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Immune-checkpoint inhibitors have profoundly changed the treatment landscape for many tumor types. Despite marked improvements in disease control for highly immunogenic cancers, the clinical impact of checkpoint inhibitors in breast cancers to date is limited. Breast cancer is a heterogeneous disease with different levels of PD-L1 expression and variable tumor microenvironment (TME) composition according to molecular subtype. With emerging evidence of the role of different factors involved in immune evasion, there are promising new immunotherapy targets that will reshape early drug development for metastatic breast cancer. This review examines the available evidence for existing and emerging immuno-oncology (IO) approaches including small molecules targeting different regulators of the cancer-immunity cycle.

Background Salivary gland tumors (SGT) are rare with limited systemic treatments. We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent unresectable or metastatic SGT. Methods GEMS-001 is an open-label phase 2 study for patients with recurrent or metastatic SGT with two parts. In part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For part 2, patients with no targetable alterations identified or no matched agents available are eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. Results Between July 2014 and September 2021, 100 patients were enrolled in GEMS-001 and underwent genomic and proteomic profiling. A total of 21 patients (12 female) with a median age of 61 years (range 36–79) who lacked actionable alterations or available matched therapies were treated with selinexor. Histological subtypes (World Health Organization classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2) and other (n = 6). Fourteen patients were treatment naïve and 7 patients had received 1 or more lines of treatment prior to enrollment. Of 18 evaluable patients, stable disease as best response was observed in 17 patients (94%) (stable disease ≥ 6 months in 7 patients (39%)). Tumor reduction of target lesions was observed in 11 patients (61%). However, no partial or complete responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4–10). The most common treatment-related grade 1–2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)] and dysgeusia [12 patients (57%)]. Most common treatment-related grade 3–4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. Conclusions Although tumor reduction was observed across participants single agent selinexor antitumor activity was limited. Trial registration This clinical trial is registered at ClinicalTrials.gov (NCT02069730) first posted February 24 2014.

Background: Phase 1 immuno-oncology (IO) trials frequently involve pharmacodynamic (PD) biomarker assessments involving tumour biopsies and/or blood collection, with increasing use of molecular imaging. PD biomarkers are set to play a fundamental role in early drug development of immuno-oncology (IO) agents. In the IO era, the impact of PD biomarkers for confirmation of biologic activity and their role in subsequent drug development have not been investigated. Methods: Phase 1 studies published between January 2014 and December 2020 were reviewed. Studies that reported on-treatment PD biomarkers [tissue-derived (tissue-PD), blood-based (blood-PD) and imaging-based (imaging-PD)] were analysed. PD biomarker results and their correlation with clinical activity endpoints were evaluated. Authors' statements on the influence of PD biomarkers on further drug development decisions, and subsequent citations of PD biomarker study results were recorded. Results: Among 386 trials, the most frequent IO agent classes evaluated were vaccines (32%) and PD-(L)1 inhibitors (25%). No PD biomarker assessments were reported in 100 trials (26%). Of the remaining 286, blood-PD, tissue-PD, and imaging-PD data were reported in 270 (94%), 94 (33%), and 12 (4%) trials, respectively. Assessments of more than one PD biomarker type were reported in 82 studies (29%). Similar proportions of blood-PD (9%), tissue-PD (7%), and imaging-PD studies (8%) had positive results that correlated with clinical activity. Results of 22 PD biomarker studies (8%) were referenced in subsequent clinical trials. Conclusions: Most phase 1 IO studies performed PD biomarker assessments. Overall, positive PD biomarker results were infrequently correlated with clinical activity or cited in subsequent trials, suggesting a limited impact on subsequent drug development. With emerging health regulatory emphasis on optimal dose selection based on PD activity, more informative and integrative multiplexed assays that capture the complexity of tumour-host immunity interactions are warranted to improve phase 1 IO trial methodology. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Despite the increased number of novel immunotherapy (IO) agents under current development, their toxicity profile remains to be fully elucidated.An IO risk stratification model was developed based on 5 different variables: treatment-related deaths; rate of grade ≥3 treatment-related adverse events or treatment-emergent adverse events; grade ≥2 encephalopathy or central nervous system toxicity; grade ≥2 cytokine release syndrome; and the number and type of dose-limiting toxicity. Phase 1 IO trials published from January 2014 to December 2020 were reviewed and categorised based on our risk stratification model into three categories: low-, intermediate- and high-risk. Clinical trial variables were associated with the high-risk category. To review the quality of reporting across phase 1 IO trials, a subset of studies was further examined by the use of the ASCO/SITC Trial Reporting in Immuno-Oncology (TRIO) standards.Different IO compounds demonstrated diverse risk profiles. In multivariable analysis, combination versus IO single agent treatment, and testing IO agents different from anti-programmed death-1/programmed death ligand-1 (anti-PD1/L1), anti-cytotoxic t-lymphocyte antigen-4 (anti-CTLA4) antibodies and anti-cancer vaccines were associated with a higher toxicity risk. None of the studies examined in our dataset reported all the items included in the TRIO standards.Our results have important implications for future clinical trial design. Additionally, standards for reporting are urgently needed.

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.

2510 Background: VIGex is a 12- gene GES classifier initially developed on the Nanostring platform and validated for RNA-seq. VIGex classifies samples into Hot, intermediate-Cold (I-Cold) and Cold subgroups. The Hot subgroup as defined by VIGex has been associated with better (PFS) in patients (pts) treated on phase 1 ICT trials at Vall D’Hebron Hospital (VH) (ESMO2020). We investigated the performance of VIGex in pts treated with Pembrolizumab (P) in the INSPIRE clinical trial (NCT02644369) at Princess Margaret Cancer Centre (PM) and compared VIGex with other predictive ICT biomarkers. Methods: Pts with advanced solid tumors were treated with P 200 mg IV Q3wks. RNA-seq from baseline biopsies was performed using the Illumina NextSeq550 platform. Tumor RNA-seq data were transferred from PM to VH and classified by the VIGex algorithm blinded to clinical data. Bespoke circulating tumor DNA (ctDNA) was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera). Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per megabase and PD-L1 was assessed by immunohistochemistry (22C3). Hot subgroup (HOT) was compared to I-Cold + Cold (COLD). We defined 4 groups based on the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). Survival times were calculated with the Kaplan–Meier method and Cox proportional-hazard models were constructed. Results: Out of 76 pts, median age was 55y (range 21-81y), M:F 31:45, all ECOG 0-1, 16 High-grade serous ovarian, 12 triple negative breast, 12 head and neck, 10 melanoma and 26 other. Median no. of P cycles was 3 (range 1–35); follow up was 14m (range 1-67); Median PFS 10.9m and median overall survival (OS) 14m. Overall response rate (RECIST 1.1) was 24% in HOT and 10% in COLD (p = 0.22 two-sided Fisher's exact test). The HOT subgroup was significantly associated with higher OS and PFS when included in a multivariate model adjusted by tumor histology, TMB and PD-L1 (HR 0.43; 95%CI 0.23-0.81; p = 0.009) and (HR: 0.48; 95%CI 0.25-0.95; p = 0.036) respectively. A total of 57 pts had both VIGex and ΔctDNA data. The addition of ΔctDNA further improved the predictive performance of VIGex for OS (Table). Conclusions: VIGex maintained its predictive power for ICT outcomes when applied to an independent external dataset using RNA-seq. The predictive information provided by VIGex was independent of PD-L1 and TMB. Our data indicates that the addition of ΔctDNA to baseline VIGex may refine prediction for ICT outcomes. [Table: see text]

6092 Background: Sinonasal cancers (SC) are heterogeneous diseases. Despite multimodality treatment, overall survival (OS) remains unsatisfactory. We aimed to identify prognostic factors (PFs) associated with patterns of failure and OS in non-metastatic SC (nmSC). Methods: We retrospectively reviewed a pooled dataset of nmSC from Princess Margaret (Canada) and Catalan Institute of Oncology (Spain) treated with definitive surgery ± postop radiotherapy (RT) or RT ± chemo according to institutional protocols between 2010-2019. In squamous cell carcinoma (SCC), HPV status was tested by p16 staining, and HPV DNA (ISH or PCR) if equivocal. The primary goal was to assess the association of tumor histology, stage (by 7th edition TNM), and other clinicopathological variables on locoregional control (LRC), distant control (DC) and OS. Actuarial rates were calculated with Kaplan–Meier (KM) method. Multivariable analysis (MVA) calculated hazard ratios (aHR) adjusted for histology type, T-/N-categories, and primary treatment. Results: Out of 342 pts, median age was 62 years (y) (range 21-96), Male:Female = 212:130, 95% had ECOG 0-1. Tumor histology types were: 192 (56%) SCC (p16+: 35; p16-/untested: 157), 40 (12%) adenocarcinoma (AD), 33 (10%) sinonasal undifferentiated carcinoma or sinonasal neuroendocrine tumors (SNUC/SNEC), 28 (8%) malignant melanoma (MM), 27 (8%) esthesioneuroblastoma (ES) and 22 (6%) adenoid cystic carcinoma (ACC). Median follow up was 3.6 y (range 0.1-11.3). Three-year actuarial rates for each endpoint are included in table. The PFs for LRC by MVA were: SNUC/SNEC (vs SCC) histology, T3-4 (vs T1-2: aHR 2.4, p = < 0.01) and N+ (vs N-: aHR 1.7, p = 0.02) diseases. The PFs for DC were: MM (vs SCC) and SNUC/SNEC (vs SCC) histology, and T3-4 (vs T1-2: aHR 6.0, p = 0.01) disease. The PFs for OS were: MM (vs SCC) histology, older age (aHR 1.0, p < 0.01), T3-4 (vs T1-2: aHR 5.6, p < 0.01), and N+ (vs N-: aHR 2.5, p < 0.01) disease. There was no difference in primary surgery vs RT in any outcome endpoint (all p > 0.05). p16+ SCC had a marginally higher LRC but similar DC and OS vs p16-/untested SCC (table). Conclusions: This large multicentre cohort of nmSC shows different patterns of relapse and survival with different tumor histologies. Our results suggest that individualization of treatment and follow-up strategies by histologic type is recommended to optimize outcomes in these orphan diseases. [Table: see text]

Immune-checkpoint inhibitors have profoundly changed the treatment landscape for many tumor types. Despite marked improvements in disease control for highly immunogenic cancers, the clinical impact of checkpoint inhibitors in breast cancers to date is limited. Breast cancer is a heterogeneous disease with different levels of PD-L1 expression and variable tumor microenvironment (TME) composition according to molecular subtype. With emerging evidence of the role of different factors involved in immune evasion, there are promising new immunotherapy targets that will reshape early drug development for metastatic breast cancer. This review examines the available evidence for existing and emerging immuno-oncology (IO) approaches including small molecules targeting different regulators of the cancer-immunity cycle.

Background Salivary gland tumors (SGT) are rare and heterogeneous diseases with limited systemic options available. Results from recent basket trials including SGT cohorts for specific actionable alterations (AA) have described promising outcomes with molecularly targeted approaches (TA). Methods The GEMS-001 study (NCT02069730) is an ongoing multi-arm trial with two phases. In part 1, recurrent or metastatic (R/M) SGT patients (pts) undergo comprehensive immunohistochemistry (IHC) including HER2, androgen receptor (AR) and ALK translocation and multigene panel testing (NGS). Based on the molecular profiling results in part 1, R/M SGT pts are matched to available targeted therapies on disease progression. Here, we present the efficacy results for the matched cohort of the GEMS-001 study. Results As of July 2021, 100 pts underwent molecular profiling within part 1. According to the SGT subtype (WHO 2017): 49% adenoid cystic carcinoma (ACC), 18% salivary duct carcinoma (SDC), 9% acinic (ACI) and 24% other subtypes (O). Overall, on IHC HER2 overexpression was present in 10%, AR 24% and ALK translocation 0%. On NGS, PIK3CA mutation (mut) was in 10%, HRAS mut 7%, ERBB2/3 alterations (alt) 5%, NOTCH1-3 mut 2% and ETV6-NTRK3 fusion 2%. Up to 45% pts displayed at least 1 AA and 25% had ≥2 AA. AA were enriched in SDC (100% ≥1 AA) as compared to ACI (33% ≥1 AAs), O (58% ≥1 AA) or ACC (22% ≥1 AA) (p Citation Format: Alberto Hernando-Calvo, Eoghan Malone, Daphne Dai, Amy Prawira, Ilan Weinreb, Anneli Eliason, Angela Rodriguez, Katherine Lajkosz, Sarah Jennings, Anna Spreafico, Lillian L. Siu, Aaron Hansen. Genomic profiling and matched therapy for recurrent or metastatic salivary gland neoplasms. Results from the matched cohort of the GEMS-001 clinical trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P154.

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.

2597 Background: In order to improve the expected response rate (ORR) of less than 10% in cold tumors, several ICI combinations are being evaluated in clinical trials. However, most of these trials don’t require any biomarker and pts are included based solely in histology. We aimed to assess the benefit of ICI combinations in pts with unselected cold tumors included in early CT. Methods: ICI naïve pts with cold tumors treated from 2015 to 2021 with ICI combinations in early CT at VHIO were reviewed. Clinico-pathological data and anti-tumor activity were extracted from a prospective database. ORR was defined as per RECIST v1.1 and clinical benefit rate (CBR) as complete/partial response (CR/PR) + stable disease (SD) for ≥ 4 months (m). Kaplan Meier estimates of progression-free survival (PFS) and overall survival (OS) were calculated and a Cox model according to LIPI (Lung Immune Prognostic Index = baseline LDH and derived neutrophil to lymphocyte ratio) was constructed. Immune-related adverse events (irAE) were classified as per CTCAE v.4.03. Hyperprogressive disease (HPD) was evaluated using RECIST v1.1 (Matos et al, 2020). Results: Out of 97 pts, median age was 62y, 61% had ECOG 0 and 29.8% had LIPI 0 (good prognostic score). Most pts had microsatellite stable (MSS) colorectal cancer (60.8%) or ovarian cancer (14.4%). Regimens included anti-PD1/L1 + another ICI in 69% (most commonly anti-LAG3 [26,8%] and CD40 agonist [20.9%]), anti-PD1/L1 + other molecule in 21.7% (most commonly SHP2 inhibitor [33.3%] and anti p53-HDM2 [28.5%]) and bispecific antibodies in 9.3% (anti-PD1/L1 + anti-LAG3 or CD137 agonist). No patient achieved a response. CBR was 15.3% (11 pts with MSS colorectal cancer, 2 ovarian cancer, 1 olfactory neuroblastoma, 1 paraganglioma). 33 pts (34%) presented irAE, 15 pts (15.5%) had irAE ≥ G2, 4 pts (4.1%) had G3 irAE (dry mouth, hypertransaminasemia, myocarditis and neutrophils count decreased) and 1 patient (1%) had G4 hyperglicemia. 58 pts (59.7%) had progressive disease (PD) as best response, 19 of these pts (32.7%) presented irAE. Overall, 20 pts (20.6%) met definition of HPD, representing 34.4% of pts with PD as best response. Median PFS for overall and CBR population were 1.9 m (CI95% 1.7-2.0) and 5.9 m (5.4-NR), respectively. Median OS for overall population was 7.6 m (5.9-9.5), with a trend for improved OS if LIPI good score vs. others (12.6 m vs. 6.2 m, hazard ratio 1.9, (CI 95% 1.1-3.3), p = 0.02). Among hyperprogressors, median OS was 5.33 m (3.39 - NR) and significantly worse LIPI scores (intermediate [1] or poor [2]) were observed as compared to pts with CBR (75% vs 53.3% p = 0.001). Conclusions: ICI combinations demonstrated very limited activity in pts with unselected cold tumors. However, the risk for irAE and HPD remain substantial. Further drug-biomarker co-development strategies are urgently needed to increase the risk benefit ratio for these pts.

2648 Background: Despite an exponential increase in the number of potential targets in the immuno-oncology (IO) field, lack of risk models to predict toxicities remains a challenge in early drug development. We proposed a risk stratification strategy and investigated whether different IO classes may be associated with incremental risk of toxicities. Methods: A systematic search for IO studies from 01/2014 to 10/2020 was conducted. Among the 12053 abstracts screened, 254 reporting phase I-IO trials were selected. Type of IO treatment (IO monotherapy [mono] vs IO combination [comb]), therapeutic class (e.g. IO, molecularly targeted agents [MTA]), and dose escalation method (rule-based, model-based and model-assisted) were collected. A risk scoring model was developed after expert consensus: treatment-related deaths (1:yes, 0:no), incidence of G3/G4 treatment related adverse events (TRAE) or treatment emergent adverse events (TEAE) (0 if 1-29%,1 if ≥30-49%, 2 if ≥50%), incidence of ≥G2 cytokine release syndrome (1:yes, 0:no), incidence of ≥G2 encephalopathy (1:yes 0:no) and incidence of dose-limiting toxicity (DLT) (0:no, 1:lab, 2:clinical). Risk categories were defined by summing all points (0 = low, 1-2 = intermediate, 3+ = high) and were correlated with type of IO treatment, therapeutic class and dose escalation method. Results: Of 254 P1-IO trials reviewed, 228 (90%) were scorable, 26 were not (25 due to lack of AE data). Up to 10/26 (38%) of non-scorable studies were cell therapies. Among the 228 scorable studies, 120 (53%) scored 0, 65 (28%) scored 1-2, 43 (19%) scored 3+; 24 (11%) and 125 (55%) did not provide no. of pts with G3/G4 TRAEs or TEAEs respectively. A significant association was observed between risk categories and therapeutic class (p

2653 Background: Pharmacodynamic biomarkers (PD) are considered fundamental for go/no-go decisions in phase 1 trials. Despite an increase in the availability of blood-based biomarker assays, the requirement of invasive non-diagnostic research tumor biopsies for trial eligibility remains common. In the immuno-oncology (IO) era, the impact of PD analysis for the confirmation of biologic activity and recommended phase 2 dose (RP2D) has not been investigated. Methods: Phase 1 studies from 01/2014 to 12/2018 were reviewed. Among 12053 abstracts screened, a total of 143 phase I-IO trials were identified. Characteristics of studies that included on-treatment PD biomarkers (tissue-derived, blood-based and radiomic) were extracted and analyzed. Outcomes from the biomarker data in terms of proof of mechanism/biologic activity and statistically significant correlation with clinical benefit (objective response or survival) were collected. Authors’ statements on the influence of PD results on RP2D were also noted. Results: Out of 143 phase 1 IO trials, 107 (75%) were monotherapy. The most frequent IO evaluated were vaccines (41%), cell therapy (16%), immunomodulators (13%) and cytokines (7%). Of the 36 combination studies, 20 (61%) included a second IO drug while 16 (39%) included molecular-targeted agents. Only 18 of 143 studies (12%) did not report any PD data. Of the remaining 125 studies, tissue-derived PD (t-PD) biomarkers alone, blood-based PD (b-PD) biomarkers alone, both t-PD and b-PD biomarkers, and imaging biomarkers were tested in 3 (2%), 97 (78%), 25 (20%), and 7 (6%), respectively. Demonstration of proof of mechanism/biologic activity only were reported in 16/28 (57%), 80/122 (66%) and 4/7 (57%) of the t-PD, b-PD and imaging biomarker studies, respectively. Significant correlation with clinical benefit was reported in 2/28 (7%), 7/122 (6%) and 0/7 (0%) of the t-PD, b-PD and imaging biomarker studies, respectively; these involved 4 vaccines (1 in combination with PD1 blockade), 1 cell therapy and 1 oncolytic virus (in combination with CTLA4 blockade). Among 35 b-PD studies with negative results, 5 also performed t-PD biomarkers, all with negative results. Notably, 3 out of 10 t-PD studies with negative results reported concurrent positive b-PD results. Based on the published reports, authors stated that biomarker results helped with RP2D determination in 16/28 (57%) of t-PD and 78/122 (64%) of b-PD studies. Conclusions: Our results suggest that in the IO era, most studies perform PD analysis, with similar proportions of t-PD and b-PD showing proof of mechanism/biologic activity. IO PD biomarkers have limited correlation with clinical benefit. Many authors considered IO PD biomarkers to be relevant in RP2D decisions, but this needs confirmation by other measures of impact. With continued technological developments utilizing circulating biomarkers, b-PD may ultimately replace many t-PD tests in future IO studies.