Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors. The primary objective was safety and tolerability; exploratory objectives included evaluation of pharmacokinetics, pharmacodynamics, preliminary antitumor activity and immunogenicity. Non-prespecified interim analysis showed that autogene cevumeran was well tolerated and elicited poly-epitopic neoantigen-specific responses, encompassing CD4+ and/or CD8+ T cells, in 71 NCT03289962 . In this phase 1 trial, patients with locally advanced or metastatic solid tumors were treated with the individualized mRNA neoantigen-specific immunotherapy (iNeST) autogene cevumeran alone or in combination with the anti-PD-L1 agent atezolizumab, showing long-lasting neoantigen-specific immune responses and preliminary clinical activity, supporting further development of this therapeutic approach.

Incidence of treatment-emergent adverse events, all grades, occurring in {greater than or equal to}20% of patients in either cohort

CTC enumeration and pERK analysis in course 1

Grade 3 or 4 adverse events possibly related to refametinib or sorafenib, occurring in {greater than or equal to}2 patients in either cohort

BACKGROUND:Sasanlimab is an antibody to the programmed cell death protein 1 receptor. We report updated data of subcutaneous sasanlimab in non-small-cell lung cancer (NSCLC) and urothelial carcinoma dose expansion cohorts from a first-in-human phase Ib/II study. PATIENTS AND METHODS:Patients were ≥18 years of age with NSCLC or urothelial carcinoma, and no prior immunotherapies, who progressed on or were intolerant to systemic therapy, or for whom systemic therapy was refused or unavailable. Patients received subcutaneous sasanlimab at 300 mg every 4 weeks (q4w). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). RESULTS:Sixty-eight and 38 patients with NSCLC and urothelial carcinoma, respectively, received subcutaneous sasanlimab. Overall, sasanlimab was well tolerated; 13.2% of patients experienced grade ≥3 treatment-related adverse events. Confirmed ORR was 16.4% and 18.4% in the NSCLC and urothelial carcinoma cohorts, respectively. ORR was generally higher in patients with high programmed death-ligand 1 (PD-L1) expression (≥25%) and high tumor mutational burden (TMB; >75%). In the NSCLC and urothelial carcinoma cohorts, median progression-free survival (PFS) was 3.7 and 2.9 months, respectively; corresponding median overall survival (OS) was 14.7 and 10.9 months. Overall, longer median PFS and OS correlated with high PD-L1 expression and high TMB. Longer median PFS and OS were also associated with T-cell inflamed gene signature in the urothelial carcinoma cohort. CONCLUSIONS:Subcutaneous sasanlimab at 300 mg q4w was well tolerated with promising clinical efficacy observed. Phase II and III clinical trials of sasanlimab are ongoing to validate clinical benefit. Subcutaneous sasanlimab may be a potential treatment option for patients with NSCLC or urothelial carcinoma.

Figure S1. shows total epirubicin concentrations (mean {plus minus} SD) at the end of infusion of 170 mg/m2 NC-6300 across cycles.

Gastroesophageal cancers, including esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma and gastric adenocarcinoma, accounted for >1.6 million new cases and >1.2 million deaths worldwide in 2020. Because high Nectin-4 expression in gastric and esophageal cancer is associated with advanced tumor stage and poor prognosis, targeting this transmembrane cell adhesion protein is a rational treatment approach. Enfortumab vedotin (EV) is a Nectin-4 directed antibody-drug conjugate comprised of a fully human anti-Nectin-4 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E, via a protease-cleavable linker.

Despite therapeutic advances, lung cancer remains a leading cause of cancer death worldwide. Nectin-4, a cell adhesion molecule, is highly expressed in several epithelial tumor types, including non-small cell lung cancer (NSCLC). Targeting Nectin-4 in NSCLC provides a novel treatment approach. Enfortumab vedotin (EV) is an antibody-drug conjugate comprised of a fully human monoclonal antibody directed against Nectin-4, and monomethyl auristatin E (MMAE), a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker.

5509 Background: The accelerated FDA approval of pembrolizumab validated the efficacy of anti–PD-(L)1 therapy for pts with recurrent/metastatic cervical cancer; however, the objective response rate (ORR) with pembrolizumab was 14.3% in pts with PD-L1 expressing tumors. HPV infection is implicated in > 95% of cervical cancers and is linked to upregulation of TGF-β signaling. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. We report pooled safety and efficacy in pts with immune checkpoint inhibitor–naive, recurrent/metastatic cervical cancer treated with bintrafusp alfa in phase 1 (INTR@PID 001; NCT02517398) and phase 2 (study 012; NCT03427411) studies. Methods: Pts with pretreated, immune checkpoint inhibitor–naive, recurrent/metastatic cervical cancer received bintrafusp alfa 0.3-30 mg/kg (phase 1 dose escalation) or 1200 mg Q2W (phase 1 expansion/phase 2) until progressive disease, unacceptable toxicity, or withdrawal. Treatment past progression was allowed. Primary endpoints were safety for the dose-escalation part of the phase 1 study and best overall response per RECIST 1.1 for the expansion part of phase 1 and phase 2 studies. Secondary endpoints for the expansion part of the phase 1 and 2 studies included safety. Results: As of May 15, 2020 (phase 1) and December 22, 2020 (phase 2), 39 pts had received bintrafusp alfa for a median duration of 2.8 months (range, 0.5-19.3). The median follow-up to data cutoff was 35.0 months and 24.1 months for the phase 1 and phase 2 studies, respectively. All pts had received prior anticancer therapy; 16 pts (41.0%) had received ≥3 prior anticancer regimens. There were 2 complete responses and 9 partial responses (PRs; ORR per RECIST 1.1, 28.2%). Median duration of response was 11.7 months (range, 1.4-41.2), and 5 pts (45.5%) had ongoing responses (duration 1.5-41.2 months). An additional delayed PR was observed (duration 23.7 months). Reponses occurred irrespective of tumor histology or prior bevacizumab or radiation treatment. Median overall survival (mOS) was 13.4 months (95% CI, 5.5 to not reached); 24-month OS rate was 33.2%. Any-grade treatment-related adverse events (TRAEs) occurred in 33 pts (84.6%). Grade 3 TRAEs occurred in 8 pts (20.5%; anemia, colitis, gastroparesis, upper gastrointestinal hemorrhage, keratoacanthoma, cystitis noninfective, hematuria, pneumonitis, rash macular [n = 1 each]); 1 patient (2.6%) had a grade 4 TRAE (asymptomatic hypokalemia related to the above grade 3 gastroparesis). No treatment-related deaths occurred. Conclusions: Bintrafusp alfa had a manageable safety profile and demonstrated clinical activity in pts with heavily pretreated, immune checkpoint inhibitor–naive recurrent/metastatic cervical cancer. Clinical trial information: NCT02517398 , NCT03427411.

The integrins comprise a multifaceted family of membrane-associated proteins that regulate cellular adhesion, motility and cytokinesis. Higher levels of integrin beta-6 predict poorer outcomes in patients with solid tumors such as colorectal, non-small cell lung, gastric and cervical cancers. The vedotin SGN-B6A is an investigational antibody–drug conjugate designed to deliver the cytotoxic agent monomethyl auristatin E (MMAE) to integrin beta-6-expressing cells. Once internalized, intracellular MMAE disrupts microtubules causing cell cycle arrest and apoptosis. Several xenograft models have demonstrated SGN-B6A-mediated tumor growth delay and regression in tumor volume. SGNB6A-001 (NCT04389632) is a phase 1, first-in-human, open-label, multicenter study assessing the safety, tolerability, pharmacokinetics and anti-tumor activity of SGN-B6A in adults with histologically or cytologically confirmed metastatic or unresectable advanced solid tumors. Primary study objectives include evaluation of safety and tolerability of SGN-B6A, identification of the maximum tolerated dose (MTD) and selection of a recommended dosage. Part A enrolls dose-escalation cohorts in which SGN-B6A will initially be given IV to patients on Days 1, 8 and 15 of 21-day cycles. The mTPI design is used to guide dose escalation and identify the MTD with a target dose-limiting toxicity rate of 25% and a 5% margin. Part B will have up to 6 disease-specific dose cohorts and a biology cohort. Pre- and post-treatment tumor samples will be collected from the biology cohort to further characterize SGN-B6A activity. The Part B dosage will be based on findings from Part A. Preliminary anti-tumor activity of SGN-B6A will be assessed using RECIST v1.1. Patients must be ≥18 years old with an ECOG performance status 0–1, and standard therapy must have been unsuccessful, intolerable or deemed inappropriate. Patients must have pancreatic adenocarcinoma, non-small cell lung, head and neck squamous cell or cutaneous squamous cell cancer, or breast, esophageal, ovarian, bladder, cervical or gastric cancer. This study is active at sites across the US and Europe. NCT04389632. Medical writing support was provided by Elliot Piper-Brown, PhD, and editorial support by Travis Taylor, BA, all of Scion, London, supported by Seagen Inc. Seagen Inc. Seagen Inc.

FB Hepatocellular carcinoma (HCC) is one of the fastest-growing cancers in the United States as well as one of the most common causes of cancer-related death. Currently, the only cure for early-stage disease remains liver transplantation. However, few patients qualify for transplantation, and often patients progress before a transplant is made available. More often, patients are diagnosed at an advanced stage that does not qualify for liver transplantation. Thus, physicians are left to offer palliative treatments to slow the progression of the disease and extend survival, as well as supportive care to address numerous comorbidities, such as viral infections, liver cirrhosis, and other organ dysfunctions. The traditional antimitotic and other cytotoxic agents that have been used in other solid tumors and lymphomas have produced little improvement in the advanced stage of HCC until 2007, with the approval of the tyrosine kinase inhibitor sorafenib (Nexavar, Bayer), the first biologic for systemic frontline treatment of advanced HCC. Since then, doctors have been trying to improve on the clinical endpoints of overall survival and progression-free survival, and have looked for options for second-line treatment. It took until 2017 for the first second-line treatment option, regorafenib (Stivarga, Bayer), to be approved in the Fadi Braiteh, MD Director of GI Malignancies at Comprehensive Cancer Centers of Nevada Clinical Associate Professor of Medicine University of Nevada School of Medicine Las Vegas, Nevada

Nectin-4, a transmembrane cell adhesion protein, is highly expressed in several epithelial tumor types, including gastrointestinal cancers; targeting Nectin-4 on these tumors may provide a novel treatment approach. Enfortumab vedotin (EV), an antibody-drug conjugate directed against Nectin-4, is comprised of a fully human monoclonal antibody specific for Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent; targeted delivery and internalization of MMAE results in cell cycle arrest and apoptosis. In 2019, EV received accelerated approval by the United States Food and Drug Administration for the treatment of adults with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. In EV-301, a phase 3, randomized clinical trial of patients with previously treated la/mUC, EV was shown to significantly prolong overall survival compared with physician's choice of standard chemotherapy (docetaxel, paclitaxel, and vinflunine). The use of EV for gastroesophageal cancers in this study is investigational. This ongoing, multicohort, open-label phase 2 study (NCT04225117) evaluates the efficacy and safety/tolerability of EV in patients with previously treated locally advanced/metastatic malignant solid tumors. Approximately 240 adult patients with histologically or cytologically confirmed disease and an ECOG performance status of ≤1 will be enrolled into one of six tumor-specific cohorts, including a gastrointestinal cohort of patients with gastric, gastroesophageal junction, or esophageal cancer; other tumor cohorts include breast, non-small cell lung, and head and neck cancer. Each cohort will enroll approximately 40 patients. Within the gastrointestinal cohort, patients must have previously received a HER2-directed therapy if known to have HER2-positive cancer and must have progressed, relapsed, or discontinued treatment due to toxicity after one platinum-based therapy for locally advanced or metastatic disease, but no more than two lines of cytotoxic therapy in this setting. While Nectin-4 expression is not required for enrollment, it is being tested retrospectively for exploratory outcomes. Patients with active CNS metastases, preexisting grade ≥2 sensory or motor neuropathy, ongoing grade ≥3 immunotherapy-related hypothyroidism or panhypopituitarism, ongoing immunotherapy-related adverse events requiring high-dose steroids, or a history of uncontrolled diabetes mellitus within the 3 months prior to the study are excluded. All patients will receive EV 1.25 mg/kg (maximum dose of 125 mg) intravenously on Days 1, 8, and 15 of each 28-day cycle until treatment discontinuation criteria are met; dose reductions/interruptions will be permitted. Disease assessments will be performed every 8 weeks and complete or partial response will be confirmed 4 weeks after the first response. For all cohorts, the primary endpoint is investigator-assessed confirmed objective response rate (RECIST v1.1); secondary endpoints include duration of response, disease control rate, progression-free and overall survival, and safety/tolerability of EV. For each cohort, an interim analysis is planned based upon prespecified response criteria. Recruitment for this study is ongoing at approximately 50 sites in North America and Japan as of March 2020. NCT04225117. Writing and editorial assistance was provided by Stephanie Phan, PharmD, and Elizabeth Hermans, PhD, from Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and funded by the study sponsors. Astellas Pharma, Inc. and Seagen Inc. This study is sponsored by Astellas Pharma, Inc. and Seagen Inc.

Introduction STRO-002 is a novel FRα-targeting ADC that delivers SC209, a potent tubulin-targeting hemiasterlin cytotoxin-warhead. Methods All patients in the ongoing dose escalation study (NCT03748186) had platinum resistant/refractory OC without selection for FRα expression. STRO-002 is given IV on Day 1 of each 21-day cycle. Results 38 patients have been dosed at 9 dose levels (0.5 to 6.4 mg/kg). Median number of cycles given is 3 (1–18). Median age is 61 (48–79). Median prior therapies - 5 (2–10). Clinically active doses (≥ 2.9 mg/kg) have been administered to 33 patients. 21/33 (64%) remain on treatment. Partial response was seen in 5 of 29 evaluable patients (17%) with 2 confirmed on second scan. 9 pts have confirmed SD for a clinical benefit rate of 48% (14/29). CA125 reduction of >50% was seen in 14/22 (64%) evaluable patients per GCIG. Clinical activity appears to be durable with 36% and 24% on study >16 and >24 weeks, respectively. 88% of AEs are grade 1 or 2. Grade 3–4 neutropenia, an expected and reversible effect of STRO-002 occurred in 15/38 (39%). DLTs reported – grade 3 neuropathy (6.0 mg/kg) and grade 3 bone pain (6.4 mg/kg). Conclusions STRO-002 is a novel FRα-targeting ADC with a promising emerging safety and efficacy profile and preliminary clinical benefit/disease control rate of 48% in patients with relapsed/refractory OC treated at ≥ 2.9 mg/kg. No ocular toxicity signals have been observed, suggesting potential differentiation from other FRα-targeting investigational therapies. Expansion cohorts in less heavily pre-treated patients are planned for 4Q20.

Abstract Introduction: FRα is overexpressed in 80% of OC with minimal expression in normal tissues. STRO-002 is a novel FRα-targeting ADC designed to circumvent limitations of current ADCs. STRO-002 was generated with a cell-free antibody production system (XpressCF™) and site-specific conjugation (XpressCF+™) platform. STRO-002 has a DAR of 4 and contains the tubulin-targeting 3-aminophenyl hemiasterlin warhead SC209, a potent cytotoxin that is rapidly cleared and a weak substrate for P-gp efflux pumps. STRO-002 demonstrated potent cytotoxic activity in multiple FRα-positive tumor cell lines and significant efficacy in OC xenograft models. Herein we report the results of our dose escalation study of STRO-002 in patients (pts) with OC. Methods: STRO-002-GM1 is a Phase I, open-label, multicenter, dose escalation study with dose expansion to identify the maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) in pts with advanced, platinum resistant or refractory OC. There is no patient selection based on FRα expression. STRO-002 is given IV on Day 1 of each 21-day cycle (C) until disease progression. Ocular exams are performed at baseline and every other cycle. No prophylactic corticosteroid eye drops are used. Results: 20 pts have been dosed & 18 pts have completed at least 1 cycle of STRO-002 at 7 dose levels: 0.5, 1.0, 1.8, 2.9, 4.3, 5.2 and 6.0 mg/kg. Median age is 60.5 (r, 48-70). Median ECOG status is 0 (r, 0-1). Median # of prior therapies is 6 (r, 2-10). 55% of pts have prior PARP inhibitors, 85% have prior bevacizumab. Median # of STRO-002 cycles is 3 (r, 1-15). One DLT of grade 3 neuropathy was reported at the 6.0 mg/kg dose level. Two patients have experienced grade 4 neutropenia, an expected and reversible side effect of STRO-002 treatment. 92% of AEs are grade 1 or 2. The most common TEAEs in ≥ 30 % of pts includes fatigue, nausea, decreased appetite and dizziness. No ocular findings have been observed. Emerging PK profile: after 1 hour infusion, total antibody concentrations declined in a log-linear manner with a 22-84 h half-life, dose-exposure relationship appeared linear without accumulation after repeat administration. Six pts have discontinued due to disease progression. 14 pts remain on treatment and dose escalation is ongoing. One patient has achieved a confirmed partial response (PR); 2 patients have confirmed stable disease (cSD) at C5, 2 pts have cSD at C7 and 1 pt has cSD at C13; 3 patients have achieved a confirmed CA-125 response. Conclusions: STRO-002 is the first hemiasterlin-containing ADC generated with cell-free protein synthesis technology to be tested in pts with solid tumors. The preliminary safety profile and evidence of efficacy and clinical benefit in the first 20 OC pts treated with STRO-002 is encouraging, particularly in this heavily pre-treated, platinum resistant/refractory patient population. No ocular toxicity signals have been observed. MTD has not been reached. Updated results and the recommended phase 2 dose will be presented. This study is registered with clinicaltrials.gov identifier NCT03748186. Citation Format: R. Wendel Naumann, Denise Uyar, John W. Moroney, Fadi S. Braiteh, Russell J. Schilder, John P. Diaz, Erika Hamilton, Sami Diab, Lainie P. Martin, David M. O'Malley, Richard T. Penson, Clifford DiLea, Michael Palumbo, Venita DeAlmeida, Shannon Matheny, Arturo Molina. STRO-002-GM1, a first in human, phase 1 study of STRO-002, an anti-folate receptor alpha (FRα) antibody drug conjugate (ADC), in patients with advanced platinum-resistant/refractory epithelial ovarian cancer (OC), including fallopian tube or primary peritoneal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT125.

AbstractPurpose: NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft-tissue sarcomas. Patients and Methods: This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 to 215 mg/m2. Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated. Results: Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma, one with osteosarcoma, and 11 with other solid tumors. Observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m2 and 150 mg/m2, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations. Conclusions: NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma.

e16050 Background: The PI3K/mTOR pathway overactivation and loss of PTEN occur in 20-40% of mCRC pts. A recent phase 1/2 study in mCRC pts showed evidence that everolimus added to 1L SOC treatment improved outcomes, in particular in pts with PTEN loss (Gilcrease, 2019). This prospective, single-arm phase 1/2 study aims to identify the optimal dose and schedule of nab-sirolimus (ABI-009), an mTOR inhibitor, plus FB and evaluate the safety and preliminary efficacy of this regimen. Methods: Eligible pts have no prior therapy, ≥18 years old, ECOG performance status of 0-2. PTEN loss (by IHC) is evaluated for all pts. nab-Sirolimus IV starting dose and schedule was 30mg/m2 weekly for 3 weeks followed by a week of rest (on D1, 8, and 15 in a 28-day cycle, qw3/4) plus standard doses of FB on D1 and D15. Dose escalation to 45 and 60mg/m2 or de-escalation to 20 and 10mg/m2 followed the 3+3 design. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: As of Jan 31, 2020, 24 pts were treated in the phase 1 study and 18 were evaluable for response. No DLTs were observed in the first 3 pts treated with nab-sirolimus at 30mg/m2 qw3/4; however, all 3 pts missed D8 doses (due to G2 thrombocytopenia and G3 neutropenia) and the cohort expanded to additional 3 pts for further observation. 5/6 pts missed D8 doses and a new dose cohort enrolled pts at 20mg/m2 qw3/4. No DLTs were observed and the cohort was expanded to 10 pts. A safety review of the first 18 pts observed that 9/18 pts missed doses on D8 and a new cohort was added to enroll pts at 20 mg/m2 q2w (D1 and D15, as for FB). This cohort enrolled 8 pts with no DLTs and represents the recommended-phase-2-dose (RP2D) and continues enrollment in phase 2. For all pts, 15/24 (63%) pts had G3-4 treatment-related adverse events (TRAEs); most common were neutropenia (6/24, 25%) and thrombocytopenia (4/24, 17%). At the RP2D 3/8 (38%) pts had G3-4 TRAEs (thrombocytopenia, weight loss, and hypertension, 1 pt each). Among 18 evaluable pts, best response was: 7/18 (39%) partial response, 10/18 (56%) stable disease, and 16/18 (89%) had tumor shrinkage. PTEN was assessed in 14 pts: 4/14 (29%) had PTEN loss, 2/4 (50%) PTEN loss pts responded, while 3/10 (30%) pts that were PTEN+ (WT) had a response. Conclusions: The RP2D of nab-sirolimus is 20mg/m2 q2w in combination with standard mFOLFOX+bevacizumab. The phase 2 portion of the study is ongoing. Clinical trial information: NCT03439462 .

TPS3647 Background: Nectin-4, a transmembrane cell adhesion protein, is highly expressed in urothelial carcinoma (UC), breast cancer (BC), non-small cell lung cancer (NSCLC), and gastroesophageal cancers (GEC); targeting Nectin-4 on these tumors may provide a novel treatment approach. Enfortumab vedotin (EV), an investigational human monoclonal antibody-drug conjugate, binds to Nectin-4 and upon internalization releases MMAE resulting in cell cycle arrest and cell death. Recently, EV received accelerated approval by the FDA for the treatment of adults with locally advanced/metastatic UC who previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Use of EV in this study is investigational. Methods: This open-label phase 2 study (NCT04225117) will assess the efficacy and safety/tolerability of EV in patients (pts) with previously treated locally advanced/metastatic malignant solid tumors. Adult pts (~240) with histologically or cytologically confirmed disease and an ECOG ≤1 will be enrolled into 1 of 6 tumor-specific cohorts (Table), with ~40 pts each. While Nectin-4 expression is not required for enrollment, it is being tested retrospectively. Patients with active CNS metastases, grade ≥2 preexisting sensory or motor neuropathy, grade ≥3 immunotherapy-related hypothyroidism or panhypopituitarism, ongoing grade >3 immunotherapy-related AEs requiring high-dose steroids, or a history of uncontrolled diabetes mellitus within 3 months of the study will be excluded. All pts will receive EV 1.25 mg/kg IV on Days 1, 8, and 15 of each 28-day cycle until treatment discontinuation criteria are met; dose reductions/interruptions will be permitted. For all cohorts, the primary endpoint is investigator-assessed confirmed objective response rate (RECIST v1.1); secondary endpoints include duration of response, disease control rate, progression-free and overall survival, and safety/tolerability of EV. This study is recruiting as of February 2020. Clinical trial information: NCT04225117 . [Table: see text]

Introduction/Background Globally, cervical cancer is one of the most common and lethal gynaecological cancers. Advanced/metastatic disease is typically treated with chemotherapy, often with poor objective response rates (ORRs) and durations of response (DORs) in pretreated patients; ORRs with anti-PD-1 therapies range from 12%-26%. Bintrafusp alfa* (M7824) is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking PD-L1. We report safety and efficacy in patients with cervical cancer treated with bintrafusp alfa in dose-escalation and expansion phases of an ongoing phase 1 trial (NCT02517398). Methodology Patients with advanced/metastatic disease received bintrafusp alfa 0.3–30 mg/kg (dose-escalation, n=10) or 1200 mg (expansion, n=15) Q2W until PD, unacceptable toxicity, or withdrawal. Treatment past PD was allowed if adverse events (AEs) were tolerable and no new treatment was indicated. Primary endpoints were safety (dose-escalation) and BOR (expansion). Results As of 9 January 2019, 25 patients were treated for a median duration of 9.6 (range, 2.0–72.0) weeks. Six patients had confirmed responses per RECIST 1.1 (ORR, 24.0%); 5/6 responses were ongoing at data cutoff (median DOR not reached; range, 2.3±24.9+ months). One additional patient had a delayed PR that was ongoing for 8.7 months at data cutoff, with 73.3% disease shrinkage after initial PD (total clinical response rate, 28.0%). Responses occurred irrespective of PD-L1 protein expression: 1 patient with PD-L1-negative disease had a response. Grade 3 treatment-related AEs (TRAEs) occurred in 6 patients (24.0%); 1 patient experienced a grade 4 TRAE (4.0%; hypokalaemia). Six patients discontinued treatment due to TRAEs. No treatment-related deaths occurred. Conclusion Bintrafusp alfa has a manageable safety profile and promising clinical activity with durable responses. Further investigation of bintrafusp alfa in cervical and other HPV-associated cancers is ongoing (NCT03427411). Updated results will be presented. Disclosure TL discloses honoraria from Foundation Medicine, Takeda, and PUMA, and receives grant/research support from Foundation Medicine, Pfizer, AstraZeneca, Hengrui, and Eureka. JS discloses inventorship on a National Institutes of Health patent related to the work. LSO and ID disclose employment with EMD Serono, Inc. CH discloses employment with Merck Healthcare KGaA. JLG discloses that National Cancer Institute has a cooperative research and development agreement with EMD Serono, Inc. and discloses inventorship on a National Institutes of Health patent related to the work. All remaining authors have nothing to disclose. Funding for this trial was provided in part by the Center for Cancer Research, National Cancer Institute, and National Institutes of Health Clinical Center. This trial was sponsored by Merck Healthcare KGaA, Darmstadt, Germany, and is part of an alliance between Merck Healthcare KGaA and GlaxoSmithKline. *Proposed INN Abstract P37 Table 1 Response rates of bintrafusp alfa in cervical cancer

Results from the Phase III IMpower133 study (NCT02763579) were previously made public. Based on improvements in overall survival in patients with extensive-stage small cell lung cancer (ES-SCLC) who received atezolizumab plus carboplatin and etoposide (IMpower133 regimen) vs chemotherapy administered in the 1L setting, the NCCN added this regimen to its guidelines (category 1, preferred) on October 10, 2018. Accordingly, some providers began implementing this regimen in their clinical practice, creating a unique opportunity to characterise its early and broad use in a real-world setting. Patients with ES-SCLC who started treatment within 90 days of initial diagnosis and had a confirmed administration of atezolizumab with carboplatin or cisplatin and etoposide (atezo regimen) on or after September 25, 2018, were included from the de-identified Flatiron Health electronic health records–derived database, representing > 280 US cancer clinics (≈ 800 sites of care). Treatment data were analysed through April 30, 2019. Broad use was defined as treatment with the atezo regimen outside of several main clinical trial restrictions (ECOG PS ≥ 2, abnormal laboratory values, cisplatin use or as 2L treatment). Frequencies and percentages are reported. Monthly uptake was defined as the percentage of ES-SCLC patients starting 1L therapy each month who were treated with the atezo regimen. Uptake of the atezo regimen increased from 10% in October 2018 to 46% in February 2019 (before FDA approval on March 18, 2019) and 66% in April 2019 (after FDA approval); 143 patients were identified, 92% of whom had ES-SCLC at initial diagnosis (Table). The atezo regimen was used broadly among 46% of patients (18% with ECOG PS ≥ 2, 18% with an abnormal laboratory value, 1% on cisplatin, 17% as 2L ES-SCLC treatment). The median time from ES-SCLC diagnosis to start of the atezo regimen was 16 days for 1L patients and 78 days for 2L patients. Patients treated with the atezo regimen in the 1L were administered atezolizumab at a median of 8 days after start of chemotherapy; those treated in the 2L were typically administered atezolizumab immediately at the start of the line. This real-world analysis demonstrates the broad use of the atezo regimen, with nearly half of patients treated outside of several main IMpower133 trial restrictions. Further, a rapid uptake of the regimen even before FDA approval underscores its impact on changing clinical practice and the high unmet need of this patient population.TableCharacteristics of Patients Treated With the Atezolizumab Plus Carboplatin/Cisplatin and Etoposide Regimen in Routine Clinical CarePatients, n143Treated prior to FDA approval (March 18, 2019), n (%)101 (71)Median age at ES-SCLC diagnosis (IQR), years67 (61, 73)Aged ≥ 65 years at ES-SCLC diagnosis, n (%)90 (63)Female, n (%)71 (50)White, n (%)100 (70)Smoking history, n (%)137 (96)Stage at initial diagnosis, n (%)LS7 (5)ES132 (92)Unknown4 (3)ECOG PS, n (%)a0 or 176 (53)2+26 (18)Unknown41 (29)Radiation therapy, n (%)b14 (10)LS setting, n7ES setting, n7Regimen, n (%)Atezolizumab, carboplatin, etoposide141 (99)Atezolizumab, cisplatin, etoposide2 (1)Line of therapy of atezo regimen in ES setting, n (%)1L119 (83)2L24 (17)Median time from ES-SCLC diagnosis to start of line of therapy containing atezo regimen (IQR), days1L16 (11, 26)2L78 (59, 98)Median time from ES-SCLC diagnosis to first administration of atezo within line (IQR), days1L24 (14, 27)2L78 (59, 98)Abnormal baseline laboratory value, n (%)c26 (18)1L, first line; 2L, second line; atezo, atezolizumab; ECOG, Eastern Cooperative Oncology Group; FDA, US Food and Drug Administration; IQR, interquartile range; LS, limited stage; PS, performance status. a ECOG PS value closest to within −30 to +7 days of treatment start. b Includes radiation therapy to chest following initial diagnosis of SCLC, including concurrent radiation therapy with systemic chemotherapy, chemotherapy followed by radiation therapy, up-front palliative radiation therapy to the chest or for superior vena cava syndrome. c Abnormal values defined as those not meeting the following definitions: absolute lymphocyte count ≥ 500/μL, lymphocyte count ≥ 500/μL, absolute neutrophil count ≥ 1500 cells/μL, platelet count ≥ 100,000/μL, hemoglobin ≥ 9.0 g/dL, aspartate aminotransferase ≤ 5 × upper limit of normal (ULN), alanine aminotransferase ≤ 5 × ULN, alkaline phosphatase ≤ 5 × ULN, serum bilirubin ≤ 1.25 × ULN, serum creatinine ≤ 1.5 × ULN, serum calcium ≤ 12 mg/dL. Open table in a new tab