Abstract PD-1/PD-L1-targeting antibodies have revolutionized cancer treatment but most pts fail to respond (primary resistance) or lose response (secondary resistance). Anti-PD-1 therapy resistance mechanisms are poorly understood; other checkpoint inhibitor pathways are important investigational targets based on animal model studies. Co-expression of PD-1, LAG3, and TIM3 is associated with functional T-cell exhaustion and may contribute to resistance. Antibodies targeting LAG3 and TIM3 are potential candidates for overcoming anti-PD-1 resistance; LAG3 is also clinically supported as a target for resistance in pts with melanoma. INCAGN2385-203 is a randomized, phase 2 study to evaluate the efficacy and safety of retifanlimab (anti-PD-1) + INCAGN02385 (anti-LAG3) and retifanlimab + INCAGN02385 + INCAGN02390 (anti-TIM3) combinations vs retifanlimab alone in immunotherapy naïve PD-L1-positive (CPS ≥1) recurrent/metastatic SCCHN. Objective response rate was numerically higher in anti-LAG3-containing arms (∼30%) vs the retifanlimab monotherapy arm (20%). Median progression-free survival was similar in all 3 arms. To evaluate pharmacodynamic biomarkers associated with LAG3 and/or TIM3 blockade in the context of PD-1 inhibition, flow cytometry was used to evaluate frequency changes of CD4 and CD8 T cells, regulatory T cells, and memory T cells, as well as activation and proliferation markers in whole blood samples. T-cell proliferation and activation were observed in all 3 arms. T-cell proliferation (CD4 and CD8) measured by frequency change of Ki67-positive T cells and HLA-DR expression was more pronounced in both anti-LAG3-containing arms vs the retifanlimab alone arm. No significant difference in regulatory T cells was observed between the 3 arms. Naïve CD4 and CD8 T cells decreased at similar levels at cycle 1, day 8 across all arms. A steady decrease of central memory CD4 and CD8 T cells up to cycle 4, day 1 was observed with retifanlimab alone, whereas retifanlimab + anti-LAG3 showed elevation of central memory T-cell frequencies in both CD4 and CD8 T cells up to cycle 1, day 15, before decreasing steadily up to cycle 4, day 1; there was no obvious change from baseline to cycle 4, day 1 in the triplet arm. Opposite trends were observed in effector memory CD4 and CD8 T cells. Retifanlimab alone produced a steady increase, whereas retifanlimab + anti-LAG3 showed decreases in CD4 (up to cycle 1, day 15) and CD8 (up to cycle 2, day 1) effector memory T cells before increasing steadily. These preliminary results suggest that LAG3 and/or TIM3 blockade may have unique effects on T-cell function. LAG3 with PD-1 blockade may overstimulate T cells and lead to T-cell elimination, highlighting the need for dose optimization. Further evaluation of T-cell responses of PD-1/PD-L1 blockade with other checkpoint inhibitors, including those targeting LAG3 and TIM3, is warranted. Citation Format: Robert I. Haddad, Denis Soulières, Prakash Neupane, Amaury Daste, Zhiwan Dong, Jin Lu, Michelle Kinder, Jeff Jackson, Richard Schaub, Nawel Bourayou, John Janik, Christophe Le Tourneau. Comparison of T-cell activation status in patients treated with retifanlimab in combination with anti-LAG3/Anti-TIM3 vs retifanlimab alone [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 7747.

BACKGROUND:Modulating tumor-mediated immunosuppression with immunotherapies is an effective therapeutic approach for solid tumors. INCAGN01876 is a humanized IgG1 anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) monoclonal antibody. This phase 1/2 trial evaluated INCAGN01876 plus nivolumab and/or ipilimumab for advanced malignancies. METHODS:In phase 1 (dose escalation), patients received various INCAGN01876 plus nivolumab and/or ipilimumab regimens. In phase 2 (dose expansion), patients with select tumors received INCAGN01876 plus ipilimumab (treatment group [TG] C2) or INCAGN01876 plus nivolumab (TGF). Primary endpoints: safety (phase 1), objective response rate (ORR; phase 2). RESULTS:Overall, 145 patients were enrolled: 51 and 94 in phases 1 and 2, respectively (TGC2, n = 8; TGF, n = 86 [squamous cell carcinoma of the head and neck, SCCHN, n = 46]). Four patients had dose-limiting toxicities; maximum tolerated dose was not reached; INCAGN01876 300 mg Q2W was selected as the recommended phase 2 dose based on safety with nivolumab and/or ipilimumab and safety and pharmacokinetic/pharmacodynamic monotherapy data from the INCAGN 1876-101 phase 1 study. INCAGN01876-related treatment-emergent adverse events (TEAEs) occurred in 62.8% of patients (most commonly pruritus, 16.6%); grade ≥3, 13.8%. Immune-related TEAEs occurred in 31.0% of patients (most frequently pruritus, 11.7%) most were (75.6%) grade 1/2 events. Antitumor activity was observed in TGF cohorts with SCCHN or cervical cancer (ORR 23.9% and 16.7%, respectively). CONCLUSION:INCAGN01876 plus nivolumab and/or ipilimumab was generally well tolerated, with a safety profile consistent with previous reports. This observation, along with encouraging antitumor activity in SCCHN and cervical cancer, supports development of INCAGN01876 combined with immune checkpoint inhibitors.

BACKGROUND:T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) is an immune checkpoint receptor upregulated during anti-programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy for cancer. TIM-3 blockade may improve the antitumor activity of PD-1/PD-L1inhibition. This phase 1 study evaluated INCAGN02390, a novel, fully human Fc-engineered antibody against TIM-3. METHODS:INCAGN02390 was evaluated by dose escalation at 10-1600 mg infused in 14-day cycles (every 2 weeks [Q2W]) in pretreated patients with select advanced/metastatic immunogenic solid tumors. Objectives included evaluation of safety/tolerability and maximum tolerated dose (MTD) (primary), pharmacokinetics, preliminary antitumor activity, pharmacodynamics, and immunogenicity (secondary). RESULTS:Forty patients were enrolled and treated with INCAGN02390; 60% had previously received ≥3 lines of systemic therapy. Forty-eight percent had received a prior immune checkpoint inhibitor (anti-PD-1/PD-L1 therapy, 43%; anti-cytotoxic T-lymphocyte associated protein-4 therapy, 23%). No dose-limiting toxicities (DLTs) were observed and MTD was not reached. Twelve patients (30%) had treatment-related adverse events (TRAEs), most commonly fatigue and pruritus (n = 3 each); 3 (8%) had grade ≥3 TRAEs. Four patients (10%) experienced sponsor-assessed irAEs. One patient (3%) achieved partial response (duration, 5.7 months) and 6 had stable disease (≥56 days in all patients, >18 months in 2 patients). CONCLUSIONS:In this heavily pretreated population, no DLTs were reported and modest efficacy was exhibited. A 400-mg Q2W dose was selected for phase II studies investigating INCAGN02390 as part of combination immunotherapies for advanced cancers.

BACKGROUND:Immune checkpoint receptor lymphocyte-activation gene 3 (LAG-3) is an activation marker for CD4+ and CD8+ T cells. Prolonged LAG-3 expression downregulates T-cell activation; therefore, LAG-3 blockade may restore antitumor immune response. INCAGN02385 is a humanized monoclonal LAG-3-targeting antibody. This first-in-human phase I study evaluated INCAGN02385 for advanced/metastatic solid tumors. MATERIALS AND METHODS:In this dose escalation study, patients with select immunogenic advanced or metastatic solid tumors received a single INCAGN02385 infusion (25 mg to 750 mg) every 2 weeks (Q2W). Objectives included evaluation of safety/tolerability, maximum tolerated dose (MTD) (primary), pharmacokinetics (PK), antitumor activity (secondary). RESULTS:Twenty-two patients were enrolled and treated. Sixty-four percent had received ≥ 3 lines of systemic therapy. Sixty-eight percent had received prior immune checkpoint inhibitor (ICI) therapy; anti-programmed death protein-1/anti-programmed death ligand-1, 68%, anti-cytotoxic T-lymphocyte-associated protein-4 therapy, 18%. No dose-limiting toxicities occurred, and an MTD was not reached. Sixteen patients (73%) experienced treatment-related adverse events (TRAEs), most frequently fatigue (n = 7). Except for one grade 3 lymphopenia TRAE, all were grade 1/2 severity. Two patients experienced sponsor-assessed immune-related AEs (pneumonitis, peripheral sensory neuropathy [n = 1] patient each). INCAGN02385 PK parameters were dose proportional across all doses evaluated. Six patients achieved stable disease lasting ≥ 56 days (range, 57-413 days). CONCLUSIONS:INCAGN02385 exhibited linear PK and preliminary evidence of disease control in this heavily pretreated population, consistent with other LAG-3-targeting monotherapies. A 350-mg Q2W dose was selected for phase II studies that will focus on combinations of INCAGN02385 with other ICIs.

2541 Background: INCAGN01876 is a GITR agonist designed to induce antitumor immunity by promoting effector T cells while inhibiting Tregs. Recent clinical studies suggest that combining IO with immune agonists such as INCAGN01876 may extend clinical benefit in pts with cancer. Methods: This global open-label nonrandomized phase 1/2 study assessed the safety, tolerability, recommended phase 2 dose (RP2D), and efficacy of INCAGN01876 + nivolumab (NIVO) and/or ipilimumab (IPI) (NCT03126110). Eligible pts (≥18 y) had locally advanced/metastatic cancer. Phase 1 (dose escalation) consisted of 4 treatment groups: A, INCAGN01876 1, 3, 5, 10 mg/kg Q2W + NIVO 240 mg Q2W; B, INCAGN01876 1, 3, 5, 10 mg/kg for 2 doses then NIVO 240 mg Q2W; C, INCAGN01876 1, 3, 5 mg/kg Q2W + IPI 1 mg/kg Q6W; D, INCAGN01876 1 mg/kg Q2W + NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. INCAGN01876 RP2D was assessed via a 3+3+3 design. Phase 2 (dose expansion) evaluated INCAGN01876 RP2D in combination IO in select tumors; data will be presented elsewhere. Results: As of Nov 9, 2021, 51 pts (A, n=17; B, n=13; C, n=15; D, n=6) were enrolled (most common tumors: breast, gastric, and ovarian [each n=8]; prior PD-(L)1 therapy, n=12). One pt in D had DLTs (nonserious grade [gr] 3 pruritis and rash); MTD was not reached; INCAGN01876 300 mg Q2W was selected as RP2D. All pts in A, B, D, and 93.3% in C had TEAEs. Twenty-six pts had gr ≥3 TEAEs (A, n=10; B, n=5; C, n=7; D, n=4), most commonly, pneumothorax (A [5 mg/kg], n=2) and anemia (B [1, 5 mg/kg], n=2; C [1, 3, 5 mg/kg], n=3). INCAGN01876-related TEAEs occurred in 8, 6, 10, and 5 pts in A, B, C, and D, respectively. Most common immune-related AEs in A: pruritus (gr 1/2, n=2); in B: rash (gr 1, n=2), simultaneous rash and pruritus (gr 1, n=4); in C: pruritus (gr 1/2, n=2), rash (gr 1, n=2), simultaneous rash and pruritus (gr 1, n=2); in D: simultaneous pruritus and rash (gr 3, n=1); 3 pts (A [1 mg/kg], n=1; C [3 mg/kg], n=1; D, n=1) had infusion-related reactions. One pt in A (10 mg/kg Q2W) discontinued treatment due to a pneumonia TEAE. Best unconfirmed overall responses (per RECIST v1.1) were 1 complete response (CR; duration of response [DOR], 1065 days) in renal cancer and 1 partial response (PR; DOR, 573 days) in breast cancer in A; 1 CR (DOR, 876 days) in cervical cancer in B; 1 PR (DOR, 169 days) in ovarian cancer and 1 PR (DOR, 281 days) in lung cancer in C; none in D. The disease control rate was 35.3% in A, 23.1% in B, 33.3% in C, and 0% in D. Conclusions: INCAGN01876 plus NIVO and/or IPI was generally well tolerated in pts with advanced tumors; most common toxicities were mild to moderate pruritus and rash. No novel safety signals were seen. INCAGN01876 300 mg Q2W was selected as RP2D based on safety and preliminary PK/PD data and used for expansion in combination with NIVO or IPI. Clinical trial information: NCT03126110 .

Background Although anti–programmed cell death (PD)-ligand (L)1 therapies have improved clinical outcomes in patients with PD-L1+ recurrent or metastatic head and neck squamous cell carcinoma (r/m HNSCC), many patients do not respond or develop resistance. Reactivation of antitumor immune responses through a combination of co-inhibitory and co-stimulatory pathways may offer improved patient outcomes. Engagement of the glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) promotes effector T-cell proliferation and activation while inhibiting regulatory T cells. In preclinical cancer models, the combination of PD-1 blockade and anti-GITR agonist monoclonal antibodies has led to long-term survival. Preliminary clinical data suggest that combined blockade using anti–PD-(L)1 and anti-GITR antibodies has an acceptable safety profile and antitumor activity in solid tumors including HNSCC. Therefore, this study aims to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCAGN01876 (anti-GITR agonist) in combination with retifanlimab (anti–PD-1) in patients with r/m HNSCC with GITR+ tumors whose disease has progressed on or after prior systemic treatment. Methods This open-label, multicenter, single-arm, phase 2 clinical study (NCT05359692) will enroll approximately 50 patients into part 1 (safety lead-in; n≤12) and part 2 (expansion; n≤38). In part 1, patients will receive intravenous (IV) INCAGN01876 at 2 dose levels (300 or 600 mg) every 2 weeks (q2w) plus IV retifanlimab 500 mg every 4 weeks (q4w). Dose escalation will follow the BOIN design algorithm until identification of a pharmacologically active dose or the maximum tolerated dose, or the maximum dose of 600 mg q2w is reached. Part 2 will enroll up to 32 anti–PD-(L)1 treatment-experienced and 6 anti–PD-(L)1-naive patients. Patients will receive IV INCAGN01876 at the recommended phase 2 dose in combination with IV retifanlimab 500 mg q4w for up to 2 years. The primary endpoints are the safety and tolerability of INCAGN01876 in combination with retifanlimab (part 1) and the objective response rate determined by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in all patients previously treated with anti–PD-(L)1 therapy (parts 1 and 2). Secondary endpoints include duration of response, disease control rate, progression-free survival according to RECIST v1.1, and safety and tolerability of INCAGN01876 in combination with retifanlimab in anti–PD-(L)1-naive and previously treated patients. Exploratory endpoints include pharmacokinetics, pharmacodynamics, and overall survival assessments of INCAGN01876 in combination with retifanlimab. Trial Registration Clinicaltrials. gov identifier NCT05359692 Ethics Approval The study protocol was approved by institutional review boards or independent ethics committees at participating centers.

Background Anti–programmed cell death (PD)-ligand (L)1 therapies have improved clinical outcomes in patients with various cancers.1 However, many patients either do not respond or develop resistance, partly due to additional immune checkpoint receptors including lymphocyte activation gene-3 (LAG-3), which is frequently co-expressed with PD-1 on tumor-infiltrating lymphocytes.2, 3 Combined anti–PD-1 and anti–LAG-3 therapy has demonstrated improvements in clinical outcomes compared with anti–PD-1 alone.4 Co-targeting PD-1 and LAG-3 with a bispecific antibody has the potential to demonstrate enhanced clinical activity compared with individual monoclonal antibodies by achieving synergistic blockade. Therefore, this study aims to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy of INCA32459, a bispecific anti–PD-1 × anti–LAG-3 antibody, in patients with advanced malignancies. Methods This first-in-human, multicenter, open-label, dose-escalation, dose-expansion phase 1 clinical study will enroll approximately 120 patients into separate dose-escalation (n≈40) and dose-expansion phases (n≈80; figure 1). Patients with select advanced malignancies will be eligible to participate in the dose-escalation phase and will receive intravenous INCA32459 starting at dose level 1 every 3 weeks. Dose escalation will proceed according to a protocol-defined statistical hybrid design5 to assess the safety and tolerability of INCA32459 and determine the maximum tolerated dose and/or the recommended doses for expansion. The dose-expansion phase will consist of 2 tumor-specific cohorts. Cohort 1 will enroll patients with unresectable or metastatic melanoma who have experienced disease progression after standard therapy (n≈40). Cohort 2 will enroll patients with recurrent or metastatic PD-L1+ (combined positive score ≥1) squamous cell carcinoma of the head and neck who have experienced disease progression after standard therapy (n≈40). Treatment will be administered in 3-week cycles up to a maximum duration of 2 years. The primary endpoints are safety and tolerability as assessed by occurrence of dose-limiting toxicities and incidence of treatment-emergent adverse events (TEAEs), including overall TEAEs and TEAEs that lead to treatment interruption or withdrawal. Secondary endpoints include objective response rate, disease control rate, and duration of response as determined by investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Lugano criteria (for patients with B-cell lymphomas); pharmacokinetic parameters; and PD-1 receptor occupancy in peripheral blood samples. Trial Registration ClinicalTrials. gov registration pending References Sun L, Zhang L, Yu J, et al. Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis. Sci Rep. 2020;10(1):2083. Gros A, Robbins PF, Yao X, et al. PD-1 identifies the patient-specific CD8? tumor-reactive repertoire infiltrating human tumors. J Clin Invest. 2014;124(5):2246-2259. Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer. 2018;9(5-6):176-189. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. Liao JJZ, Zhou F, Zhou H, et al. A hybrid design for dose-finding oncology clinical trials. Int J Cancer. 2022. doi: 10.1002/ijc.34203. Online ahead of print. Ethics Approval The study protocol was approved by institutional review boards or independent ethics committees at participating centers.

Lymphocyte activation gene 3 (LAG-3) is a cell-surface immune checkpoint receptor that negatively regulates cell activation and proliferation. INCAGN02385 is a humanized Fc-engineered IgG1κ monoclonal antibody with selective and potent LAG-3 antagonist action against LAG-3 binding to MHC class II, leading to enhanced TCR signaling and cytokine secretion of activated T cells. This study primarily aims to determine safety and tolerability and define the MTD or PAD of INCAGN02385 monotherapy. This phase 1, multicenter, open-label, dose-escalation study enrolled patients (pts) with advanced solid tumors who failed available therapies, were intolerant to treatment, or refused noncurative standard treatment. A 3+3 dose-escalation design was used; pts received intravenous INCAGN02385 Q2W at 1 of 5 dose levels (DL): 25 mg, 75 mg, 250 mg, 350 mg, or 750 mg. The primary endpoint was safety and tolerability; other endpoints included assessments of PK, pharmacodynamics, and preliminary efficacy per RECIST v1.1. 22 pts (median age, 63 y) were enrolled, 55% were male and 82% had ECOG PS 1. Lead cancer types were lung (n=4), endometrial, breast, gastric, melanoma, and ovarian cancer (n=2 each). All pts received prior systemic therapy (64% ≥ 3 lines) and 82% had prior immunotherapy. No DLT was observed and MTD was not reached. Most common treatment-emergent adverse events (TEAEs) were fatigue (36%) and cough (27%); 1 drug-related grade 3 lymphopenia occurred at 75 mg and 1 pt in the 350-mg DL had a drug-unrelated stroke leading to discontinuation. One drug-unrelated fatal TEAE of failure to thrive occurred at 250-mg DL. INCAGN02385 trough plasma concentrations increased across cycles in all DLs, and maximum concentration and area under the serum concentration-time curve were dose-proportional across DLs. Doses ≥250 mg led to trough LAG-3 receptor occupancy of ≥90% in peripheral blood and increased markers for CD4+ T-cell proliferation. Overall disease control rate (DCR) was 27%. INCAGN02385 monotherapy was generally well tolerated and exhibited linear PK. The 350 mg Q2W dose is selected for further investigation in phase 1b/2 studies in combinations with other immunotherapies (NCT04370704, NCT05287113).

Background Management of patients with recurrent endometrial cancer after failure on platinum-based therapy remains a clinical challenge. Retifanlimab (INCMGA00012) is an investigational humanized immunoglobulin G4 monoclonal antibody against programmed cell death 1 (PD-1). We previously reported encouraging results from a preplanned interim analysis in patients with microsatellite instability-high (MSI-H) recurrent endometrial cancer treated with retifanlimab in POD1UM-101 [1]. Here, we provide top-line results from the full cohort of patients in the POD1UM-101 study. Methods Eligible patients have histologically proven, unresectable recurrent MSI-H or deficient mismatch repair (dMMR) endometrial cancer (per local testing), ECOG PS ≤1, disease progression during or following 1 to ≤5 prior systemic treatments, measurable disease (per RECIST v1.1), and are naïve to prior immune checkpoint inhibitors. MSI-H and dMMR status were centrally confirmed using PCR and IHC, respectively. Patients receive retifanlimab 500 mg every 4 weeks for up to 2 years. The primary study endpoint is safety. Confirmed best overall response and duration of response (DOR) were evaluated by independent central review (ICR) using RECIST v1.1. Results As of July 6, 2021, 76 patients with centrally confirmed MSI-H (65 [85.5%]) or dMMR (11 [14.5%]) endometrial cancer had received ≥1 dose of retifanlimab; median age was 67.0 (49–88) years, 70 (92.1%) had endometrioid histology, 67 (88.2%) had metastatic disease, and 61 (80.3%) had visceral metastases. Sixty-eight (89.5%) patients had prior surgery or procedure, 54 (71.1%) patients were treated with radiotherapy, and 75 (98.7%) patients had received prior systemic therapy for advanced disease (33 [43.4%] received ≥2 prior systemic therapies for advanced disease). Median retifanlimab exposure was 7.4 (0.03–23.0) months. At data cutoff, 2 (2.6%) patients completed treatment and 30 (39.5%) were on treatment. Grade ≥3 treatment emergent AEs (TEAEs) occurred in 33 (43.4%) patients, including 10 (13.2%) with anemia and 7 (9.2%) with an immune-related AE (nephritis, n=2; autoimmune hepatitis, hepatitis, myositis, rash, and pneumonitis, n=1 each). There were no treatment-related AEs with fatal outcome. Centrally confirmed objective responses were observed in 33 (43.4%) patients (95% CI, 32.1–55.3), with 11 (14.5%) complete and 22 (28.9%) partial responses. Of the 33 patients with objective response, 25 (75.8%) had DOR for ≥6 months; median DOR was not reached. Median follow-up time for response was 8.4 (range, 1.9–28.3) months. Conclusions Retifanlimab was well tolerated and demonstrated encouraging antitumor activity in patients with pretreated recurrent MSI-H or dMMR endometrial cancer, consistent with that achieved with other PD-1 therapies. Acknowledgements This study is sponsored by Incyte Corporation (Wilmington, DE). Trial Registration Clinicaltrials gov NCT03059823 , EudraCT 2017-000865-63 Reference Berton-Rigaud D, et al. J ImmunoTher Cancer 2020; 8 (Suppl 3):A164–A165 [Abstract 268]. Ethics Approval This study was approved by institutional review boards or independent ethics committees in Belgium (Aan de Commissie Medische Ethiek University Hospitals Leuven [CEC: S62335]; Ethics Committee of Hospital-Faculty University of Liège [LEC: 2019/48]); Bulgaria (Ethics Committee for Clinical Trials, Sofia [RA: IAL-24443/08.06.2017; CEC: КИ-80/08.06.2017]); Finland (HUS Tutkimuseettiset toimikunnat Biomedicum Helsinki [RA: KLnro 124/2019]); France (CPP Île-de-France X Hôpital, Aulnay-sous-Bois cedex [RA: MED MSA NAT-2019-08-00080; CEC: CN-RIPH 19.02.17.56415/CPP 27-2019]); Germany (Ethik-Kommission der Albert-Ludwigs-Universität Freiburg, Freiburg [RA: 3102/012; EC: 506/18]; Ethics Committee at the Technical University of Dresden, Dresden [RA: 3102/012; EC: EK 4854 AB]; Ethics Committee of the State of Berlin, Berlin [RA: 3102/012; EC: 17/0411 EK 12/15]); Italy (Comitato Etico del Policlinico Gemelli Fondazione Policlinico Universitario ”Agostino Gemelli”, Roma (RM) [no approval number issued by RA or EC]; Comitato Etico IRCCS di Candiolo, Candiolo-TO [no approval number issued by RA or EC]); Latvia (Ethics Committee for Clinical Research at Development Society of Pauls Stradins Clinical University Hospital, Riga [no approval number issued by RA or EC]); Lithuania (Lithuanian Bioethics Committee, Vilnius [no approval number issued by RA or EC]); Poland (Komisja Bioetyczna przy Uniwersytecie Medycznym, Poznań [RA: UR.DBL.474.0350.2017; CEC: 622/17]); Spain (Comité de Ética de Investigación con Medicamentos, Madrid Centro Actividades Ambulatoria [RA: 17-073 (Locator: 2VK42NE57D); CEC: 17/211]); Ukraine (Ethical Committee at Prykarpatsky Regional Clinical Oncology Center of Ivano-Frankivsk Regional Rada, Ivano-Frankivsk [no approval number issued by RA or EC]); United States (IntegReview IRB, Austin, TX [no approval number issued by IRB]; The University of Texas MD Anderson Cancer Center Institutional Review Board, Houston, TX [no approval number issued by IRB]).

Background Management of advanced endometrial cancer after failure with platinum therapy remains a challenge. Tumors characterized by DNA repair abnormalities are associated with high numbers of neoantigens; immunotherapy is promising in this setting as demonstrated in studies with checkpoint inhibitors (CPI). 1–6 Overcoming emerging resistance to CPI through novel combinations is a focus of research. Retifanlimab is an investigational humanized immunoglobulin G4 monoclonal antibody against programmed cell death 1 (PD 1). In POD1UM-101, retifanlimab monotherapy demonstrated acceptable tolerability and durable clinical benefit in multiple advanced tumor types, including pretreated endometrial cancer.7 POD1UM-204 is designed to further investigate efficacy and safety of retifanlimab alone or in combination with other immunotherapy or targeted agents in patients with advanced/metastatic endometrial cancer. Methods POD1UM-204 is a phase 2, multicenter, nonrandomized, open-label, umbrella study in women =18 years of age, with histologically confirmed diagnosis of advanced/metastatic endometrial cancer that has progressed on or after platinum-based chemotherapy. Patients must have an ECOG performance status =1, at least 1 measurable tumor lesion by Response Evaluation Criteria in Solid Tumors v1.1, and provide tumor tissue at baseline.Approximately 220 patients will be enrolled into 4 treatment groups: Group A–patients with MSI-H (microsatellite instability high) endometrial cancer and no prior CPI therapy (up to 100 patients) receiving retifanlimab monotherapy; Group B–patients with dMMR (deficient DNA mismatch repair) or POLE (DNA polymerase epsilon) endometrial cancer and no prior CPI therapy (up to 40 patients) receiving retifanlimab monotherapy; Group C–patients with unselected endometrial cancer and regardless of prior CPI treatment (up to 40 patients) receiving retifanlimab plus epacadostat (indoleamine 2,3-dioxygenase inhibitor); and Group D–patients with endometrial cancer and activating fibroblast growth factor receptor (FGFR1, 2 or 3) mutations or alterations outside of the kinase domain and regardless of prior CPI treatment (up to 40 patients) receiving retifanlimab plus pemigatinib (FGFR1, 2, 3 inhibitor) (figure 1). Patients can receive up to 26 treatment cycles if they continue to derive benefit and have not met criteria for withdrawal.The primary study objective is evaluating retifanlimab monotherapy antitumor activity (objective response rate [ORR] determined by independent central review [ICR]) in Group A. Secondary study objectives include assessing additional efficacy measures (duration of response, disease control rate and progression-free survival by ICR, and overall survival) in Group A; determining clinical activity (ORR by the investigator) in Groups B, C and D; and evaluating safety and tolerability of retifanlimab. Results N/A Conclusions N/A Acknowledgements This study is sponsored by Incyte Corporation (Wilmington, DE). Trial Registration ClinicalTrials. gov Identifier: NCT04463771; EudraCT 2020-000496-20 Ethics Approval The study was approved by institutional review boards or independent ethics committees of participating institutions. Consent N/A References Mittica G, Ghisoni E, Giannone G, et al. Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity. Oncotarget 2017;8:90532–544. Di Tucci C, Capone C, Galati G, et al. Immunotherapy in endometrial cancer: new scenarios on the horizon. J Gynecol Oncol 2019;30:e46. Brooks R, Fleming G, Lastra R, et al. Current recommendations and recent progress in endometrial cancer. CA Cancer J Clin 2019;69:258–79. Makker V, Rasco D, Vogelzang N, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019;20:711–8. Marabelle A, Le D, Ascierto P, et al. Efficacy of Pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1–10. Oaknin, A, Duska L, Sullivan R, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-h and MSS endometrial cancer. Gynecol Oncol 2019;154(suppl 1):17 [Abstract 33]. Mehnert JM, Joshua AM, Lakhani N, et al. First-in-human phase 1 study of INCMGA00012 in patients with advanced solid tumors: interim results of the cohort expansion phase. J Immunother Cancer 2018;6(suppl 1):115 [Abstract P669].

Background Management of patients with recurrent endometrial cancer after failure of platinum therapy remains an important clinical challenge. Tumors characterized by abnormalities in DNA repair are associated with high numbers of neoantigens, making immunotherapy a promising approach. Retifanlimab (INCMGA00012) is an investigational humanized immunoglobulin G4 monoclonal antibody against PD-1. In the dose escalation and tumor expansion portions of the POD1UM-101 phase 1 study, retifanlimab monotherapy demonstrated acceptable tolerability and durable clinical activity in multiple advanced tumor types, including pretreated endometrial cancer. Here we present interim clinical activity and safety data from a preplanned futility assessment in patients with microsatellite instability-high (MSI-H) recurrent endometrial cancer. Methods Patients eligible for this cohort had histologically proven, unresectable recurrent endometrial cancer that was MSI-H or deficient mismatch repair (dMMR) based on local testing (either by PCR or IHC), ECOG performance status (PS) ≤1, disease progression during or following ≤5 prior systemic treatments, measurable disease per RECIST v1.1, and no prior treatment with immune checkpoint inhibitors. The primary endpoint is safety (using CTCAE v4.03 grading). Confirmed best overall response rate and duration of response were evaluated by RECIST v1.1 (investigator’s assessment). Retifanlimab 500 mg Q4W was administered up to 2 years. Results As of April 7, 2020, 44 patients who received at least 1 dose of retifanlimab were assessed for safety, including 24 patients who were fully assessable for the planned futility analysis. Median age was 63 (49–86) years, 45.5% had an ECOG PS of 1, and 97.7% had adenocarcinoma (1 had missing histology data at cut-off). Of the 44 patients treated, all but 1 were pretreated with at least 1 prior platinum-based chemotherapy, 72.7% were treated with radiotherapy, and 90.9% underwent surgery. Median drug exposure was 1.9 (0.03–11.1) months. Eight patients (18.2%) experienced Grade (G) 3/4 AEs regardless of causality with anemia being the leading event (n=3, 6.8%). Two patients (4.5%) had immune-related AEs (n=1 each: dry mouth [G3] and myositis [G3]); both patients discontinued study treatment because of the event. No treatment-related deaths occurred. Confirmed responses (7 PR, 1 CR) per RECIST v1.1 were observed, supporting study continuation. Median duration of response was not reached, as no confirmed responders had disease progression or died at time of this analysis. Conclusions Retifanlimab was generally well tolerated with preliminary evidence of encouraging antitumor activity in MSI-H pretreated advanced endometrial cancer. Enrollment is ongoing. Acknowledgements This study is sponsored by Incyte Corporation (Wilmington, DE). Trial Registration NCT03059823, EudraCT 2017-000865-63 Ethics Approval The study was approved by institutional review boards or independent ethics committees of participating institutions. Consent n/a

Abstract Background: Abemaciclib is an oral, selective inhibitor of cyclin-dependent kinases 4 & 6 that is dosed on a twice daily continuous schedule. In patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), abemaciclib has demonstrated clinical efficacy with a tolerable safety profile when administered as monotherapy in MONARCH 1 (NCT02102490), in combination with fulvestrant in MONARCH 2 (NCT02107703), and in combination with non-steroidal aromatase inhibitors (NSAI) in MONARCH 3 (NCT02246621). Inducing tumor response and delaying disease progression is of critical need in pts with liver metastases (mets). Methods: An exploratory subgroup analysis was conducted in pts with liver mets at baseline across the MONARCH 1, 2, and 3 studies. All pts had HR+, HER2- ABC. The primary endpoint of MONARCH 1 was objective response rate (ORR), and the primary endpoint of MONARCH 2 and 3 was investigator-assessed progression-free survival (PFS). Analysis methods for these endpoints were previously described. Key enrollment criteria and dosing information are listed in Table 1. Table 1. Eligibility criteria and dosing information for the MONARCH 1, 2, and 3 studiesKey enrollment criteriaMONARCH 1MONARCH 2MONARCH 3Prior endocrine therapyProgressed on or after ETProgressed while receiving adjuvant or first-line ET, or ≤ 12 months from the end of adjuvant ETET naïve or disease relapse >12 months after (neo)adjuvant ETChemotherapy regimens in advanced setting1 or 200Visceral crisisNo restrictionNot permittedNot permittedDose and Schedule abemaciclib200 mg, twice daily, continuous150 mg1, twice daily, continuous150 mg, twice daily, continuousfulvestrant-500 mg, per label-anastrozole2--1 mg, dailyletrozole2--2.5 mg, daily1post-amendment; 2physician's choice of NSAI (anastrozole or letrozole); ET: endocrine therapy Results: Efficacy results of pts with liver mets are described in Table 2. The most frequent adverse events observed in pts with liver mets in MONARCH 1 were diarrhea, nausea, and fatigue and in the abemaciclib arms of MONARCH 2 and 3 were diarrhea, neutropenia, and nausea. Table 2. PFS and response rates of pts with liver mets in MONARCH 1, 2, and 3 MONARCH 1MONARCH 2 abemaciclib armMONARCH 2 placebo armMONARCH 3 abemaciclib armMONARCH 3 placebo armPts with liver mets, n93115594830PFS, HR (95% CI)N/A.45 (.31, .64).47 (.25, .87)Median PFS, months5.611.63.115.07.2ORR, n (%)20 (21.5)54 (47.0)9 (15.3)26 (54.2)6 (20.0)CBR, n (%)39 (41.9)77 (67.0)21 (35.6)32 (66.7)12 (40.0)CBR: clinical benefit rate (complete response [CR] + partial response [PR] + stable disease ≥6 months); HR: hazard ratio; ORR: objective response rate (CR+PR); PFS: progression-free survival; pts: patients Conclusions: The results suggest that the combination of abemaciclib and endocrine therapy was an effective treatment option in pts with liver metastases, a population deriving modest benefit from single-agent endocrine therapy. Tolerability results were generally consistent with the safety populations previously reported for each study. Citation Format: Di Leo A, Dickler M, Sledge GW, Toi M, Forrester T, Nanda S, Koustenis A, Bourayou N, Johnston S. Efficacy and safety of abemaciclib in patients with liver metastases in the MONARCH 1, 2, and 3 studies [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-02.

Background: Abemaciclib, an oral, selective inhibitor of cyclin-dependent kinases 4 and 6 dosed on a twice daily continuous schedule, has demonstrated clinical efficacy and tolerability in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer when administered as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET) in MONARCH 2 and MONARCH 3. In neoMONARCH, abemaciclib plus anastrozole as neoadjuvant therapy reduced the breast tumor cell proliferation marker Ki67 to a greater extent than anastrozole alone after 2 weeks of treatment. Endocrine monotherapy is the current standard of care in the adjuvant setting. However, a proportion of pts relapse despite this therapy. A population with a higher risk of recurrence (15% at 5 years) may be identified based on the clinical and pathological characteristics of disease. Optimizing adjuvant therapy for these pts is an important need. Trial Design: MonarchE (NCT03155997) is a multicenter, randomized, open-label Phase 3 trial that will evaluate the potential for abemaciclib to enhance adjuvant ET. Pts will be randomized 1:1 to abemaciclib 150 mg twice daily continuous schedule plus standard of care (SOC) adjuvant ET versus SOC adjuvant ET alone and stratified by prior chemotherapy (neoadjuvant, adjuvant, or none), menopausal status (pre- or post-), and region (N. America/Europe, Asia, or other). Pts may have started ET within 8 weeks prior to randomization. Pts will receive abemaciclib for up to 2 years in combination with ET per physician9s choice (such as tamoxifen or an aromatase inhibitor, +/- ovarian suppression). ET alone will be continued as clinically indicated. All randomized pts will be followed for a total of 10 years. Eligibility Criteria: Eligible pts (male or female) must have early stage resected HR+, HER2- invasive breast cancer with either ≥ 4 positive pathological axillary lymph nodes (pALNs), or 1 to 3 positive pALNs and at least one of the following high risk markers: primary tumor size ≥5 cm, histological grade 3 tumor, or centrally assessed Ki67 index of ≥20% (in a subset of pts). Pts must have completed definitive locoregional therapy (+/- (neo)adjuvant chemotherapy) and be randomized no more than 12 weeks after completion of last non-ET (surgery, chemotherapy, or radiotherapy). Pts must have tumor tissue available for biomarker analysis prior to randomization. Specific Aims: The primary objective of monarchE is to evaluate invasive disease-free survival (IDFS) per the STEEP System. 1 Secondary objectives include evaluation of IDFS in pts with Ki67 index of ≥20%, distant relapse-free survival, overall survival, safety, pharmacokinetics, and pt health outcomes. Statistical Methods: Assuming an IDFS hazard ratio of .73, the study is powered to approximately 80% to test the superiority of abemaciclib plus standard ET at a 1-sided α=0.025 using a stratified log-rank test. Target accrual: Approximately 3580 pts Contact information: 1-877-285-4559 Reference: 1. Hudis et al. J Clin Oncol. 2007;25(15):2127-2132. Citation Format: Rastogi P, Toi M, Harbeck N, Bourayou N, Frenzel M, Johnston S. MonarchE: A randomized, open-label, phase 3 study of abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in patients with high risk, node positive, early stage, HR+, HER2- breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-05.

Abstract Background: Abemaciclib, an oral, selective inhibitor of cyclin-dependent kinases 4 and 6 dosed on a twice daily continuous schedule, has demonstrated clinical efficacy and tolerability in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer when administered as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET) in MONARCH 2 and MONARCH 3. In neoMONARCH, abemaciclib plus anastrozole as neoadjuvant therapy reduced the breast tumor cell proliferation marker Ki67 to a greater extent than anastrozole alone after 2 weeks of treatment. Endocrine monotherapy is the current standard of care in the adjuvant setting. However, a proportion of pts relapse despite this therapy. A population with a higher risk of recurrence (15% at 5 years) may be identified based on the clinical and pathological characteristics of disease. Optimizing adjuvant therapy for these pts is an important need. Trial Design: MonarchE (NCT03155997) is a multicenter, randomized, open-label Phase 3 trial that will evaluate the potential for abemaciclib to enhance adjuvant ET. Pts will be randomized 1:1 to abemaciclib 150 mg twice daily continuous schedule plus standard of care (SOC) adjuvant ET versus SOC adjuvant ET alone and stratified by prior chemotherapy (neoadjuvant, adjuvant, or none), menopausal status (pre- or post-), and region (N. America/Europe, Asia, or other). Pts may have started ET within 8 weeks prior to randomization. Pts will receive abemaciclib for up to 2 years in combination with ET per physician's choice (such as tamoxifen or an aromatase inhibitor, +/- ovarian suppression). ET alone will be continued as clinically indicated. All randomized pts will be followed for a total of 10 years. Eligibility Criteria: Eligible pts (male or female) must have early stage resected HR+, HER2- invasive breast cancer with either ≥ 4 positive pathological axillary lymph nodes (pALNs), or 1 to 3 positive pALNs and at least one of the following high risk markers: primary tumor size ≥5 cm, histological grade 3 tumor, or centrally assessed Ki67 index of ≥20% (in a subset of pts). Pts must have completed definitive locoregional therapy (+/- (neo)adjuvant chemotherapy) and be randomized no more than 12 weeks after completion of last non-ET (surgery, chemotherapy, or radiotherapy). Pts must have tumor tissue available for biomarker analysis prior to randomization. Specific Aims: The primary objective of monarchE is to evaluate invasive disease-free survival (IDFS) per the STEEP System.1 Secondary objectives include evaluation of IDFS in pts with Ki67 index of ≥20%, distant relapse-free survival, overall survival, safety, pharmacokinetics, and pt health outcomes. Statistical Methods: Assuming an IDFS hazard ratio of .73, the study is powered to approximately 80% to test the superiority of abemaciclib plus standard ET at a 1-sided α=0.025 using a stratified log-rank test. Target accrual: Approximately 3580 pts Contact information: 1-877-285-4559 Reference: 1. Hudis et al. J Clin Oncol. 2007;25(15):2127-2132. Citation Format: Rastogi P, Toi M, Harbeck N, Bourayou N, Frenzel M, Johnston S. MonarchE: A randomized, open-label, phase 3 study of abemaciclib combined with standard adjuvant endocrine therapy versus standard adjuvant endocrine therapy alone in patients with high risk, node positive, early stage, HR+, HER2- breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-05-05.