In the open-label, single-arm, phase II KEYNOTE-427 study (NCT02853344), first-line pembro monotherapy showed antitumor activity in pts with advanced ccRCC (cohort A). Updated efficacy and safety results after a minimum of 40.9 mo of follow-up for pts with ccRCC are presented.

PD-L1 testing of CPIs guides treatment decisions for mUC pts. However, there are different assays and methods. The tumor proportion score (TPS) method evaluates PD-L1 tumor cells, whereas combined positive score (CPS) captures tumor and immune cells. Two assays, PD-L1 immunohistochemistry (IHC) 22C3 (CPS) and 28-8 pharmDx (TPS) are approved for pembrolizumab and NIVO, respectively. In PIVOT-10, a phase 2 study of bempegaldesleukin + NIVO in cis-ineligible mUC, both assays are being tested contemporaneously to explore concordance. Pts without prior systemic therapy or recurrence >12 mo from perioperative chemotherapy were eligible. Archival baseline tumor (≤12 mo prior to enrollment) or fresh samples (N=259) were tested using both assays and scored using CPS (no. of PD-L1-stained cells [tumor cells, lymphocytes, macrophages]/ total no. of viable tumor cells x 100). Samples were analyzed using a CPS cut-off < vs ≥10 and concordance was analyzed statistically. There was agreement between the assays (absolute mean difference= 0.96 [Lin’s Concordance Correlation Coefficient]). Similar % of PD-L1-low tumors were seen (28-8: 68%; 22C3: 67%) and binary results showed good quality of agreement (Cohen’s k value: 0.89). The overall % agreement (OPA), +ve % agreement (PPA), and –ve % agreement (NPA) (22C3 or 28-8 assay as ref) were 95%, 93%, and 97%, respectively (Table).Table: 83PAgreement between the 28-8 and 22C3 assays in matched samples* in the overall population (CPS 10 cut-off)Ref: 22C3 assayRef: 28-8 assayOPAPPANPAPPANPAAgreement, % (95% CI)93 (85–97)97 (93–99)93 (85–97)97 (93–99)95 (92–98)n/N75/81172/17875/81172/178247/259*Pts with matched biopsy and single test results for 28-8 and 22C3 assays.CI, confidence interval; CPS, combined positive score; NPA, negative (–ve) % agreement; OPA, overall % agreement; PPA, positive (+ve) % agreement. Open table in a new tab *Pts with matched biopsy and single test results for 28-8 and 22C3 assays. CI, confidence interval; CPS, combined positive score; NPA, negative (–ve) % agreement; OPA, overall % agreement; PPA, positive (+ve) % agreement. When evaluated in the controlled setting of a clinical trial, the PD-L1 IHC 22C3 and 28-8 pharmDx assays detected similar rates of PD-L1-low tumors in baseline biopsies from mUC pts and demonstrated high concordance at CPS cut-off < vs ≥10. This study is unique in that it was conducted contemporaneously on fresh or recently obtained archival tumors. These data suggest high concordance and potential interchangeability of the 28-8 and 22C3 assays for evaluating baseline PD-L1 status, based on CPS, for mUC pts.

Background INDUCE-1 is a first in human study investigating GSK609 alone (mono) and in combination (combo) with other regimens including pembro. The study consists of dose escalation (DE) and expansion phases. Findings from DE and the PK/PD mono cohort demonstrated that a range of GSK609 doses (≥0.1-1 mg/kg) have biological and clinical activity supporting the mechanism of action of a non-T cell depleting IgG4 ICOS agonist antibody as a clinical target. Methods Eligible patients (pts) for the HNSCC EC had recurrent or metastatic disease, ≤5 prior lines of therapy, measurable disease, and no active autoimmune disease. Pts received 1 mg/kg GSK609 in the mono EC and 0.3 mg/kg GSK609 + 200 mg pembro in the combo EC until disease progression or unacceptable toxicity, up to 2 years (yrs). Disease assessments were performed every 9 weeks (wks) through wk 54 then every 12 wks. Overall response rate (ORR) was assessed for futility in ≥ 10 pts/EC, analyzed by prior PD-1/L1 treatment status (naive vs. experienced). PD-L1 expression was determined by the 22C3 pharmDx assay. Results As of 16 April 2019, 12 of 17 PD-1/L1 experienced pts in the mono and 29 of 34 PD-1/L1 naive pts in the combo HNSCC ECs had at least 1 disease assessment (evaluable population). In the mono EC, median age was 56 yrs (range: 27-73); 88% were male; 82% received ≥1 prior lines in the metastatic setting. In the combo EC, median age was 61 yrs (range: 33-77); 85% were male; 68% received ≥1 prior lines in the metastatic setting. ORR was 8% (95% CI: 0.2%, 38.5%) and 28% (95% CI: 12.7%, 47.2%) in mono (1 of 8 pts) and combo (8 of 29 pts) ECs, respectively. Median PFS in the combo EC was 5.6 months (95% CI: 2.4, NR). Treatment-related adverse events occurring in the overall mono (n = 208) and combo populations (n = 178) were consistent with that previously reported (Hansen, et al. ESMO, 2018). PD-L1 IHC testing is ongoing. Conclusions Preliminary data demonstrate GSK609 has single agent activity in PD-1/L1 experienced HNSCC. The combo of GSK609 with pembro shows promising antitumor activity and a manageable safety profile in pts with previously treated, PD-1/L1 naive HNSCC. Clinical trial identification NCT02723955; March 31, 2016. Legal entity responsible for the study GlaxoSmithKline. Funding GlaxoSmithKline. Disclosure D. Rischin: Advisory / Consultancy, Uncompensated: MSD; Research grant / Funding (institution): MSD; Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Uncompensated: GSK; Research grant / Funding (institution): GSK; Advisory / Consultancy, Uncompensated: BMS; Research grant / Funding (institution): BMS; Advisory / Consultancy, Uncompensated: Regeneron; Research grant / Funding (institution): Roche. A.M.L. Lim: Travel / Accommodation / Expenses: BMS; Research grant / Funding (self): Department of Health (WA) / Raine Medical Research Foundation Clinician Research Fellowship. J. Martin-Liberal: Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Pierre Fabre; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Ipsen. V. Moreno: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: Regeneron/Sanofi; Travel / Accommodation / Expenses: BMS; Speaker Bureau / Expert testimony, Presentation: BMS; Speaker Bureau / Expert testimony, Presentation: Nanobiotix; Research grant / Funding (self), Educational Grant: Medscape/Bayer. J.M. Trigo Perez: Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Boehringer; Travel / Accommodation / Expenses: Boehringer. C. Le Tourneau: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: GSK; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Nanobiotix. D.C. Cho: Advisory / Consultancy: PureTech; Advisory / Consultancy: Torque; Advisory / Consultancy: Nektar Therapeutics; Advisory / Consultancy: HUYA Pharmaceuticals. A.R. Hansen: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: GSK; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy: Medimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer-Ingelheim. M. Maio: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies, Press Conference: BMS; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies, Press Conference: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eli Lilly; Honoraria (institution): AstraZeneca; Honoraria (institution): Patients’ fee to the University Hospital of Siena. A. Italiano: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Epizyme; Advisory / Consultancy: ImmuneDesign; Advisory / Consultancy: Eli Lily; Advisory / Consultancy: Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): PharmaMar. J.R. Bauman: Advisory / Consultancy: Pfizer. M. Chisamore: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co. Inc. H. Zhou: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. C. Ellis: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. M. Ballas: Full / Part-time employment: GlaxoSmithKline; Shareholder / Stockholder / Stock options: GlaxoSmithKline. A. Hoos: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. E. Angevin: Advisory / Consultancy: GSK; Advisory / Consultancy: MSD; Advisory / Consultancy: Medimmune; Advisory / Consultancy: Celgene; Travel / Accommodation / Expenses: AbbVie; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: MedImmune; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Innate Pharma. All other authors have declared no conflicts of interest.

Background Current treatment options for PDAC are limited. While PD-1/PD-L1 antagonists have shown promising results in other cancer types, this approach has been ineffective in PDAC. In Cohort 1 of the COMBAT study, the dual combination of BL-8040 (a CXCR4 inhibitor) and Pembrolizumab was safe and showed a promising 7.5 mo OS in 2L patients. BL-8040 modified the TME by promoting infiltration of effector T cells and decreasing immune suppressor cells. Based on these encouraging results, as well as preclinical data supporting the combination of BL-8040, Pembrolizumab and chemotherapy, the study was expanded to include a combination arm (Cohort 2) composed of BL-8040, Pembrolizumab and chemotherapy (Onivyde/5-FU/LV). Here we report the preliminary safety and efficacy of BL-8040 in this expansion cohort. Methods Phase IIa study, Cohort 2, treatment regimen consists of 5 days BL-8040 priming monotherapy followed by combination treatment of Onivyde/5-FU/LV every 2 weeks, Pembrolizumab every 3 weeks and BL-8040 twice a week. Eligibility criteria includes metastatic PDAC subjects with measurable disease by RECIST1.1 that have progressed following first-line treatment with gemcitabine-based chemotherapy. Results This is a snapshot of Cohort 2 of the COMBAT study. As of September 2019, 22 patients have been enrolled, of which 15 are evaluable (i.e. received at least 1 dose of combination and have post-baseline CT). Median age 68, ECOG≤1 and 60% males. 15 SAEs were reported by 10 patients. 2 subjects were discontinued due to SAEs. Best Response by RECISTv1.1 for the evaluable population showed 4 partial response (PR) and 8 stable disease (SD) patients, a total of 12 subjects with disease control (DC) out of 15. Median PFS and OS were not reached. Notably all patients with PR and SD had an initial increase in CA 19-9 followed by a decrease. Tumor shrinkage began during the transient increase of CA 19-9. Conclusion Preliminary data from the ongoing COMBAT study Cohort 2 with the triple combination of BL-8040, Pembrolizumab and chemo, show promising ORR (4/15) and DC (12/15) results. Median PFS and OS have not yet been reached. Clinical trial identification NCT02826486. Legal entity responsible for the study The authors. Funding Biolinerx. Disclosure M. Hidalgo: Full / Part-time employment: Beth Israel Deaconess Medical Center; Full / Part-time employment: Harvard Medical School; Full / Part-time employment: Weill Cornell Medical College. V. Semenisty: Full / Part-time employment: Rambam Health Care Campus. B. Bockorny: Full / Part-time employment: Beth Israel Deaconess Medical Center; Research grant / Funding (institution): NanoView Biosciences. E. Borazanci: Full / Part-time employment: Honor-Health/TGen. D.D. von Hoff: Full / Part-time employment: Honor-Health/TGen. J. Feliu: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Seriver. M. Ponz Sarvise: Full / Part-time employment: Clinica Universidad de Navarra. D. Gutierrez Abad: Full / Part-time employment: Grupo Oncologia Fuenlabrada. A. Peled: Full / Part-time employment: Goldyne Savad Institute of Gene Therapy; Leadership role: Biokine Therapeutics Ltd. O. Bohana-Kashtan: Full / Part-time employment: Biolinerx. Y. Gozlan: Full / Part-time employment: Biolinerx. E. Sorani: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Biolinerx. M. Chaney: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. S. Kadosh: Full / Part-time employment: StatExcellence. A.V. Vainstein: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Biolinerx. T. Macarulla: Full / Part-time employment: Vall d´Hebron University Hospital.

Abstract Background: Probody™ therapeutics are novel, fully recombinant antibody prodrugs designed to remain relatively inactive in healthy tissue and to be specifically activated by proteases in the tumor microenvironment. In this way, Probody therapeutics may broaden the therapeutic window for effective but potentially toxic anticancer agents. CX-072 is a Probody therapeutic directed against programmed death-ligand 1 (PD-L1) for the treatment of cancer patients. In a first-in-human, open-label, multicenter, dose-escalation, 3+3 design, phase 1-2 study, PROCLAIM-CX-072 (PRObody CLinical Assessment In Man) (NCT03013491), 22 patients were enrolled in the phase 1 dose escalation portion. Twenty patients were evaluable per RECIST v1.1. Three patients had confirmed partial response (15%), including a 39-year-old woman with stage IV triple negative breast cancer (TNBC) treated with 10 mg/kg CX-072 monotherapy whose disease had progressed on one previous line of chemotherapy for metastatic disease. Metastatic sites included extensive nodal disease and skin/chest wall lesions. The tumor was negative for PD-L1 expression, was microsatellite stable, and had a low tumor mutational burden (4 mutations/megabase). Positive results from the phase 1 study suggest that additional exploration of treatment with CX-072 monotherapy in the TNBC patient population is warranted. Dose expansion trial design: The phase 2 dose expansion part of the PROCLAIM-CX-072 study will include enrollment of TNBC patients with skin metastases. Key inclusion criteria for patients in the TNBC cohort are as follows: naive to immunotherapy (PD-1/PD-L1 and CTLA-4 inhibitors), approved immune checkpoint inhibitor agents not available, histologically confirmed triple negative (estrogen receptor–, progesterone receptor–, and human epidermal growth factor receptor-2–negative cancer per ASCO-CAP guidelines), previously treated with 1 to 3 systemic chemotherapy regimens, and locally advanced and recurrent skin or subcutaneous metastases not suitable for surgical resection or radiotherapy. Patients will receive doses of 10 mg/kg CX-072 intravenously every 2 weeks. Efficacy will be evaluated using RECIST v1.1 and immune-related RECIST criteria. Safety and tolerability will be assessed based on the incidence and severity of adverse events (categorized by NCI CTCAE criteria, v4.03) and relationship to study drug. Other analyses will include pharmacokinetics, incidence of anti-drug antibodies against CX-072, exploratory analysis for immune response, and CX-072 activation in the tumor. PROBODY is a trademark of CytomX Therapeutics, Inc. Citation Format: Adams S, Hamilton E, Ott PA, Cho D, Kalinsky K, LoRusso P, Will M, Huels V, Benson B, Murias C, Arkenau H-T. PROCLAIM-CX-072: Monotherapy for advanced triple negative breast cancer with skin metastases in a phase 1-2 trial of the PD-L1 probody therapeutic CX-072 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-31.

Background: ICOS, a member of CD28/B7 superfamily, is expressed on T cells (TC) after TC receptor engagement with cognate antigen. ICOS provides a costimulatory signal augmenting TC expansion, function and survival. GSK609 is a humanized, IgG4 antibody engineered to reduce Fc-mediated depleting effects yet retain cross-linking for potent agonist activity against human ICOS. GSK609's unique profile as a pure TC agonist void of TC depleting effects offers antitumor potential as monotherapy and in rational combinations with agents that modulate key immune pathways. Methods: INDUCE-1 evaluates safety, PK, PD, and antitumor activity of GSK609 given as an intravenous (IV) infusion every 3 weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab [P] Q3W (Part 2). Modified toxicity probability interval informed dose escalation [DE] decisions (≥ 3 pts/dose level [DL]). Eligible pts must have relapsed disease, adequate organ function, no active autoimmune disease requiring treatment; prior immunotherapy was allowed. Pts remained on treatment until progression or unacceptable toxicity. Blood was collected for safety, PK, PD; tumor biopsies collected for PD. Results: To date, 79 pts enrolled, Part 1: 22 in DE and 30 in PK/PD cohort; Part 2: 27 in DE. In Part 1, 45 pts (87%) had adverse events (AEs); most frequent (≥20%) regardless of cause were fatigue (29%) and pain (19%). Fatigue was the most frequent treatment-related (TR) event (15%); liver enzyme increases in 1 pt were the only TR AEs leading to discontinuation. In Part 2, 25 pts (93%) had AEs; most frequent were nausea (33%), fatigue (26%), arthralgia (22%), decreased appetite (22%) and vomiting (22%). Pyrexia was the most frequent TR AE (7%); no TR AE led to discontinuation. No DLTs were reported in DE with Part 2 ongoing at planned, top DL. In Part 1, GSK609 showed approximate dose proportional increases in systemic exposures over the 0.01 – 3 mg/kg DLs. Clinical activity was seen in Part 1 and Part 2. Conclusions: GSK609 +/- P was well tolerated; MTD was not reached. AEs were manageable and most were unrelated to study treatment. Complete safety, PD and clinical activity data from DE and PK/PD will be presented. Clinical trial identification: NCT02723955, first posted date: March 31, 2016. Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline. Disclosure: A. Hansen: Research support: Genentech/Roche, Merck, GlaxoSmithKline, Bristol Myers Squibb, Novartis, Boston Biomedical, Boehringer-Ingelheim. T.M. Bauer: Consulting/advisory: Ignyta, Guardant Health, Loxo, Pfizer, Moderna Therapeutics; Research funding: Daiichi Sankyo, Medpacto, Inc, Incyte, Mirati Therapeutics, Medimmune, Abbvie, AstraZeneca, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Pfizer, Principa Biopharma, Genentech/Roche, Deciphera, Merrimack, Immunogen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Peleton, Immunocore, Roche, Aileron Therapeutics, Amgen, Moderna Therapeutics, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio. M. Maio: Patient's fee for subjects enrolled in clinical trials: BMS, GSK, AZ, Roche, MSD, Incyte, Novartis; Advisor/Board member: BMS, GSK, AZ, Roche, MSD, Incyte; Honorarium, compensation for Advisory Boards: BMS, GSK, AZ, Roche, MSD, Incyte; Travel expenses related to participation to Ad Boards/Scientific meetings: BMS, GSK, AZ, Roche, MSD, Incyte. H. Gan: Consulting/advisory: Abbvie, Merck Serono; Speakers' bureau: Abbvie, Bristol Myers Squibb, Ignyta; Research funding: Abbvie; Travel/accommodation expenses: Abbvie, Ignyta, MSD. D. Rischin: Research funding: Genentech/Roche, Merck, Amgen, Regeneron, Bristol-Myers Squibb, GSK. M. Millward: Consulting/advisory: Bristol-Meyers Squibb, Roche, Merck, Sharp & Dohme, Novartis, AstraZeneca. A.J. Olszanski: Consulting/advisory: Array, Bristol-Meyers Squibb, Merck, Takeda; Research funding: Amgen, Bristol-Meyers Squibb, EMD Serono, Immunocore, Incyte, Kura, Kyowa Hakko Kirin, Lilly, Pfizer, GSK, Takeda, Checkmate, Boston Biomedical, Astellas, Targovax. D.C. Cho: Honoraria: Bristol-Myers Squibb, Exelixis, Genentech; Consulting/advisory: Pfizer, Prometheus E. Paul, S. Yadavilli, J. Sadik Shaik, C. Ellis, H. Zhou: Employee and shareholder: GSK. M. Ballas: Employee and shareholder: GSK; Stockholder: BMS. E.V. Schmidt: Employment and stock holder: Merck. A. Hoos: Employee and shareholder: GSK; Non-Executive Director and stockholder: Imugene. E. Angevin: Consulting/advisory: GSK, MSD; Research funding: Abbvie, Roche, Sanofi. All other authors have declared no conflicts of interest.

Background: Life expectancy estimation is critical to select patients in clinical trials, notably in the phase I setting. However, most protocols use subjective criteria to meet this goal. Several scores have been developed from retrospective studies, but their utility in the immuno-oncology (IO) context remains unknown. The recent recognition of fast progressors under IO treatment further underscores the need for more objective prediction. Methods: NSCLC and UBC patients (n = 972) prospectively enrolled in 3 phase I trials investigating durvalumab (anti-PDL1) ± tremelimumab (anti-CTLA4) across 160 centers were analyzed. We assessed the variability in the 8- and 12-week life expectancy rate across centers. Clinicopathological variables were used to train (n = 648) and validate (n = 324) a tool (FastProgIO) predicting 12-week life expectancy using a multivariate regression method. We compared FastProgIO to existing published scores (RMH, GRIM, LIPI). The performance was assessed by time dependent true positive rate (TPR) and false positive rate (FPR). Results: Substantial variability was observed across sites with 26% and 65% of centers having enrolled > 15% of patients with life expectancy < = 8 and 12 weeks, respectively. FastProgIO includes neutrophils, AST, alkaline phosphatase and hemoglobin as the predictive markers. Overall, the TPR of FastProgIO was superior across a 4 to 12 weeks range to RMH, GRIM and LIPI. At 12 weeks, the TPR for FastProgIO was 73%, (90% CI: 67-80%) versus 69%, 65% and 41% for RMH, GRIM and LIPI, respectively. Furthermore, the FPR of FastProgIO (11%, 90%CI: 9.3-13%) was comparable to LIPI (10%), but better controlled than RMH and GRIM (20%, 17%). Conclusions: The use of subjective criteria to estimate the 12-week life expectancy of patients enrolled in IO trials is clearly suboptimal and can lead to ethical, scientific, medical, and public health conundrums. In this large cohort of patients, FastProgIO appears superior to RMH, GRIM and LIPI to define life expectancy of patients based on easily available baseline clinical characteristics, and can be used to better select patients for IO clinical trials. An extended validation of this model in other tumor types is ongoing and will be presented. Clinical trial identification: Study 006: NCT02000947 December 4, 2013 Study 1108: NCT01693562 September 26, 2012 Study 10: NCT02261220 October 10, 2014. Legal entity responsible for the study: MedImmune. Funding: MedImmune. Disclosure: C. Massard: Advisory board member: Amgen, Astellas, AstraZeneca, Bayer, Celgene, Genentech, Ipsen, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, and Orion. N.H. Segal: Honoraria: MedImmune; Consulting or advisory role: Bristol-Myers Squibb, Pfizer, AstraZeneca, MedImmune, MacroGenics, Imugene, Roche, Genentech, Kyocera, Amgen, Calithera Biosciences; Research funding: MedImmune, Bristol-Myers Squibb, Pfizer, Roche, Genentech, Merck. D.C. Cho: Consultant or advisory board member: Pfizer, BMS, Genentech. Exelixis, Prometheus. V.A. Papadimitrakopoulou: Grant research support and consultancy or advisory board member role: AstraZeneca. N.A. Rizvi: Honoraria or consultants fees: Roche, AstraZeneca, Novartis, Merck, Pfizer, Lilly, and BMS; Equity ownership: Gritstone Oncology and Armo Biosciences. B.C. Cho: Research grant support: Novartis, AstraZeneca, Yuhan, Ono/BMS, MSD, and Bayer; Consultancy or advisory board member: AstraZeneca, Roche, Boehringer Ingelheim, Yuhan, BMS, MSD, and Novartis; Speaker's bureau: AstraZeneca, BMS, MSD, and Novartis; Honorarium: AstraZeneca, Roche, Boehringer Ingelheim, Yuhan, BMS, MSD, and Novartis. L. Yu H. Yang: Employment: MedImmune; Equity ownership: AstraZeneca. H-J. Hsieh: Employment: Genentech, AstraZeneca, and MedImmune; Equity ownership: Genentech. J. Zhang, W. Zhao, G. Gao, X. Guo, S. Abdullah, J. Englert, M. Dar, L. Roskos: Employment: MedImmune and AstraZeneca; Equity ownership: AstraZeneca. J-C. Soria: Employment: MedImmune and AstraZeneca; Equity ownership: AstraZeneca. C. Ferte: Employment: MedImmune and Astrazeneca; Honoraria: Roche, MSD, Merck, and BMS; Consultancy or advisory role: Roche, MSD, Merck, Amgen, and BMS; Travel expenses: BMS, MSD, Merck, Amgen. S.J. Antonia: Research grant support: Novartis; Consultancy or advisory role: BMS, Novartis, Merck; Honoraria: BMS, Novartis, Merck, CBMG, Boehringer Ingelheim, AstraZeneca, MedImmune, Memgen.

Background: For pts who progress after first–line platinum based therapy for recurrent/metastatic cervical cancer, there are no therapies available that have been demonstrated to improve survival or quality of life. Cemiplimab (REGN2810), a human monoclonal antibody to PD-1, exhibited encouraging efficacy and acceptable tolerability in a phase 1 dose escalation study. The present report focuses on interim data from the phase 1 cervical cancer expansion cohorts (ECs) of cemiplimab as a monotherapy (EC 23) or in combination with hypofractionated radiotherapy (hfRT) (EC 24) (NCT02383212). Methods: Pts with recurrent or metastatic cervical cancer resistant to or intolerant of platinum and taxane doublet therapy received cemiplimab 3 mg/kg Q2W for up to 48 weeks, in ECs 23 and 24, and hfRT (9 Gy x 3 times/week given 1 week after first dose of cemiplimab) in EC 24. The co-primary objectives were to evaluate the safety, tolerability, and efficacy of cemiplimab monotherapy or in combination with hfRT. Tumour response assessments (in non-irradiated target lesions) were performed by RECIST 1.1 Q8W. Results: As of 1 Sept, 2017, these ECs were fully enrolled with 20 pts (EC 23, n = 10, EC 24, n = 10). Median (range) age was 55.0 (31–76) years (EC 23) and 51.5 (29–65) years (EC 24). ECOG performance status 1 vs. 0 was 60% vs. 40% and 80% vs. 20%, respectively, for EC 23 and EC 24. Investigator-assessed overall response rate (ORR; complete response [CR] + partial response [PR]) was 10.0% (0 CR and 1 PR) in each of EC 23 and EC 24. At the time of data cut-off, both responses were ongoing with durations of 3.7+ months. The most common treatment-emergent adverse events (TEAEs) of any grade were diarrhoea (40.0%), fatigue, hypokalaemia and pain in extremity (each 30.0%) in EC 23, and diarrhoea and urinary tract infection (each 30.0%) in EC 24. There was no grade ≥3 TEAE reported in > 1 patient in either cohort. Conclusions: Cemiplimab as monotherapy and in combination with hfRT demonstrated antitumour activity with an acceptable safety profile in pts with metastatic or recurrent cervical cancer. Cemiplimab monotherapy vs. chemotherapy in ≥ 2nd line cervical cancer is currently being evaluated in a global randomised phase 3 study (NCT03257267). Clinical trial identification: NCT02383212. Editorial acknowledgement: Medical writing support under the direction of the authors was provided by Emmanuel Ogunnowo, PhD, of Prime (Knutsford, UK) and funded by Regeneron Pharmaceuticals, Inc. and Sanofi. Legal entity responsible for the study: Regeneron Pharmaceutical, Inc. and Sanofi. Funding: Regeneron Pharmaceutical, Inc. and Sanofi. Disclosure: D. Rischin: Research funding: Genentech/Roche, Merck, Amgen, Regeneron, Bristol-Myers Squibb. A. González-Martín: Consulting, Advisory, Speakers' bureau and Travel accommodation expenses: AstraZeneca, Tesaro, Roche, Pharmamar. J.Y. Hou: Consultant and receives fees: Foundation Medicine, Massive Bio, Inc. D. Cho: Consulting fees: Pfizer, BMS, Exelixis, Genentech, Prometheus. G.S. Falchook: Funding: Regeneron Pharmaceuticals for trial for submitted work. S. Jabbour: Research funding grants: Merck, Nestle outside of the submitted work. K. Moore: Institutional consultancy (honorarium and ad board) fees: Tesaro, Genentech Roche, Clovis, AstraZeneca (for agents not involved in the SOLO-1 study), Immunogen, VBL Therapeutics, Janssen. M.G. Fury: Employee of and shareholder: Regeneron Pharmaceuticals, Inc.; Patents, royalties, other intellectual property: Regeneron Pharmaceuticals, Inc. M. Feng: Employee and shareholder: Regeneron Pharmaceuticals, Inc., Bayer. J. Li: Employee and shareholder: Regeneron Pharmaceuticals, Inc., Novartis. I. Lowy: Employee of, shareholder of, and fees for travel and accommodation expenses as well as leadership: Regeneron Pharmaceuticals, Inc. M. Mathias: Employee and shareholder: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background: Abundance and functional quality of tumor infiltrating lymphocytes are positively linked with tumor response and improved survival with checkpoint inhibitors. NKTR-214 is a CD122-biased agonist that targets the IL2 pathway and is designed to provide sustained signaling through the heterodimeric IL2 receptor pathway (IL2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells within the tumor microenvironment. NKTR-214 has been administered to 28 patients with advanced cancers. NKTR-214 as a single agent demonstrated a substantial increase in both CD8+ T and NK cells within the tumor microenvironment in patients with prior immune checkpoint therapy (Bernatchez et al 2016). Given the favorable safety profile and strong biomarker data, a trial combining NKTR-214 and nivolumab was initiated. Trial design: PIVOT-02 is a phase 1/2 open-label trial in patients (pts) with locally advanced or metastatic melanoma (mM), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple-negative breast cancer (TNBC). The primary objectives are to evaluate safety and tolerability, determine the recommended phase 2 dose (RP2D), and assess tumor response by RECIST 1.1. In an outpatient setting, NKTR-214 is administered at dose levels of 0.003, 0.006 and 0.009 mg/kg in combination with nivolumab at two flat dose schedules of either 240 mg @ q2w or 360 mg @ q3w. As of May 8, 17 pts (7 mM, 8 RCC, and 2 NSCLC) have been enrolled into 4 cohorts in the dose-escalation phase. In the dose-expansion phase, approximately 250 pts will be enrolled in five tumor types and eight indications; immunotherapy naïve patients and patients who are relapsed/refractory to checkpoint therapy are being studied separately. Extensive blood and tumor tissue samples are being collected to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T cell clonality and gene expression analyses. Enrollment is ongoing. Clinical trial identification: NCT02983045 Legal entity responsible for the study: Nektar Therapeutics Funding: Nektar Therapeutics Disclosure: A. Diab: Consulting or Advisory Role - Celgene; CureVac; Nektar Research Funding - Celgene (Inst); Idera (Inst); Nektar (Inst); Pfizer (Inst) Travel, Accommodations, Expenses – Nektar. M.E. Hurwitz: Employment - Pfizer Consulting or Advisory Role – Nektar. N. Tannir: Honoraria - Bristol-Myers Squibb; Exelixis; GSK; Nektar; Novartis; Pfizer Advisory Role - Bristol-Myers Squibb; Exelixis; GSK; Nektar; Novartis Research Funding - Bristol-Myers Squibb; Epizyme; Exelixis; Novartis Travel - Bristol-Myers Squibb; Exelixis; GSK; Nektar; Novartis; Pfizer. C. Bernatchez: Employment - Lexicon (I) Stock - Lexicon (I) Advisory Role - Lion Biotechnologies Research Funding - Idera; Nektar Patents - Patent pending on BTLA as a marker for better CD8 T cells for adoptive immunotherapy. C. Haymaker: Cara L. Haymaker Research Funding - Idera; Nektar. B.D. Curti: Honoraria - Prometheus Speakers' Bureau - Prometheus Research Funding - Bristol-Myers Squibb; Galectin Therapeutics; MedImmune; Prometheus; Viralytics Travel, Accommodations, Expenses - Agonox; MedImmune; Nektar; Prometheus. I. Gergel: Employment - Nektar Leadership - Corium International; Nektar Stock and Other Ownership Interests - Corium International; Nektar. M. Tagliaferri: Employment - Nektar Travel, Accommodations, Expenses - Nektar J. Zalevsky: Employment - Nektar. U. Hoch, S. Aung, M. Imperiale: Employment - Nektar Stock and Other Ownership Interests - Nektar D. Cho: Honoraria - Bristol-Myers Squibb; Exelixis; Roche/Genentech Consulting or Advisory Role - Pfizer; Prometheus. S.S. Tykodi: Consulting or Advisory Role - Amgen; Prometheus Research Funding - Argos Therapeutics (Inst); Bristol-Myers Squibb (Inst); Exelixis (Inst); Genentech (Inst); GlaxoSmithKline (Inst); Prometheus (Inst). I. Puzanov: Consulting or Advisory Role - Amgen; Bristol-Myers Squib; Roche/Genentech. H. Kluger: Honoraria - Merck Consulting or Advisory Role - Alexion Pharmaceuticals; Prometheus; Regeneron Research Funding - Merck (Inst) Travel, Accommodations, Expenses - Bristol-Myers Squib P. Hwu: Stock and Other Ownership Interests - immatics; Lion Biotechnologies Consulting or Advisory Role - Lion Biotechnologies Research Funding - Bristol-Myers Squibb (Inst); Genentech (Inst). M. Sznol: Stock -Adaptive Bio; Amphivena; Intensity Thera Advisor -Adaptimmune; Alexion; Amgen; AstraZeneca; Biodesix; Bristol-Myers Squibb; Genentech; Immune Design; Janssen; Kyowa; Lilly; Lion Bios; Lycera; MSD; Merus; Modulate; Nektar; Novartis; Pfizer; Symphogen; Theravance. All other authors have declared no conflicts of interest.

Abundance and functional quality of tumor infiltrating lymphocytes are positively linked with tumor response and improved survival with checkpoint inhibitors. NKTR-214 is a CD122-biased agonist that targets the IL2 pathway and is designed to provide sustained signaling through the heterodimeric IL2 receptor pathway (IL2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells within the tumor microenvironment. NKTR-214 is administered on an outpatient basis as a 15-minute IV infusion and has been administered to 28 patients with advanced solid tumors. Single-agent NKTR-214 demonstrates a substantial increase in both CD8+ T and NK cells within the tumor microenvironment in those patients with prior immune checkpoint therapy (Bernatchez et al, SITC poster 2016). Given the favorable safety profile and strong biomarker data, a trial combining NKTR-214 and nivolumab was initiated. PIVOT-02 is a phase 1/2 open-label trial in patients with locally advanced or metastatic melanoma (MM), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple-negative breast cancer (TNBC). Approximately 250 patients will be enrolled across 5 tumor types and 8 indications, with 26-38 patients per indication. Patients who are immunotherapy naïve will be studied for all 5 tumor types. MM, RCC, or NSCLC patients who are relapse/refractory on one prior anti-PD-1/PD-L1 containing regimen will be studied separately. The primary objectives are to evaluate safety and tolerability, determine the recommended phase 2 dose (RP2D), and assess tumor response by RECIST 1.1. The dose-escalation portion of the trial has enrolled 23 patients (MM= 8, RCC= 11, NSCLC=4), in 5 different cohorts including NKTR-214 at 0.003 (q2w), 0.006 (q2w or q3w), or 0.009 (q3w) mg/kg in combination with a flat dose of nivolumab at 240 (q2w) or 360 (q3w) mg. Extensive blood and tumor tissue samples are being collected in both escalation and expansion phase to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T-cell clonality and gene expression analyzes. Based on safety/tolerability, PK/PD and early biomarker data, the recommended phase 2 dose of NKTR-214 is 0.006 mg/kg q3w with nivolumab 360 mg q3w. The expansion phase of the study is now open for accrual. Not applicable. Not applicable.

Background: KPT-9274 is an oral, small molecule modulator of PAK4 (p21 activated kinase) and NAMPT (nicotinamide phosphoribosyltransferase). PAK4 is a major player in cell morphology and WNT/β-catenin signaling. NAMPT is the rate-limiting enzyme in NAD biosynthesis. Co-inhibition of these targets leads to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, and ultimately apoptosis. Cells can utilize niacin to make NAD through an alternative pathway using NAPRT1.

Axitinib, an inhibitor of vascular endothelial growth factor receptors, is approved for 2nd-line treatment of aRCC. Pembrolizumab is a humanized monoclonal antibody that blocks binding of the immune-checkpoint receptor programmed death-1 (PD-1) to its ligands (PD-L1/2). Here we report preliminary safety and efficacy results from an ongoing phase Ib study of axitinib plus pembrolizumab in treatment-naïve pts with aRCC. Pts included have clear-cell aRCC with primary tumor resected, ≥1 measureable lesion, ECOG performance status 0-1, controlled hypertension, and no prior systemic therapy for aRCC. Axitinib is administered orally 5 mg twice daily; pembrolizumab is administered 2 mg/kg intravenously on Day 1 of each 3-week cycle. Tumors are assessed, using RECIST v1.1, at baseline, week 12, and every 6 weeks thereafter. Study endpoints include adverse events (AEs), other safety measures and tumor response. IHC-based assay was used to stain tumor cells for PD-L1 expression. As of March 1, 2016, 52 pts (79% male; 87% white; mean age 61 years) were enrolled. Eleven (21.2%) pts discontinued both treatments: disease progression (n = 4); treatment-emergent AEs (n = 6; diarrhea, headache/joint pain, fatigue/joint pain, colitis/hepatitis, aggravated rheumatoid arthritis/psoriasis, and drug-induced liver injury); and other (n = 1). Thirty-five (67.3%) pts had objective response: 2 had complete response and 33 had partial responses; 11 pts had stable disease. For the 11 pts enrolled in the dose finding phase, 7 remained progression free at 11 months and the median PFS is not yet mature. Ten pts tested positive for PD-L1. Most common (>2 pts) grade 3 AEs included hypertension (n = 10), diarrhea, headache, hyponatraemia, alanine aminotransferase (ALT) increased, and aspartate aminotransferase (AST) increased (n = 3 each). Grade 4 AEs included dyspnea and hyperuricaemia (n = 1 each). Immune-related ≥grade 3 AEs included ALT and AST (n = 2 each), and diarrhea and colitis (n = 1 each). This preliminary analysis indicates axitinib plus pembrolizumab is well tolerated and exhibits antitumor activity in treatment-naïve pts with aRCC.

e15176 Background: mTOR inhibitors have been recently approved for use in patients with metastatic renal cell carcinoma (mRCC) and are under intense investigation in several other malignancies. We assessed the incidence, radiographic, and clinical presentation of pneumonitis associated with mTOR inhibitors in mRCC, as well as its correlation with clinical outcome. Methods: We reviewed clinical data and serial CT scans from 44 patients (pts) with mRCC treated with temsirolimus or everolimus at Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center. Serial chest CT scans were reviewed in consensus, read by two independent radiologists for presence of pneumonitis and corresponding clinical data were reviewed for symptoms and clinical outcome. The baseline and follow up CTs were also reviewed to determine radiological response by RECIST criteria. Correlation between radiographic response and radiographic pulmonary toxicity was assessed using a paired student t-test with significance at p<0.05. Results: The study population consisted of 44 pts, 21 treated with temsirolimus and 23 with everolimus (M:F 3.4:1; range 44-82 yrs). CT evidence of pneumonitis was seen in 14/44 pts (32%), at an average of 81 days on mTOR inhibitor treatment (range 31 to 214 days). Bilateral lower lobe subpleural and peribronchovascular reticular and ground glass opacities were seen in 12/14 pts (86%). 2/14 pts (14%) developed unilateral subpleural ground glass opacity. Stable disease was achieved in 12/14 pts (86%) who developed radiographic pneumonitis compared to 13/30 (43%) without pneumonitis. Progressive disease (PD) was present in 1/14 pts (7%) who developed radiographic pneumonitis compared to 16/30 (53%) without pneumonitis. The mean change of tumor long axis size for target lesions by RECIST was -2.9% in the pneumonitis group and +4.13% in the non-pneumonitis group (p=.005). Conclusions: Radiographically, pneumonitis is frequent in patients given mTOR therapy and is seen in up to one third of pts. Preliminary data suggest that pneumonitis maybe a marker of therapeutic benefit. Careful patient assessment should be taken before the drug is discontinued.

e13618 Background: The phase I first-in-human study of TLC388 (Lipotecan) examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles in patients with advanced incurable solid tumors. Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2. Results: Fifty four previously treated patients with advanced or metastatic solid tumors were enrolled The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts. MTD was reached at 50 mg/m2. DLTs above that dose were thrombocytopenia and febrile neutropenia. Treatment was well-tolerated and no accumulated toxicity seen. Treatment related G3/4 hematological toxicity include neutropenia (19%), leucopenia (15%), anemia (9%), and thrombocytopenia (7%). G3/4 non-hematological side effects were diarrhea (2%) and hyponatremia (4%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 4.5 cycles (2-12 cycles), and had stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 8 patients (23%), including renal (chromophobe and clear cell types), docetaxel refractory prostate, salivary gland, sorafenib refractory hepatic, and vaginal cancers. One minor response occurred in a heavily pretreated 70-year-old male with stage II B thymoma cancer metastatic to lung, liver and lymph nodes who was treated for 12 courses and remains on the study. PET-CT scan revealed tumor size reduction of 22% at cycle 10. Pharmacokinetics of TLC388 was dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R-TLC388 and 996 (1333) L/m2 for S,S-TLC388, and 2174 (2526) L/h-m2 for S,R-TLC388 and 2670 (2988) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.67 (1.15) hours for S,R-TLC388 and 0.64 (1.11) hours for S,S-TLC388. Conclusions: Lipotecan at dose of 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support phase II disease-specific investigations.

Background: Multiple new therapies are now approved for patients (pts) with advanced RCC. As these agents enter widespread use, their perceived toxicities may differ from those reported in the literature and limit treatment duration and clinical outcomes. Patient reporting of toxicities may more accurately identify side effects most relevant to pts. Methods: In an effort to collect patient-reported side effects from RCC pts treated with novel therapies, an on-line survey was developed. RCC pts were recruited through the Kidney Cancer Association. Results: 177 pts completed the survey and 146 (64%M/36%F) received medication for RCC. Most common geographical regions were Midwest (20.8%); Northeast (17.4%); South/Southeast (16.7%); West (11.8%); and outside the U.S. (9.7%). 68 pts (47.2%) were treated at teaching hospitals; 55 pts (38.2%) in private oncology offices; and 21 pts (14.6%) at community hospitals. First-line treatments included sunitinib (Su) (52.1%, n=73); sorafenib (So) (15.7%, n=22); high dose IL-2 (14.3%, n=20); clinical trial (12.9%, n=18); bevacizumab (Bev) (5%, n=7); interferon (4.3%, n=6) and temsirolimus (Tem) (3.6%, n=5). The most common side effects reported for Su were fatigue (92.9%, n=65), altered taste (90%, n=63) and diarrhea (83.8%, n=57); So: hand foot syndrome (95.2%, n=20) and fatigue (95%, n=19); Bev: fatigue (83.3%, n=5) and altered taste (83.3%, n=5); Tem: fatigue, altered taste and rash (100%, n=4). Pts reported that the most difficult side effects from Su were diarrhea and fatigue (25%, n=18); So: hand foot syndrome (72.7%, n=16); Bev: fatigue (42.9%, n=3); Tem: rash (60%, n=3). Side effects necessitated changing the schedule, dose, or stopping Rx in 82% (n=18) of So pts and in 40% (n=28) of Su pts. QOL was affected very much/extremely for 56.6% of pts (n=73). Conclusions: These results suggest that the patient-reported impact of molecularly targeted agent side effects may be more significant than suggested by phase III clinical trials. These results also identify specific side effects towards which improved symptom management strategies and enhanced patient education can be directed. Better side effect management may increase treatment duration and improve clinical outcomes. Abstract