensive multidimensional analysis of the immune contexture in non-small cell lung cancer

Abstract Tumors form complex ecosystems that include normal epithelial cells, fibroblasts, blood and lymphatic vessels as well as structural components, and importantly, immune cells. The density, location, and organization of various tumor-infiltrating hematopoietic cells of myeloid and lymphoid origin can impact tumor growth, spreading, and clinical outcome of various cancers, including non-small cell lung cancer (NSCLC). Here, we propose to characterize the microenvironment of lung tumors using a unique set of matched fresh tissue single cell suspensions of tumor and normal lung, paraffin-embedded tissues, and peripheral blood plasma and cells obtained at time of surgery in the same patient. We aim to query mechanisms for local immunogenicity and immunosuppression of NSCLC, by defining interactions between tumor cells and various immune cell subsets in the local microenvironment, and by correlating these findings with presence of tumor-associated antigens (TAAs) and their capacity to elicit spontaneous local and systemic immune responses, as well as immune checkpoints known to impair immune responses. We applied multiplexed immunohistochemistry for formalin-fixed paraffin embedded cancer tissues (MICSSS method; n = 40), serological assays for immunogenicity of tumor antigens from plasma samples and supernatants of B cell cultures from the same patients (ELISA; n = 40), as well as mass cytometry on cell suspensions obtained from matched fresh specimens (CYTOF, n = 20) to (1) characterize the composition and organization of the immune microenvironment, (2) identify drivers of immunosuppression in NSCLC and (3) identify the expression profile of TAAs and B cell specificity in NSCLC. We found that TAAs, such as p53, NY-ESO-1, or ERG, were expressed by lung cancer cells in a subset of patients and that protein expression at the tumor site correlated with the antibody (Ab) response found in plasma of matched patients. While circulating plasma Ab titers did not appear to be correlated with the density of infiltrating B cells, potential associations with presence of tertiary-lymphoid structure, plasma cells (CD138+ cytokeratin− cells) or T follicular helper cells (CXCR5+ CD3+ CD8−) are currently being assessed. Association between molecular alterations and immune cell composition and location will also be discussed. We will also quantify expression of checkpoint molecules (PD-L1, VISTA and HHLA-2) on immune and tumor cells. The correlation between checkpoint inhibitor expression and immune cell densities and presence of immune responses will be presented, to assess whether immune cells contribute to the modulation of T cell effector functions. In conclusion, this study is the stepping-stone to a comprehensive understanding of the complex interactions between lung tumors and their immune microenvironment. By using novel multiplexed approaches, we intend to map the immune and antigenic landscape of human NSCLC, to identify mechanisms of early disease immunogenicity and immunosuppression, and to find new prognostic and predictive markers for the development of novel therapeutic strategies and immunotherapy trials in NSCLC. Citation Format: Romain Remark, Yonit Lavin, Adeeb Rahman, Camille Bigenwald, Soma Kobayashi, Christian Becker, Raja Flores, Sacha Gnjatic, Miriam Merad. Comprehensive multidimensional analysis of the immune contexture in non-small cell lung cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A092.

1293TiP - Amethyst NSCLC trial: Phase 2, parallel-arm study of receptor tyrosine kinase (RTK) inhibitor, MGCD265 in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with activating genetic alterations in mesenchymal-epithelial transition factor (MET)

1293TiP - Amethyst NSCLC trial: Phase 2, parallel-arm study of receptor tyrosine kinase (RTK) inhibitor, MGCD265 in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with activating genetic alterations in mesenchymal-epithelial transition factor (MET)

Spotlight on pembrolizumab in non-small cell lung cancer: the evidence to date

Immunotherapy with immune checkpoint inhibitors has opened a new arena in cancer therapeutics. Pembrolizumab is a highly selective anti-programmed cell death protein 1 (PD-1) antibody that has shown efficacy, leading to survival benefit and durable responses, in some patients with non-small cell lung cancer (NSCLC). It has been approved by the US Food and Drug Administration for the treatment of patients with metastatic NSCLC, whose tumors express PD-1 ligand 1 (PD-L1), with disease progression on or after platinum-containing chemotherapy. Here, we briefly discuss the PD-1/PD-L1 pathway and pembrolizumab before delving into the clinical trials that have led to its just-mentioned approval in NSCLC and ongoing clinical trials. Finally, we discuss the use of biomarkers, primarily PD-L1, in the context of pembrolizumab and NSCLC.

Amethyst NSCLC trial: Phase 2, parallel-arm study of receptor tyrosine kinase (RTK) inhibitor, MGCD265, in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC) with activating genetic alterations in mesenchymal-epithelial transition factor (MET).

TPS9099Background: MGCD265 is an oral, potent, small molecule RTK inhibitor of MET and Axl, which are important for mediating signals for cell growth, survival, and migration. MET mutations and/or ...

Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer.

The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC.

Patients with Advanced Non–Small Cell Lung Cancer: Are Research Biopsies a Barrier to Participation in Clinical Trials?

ObjectivesClinical trials of therapies for non–small cell lung cancer (NSCLC) are increasingly requiring mandatory tumor samples or research biopsies, both of which are potential barriers to trial participation. We assessed the impact of performance of research biopsies on the enrollment of patients with advanced NSCLC in clinical trials. MethodsThe cases of patients with advanced NSCLC who had been evaluated for clinical trials of systemic therapy at the Princess Margaret Cancer Centre from January 2007 to March 2015 were reviewed. ResultsOf the 55 clinical trials identified, 38 required tumor samples for enrollment. Six mandated repeat biopsies, whereas 32 permitted use of archival samples. Trial participation was offered to 636 patients at 940 unique study encounters, with some patients enrolling in multiple trials. Of the patients in 549 encounters during which participation in a therapeutic trial was offered, 60% received study treatment. More patients received study treatment (83% versus 55%, p < 0.0001) and study treatment was started earlier (after 9 days versus after 16, p = 0.002) when the trial did not have a mandatory tissue sample requirement. A similar trend was noted for trials permitting use of archival tissue versus mandatory repeat biopsies. The most common barriers to trial enrollment included absence of a required biomarker (34%), withdrawal of consent (20%), deterioration or death (17%), other exclusion criteria (15%), and insufficient biopsy tissue (10%). ConclusionA growing number of NSCLC trials are requiring tumor tissue for treatment eligibility, which appears to be a significant barrier to trial enrollment. Potential solutions include use of available diagnostic samples (e.g., cytology samples), development of peripheral blood assays for molecular markers, faster central laboratory testing turnaround time, and more resources for rapid biopsy.