Abstract Background: Bevacizumab and other VEGF inhibitors provide clinical benefit across multiple cancers but are limited by resistance driven largely by revascularization through alternate pro-angiogenic pathways, including PDGFR and FGFR. Nintedanib, a triple kinase inhibitor targeting VEGFR, PDGFR, and FGFR, may overcome these escape mechanisms. The safety and efficacy of nintedanib plus bevacizumab was previously explored in our phase 1B study and published. We are presenting correlative biomarker studies on the plasma samples acquired at prespecified endpoints. Methods: Plasma samples were obtained from patients enrolled in a phase 1 dose-escalation study evaluating nintedanib in combination with bevacizumab for advanced solid tumors (lung n=9, colon n=8, cervical n=1). Baseline plasma biomarkers—including IL-8, ICAM-1, Angiopoietin-2, KDR/VEGFR2, E-selectin, VEGF, and SDF-1α—were analyzed and correlated with clinical outcomes. Biomarker quantification was performed using multiplex bead-based immunoassays (Luminex), with select analytes validated by ELISA. Results: Nintedanib 200 mg twice daily was well tolerated with no dose-limiting toxicities. . Among bevacizumab-pretreated patients, 55% achieved durable disease control, including one complete response and four stable diseases. Higher baseline levels of KDR/VEGFR2 and E-selectin and lower SDF-1α were associated with improved outcomes. ANOVA identified several biomarkers significantly linked to disease control, including KDR/VEGFR2 (p=0.004), PDGF-AA (p=0.037), and Endoglin (p=0.020). Conclusion: Nintedanib combined with bevacizumab was safe, well tolerated, and demonstrated meaningful clinical activity in heavily pretreated patients. Baseline KDR/VEGFR2, E-selectin, and SDF-1α emerged as potential predictive biomarkers. These data support further validation in larger cohort as a strategy to refine biomarker-driven patient selection for treatments in lung and colorectal cancers. Citation Format: Ravi Kumar Paluri, Anup Kasi, Francisco Robert, Gagan Deep, Ashish Manne. Exploring biomarker predictors of response to nintedanib and bevacizumab combination therapy in advanced cancer patients: Correlative studies from Phase 1b study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7719.

2511 Background: CD73 is implicated in tumor resistance to checkpoint immunotherapy (CPI) and plays a critical role in adenosine-mediated immune suppression. Uliledlimab, a differentiated CD73 antibody, inhibits the adenosine pathway in a non-competitive and unique intra-dimer binding mode. Uliledlimab suppresses tumor growth when combined with a PD-(L)1 inhibitor in multiple pre-clinical models. Methods: This 3+3 dose-escalation phase 1 study (NCT03835949) evaluated safety, tolerability, PK, PD and preliminary efficacy in cancer patients. Uliledlimab was administered intravenously at doses of 5, 10 or 15 mg/kg weekly (QW) or 15 or 20 mg/kg every 3 weeks (Q3W) alone in the first cycle and in combination with atezolizumab (1,200 mg Q3W) starting on week 4. Soluble CD73 in serum and CD73 receptor occupancy (RO) in circulating CD19+ B cells were measured. Expression of PD-L1, CD73 and A2A receptor was analyzed in baseline tumor specimens (n = 14). Tumor responses were assessed by RECIST/iRECIST. Results: As of 17 January 2021, 20 patients with advanced solid tumors were enrolled (M:F 8:12; mean age = 64; median prior regimens = 3 (range 1-9)). Uliledlimab was well-tolerated with no dose limiting toxicity. The most common treatment-related adverse events were first dose infusion related reactions (65%, n = 13) most commonly comprising chills/rigors, nausea, and vomiting (Grade 1 or 2) that resolved in subsequent infusions. PK appears linear at doses ≥ 10 mg/kg and modelling indicated a mean derived effective half-life of ̃19 days. Soluble CD73 was undetectable and complete RO was achieved in all patients after the first dose at ≥ 10 mg/kg. Anti-drug antibody was detected in 3/20 patients (15%). Among 13 efficacy-evaluable patients dosed at ≥ 10 mg/kg, complete response (CR = 1) and partial response (PR = 2) were observed in 3 patients (ORR = 23%) together with 3 stable disease (SD) patients (DCR = 46%). One PD-(L)1 inhibitor naïve patient with clear cell ovarian cancer achieved CR at 10 mg/kg QW and remains on study after 12 months. Two patients with NSCLC dosed at 15 mg/kg QW and 20 mg/kg Q3W, respectively, achieved PR. One patient failed nivolumab and the other received no prior PD-(L)1 inhibitor treatment. CD73 was expressed on 78% (mean) of malignant cells from archival tumor specimens in responders compared to 23% in non-responders. Conclusions: Uliledlimab is safe and well tolerated up to 20 mg/kg Q3W and 15 mg/kg QW. Full saturation of circulating and cell-bound CD73 was achieved at doses ≥ 10 mg/kg. Uliledlimab exhibited evidence of clinical activity in both PD-(L)1 treatment naïve and refractory cancer patients with high archival tumor expression of CD73. The results of this phase 1 study encourage further clinical investigation to evaluate the efficacy of uliledlimab in the treatment of solid tumors. Clinical trial information: NCT03835949.

LESSONS LEARNED Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination. BACKGROUND We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors. METHODS The study consisted of four parts: SGN-2FF monotherapy dose-escalation (Part A) and expansion (Part B), and SGN-2FF + pembrolizumab dose-escalation (Part C) and expansion (Part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab. RESULTS Forty-six patients were enrolled (Part A, n=33; Part B, n=6; Part C, n=7; Part D did not enroll any patients). During Part A (n=32) exploring 1-15 g QD and 2-5 g BID, grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In Part A, common toxicities were grades 1-2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2-5) occurred in 5/32 patients (16%). Safety measures implemented included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In Part C, despite the safety measures implemented, a thromboembolic event occurred in 1/7 patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in Part A, 1 patient with advanced head and neck squamous cell carcinoma achieved RECIST v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation. CONCLUSION SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination.

The S1400A study was designed to evaluate the activity of durvalumab in patients with squamous cell carcinoma of lung. All eligible patients had to have evidence of disease progression after first line treatment with a platinum doublet regimen. This trial was originally designed as a randomized study; however, with the approval of other checkpoint inhibitors it was re-designed as a single-arm study. An overall response rate of 16% was observed in this study with a median overall survival of 11.6 months in unselected patients. Programmed death-ligand 1 data was available for 43 patients on durvalumab, with 14 (33%) patients who were programmed death-ligand 1-positive (>= 25%) and 2 responses (overall response rate, 14%; 95% confidence interval [CI], 0%-33%), the disease control rate was 57% (95% CI, 31%-83%), the median overall survival and progression-free survival were 10.7 months (95% CI, 9.2-14.3 months) and 2.3 months (95% CI, 1.4-4.2 months), respectively. Toxicity was in line with what has been reported for other drugs in this class. Durvalumab, therefore, has single-agent activity and toxicity comparable with other drugs in this class. Introduction: The objective of the Lung-MAP sub-study S1400A was to evaluate the response rate to durvalumab, an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with squamous non-small-cell lung cancer (SqNSCLC). Patients and Methods: Patients who progressed on at least 1 prior platinum-based chemotherapy were eligible. The study was designed as a phase II/III trial comparing durvalumab with docetaxel but was modified to a single- arm, phase II trial with the primary endpoint of objective response when immunotherapy became an approved treatment. Results: A total of 116 patients were registered to this sub-study; 78 to durvalumab and 38 to docetaxel. Of the 78 patients, 9 were ineligible, and 1 was not evaluable for endpoints. Responses were achieved in 11 patients among the 68 eligible and evaluable patients on durvalumab (overall response rate, 16%; 95% confidence interval [CI], 7%-25%). The disease control rate was 54% (95% CI, 43%-66%), the median overall survival was 11.6 months (95% CI, 10.2-14.3 months), and the median progression-free survival was 2.9 months (95% CI, 2.0-4.0 months). PD-L1 data was available for 43 patients on durvalumab, with 14 (33%) patients who were PD- L1epositive (>= 25%) and 2 responses (overall response rate, 14%; 95% CI, 0%-33%), the disease control rate was 57% (95% CI, 31%-83%), the median overall survival and progression- free survival were 10.7 months (95% CI, 9.2-14.3 months) and 2.3 months (95% CI, 1.4- 4.2 months), respectively. Grade >= 3 treatment-related adverse events occurred in 22 (32%) patients on durvalumab, with 6 discontinuing owing to drug-related adverse events (9%; 95% CI, 2%-16%). Conclusions: Durvalumab shows single-agent activity and toxicities in this sub-group of patients that is comparable with other anti-programmed cell death protein 1/PD-L1 antibodies. (C) 2020 Elsevier Inc. All rights reserved.

Objectives: Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/ metastatic NSCLC. Materials and methods: Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL.min, and paclitaxel 200 mg/m(2) (C/ PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/ mL.min, and pemetrexed 500 mg/m(2) (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed. Results: Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80-240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80-240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%. Conclusion: Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug-drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

TPS3652 Background: SGN-CD228A is an investigational antibody-drug conjugate (ADC) that targets CD228, a cell-surface oncofetal protein with prevalent expression in several types of cancer and limited expression on normal tissues. SGN-CD228A consists of a humanized IgG1 anti-CD228 monoclonal antibody conjugated to an average of 8 molecules of monomethyl auristatin E (MMAE) via a PEGylated β-glucuronidase cleavable linker. MMAE is a well-studied and highly active chemotype with an established safety profile. The proposed mechanism of action involves binding CD228 on cell surfaces, ADC internalization, and trafficking to lysosomes. MMAE is then released through β-glucuronidase cleavage of the glucuronide MMAE linker. MMAE then binds tubulin, which disrupts microtubule networks and causes cell cycle arrest and apoptosis. Methods: SGN228-001 (NCT04042480) is a phase 1, open label, multicenter, dose escalation, and expansion study enrolling up to 240 subjects to evaluate the safety, tolerability, PK, and antitumor activity of SGN-CD228A in select advanced solid tumors. Eligible subjects are ≥18 years of age and have metastatic cutaneous melanoma, malignant pleural mesothelioma, human epidermal growth factor receptor 2-negative metastatic breast cancer, advanced non-small cell lung cancer, metastatic colorectal cancer, or advanced pancreatic ductal adenocarcinoma. Subjects must have relapsed, refractory, or progressive disease, and should have no appropriate standard therapy available. Measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Eastern Cooperative Oncology Group (ECOG) performance status score of ≤1, and adequate renal, hepatic, and hematologic function are required. The study includes dose escalation and dose expansion, with multiple disease-specific dose expansion cohorts and a biology cohort. Dose escalation will be conducted using the modified toxicity probability interval method (Ji 2010) to evaluate the safety and identify the maximum tolerated dose of SGN-CD228A. Following dose escalation, disease-specific expansion cohorts and a biology cohort (to evaluate exploratory biomarkers) are planned. Response assessments will be conducted every 6 weeks per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed regularly. Key efficacy endpoints include objective response rate, progression-free survival, and duration of objective response. Enrollment is ongoing in the US and planned in Europe. Clinical trial information: NCT04042480 .

TPS2614 Background: Vascular endothelial growth factor (VEGF) is a potent factor in inducing angiogenesis. VEGF inhibitors have produced demonstrable but limited and transient clinical benefit for various cancers. One mechanism of resistance includes revascularization secondary to up-regulation of alternative pro-angiogenic signals such as platelet derived growth factor receptor (PDGF) and fibroblast growth factor receptor (FGFR) pathway. Nintedanib is an oral triple kinase inhibitor that blocks the VEGFR, PDGFR and FGFR pathways. Our study is using combination of Nintedanib (Nin) and Bevacizumab (Bev) which will block VEGF as well as salvage pathway of angiogenesis (PDGFR and FGFR). Phase I dose selection studies revealed that Nin is generally well tolerated (Clin Can Res 16:47, 2010). LUME-Lung 1 phase 3, international, double blind, placebo controlled trial using Nin and docetaxel in non-small cell lung cancer (NSCLC) showed significant improvement in progression free survival (PFS) regardless of histology and improvement in overall survival (OS) in lung adenocarcinoma (Lancet oncology 15:2, 2014). Methods: This is a phase 1b, open label, single institution trial with standard 3+3 design. Primary objective is to evaluate the safety and tolerability of combination of Nin and Bev. The secondary objective is to determine clinical efficacy (objective response), PFS, and evaluation of plasma levels of angiogenic and anti-angiogenic biomarkers like VEGF, PDGF, VEGF-R and FGF. Patients (pts) in cohort I will be treated with Bev 15 mg/kg day 1 intravenously every 3 weeks and Nin 150 mg orally (PO) twice daily (BID) from day 2-21. In the absence of dose limiting toxicities, Nintedanib dose will be increased to 200 mg PO BID in cohort II. Major inclusion criteria includes advanced solid tumors for which Bev has an indication (non-squamous, NSCLC, colon, ovarian, cervical and renal cancer), progression after at least 1 line of systemic treatment, and measurable disease. Pts with prior treatment with Bev can be enrolled. We will enroll 18 patients. Cohorts I has been completed without DLT (n = 3). Cohort II has enrolled 10 patients. Clinical trial information: NCT02835833.

Nivolumab has demostrated clinical benefit in advanced non-small cell lung cancer (NSCLC) patients who have progressed following platinum-based chemotherapy.Carotuximab (TRC105) is an antibody to endoglin, a receptor expressed on proliferating endothelial cells and myeloid derived suppressor cell (MDSCs), which potently complements the activity of antibody targeting the programmed death receptor (PD-1) in preclinical models. By targeting MDSCs, carotuximab has the potential to complement nivolumab in patients with refractory metastatic NSCLC. Patients with refractory metastatic NSCLC were enrolled regardless of baseline PD-L1 tumor expression and treated with 8 mg/kg or 10 mg/kg of carotuximab weekly for four doses and then 15 mg/kg every two weeks, in combination with the approved dose of nivolumab of 240 mg every two weeks using a standard "3+3" dose escalation design. Expansion cohorts were then opened to further assess the safety, tolerability, and preliminary efficacy by iRECIST of the recommended Phase 2 dose (RP2D) of carotuximab with standard dose nivolumab. The combination of carotuximab and nivolumab was well-tolerated without dose limiting toxicitiy in 6 patients treated as part of dose escalation. One of these 6 patients, whose archival tumor did not express PD-L1 and who had not received prior PD-1/PD-L1 checkpoint inhibition treatment, developed a partial response and remains on study after 14 months. Two of the other 5 patients, one of whom who progressed following prior nivolumab treatment, achieved stable disease, one of whom remains on study at 7 months. Common adverse events regardless of relationship included low grade headache, vomiting, anemia, dyspnea, fatigue, cutaneous telangectasia, nausea, bleeding gums, diarrhea, and migraine. Target concentrations of carotuximab were achieved in all patients and anti-drug antibody was not detected. Enrollment is continuing in two parallel 12 patient expansion cohorts, one in patients who relapsed following prior PD-1/PD-L1 checkpoint inhibition and one in patients naive to PD-1/PD-L1 checkpoint inhibition. Carotuximab at its RP2D of 10 mg/kg weekly x 4 and then 15 mg/kg every 2 weeks was tolerable with nivolumab in patients with NSCLC, and demonstrated preliminary signs of efficacy

In 2007, a randomized clinical study demonstrated improved PFS and OS for patients with extensive stage small cell lung cancer (ES-SCLC) who receive prophylactic cranial irradiation (PCI). Since that time, national guidelines have recommended PCI as standard treatment for ES-SCLC patients without brain metastasis. However, more recent studies incorporating MRI brain for staging showed contradictory results, where PCI resulted in no improvement in progression free survival (PFS) or overall survival (OS). The purpose of this study is to describe survival outcomes after PCI using the National Cancer Database (NCDB), and factors influencing patient treatment with this modality. From 2010-2014, a total of 32315 ES-SCLC patients without brain metastasis at diagnosis who received systemic treatment were identified from the NCDB. Patients’ demographic, clinical, and survival data were collected and compared. A multivariate logistic regression was conducted to identify the predictors of patients receiving PCI, which was defined as radiotherapy directed to the whole brain ≤180 days from diagnosis. Patients who develop brain metastases after initial diagnosis and subsequently receive brain directed radiotherapy are not included in this NCDB analysis. To compare OS between PCI vs no PCI, a propensity score matching was performed. The survival outcomes of case and controls were estimated by the Kaplan-Meier methods. Among the 32315 patients without brain metastasis at diagnosis with ES-SCLC, 3572 (11.1%) received PCI within 180 days of diagnosis. Rates of PCI were relatively stable from 2010-2014. Variables influencing patients’ likelihood of treatment included increasing age (OR 0.99, p=0.01), facility type (academic vs. community cancer program: OR 1.37, p<0.0001), and insurance status (private vs Medicaid insurance: OR 1.23, p=0.02). Of those receiving PCI, 65.3% of patients received 25-30 Gy brain-directed radiation treatment, and 77.7% were treated at comprehensive or academic cancer centers. Median survival was not significantly different between the groups receiving brain-directed therapy compared to those without radiation therapy (9.7 vs. 8.7 months, p=0.45). Using a modern American cohort, our NCDB analysis demonstrates no improvement in overall survival with utilization of PCI for ES-SCLC, which supports a recently published large randomized trial. In addition, this study demonstrates a significantly higher rate of PCI utilization in younger and privately insured patients that are treated at comprehensive cancer and academic centers, with approximately 11% of ES-SCLC patients receiving PCI. In the era of widespread availability of brain MRI for staging of SCLC, this analysis supports consideration of omission of PCI in patients with ES-SCLC.

Abstract SGN-2FF, an orally bioavailable small molecule inhibitor of glycoprotein fucosylation, demonstrates encouraging preclinical antitumor activity in mouse models with suggested multiple mechanisms of action, including direct and indirect effects on immune cells, tumor cells, and the tumor microenvironment. The effects of SGN-2FF were evaluated on tumors implanted in multiple strains of mice to determine how differences in the immune repertoire affect the antitumor activity. SGN-2FF treatment of nude mice, which maintain functional B cells and antibody production, resulted in a delay in LS174T tumor growth compared with untreated mice, while LS174T tumors in SCID mice, which lack B cells, were unaffected by SGN-2FF. These data suggest that activity of SGN-2FF in nude mice may be dependent on residual B cells and circulating antibodies. The antitumor effect of SGN-2FF in syngeneic mouse models with intact immune systems also appears to be dependent on T cell activity. Transfer of T cells isolated from SGN-2FF-treated tumor-bearing mice to naïve tumor-bearing mice was sufficient to delay tumor growth. T cells isolated from untreated tumor-bearing mice did not have the same effect. These results demonstrate that afucosylated immune cells play a key role in the preclinical activity of SGN-2FF. Various preclinical assays were used to detect SGN-2FF-mediated changes in cellular and IgG fucosylation important for biological activity. These assays are being applied in evaluating patient samples in the ongoing phase 1, multicenter, dose-escalation study investigating the safety, tolerability, PK, and biomarkers of antitumor activity of SGN-2FF administered orally to adult patients with advanced solid tumors (NCT# 02952989). Changes in peripheral IgG fucosylation, absolute neutrophil count, and immune cell surface fucosylation were identified as initial biomarkers for proof of pharmacodynamic activity. Preliminary data following daily doses of SGN-2FF demonstrate that cell surface fucosylation on granulocytes was significantly reduced and neutrophil count was significantly increased in 6 of 7 treated subjects; additionally, IgG fucosylation was significantly decreased in 7 of 7 subjects. PK have been characterized, and preliminary results are within the expected range as predicted from preclinical studies. Following daily administration of SGN-2FF, accumulation of the active metabolite, GDP-2FF, was observed intracellularly, while no accumulation of SGN-2FF was observed in plasma. Collectively, these data demonstrate robust biological effects of SGN-2FF. The pharmacodynamic biomarkers and PK analysis are informing next steps in identifying an optimal dose and dosing schedule for SGN-2FF. Citation Format: Nicole M. Okeley, Ryan A. Heiser, Weiping Zeng, Shawna Mae Hengel, Jason Wall, Peter C. Haughney, Timothy Anthony Yap, Francisco Robert, Rachel E. Sanborn, Howard Burris, Laura Q. Chow, Khanh T. Do, Martin Gutierrez, Karen Reckamp, Amy Weise, D Ross Camidge, John Strickler, Conor Steuer, Zejing Wang, Megan M. O'Meara, Stephen C. Alley, Shyra J. Gardai. SGN-2FF: A small-molecule inhibitor of fucosylation modulates immune cell activity in preclinical models and demonstrates pharmacodynamic activity in early phase 1 analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5551.

Endoglin plays a critical role in angiogenesis and is implicated in resistance to VEGF inhibition. TRC105, an endoglin antibody, has been shown to potentiate the anti-angiogenic effect of bevacizumab (B) in pre-clinical models of human angiogenesis. Given the critical role of anti-angiogenic therapy in the treatment of advanced NSCLC and the tendency of the tumor to develop escape pathways of angiogenesis following treatment with anti-VEGF agent, investigation of dual anti-angiogenic therapy in advanced NSCLC is indicated. A standard (3+3) dose-escalation design of TRC105 with15 mg/kg bevacizumab (B), 200 mg/m2 paclitaxel (P) and 6 AUC carboplatin (C) given IV on day 1 of each 21-day cycle was employed, followed by an expanded cohort to further assess the safety and tolerability of the recommended phase 2 dose (RPTD) of TRC105. Patients completed induction therapy with TRC105 + B, P and C for a maximum of 6 cycles with those demonstrating no evidence of disease progression transitioned to a maintenance phase of TRC105 + B. Secondary endpoints: ORR, PFS, OS, PK, immunogenicity and angiogenic biomarkers. Key inclusion criteria: chemotherapy-naïve stage 4 NSQ-NSCLC, ECOG < 1, measurable disease and no significant cardiovascular comorbidities. Fifteen pts have been enrolled; three were unevaluable for efficacy due to DLT of Grade 3 rash and unrelated SAE's of Grade 3 weakness and Grade 3 hypoxia. Four of 12 evaluable pts achieved PR, one with 81% tumor reduction. Median PFS was 6.54 months. Common adverse events regardless of relationship included epistaxis, fatigue, telangiectasia, diarrhea, headache and nausea. Common TRC105 related AEs included epistaxis, telangiectasia, fatigue and headache. One patient experienced Grade 5 neutropenic sepsis considered unrelated to TRC105 or B. Analysis of the angiogenic biomarkers will be presented. Induction treatment for six 3-week cycles withTRC105 + B, P, and C, followed by maintenance therapy with TRC105 + B until disease progression was tolerable and did not potentiate the toxicity of B, P or C. The combination of TRC105 + B, P and C demonstrated signs of activity including PR in 4 of 12 evaluable pts.

3061 Background: Veliparib (V), a PARP inhibitor, combined with platinum (Pt) doublet CT has shown promise in a Phase 2 study of NSCLC. Nivolumab (N), a PD-1 inhibitor, has demonstrated single-agent activity in relapsed NSCLC. This is the first study evaluating dose and safety of V combined with N + Pt-doublet CT. Methods: This Phase 1, dose-escalation study (NCT 02944396) enrolled adult patients (pts) with metastatic or advanced NSCLC, ECOG 0-1, and no prior cytotoxic CT, anti-PD-1 or PARPi. Primary objective was to establish the recommended Phase 2 dose (RP2D) of oral V BID combined with N (360 mg) and carboplatin (C, AUC 6)/paclitaxel (Pac, 200 mg/m2) or C (AUC 6)/pemetrexed (Pem, 500 mg/m2). Combined with N, dose cohorts were 120 mg V + C/Pac or 80-200 mg V + C/Pem for 6 cycles (cycle = 21 d), or until unacceptable toxicity or disease progression, followed by N + Pem maintenance as indicated. DLTs incl. hematologic and non-hematologic AEs delaying treatment (tx), requiring dose modifications, and attributed to V. Safety, PK, and anti-tumor activity by RECIST 1.1 were assessed. Results: As of December 15, 2017, 17 pts (median age 61) with Stage IV NSCLC were enrolled (11 non-squamous for V + N + C/Pem; 1 non-squamous and 5 squamous for V + N + C/Pac). Median drug exposure was 105 d (range 3-284). Primary discontinuation of V occurred in 41% due to AE (2), PD (1), physician decision (1), pt withdrawal (1), death (1), or other (1). No DLTs were reported. Tx-emergent AEs incl. fatigue (47%), nausea (35%), anemia (35%), neutropenia (29%) and thrombocytopenia (29%). Grade 3/4 AEs additionally incl. febrile neutropenia, increased lipase, pneumonitis, and rash (6% each). SAEs additionally incl. sinus arrhythmia, acute kidney injury, pleural effusion, pulmonary embolism, and sudden death (6% each). ORR was 27% [95% CI 6, 61] for V + N + C/Pem and 17% [0, 64] for V + N + C/Pac. For V + N + C/Pem, best response was PR (50%) or SD (50%). For V + N + C/Pac, best response was PR (50%). PK data will be presented. Conclusions: RP2D is 120 mg for V + N + C/Pac, and has not been determined for V + N + C/Pem (to date, highest tolerated dose is 200 mg). V combined with N + Pt-doublet CT showed anticipated safety signals, with no additional toxicity of V when added to these regimens. Clinical trial information: NCT 02944396.

Background: Durvalumab (MEDI4736) is an engineered human IgG1 mAb targeting programmed cell death ligand-1 (PD-L1). Treatment with other anti-PD-1/PD-L1 antibodies has demonstrated meaningful clinical benefit in patients with advanced NSCLC. Methods: As part of the Lung Master Protocol S1400, a National Clinical Trials Network group "umbrella" trial for second-line SqNSCLC we conducted a phase II study of durvalumab in patients with Stage IV squamous NSCLC (ECOG PS 0-2; ≥1 prior systemic treatment regimens, including one platinum-based), EGFR/ALK wild-type. The primary endpoint was overall response rate (ORR) (RECIST v1.1); secondary endpoints included duration of response (DoR), ORR among PD-L1 positive patients, disease control rate (DCR), investigator-assessed progression-free survival (PFS), overall survival (OS) and safety (CTCAE v4.03). The initial protocol was a randomized phase II/III comparison of durvalumab to docetaxel, and was amended to be a single arm phase II trial of single agent durvalumab. PD-L1 positive tumors were defined by ≥ 25% of tumor cells with membrane staining. Results: Of the 68 eligible patients (median [range] age 66 [35-92] years, PS 0/1/2 26%/62%/12%), 11 were responders (16% ORR, 95% Confidence Interval [CI] 7%, 25%). DCR was 54% (CI 43%, 66%), median OS was 11.5 months (CI 10.1-12.4 mos), and median PFS was 2.9 mos (CI 2.0-4.1 mos). Of the 11 responders, median time to response and DoR were 3.6 mos (CI 2.8-4.2 mos) and 18.6 months (95% CI 4.4-NR mos), respectively. Of the 14 PDL1-positive patients, 2 were responders (14% ORR, 95% CI 0%, 33%), DCR was 57% (CI 31%, 83%), median OS and PFS were 10.7 mos (CI 9.2-10.7 mos) and 2.3 mos (CI 1.4-4.9 mos), respectively. Durvalumab showed a manageable safety and tolerability profile; most adverse events (AEs) were low grade and resolved with treatment delay and/or immunosuppressive interventions. Grade ≥3 treatment-related AEs occurred in 23(34%) of patients. Drug-related AEs led to discontinuation in 6 patients (9%, 95% CI 2%, 16%). Conclusions: Durvalumab demonstrated clinical benefit and durable responses in a previously treated metastatic NSCLC population with manageable toxicity profile. Results are comparable with other anti-PD-1/PD-L1 therapies in metastatic, relapsed NSCLC. Clinical trial identification: NCT02766335 Legal entity responsible for the study: Southwest Oncology Group/NCTN Funding: Lung-MAP supported in part by NIH/NCI grants CA180888, CA180819, CA180820, CA180821, CA180868, and by Amgen, AstraZeneca, Bristol-Myers Squibb Company Genentech and Pfizer through the Foundation for the National Institutes of Health, in partnership with Friends of Cancer Research. Disclosure: V. Papadimitrakopoulou: Advisory Role for: Eli Lilly&Co, Genentech, Janssen Global Sevices, Bristol-Myers Squibb, ARIAD, Astra Zeneca Pharmaceuticals, Novartis, Merck Corporate-sponsored research: Novartis, Astra Zeneca, Genentech, Merck, Janssen, ACEA, Bristol-Myers Squibb. H. Borghaei: Advisory: Bristol-Myers Squibb, Lilly, Genentech, Celgene, Pfizer, EMD-Serono, Boerhinger-Ingelheim, Trovagene, AstraZeneca, Research Support: Millenium, Merck, Celgene. K. Kelly: Advisory: Synta, AstraZeneca, Lilly, Clovis Oncology, ARIAD, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, G1 Therapeutics. Research: Millenium, Novartis, EMD Serono, Lilly, Genentech, Abbvie, Gilead, Celgene, Five Prime Therapeutics, Transgene. All other authors have declared no conflicts of interest.

INTRODUCTION:The goal of this study was to explore the efficacy and tolerability of metronomic chemotherapy, a novel anti-angiogenic treatment strategy, in combination with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC).METHODS:Subjects with newly diagnosed stage IV NSCLC were treated with 4-week cycles of paclitaxel 80mg/m2 and gemcitabine 300mg/m2 weekly for three weeks, plus bevacizumab 10mg/kg every two weeks. Radiologic assessments were performed every 8 weeks. The primary endpoint was progression free survival (PFS). An exploratory objective was to correlate plasma levels of angiogenic biomarkers with treatment response.RESULTS:Thirty-nine subjects were included in the intent to treat (ITT) analysis. The objective response rate (ORR) was 56%, the median PFS was 8.5 months, and median overall survival (OS) was 25.5 months. The PFS rate at 6, 12, and 24 months was 61%, 21%, and 11% respectively. The OS rate at 12 and 24 months was 74% and 53% respectively. Treatment was well tolerated, without significant myelosuppressive, gastrointestinal, or neurologic events. Subjects with less than median baseline values of angiopoietin-2 and IL-8 experienced significantly longer PFS. Longer OS was associated with subjects with less than the median baseline values for PLGF and angiopoietin-2. There were statistically significant differences in median values of several biomarkers between cycles 1 and 3 in subjects with objective responses.CONCLUSIONS:The combination of paclitaxel and gemcitabine, delivered in a metronomic schedule, in combination with bevacizumab, appears to be an effective and tolerable treatment strategy in patients with advanced NSCLC.

SCLC is one of the most deadly malignancies. Rovalpituzumab tesirine (SC16LD6.5, Rova-T) is a first-in-class ADC directed against DLL3, a novel target identified in tumor initiating cells and expressed in over 80% of SCLC cases. Seventy-four patients with progressive SCLC after at least one previous systemic therapy were enrolled in a first-in-human study (NCT01901653), irrespective of DLL3 expression, including 68 at active doses of 0.2-0.4 mg/kg administered intravenously every 3 or 6 weeks. Available archived tumor tissue (n=48) was assessed retrospectively by immunohistochemistry for DLL3. Among 60 evaluable subjects, active dose levels resulted in a confirmed objective response rate (ORR) of 18% and a confirmed clinical benefit rate (CBR; stable disease or better) of 68%. Among 26 evaluable subjects with DLL3 expression in at least 50% of tumor cells (DLL3-high), confirmed ORR and CBR were 39% and 89%, respectively. Median duration of response was 5.6 months. One-year survival rates among all and DLL3-high subjects were 18% and 32%, respectively. Among primary sensitive relapse patients, confirmed ORR and CBR among all subjects were 24% (8/33) and 67% (22/33); and among DLL3-high subjects were 53% (8/15) and 100% (15/15), with one-year survival rates of 17% and 33%, respectively. Among primary resistant/refractory relapse patients, confirmed ORR and CBR among all subjects were 12% (3/25) and 72% (18/25); and among DLL3-high subjects were 18% (2/11) and 73% (8/11), with one-year survival rates of 21% and 29%, respectively. The most common grade 3 or higher toxicities included thrombocytopenia (12%), serosal effusions (11%), and skin reactions (8%). ADC pharmacokinetics were linear with a terminal half-life of 10 - 14 days and anti-therapeutic antibodies did not develop. Rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity with a manageable safety profile, including among patients with disease resistant or refractory to primary chemotherapy. Further development of rovalpituzumab tesirine in SCLC is warranted.

Lung-MAP (S1400) is a master umbrella protocol designed to establish genomic screening for previously treated squamous cell lung cancer patients (SqCCA), and independently evaluate targeted therapies with matching biomarkers and alternative therapies (designated non-match therapy) in patients without putative markers. The protocol opened June 16, 2014 with four biomarker-driven sub-studies and one non-match sub-study. Eligibility stipulated advanced SqCCA, progressing after at least one prior platinum-based chemotherapy, PS 0–2, and EGFR/ALK wild-type. Tumor samples were required and analyzed for gene alterations by FoundationOne NGS assay (Foundation Medicine). The original biomarker and non-match studies were: S1400B evaluating taselisib for PI3K mutations, S1400C evaluating palbociclib for cell cycle gene alterations (CCGA), S1400D evaluating AZD4547 for FGFR mutations, S1400E evaluating rilotumumab and erlotinib for c-MET positive tumors, and S1400A evaluating durvalumab in patients with no matching biomarkers. The original design included randomization to a control arm, but was amended to a single-arm phase 2 design. The primary endpoint for each modified sub-study was response. As of June 16, 2017 all original sub-studies have been closed to accrual; 1298 patients registered to the screening component of the trial and 486 patients have registered to a sub-study. Two new sub-studies have been launched and are currently accruing. Details of the completed sub-studies are included in the table. Lung-MAP as a master genomic screening protocol has demonstrated feasibility with respect to accrual and evaluation of targeted therapies in lower prevalence patient populations. This dynamic, centralized, single-IRB platform is well positioned to efficiently assess multiple novel therapeutics for advanced SqCCA patients.