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OZGUROGLU, MUSTAFA/0000-0002-8417-8628; Senan, Suresh/0000-0003-3995-2204; Cho, Byoung Chul/0000-0002-5562-270X WOS:000535705600013 PubMed ID: 32209338 Background: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. Patients and methods: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo = 25%, = 1%, = 25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), = 1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), = 25% (0.50, 0.30-0.83; NR versus 21.1 months), = 1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not

Background Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years’ follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results After 40.3 months’ minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions After 3 years’ minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

Advanced-stage non–small cell lung cancer (NSCLC) and small cell lung cancer are cancers in which chemotherapy produces a survival benefit, although it is small. We now know that anti–PD-1/PD-L1 has substantial clinical activity in both of these diseases, with an overall response rate (ORR) of 15%–20%. These responses are frequently rapid and durable, increase median overall survival (OS) compared with chemotherapy, and produce long-term survivors. Despite these very significant results, many patients do not benefit from anti–PD-1/PD-L1. This is because of the potential for malignancies to co-opt myriad immunosuppressive mechanisms other than aberrant expression of PD-L1. Conceptually, these can be divided into three categories. First, for some patients there is likely a failure to generate sufficient functional tumor antigen-specific T cells. Second, for others, tumor antigen–specific T cells may be generated but fail to enter into the tumor parenchyma. Finally, there are a large number of immunosuppressive mechanisms that have the potential to be operational within the tumor microenvironment: surface membrane immune checkpoint proteins PD-1, CTLA-4, LAG3, TIM3, BTLA, and adenosine A2AR; soluble factors and metabolic alterations interleukin (IL)-10, transforming growth factor (TGF)-β, adenosine, IDO, and arginase; and inhibitory cells, cancer-associated fibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages. In this article, we discuss three strategies to generate more tumor-reactive T cells for patients: anti–CTLA-4, therapeutic tumor vaccination, and adoptive cellular therapy, with T cells redirected to tumor antigens using T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene modification. We also review some of the various strategies in development to thwart tumor microenvironment immunosuppressive mechanisms. Strategies to drive more T cells into tumors remain a significant challenge.

Introduction Historiquement, la survie des patients atteints de CBNPC avance etait mediocre, avec des taux a 5 ans Methodes Les patients (n = 854 ; CM 017/057 regroupes) atteints d’un CBNPC avance, avec un ECOG PS ≤ 1 et dont la maladie avait progresse pendant ou apres une premiere ligne de chimiotherapie ont ete randomises 1 :1 pour recevoir nivolumab 3 mg/kg toutes les 2 semaines ou docetaxel 75 mg/m2 toutes les 3 semaines jusqu’a progression ou toxicite inacceptable. La SG etait le critere principal d’evaluation pour les deux etudes. Resultats A 5 ans de suivi, 50 patients dans le bras nivolumab et 9 patients dans le bras docetaxel etaient en vie. Les caracteristiques initiales des survivants a 5 ans dans les deux bras etaient similaires a celles de la population globale et a celles des patients ayant survecu Conclusion Les CM 017 et CM 057 sont les premiers essais de phase III a rapporter les resultats a 5 ans d’un anti-PD1 dans le CBNPC avance prealablement traite et font etat d’une augmentation de plus de 4 fois des taux de SG a 5 ans avec nivolumab (13 %) par rapport au docetaxel (3 %). Le traitement par nivolumab reste bien tolere, sans nouveau signal de toxicite.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that causes immunosuppression in the tumor microenvironment. Indoximod is an IDO pathway inhibitor. Preclinical data suggests indoximod enhancs the activity of dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used to generate autologous dendritic cell (DC) vaccines against p53 epitopes. We initiated a phase 1/2a trial of indoximod + Ad.p53DC to explore the safety and efficacy of the combination along with response to subsequent chemo. The phase 1 safety data were previously presented and the treatment was well tolerated with no DLTs. (Soliman, ASCO 2013) This abstract includes new phase 2a safety/efficacy data and updated outcomes on all phase 1/2 metastatic breast cancer patients who received Adp53DC+indoximod and any subsequent response to salvage chemo. Methods: The phase 2a study combined indoximod 1600mg PO BID with up to 6 Ad.p53 DC vaccinations q2wks. The trial used a single arm, Simon two stage design (n=12 in 1st stage, 25 in 2nd stage) with objective response as the primary endpoint. One response out of 12 was required for progression into second stage. The study had 90% power to detect 20% response rate with a p=.09. Patients with measurable, metastatic breast cancer, 5%, ECOG 0-2, no autoimmune disease were eligible. Study treatment continued until disease progression or unacceptably toxicity. Results: Twelve phase 2 patients were accrued, 9 (7 TNBC, 2 ER+/HER2-) received ≥ 1 dose of Ad.p53DC+indoximod (3 did not due to rapid disease progression during vaccine preparation). Six patients had ≥ 1 prior line of chemo. Seven (58%) subjects experienced any grade AE, there were no treatment related AEs ≥G3. All treatment attributable AEs were G1-2, Conclusions: Indoximod+Ad.p53DC was well tolerated. Across phase 1/2 the best response to immunotherapy alone was SD in 4 pts while 10 of 21 (47%) (including 1 CR) responded to subsequent chemotherapy in this largely pretreated cohort. There may be a chemosensitization effect of indoximod+Ad.p53DC. Future trials should combine this treatment with chemotherapy in appropriately selected patients. Citation Format: Hatem H Soliman, Susan E Minton, Roohi Ismail-Khan, Hyo S Han, Nicholas N Vahanian, Charles J Link, Gene Kennedy, Howard Streicher, Daniel Sullivan, Scott J Antonia. A phase 1/2 study of Ad.p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-15-04.

The immunosuppressive enzyme, indoleamine 2,3 dioxygenase (IDO), is overexpressed in many different tumor types including breast cancer. IDO inhibitors synergize with chemotherapy in breast cancer murine models. Characterizing IDO expression in breast cancer could define which patients receive IDO inhibitors. This study analyzed IDO protein expression in 203 breast cancer cases. The relationship between IDO, overall survival (OS), disease-specific survival (DSS), clinicopathologic, molecular, and immune tumor infiltrate factors was evaluated.Expression of IDO, estrogen receptor (ER), progesterone receptor (PR), human epithelial receptor 2, cytokeratin 5/6, epithelial growth factor receptor, phosphorylated AKT, neoangiogenesis, nitrogen oxide synthetase 2 (NOS2), cyclooxygenase 2 (COX2), FoxP3, CD8, and CD11b on archival breast cancer tissue sections was evaluated by immunohistochemistry. Associations between IDO and these markers were explored by a univariate and multivariate analysis. Survival was analyzed using Kaplan-Meier (OS) and Wilcoxon two-sample (DSS) tests.IDO expression was higher in ER+ tumors compared to ER- tumors. IDO was lower in those with higher neoangiogenesis. OS was better in ER+ patients with high IDO expression. DSS was better in node-positive patients with high IDO expression. IDO activity positively correlates with NOS2. COX2 as positively correlated with IDO on univariate but not multivariate analysis. There was a trend toward greater numbers of CD11b+ cells in IDO-low tumors.IDO protein expression is lower in ER- breast tumors with greater neoangiogenesis. Future clinical trials evaluating the synergy between IDO inhibitors and chemotherapy should take this finding into account and stratify for ER status in the trial design.

The presence of hepatic portal venous gas (HPVG) is a rare finding. It is most commonly caused by bowel necrosis and typically carries a grave prognosis. Bevacizumab has emerged as an effective standard therapy in the frontline management of advanced non-small cell lung cancer (NSCLC). Although bevacizumab is associated with gastrointestinal perforation, it has not been shown to cause HPVG. A 75-year-old man, diagnosed with metastatic NSCLC, was treated with palliative chemotherapy consisting of paclitaxel, carboplatin, and bevacizumab for six cycles. He continued on maintenance bevacizumab after that for a total of six doses, given every 3 weeks, with continued stable disease. During a surveillance CT scan 4 weeks after the last dose of bevacizumab, HPVG was shown. This is the first case of HPVG associated with bevacizumab therapy in a patient with metastatic NSCLC. The HPVG may have been an early warning sign of impending bowel perforation, and bevacizumab was immediately discontinued, with HPVG completely resolving on follow-up CT scan 2 weeks later. We recommend that bevacizumab therapy be immediately and permanently discontinued whenever HPVG is observed, as this may help avoid a potentially catastrophic outcome.

The results of recent clinical trials have demonstrated that cancer vaccines continue to struggle to achieve tangible clinical benefits as monotherapy. Tumor-induced abnormalities in the immune system hamper anti-tumor T cell responses limiting the effectiveness of cancer immunotherapy. Recently, evidence has been mounting to suggest that immunotherapy has the possibility of achieving better success when used in combination with conventional chemotherapy. In clinical trials, immune responses elicited by cancer vaccines appear to augment the effectiveness of subsequent conventional cancer therapies.

Hatem Soliman,1 Melanie Mediavilla-Varela,2 Scott J Antonia,3 1Department of Women's Oncology and Experimental Therapeutics, 2Department of Immunology, 3Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA Background: There is increasing interest in using cancer vaccines to treat breast cancer patients in the adjuvant setting to prevent recurrence in high risk situations or in combination with other immunomodulators in the advanced setting. Current peptide vaccines are limited by immunologic compatibility issues, and engineered autologous cellular vaccines are difficult to produce on a large scale. Using standardized bystander cell lines modified to secrete immune stimulating adjuvant substances can greatly enhance the ability to produce immunogenic cellular vaccines using unmodified autologous cells or allogeneic medical grade tumor cell lines as targets. We investigated the efficacy of a cellular vaccine using B78H1 bystander cell lines engineered to secrete granulocyte macrophage-colony stimulating factor and CD40 ligand (BCG) in a murine model of breast cancer. Methods: Five-week-old female BALB/c mice were injected orthotopically in the mammary fat pad with 4T1 tumor cells. Treatment consisted of irradiated 4T1 ± BCG cells given subcutaneously every 4 days and was repeated three times per mouse when tumors became palpable. Tumors were measured two to three times per week for 25 days. The vaccine's activity was confirmed in a second experiment using Lewis lung carcinoma (LLC) cells in C57BL/6 mice to exclude a model specific effect. Interferon-γ (IFN-γ) and interleukin-2 (IL-2) enzyme-linked immunospots (ELISPOTS) were performed on splenic lymphocytes incubated with 4T1 lysates along with immunohistochemistry for CD3 on tumor sections. Results: Tumor growth was significantly inhibited in the 4T1-BCG and LLC-BCG treatment groups when compared to 4T1 and LLC treatment groups. There were higher levels of IL-2 and IFN-γ secreting T-cells on ELISPOT for BCG treated groups, and a trend for higher numbers of tumor infiltrating CD3+ lymphocytes. Some tumors in the 4T1-BCG demonstrated organized lymphoid structures within the tumor microenvironment as well. Conclusion: The use of BCG bystander cell lines demonstrates proof of concept for anti-tumor activity and immunogenicity in an immunocompetent murine model of breast cancer. This vaccine is being evaluated in lung cancer and should be explored further in clinical trials of breast cancer patients at high risk of recurrence or in combination with other immunomodulatory agents. Keywords: breast cancer, immunotherapy, bystander vaccine, CD40L, GM-CSF

Purpose BMS-936558 is a fully human monoclonal antibody that blocks the PD-1 co-inhibitory receptor expressed by activated T cells. We report here the activity and safety of BMS-936558 in pretreated pts with advanced NSCLC, a tumor not previously considered responsive to immunotherapy. Methods BMS-936558 was administered IV q2wk to pts with various solid tumors at 1 - 10 mg/kg during dose escalation and/or cohort expansion. Pts with advanced NSCLC previously treated with at least 1 prior line of therapy were eligible. Pts received up to 12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, confirmed progressive disease, or complete response. Clinical activity was assessed by RECIST v1.0. Results As of Feb 24, 2012, 122 NSCLC pts had received BMS-936558 at 1 (n = 31), 3 (n = 33), or 10 mg/kg (n = 58). ECOG performance status was ≤1 for 117/122 pts; 67/122 pts had received ≥3 prior therapies. Median duration of therapy was 12 weeks (range 2 - 101.3 wks). Common drug-related AEs in NSCLC pts were fatigue (18%), decreased appetite (10%), anemia (8%), and nausea (7%). The incidence of grade 3–4 related AEs was 8%. There were 2 drug-related deaths from pneumonitis. Of 76 evaluable pts, 14 had a partial response (PR) (Table); all 14 were treated ≥24 wk, and 8 had responses of ≥24 wk. 5 Five pts had stable disease (SD) lasting ≥24 wk. Additionally, 3 pts had a persistent decrease in target lesion tumor burden in the presence of new lesions and were not categorized as responders. Conclusions BMS-936558 had an acceptable risk: benefit profile in previously treated, advanced NSCLC. Activity in squamous NSCLC was particularly intriguing. Additional long-term follow-up data will be reported. Dose, mg/kg No. pts a ORR, No. pts (%) [95% CI] PFSR at 24 wks, % [95% CI] 1 18 1 (6) [0.1 - 27] 16 [0 - 34] 3 19 6 (32) [13 - 57] 41 [18 - 64] 10 39 7 (18) [8 - 34] 24 [11 - 38] All 76 b 14 (18) [11 - 29] 26 [16 - 36] All–Nonsquamous 56 7 (13) [5 - 24] 22 [11 - 34] All–Squamous 18 6 (33) [13 - 59] 33 [12 - 55] a Response-evaluable pts dosed by 07/01/2011 b Includes 2 pts with unknown histology, 1 with PR ORR = objective response rate ([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate Disclosure L. Horn: Consultant or Advisory Role: OSI/Astellas (myself, uncompensated). D. Spigel: Consultant or Advisory Role: Bristol-Myers Squibb (myself, uncompensated). L.V. Sequist: Consultant or Advisory Role: Clovis, Celgene, GlaxoSmithKline (myself, compensated); Daiichi-Sankyo, Merrimack (myself, uncompensated). J.M. Wigginton: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). G. Kollia: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). A. Gupta: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). All other authors have declared no conflicts of interest.

Background Indoleamine 2,3dioxygenase (IDO) is a tryptophan-catabolizing enzyme that plays a key role in the regulation of immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression, evading immune mediated destruction. Indoximod (D-1-methyltryptophan) is a broad IDO pathway inhibitor as it has been shown to potentially interfere with multiple targets within the IDO pathway. Preclinical studies in MMTV-neu mouse models have shown that indoximod combined with chemotherapy was more effective in causing tumor regressions than either agent alone. A phase 1 trial combining docetaxel and indoximod demonstrated safety and responses in metastatic breast cancer patients. Based on this data a phase 2 trial in first line metastatic breast cancer was initiated. Trial design The study is a 1:1 randomized, placebo controlled two arm phase 2 study. The study treatment is docetaxel 75mg/m2 IV D8 plus indoximod 1200mg PO BID D1-14 every 21 days or matching placebo. Primary endpoint is progression free survival. Secondary endpoints include overall survival, response rate, and immune response correlative assays. Patients with measurable, histologically confirmed metastatic breast cancer, no prior chemotherapies (hormonal therapies allowed) in the metastatic setting, ER+ or ER –, HER2 -, ECOG PS 0-1, no active CNS disease, no active autoimmune disease are eligible. Target enrollment is 154 patients. The trial is currently open at multiple clinical sites all around the US and actively enrolling patients. Expansion to the EU is underway. NCT01191216. Disclosure E.P. Kennedy: Employee of NewLink Genetics who is the sponsor for this clinical trial; G. Rossi: Author is an employee of NewLink Genetics; N. Vahanian and C. Link: Author is an officer and employee of NewLink Genetics. All other authors have declared no conflicts of interest.

Aim: MEDI4736 is a human IgG1 mAb, engineered to prevent antibody-dependent cell-mediated cytotoxicity (ADCC) activity, that blocks PD-L1 binding to PD-1 and CD-80. This expansion study (NCT01693562) assessed MEDI4736 in pts with NSCLC, melanoma (cutaneous and uveal), hepatocellular carcinoma (ca), squamous cell ca of the head and neck (SCCHN), gastroesophageal ca, pancreatic ca, and triple negative breast ca. Methods: 10–20 pts (performance status [PS] 0–1) were initially enrolled per tumor type/study arm, with expansion allowed upon observation of clinical activity. MEDI4736 was administered as 10 mg/kg IV every 2 wks (q2w) for up to 12 months, with retreatment permitted for progression during follow-up. Response was assessed by RECIST v1.1. Results: This multi-arm dose expansion study was initiated in Sep 2013. As of 14 April 2014, 288 pts median age 61y (20–96), 57% male, PS 0/1/unknown (31%/65%/4%), median 3 (1–11) prior treatments, had received a median of 3 (1–20) doses of MEDI4736 10 mg/kg q2w and were evaluable for safety. Safety profile appeared to be consistent across tumor types and with previous reports. Treatment-related adverse events (AE) in 34% of pts (any Grade [Gr]); Gr ≥3 in 5.6%; no Gr 4–5); AEs led to discontinuation of study drug in 5.8% (drug-related in 1 pt). Most frequent treatment-related AEs were fatigue (14%), nausea (8.7%), and rash (5%). Gr 2 pneumonitis (resolved with drug interruption/steroids) was seen in 1 pt (0.4%). No colitis reported. No immunogenicity detected at the 10 mg/kg dose; 1/89 with antidrug antibodies impacting PK. Tumor shrinkage has been seen across all histologies, with responses as early as 6 wks and after initial progression in some pts. Clinical activity to date appears durable (maintained ≥ 48 wks in 5 pts). Analysis of correlation between activity and clinical attributes or biomarkers including PD-L1 expression is ongoing. Conclusions: Results indicate that MEDI4736 has a manageable safety profile even in heavily pretreated pts. Evidence of clinical activity has been seen across all 9 tumor types; other tumor types will be evaluated. Current experience supports development of MEDI4736 as monotherapy and in combination with other anti-cancer therapies for multiple tumor types. Disclosure: N.H. Segal: Ad Board participation with MedImmune, Alkermes Scientific and Imugene. Research funding from BMS and Pfizer. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; O. Hamid: My only conflict here is the research funding that I received from Medimmune. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; W. Hwu: No financial interest in MedI4736,process involved in the research.I dont own stock,serve on ad board,board of director or other substantive relationship with research sponsor who consider research fund rec'd for conduct of Medi-sponsored study a COI; C. Massard: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; M. Butler: Received financial support from MedImmune Inc. to cover the costs of conducting MedImmune-sponsored clinical studies of Medi4736. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Antonia: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins: Employee of MedImmune and owns stock/stock options in AstraZeneca; P.B. Robbins: Employee of MedImmune and owns stock/stock options in AstraZeneca; X. Li: Employee of MedImmune and owns stock/stock options in AstraZeneca; J. Vasselli: Employee of MedImmune and owns stock/stock options in AstraZeneca; S. Khleif: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I also function as a clinical advisor.

Aim: Robust responses to nivolumab (Nivo, anti-PD1 antibody) are seen in both melanomas and NSCLCs. Both of these cancers are characterized by high somatic mutation burden, suggesting a potential link between mutational burden and immunogenicity. Since smoking-related NSCLCs have significantly greater mutation burden compared to never smokers, we hypothesized that smoking history may be associated with response to nivolumab in pts with NSCLCs. Methods: Smoking status, histology, and EGFR/KRAS genotype were recorded from 88 of 129 pretreated, advanced NSCLCs treated with Nivo monotherapy at 5 of 11 centers that participated in a previously reported study (NCT00730639, Topalian et al, NEJM 2012). Self-reported smoking history was categorized as never ( 5 pk-yrs, quit > 1 yr prior), or current smokers. In smokers, time-since-quitting was also recorded. Response was assessed every 8 wks by RECIST v1.0. Associations between smoking, histology, genotype, and response were assessed using the Fisher's exact, unpaired T-, log-rank tests. Results: The response rate was significantly higher in former/current smokers (20/75, 27%, 95% CI 17-38%) vs minimal/never smokers (0/13, 0%, 95% CI 0-25%) (p = 0.034). Responders had significantly more tobacco exposure than non-responders (median 50 pk-yrs [range 15-150] vs 36 pk-yrs [range 0-100], p=0.036). Among smokers, there was no association between response and time-since-quitting (Current smokers ORR 27%; Quit 1-15 yrs ago 24%; Quit >15 yrs ago 24%, p=0.18). There was no significant difference in response rate in adeno vs squamous histology (16 vs 21%, p=0.58). In adenos, response rates in EGFR muts vs KRAS muts vs all others were 1/9 vs 3/13 vs 4/27; the one EGFR mut responder was a 40 pk-yr current smoker. Conclusions: In advanced NSCLCs, the response rate to Nivo was significantly higher in former/current smokers compared to never/minimal smokers. There were no objective responses in never or minimal smokers in this subset of pts. Smoking history should be considered as a stratification factor for trials of PD-1 pathway inhibitors in lung cancer. Further work is needed to identify the underlying basis of this differential response rate. Disclosure: S.J. Antonia: Dr. Antonia receives research funding and/or serves as an advisor for Bristol-Myers Squibb. L. Horn: Dr. Horn receives research funding and/or serves as an advisor for Bristol-Myers Squibb; J.R. Brahmer: Dr. Brahmer receives research funding and serves as an advisor for Bristol-Myers Squibb; S. Gettinger: Dr. Gettinger receives research funding and serves as an advisor for Bristol-Myers Squibb; C. Harbison: Dr. Harbison is an employee and stock holder of Bristol-Myers Squibb; N. Rizvi: Dr. Rizvi receives research funding and serves as an advisor for Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Aim: This ongoing Phase I, multicenter, open-label study (NCT01693562) evaluates the safety and efficacy of MEDI4736 in patients (pts) with multiple solid tumor types including non-small cell lung cancer (NSCLC). MEDI4736 is a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. PD-L1 is expressed in many NSCLC tumors and may be associated with poor prognosis. Methods: MEDI4736 was administered IV every 2 weeks (q2w) or every 3 weeks (q3w) using a standard 3 + 3 dose escalation (6 dose levels: 0.1–10 mg/kg q2w; 15 mg/kg q3w). In dose expansion, NSCLC pts were assigned to cohorts by histology and line of therapy and administered MEDI4736 10 mg/kg q2w. Retreatment was permitted for progression after 12 months of therapy. Response is assessed by immune-related response criteria in escalation and RECIST v1.1 in expansion. Results: As of 14 April 2014, 114 NSCLC pts have been treated with MEDI4736 in dose escalation and expansion cohorts. Of the 101 pts treated at the 10 mg/kg q2w dose (median 3 doses received; range 1–14), mean age 63 y (37–83), all were PS 0–1, with a median of 2.5 prior treatments (range1–8). In this group, treatment-related adverse events (AEs) were reported in 20% of pts; most frequently dyspnea (16%), fatigue (15%) and nausea (15%). Grade ≥ 3 treatment-related AEs were reported in 4 pts. AEs led to study discontinuation in 6 pts, none of which were treatment-related. Pneumonitis (grade 2) occurred in 1 pt. With a median follow up of 10 wks, 46 pts were followed ≥ 12 wks. Objective response + stable disease was observed in 18 pts to date. While some responses or stabilization were reported at first assessment (6 wks), others appeared following initial progression. Benefit was durable; 72/114 pts remain on study (including 4 pts >52 wks) at data cutoff. Assessment of clinical activity by PD-L1 expression, underlying mutation, smoking history, and line of therapy continues. Conclusions: Durable clinical activity has been observed with manageable AEs, no grade ≥3 pneumonitis, and no colitis of any grade. Further development of MEDI4736 alone and in combination is ongoing in NSCLC. Disclosure: S. Antonia: Received honoraria from BMS and MedImmune/AstraZeneca for work related to designing, implementing, and analyzing various clinical trials. MedImmune considers research funding received for conduct of a MedImmune-sponsored study as conflict of interest; Ou: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Khleif: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I also function as a clinical advisor; J.R. Brahmer: My institution receives funding for the conduct of a MedImmune-sponsored study. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins: Employee of Medimmune and own stock/stock options in AstraZeneca; P.B. Robbins: Employee of Medimmune and own stock/stock options in AstraZeneca; X. Li: Employee of Medimmune and own stock/stock options in AstraZeneca; J. Vasselli: Employee of Medimmune and own stock/stock options in AstraZeneca; N. Rizvi: I receive consulting income from MedImmune, Roche, Merck and BMS MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

10538 Background: Indoleamine 2,3-dioxygenase (IDO) has recently been proposed as an inducible promoter of tumor-related immunosuppression through the metabolism of tryptophan into kynurenine. Our ...