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6081 Background: Treatment selection based on actionable alterations (AAs) is an appealing strategy for pts with R/M SGT. The GEMS-001 study (NCT02069730) at Princess Margaret Cancer Centre (PM) and the Vall D´Hebron Institute of Oncology (VHIO) pre-screening program facilitate the identification of AAs for R/M SGT pts and treatment selection. Methods: We analyzed R/M SGT treated at PM and VHIO from 2015 to 2020. Clinicopathological features, molecular alterations and treatment modalities were correlated with outcomes. The primary endpoint was overall response rate (ORR) by RECIST 1.1. Clinical benefit rate (CBR) was defined by pts with partial response or stable disease ≥4 months. Clinical actionability of multigene panel testing (NGS) and immunohistochemistry (IHC) were assessed as per institutional molecular tumor boards or investigators. Pts were opportunistically matched to available therapies from each center. Results: In total 206 pts were enrolled. On IHC, HER2 overexpression was present in 9%, Androgen Receptor (AR) 33%, Estrogen/Progesterone Receptor (ER/PR) 11% and ALK overexpression 0%. On NGS, PIK3CA mutation (mut) was in 9%, NTRK fusion 6%, NOTCH1-3 mut 5%, HRAS mut 6%, ERBB2/3 alterations (alt) 4% and FGFR1-4 alt 3%. Up to 92 pts (45%) displayed at least 1 AA and 36 pts (18%) had ≥2 AAs. A total of 60 pts (29%) were matched to AAs. Of those matched, median age was 60 years (range 33-84), M:F 21:39, 95% ECOG≤1 with a median number of prior treatment lines 0 (range 0-3), and their AAs included 26 AR, 9 HER2 or ERBB2 overexpression, 9 PIK3CA mut, 3 NTRK fusion, 3 FGFR1-3 alt and 10 other AAs (2 ER/PR overexpression, 2 EGFR mut, 1 c-kit mut, 1 BAP1 mut, 1 Non-V600 BRAF mut, 1 CDKN2A mut, 1 CHEK2 mut and 1 PTCH1 mut). Overall, ORR was 27% for the matched population. See table for outcomes. Conclusions: In our cohort, almost one third of the population received therapies matched to AAs. Our results suggest that targeted therapies have promising activity in pts with R/M SGT supporting comprehensive molecular and IHC profiling in treatment determination.[Table: see text]

3074 Background: Therapeutic targeting of EGFR has demonstrated efficacy in common advanced malignancies such as colorectal cancer (CRC), squamous cell of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). TGFβ has pro-tumorigenic effects on migration, invasion and tumor-specific immunosuppression, which may enhance the oncogenic effects of activated EGFR. Inhibition of EGFR signaling can lead to TGFβ upregulation as a resistance mechanism. BCA101 is a bifunctional recombinant fusion protein consisting of a chimeric anti-EGFR antibody and an extracellular domain (ECD) of human TGFβRII which demonstrated anti-tumor activity in several preclinical models. Methods: Patients with EGFR-driven advanced solid cancers refractory to standard therapies received BCA101 at escalating doses from 64 mg to 1000 mg intravenously (IV) weekly across 6 dose levels using a 3+3 design to determine dose limiting toxicities (DLT, established within 21 days of initial dosing), maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary endpoints include detailed pharmacokinetic (PK), pharmacodynamic (PD) studies in serial tumor and/or blood samples and assessment of anti-tumor activity. Results: As of 2/11/2021, 21 patients received single agent BCA101 at 64 (n = 3), 240 (n = 7), 500 (n = 2), 750 (n = 3), 800 (n = 3) or 1000 (n = 3) mg IV weekly, including patients with CRC (n = 6), SCCHN (n = 5) uveal melanoma (n = 2), ovarian cancer (n = 2), glioblastoma multiforme (n = 2), conjunctival melanoma, chordoma, pancreatic cancer and anal squamous cell carcinoma (all n = 1). These patients had 1-7 prior lines of antineoplastic therapy (median 4), including 3 patients with prior EGFR inhibitor exposure. Adverse events (AE) related to BCA101 observed in > 1 patient included grade (G) 1-2 rash (n = 9), G 1-2 lipase elevation (n = 2). G3 vitreous hemorrhage at the 240 mg dose level has been the only DLT. The MTD has not been reached and the RD will be based on safety, exposure and pending PD data. Saturation of the clearance was observed at doses above 500mg. Dose proportional increase in Cmax and AUC were observed with doses of 750-1000mg. Best RECISTv1.1 response was stable disease (SD) in 3/10 evaluable patients, with 1 patient on drug ≥4 months. Conclusions: BCA101 is well tolerated at biologically active doses. BCA101 is now being tested in combination with the PD-1 antibody pembrolizumab in patients with SCCHN and anal carcinoma. Clinical trial information: NCT04429542.

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Background: Despite approvals of immune checkpoint inhibitors (ICI), there is still a subset of histologies classified as "cold" with objective response rates (ORR) <10% and no drug approvals. We assessed the benefit of anti-PD1/L1 combinations in early clinical trials in patients (pts) with advanced cold tumors. abstracts Annals of Oncology Volume 31 -Issue S4 -2020 S489

Background: Despite approvals of immune checkpoint inhibitors (ICI), there is still a subset of histologies classified as "cold" with objective response rates (ORR) <10% and no drug approvals. We assessed the benefit of anti-PD1/L1 combinations in early clinical trials in patients (pts) with advanced cold tumors. abstracts Annals of Oncology Volume 31 -Issue S4 -2020 S489

2513 Background: BCA101 is a first-in-class bifunctional fusion protein consisting of an anti-EGFR monoclonal antibody (mAb) and TGFβ receptor 2 extracellular domain (TGFβRII-ECD). Herein, we report the safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data of BCA101 as monotherapy and in combination with pembrolizumab among patients (pts) with advanced solid tumors refractory to standard therapies. Methods: Pts received BCA101 as a single agent (SA) or in combination with pembrolizumab at escalating doses in a parallel 3+3 design starting at 64 mg intravenously (IV) weekly (qw); and at 240 mg IV qw with pembrolizumab 200 mg IV q3w. Primary endpoint: safety and tolerability (CTCAE v5.0); dose limiting toxicity (DLT) period: 21 days. Secondary endpoints: overall response rate (ORR), PK/PD profile, progression-free survival (PFS), and changes in plasma and intra-tumoral TGFβ signaling assessed by SMAD2 phosphorylation. Results: As of 08-Feb-2022, 60 pts have received BCA101 (part A). Forty-five pts (colorectal, n=14; pancreatic, n=7; head and neck squamous cell carcinoma [HNSCC], n=6) received SA BCA101 at doses up to 1500 mg IV weekly. Fifteen subjects (SCC of the anal canal [SCAC], n=8; HNSCC, n=7) received BCA101 doses ranging from 240 to 1500 mg IV qw in combination with pembrolizumab. Maximum tolerated dose has not been reached. Common adverse events (AEs) attributed to BCA101 include rash (70%), fatigue (23%), pruritis and epistaxis (17% each); all grade (G)2 or less. One DLT was observed at the 1250 mg SA dose (G3 anemia, hematuria). No drug-related G4 AEs or deaths were observed. At data cutoff, best response in the SA arm was stable disease (SD) in 15/39 (39%) evaluable pts. In combination, partial response (PR) was observed in 3/11 (27%) evaluable pts (2 in SCAC, 1 in HNSCC) and a disease control rate (DCR) of 9/11 (82%). Two of 3 responders have been on study >4 months; including 1 confirmed PR in a HNSCC pt refractory to anti-PD-1 therapy and cetuximab. Saturation of the EGFR target was observed at BCA101 doses ≥750 mg. Dose proportional increase in Cmax and AUC were observed with doses of BCA101 750-1500 mg. Prolonged neutralization of plasma TGFβ1 was achieved at all doses ≥500 mg. Among paired tumor biopsies (n=23), pSMAD2 reduction up to 62% was observed at doses ≥500 mg. Conclusions: BCA101 is well tolerated and clinically active as a SA and in combination with PD-1 blockade with a predictable PK/PD profile. A recommended dose of 1500 mg both as SA and in combination has advanced to the part B expansion phase for pts with HNSCC, SCAC, and cutaneous SCC. Clinical trial information: NCT04429542.