INCB123667 / Incyte - LARVOL DELTA

Cyclin E1 as a driver of oncogenesis; high grade serous ovarian cancer as an exemplar. (PubMed, Crit Rev Oncol Hematol) - "The WEE1 inhibitor adavosertib and the CDK2 inhibitor INCB123667 achieved response rates of 53% and 33% respectively in platinum-resistant ovarian cancer patients whose tumours overexpressed cyclin E1. Targeting of cyclin E dysregulation via a synthetic lethality approach is therefore a key area of focus for improving treatment strategies in HGSOC and other cancers with high unmet clinical need. In this review we discuss the functions of cyclin E1, mechanisms and consequences of dysregulation, and strategies for therapeutic exploitation of cyclin E1 dysregulated tumours, combining fundamental biology with clinical perspectives."

Journal • Review • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1

A Study to Evaluate the Effect of Food on the Single-Dose Pharmacokinetics and a Drug-Drug Interaction Evaluation of Itraconazole and Rifampin on INCB123667 When Administered Orally to Healthy Adult Participants (clinicaltrials.gov) - P1 | N=51 | Recruiting | Sponsor: Incyte Corporation | Completed ➔ Recruiting | N=15 ➔ 51 | Trial completion date: May 2025 ➔ Mar 2026 | Trial primary completion date: May 2025 ➔ Feb 2026

Enrollment change • Enrollment open • Trial completion date • Trial primary completion date

MAESTRA 1: A phase II, single-arm study of INCB123667 in patients with platinum-resistant ovarian cancer (PROC) with cyclin E1 (CCNE1) overexpression (ESMO 2025) - "PROC standard treatment is mirvetuximab soravtansine (mirv) for pts with folate receptor α (FRα)-positive PROC or non-platinum chemotherapy +/- bevacizumab (bev). Secondary endpoints include safety and tolerability, duration of response, progression-free survival and overall survival. Table: 1220TiP Study cohorts Cohort Cyclin E1 expression levels 1 (n≈100) ≥75% tumor cells with ≥1+ staining intensity 2 (n≈30) ≥50% to <75% tumor cells with ≥1+ staining intensity 3 (n≈30) <50% tumor cells with ≥1+ staining intensity"

Clinical • P2 data • Platinum resistant • Epithelial Ovarian Cancer • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor • CCNE1 • FOLR1

MAESTRA 2: Study to Evaluate INCB123667 Versus Investigator's Choice of Chemotherapy in Participants With Platinum-Resistant Ovarian Cancer With Cyclin E1 Overexpression (clinicaltrials.gov) - P3 | N=466 | Not yet recruiting | Sponsor: Incyte Corporation

New P3 trial • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor

INCB123667-103: Study Assessing the Mass Balance, Pharmacokinetics, and Metabolite Profiles of a Single Oral Dose of [14C]-INCB123667 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=9 | Recruiting | Sponsor: Incyte Corporation | Not yet recruiting ➔ Recruiting

Enrollment open

Study Assessing the Mass Balance, Pharmacokinetics, and Metabolite Profiles of a Single Oral Dose of [14C]-INCB123667 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=9 | Not yet recruiting | Sponsor: Incyte Corporation

New P1 trial

First-in-human phase I dose finding study of INCB123667, a selective CDK2 inhibitor, in patients with advanced solid tumors (ESMO 2025) - P1 | "The totality of safety, PK and antitumor activity supports 50 mg bid as the recommended dose for further development. Table: 974P Patients, n (%) INCB123667 RDEs 50 mg bid (n=99) 100 mg qd (n=14) 125 mg qd (n=71) Any grade Grade 3/4 Any grade Grade 3/4 Any grade Grade 3/4 Hematologic AEs Thrombocytopenia 43 (43.4) 10 (10.1) 5 (35.7) 0 28 (39.4) 8 (11.3) Anemia 32 (32.3) 6 (6.1) 5 (35.7) 1 (7.1) 35 (49.3) 7 (9.9) Neutropenia 25 (25.3) 5 (5.1) 6 (42.9) 0 30 (42.3) 7 (9.9) Non-hematologic AEs Fatigue 17 (17.2) 3 (3.0) 3 (21.4) 0 25 (35.2) 1 (1.4) Asthenia 11 (11.1) 0 2 (14.3) 0 16 (22.5) 2 (2.8) GI AEs Nausea 23 (23.2) 0 10 (71.4) 0 48 (67.6) 0 Vomiting 15 (15.2) 0 4 (28.6) 0 29 (40.8) 0 Diarrhea 7 (7.1) 0 2 (14.3) 0 14 (19.7) 1 (1.4)"

Clinical • First-in-human • Metastases • P1 data • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • CDK1

INCB 123667-101: Study of INCB123667 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=604 | Recruiting | Sponsor: Incyte Corporation | Trial completion date: Jul 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2025 ➔ Jul 2027

Monotherapy • Trial completion date • Trial primary completion date • Breast Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

A Study of INCB123667 in Participants With Platinum-Resistant Ovarian Cancer With Cyclin E1 Overexpression (clinicaltrials.gov) - P2 | N=160 | Recruiting | Sponsor: Incyte Corporation | Not yet recruiting ➔ Recruiting

Enrollment open • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor

Incyte...Provides Updates on Key Clinical Programs (Businesswire) - "The Phase 1 data in patients with myelofibrosis (MF) as monotherapy and in combination with ruxolitinib are anticipated in the second half of 2025...A Phase 1 study evaluating JAK2V617Fi in MPNs is ongoing. Initial proof of concept data are anticipated in the first half of 2026...Incyte plans to initiate Phase 3 studies for its potentially first-in-class CDK2 inhibitor (INCB123667), in ovarian cancer in 2025 and is also evaluating INCB123667 in combination with other treatments; The Phase 3 study evaluating tafasitamab as first-line treatment for diffuse large B-cell lymphoma (DLBCL) is ongoing. The Phase 3 data are anticipated in the second half of 2025; The Phase 1 studies evaluating KRASG12D and TGFßR2×PD-1 in solid tumors are ongoing. Initial proof of concept data for both studies are anticipated in the second half of 2025."

Clinical data • New P3 trial • Diffuse Large B Cell Lymphoma • Myelofibrosis • Myeloproliferative Neoplasm • Ovarian Cancer • Solid Tumor

A Study of INCB123667 in Participants With Platinum-Resistant Ovarian Cancer With Cyclin E1 Overexpression (clinicaltrials.gov) - P2 | N=160 | Not yet recruiting | Sponsor: Incyte Corporation

New P2 trial • Platinum resistant • Oncology • Ovarian Cancer • Solid Tumor

Safety and preliminary efficacy from a phase 1 study of INCB123667, a selective CDK2 inhibitor, in patients with advanced platinum-resistant and refractory ovarian cancer (OC). (ASCO 2025) - P1 | "In this phase 1 study of pts with heavily pretreated advanced/metastatic platinum-r/r OC, single agent INCB123667 at various doses showed an acceptable safety profile including expected cytopenia and nausea. The encouraging antitumor activity in this difficult-to-treat population support the advancement of INCB123667 into pivotal studies in pts with platinum-resistant OC."

Clinical • Metastases • P1 data • Platinum resistant • Anemia • Gastrointestinal Disorder • Neutropenia • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • Thrombocytopenia • CCNE1

Interim safety and antitumor activity data from a phase 1 study of INCB123667, a selective CDK2 inhibitor, in patients with metastatic recurrent endometrial cancer. (ASCO 2025) - P1 | "In this interim analysis, single-agent INCB123667 at various doses has shown an acceptable safety profile in pretreated pts with metastatic recurrent endometrial cancer, including expected cytopenia. The encouraging antitumor activity including post-PD-1 based therapy failure supports future development of INCB123667 in advanced/metastatic endometrial cancer."

Clinical • IO biomarker • Metastases • P1 data • Anemia • Carcinosarcoma • Endometrial Cancer • Neutropenia • Oncology • Pain • Sarcoma • Solid Tumor • Thrombocytopenia • CCNE1

A Study to Evaluate the Effect of Food on the Single-Dose Pharmacokinetics of INCB123667 When Administered Orally to Healthy Adult Participants (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Incyte Corporation | Not yet recruiting ➔ Completed

Trial completion

Incyte to Showcase New Data from its Oncology Portfolio at 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (Businesswire) - "Incyte...that multiple abstracts featuring new data from its oncology portfolio will be presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 30 – June 3, 2025, in Chicago."

Clinical data • Platinum resistant • Anal Squamous Cell Carcinoma • Endometrial Cancer • Glioblastoma • Merkel Cell Carcinoma • Myelofibrosis • Ovarian Cancer

A Study to Evaluate the Effect of Food on the Single-Dose Pharmacokinetics of INCB123667 When Administered Orally to Healthy Adult Participants (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Incyte Corporation

New P1 trial

Incyte Reports 2024 Fourth Quarter and Year-End Financial Results, Provides 2025 Financial Guidance and Highlights 2025 R&D Milestones (Businesswire) - "Other Hematology/Oncology – key highlights: Incyte plans to initiate Phase 3 studies for its potentially first-in-class CDK2 inhibitor (INCB123667), in ovarian cancer in 2025 and is also evaluating INCB123667 in combination with other treatments. The Phase 3 study evaluating tafasitamab in first-line DLBCL is ongoing. The Phase 3 data are anticipated in the first half of 2025. The Phase 1 studies evaluating KRASG12D and TGFßR2×PD-1 in solid tumors are ongoing and enrolling patients. Initial proof of concept data for both studies are anticipated in 2025."

New P3 trial • P1 data • P3 data • Diffuse Large B Cell Lymphoma • Ovarian Cancer • Solid Tumor

INCB 123667-101: Study of INCB123667 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=604 | Recruiting | Sponsor: Incyte Corporation | N=340 ➔ 604 | Trial primary completion date: Apr 2024 ➔ Aug 2025

Enrollment change • Monotherapy • Trial primary completion date • Breast Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Safety and tolerability of INCB123667, a selective CDK2 inhibitor, in patients (pts) with advanced solid tumors: A phase I study (ESMO 2024) - P1 | "INCB123667 was generally well tolerated with promising antitumor activity in pts with cyclin E1 overexpressing or CCNE1 amplified advanced/metastatic solid tumors. Dose expansion is ongoing in 6 tumor-specific cohorts. Evaluation of INCB123667 combination tx has been planned."

Clinical • Metastases • P1 data • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • CCNE1

Incyte’s CDK2 Inhibitor INCB123667 Shows Promising Evidence of Clinical Activity in Patients with Advanced Solid Tumors, Notably Ovarian Cancer (Businesswire) - P1 | N=340 | NCT05238922 | Sponsor: Incyte Corporation | "New data from the Phase 1b dose expansion portion of the trial (data cut-off August 26, 2024) presented today during Incyte’s investor event....Of the 37 evaluable participants with platinum-resistant ovarian cancer treated at three (3) selected dose levels (50mg BID, 100mg QD and 125mg QD) in the expansion portion of the trial, nine participants (24.3%) experienced an overall response (OR; 2 complete responses [CR] and 7 partial responses [PRs]). The highest OR rate of 31.3% (5 responders, including 2 CRs) was found in the 50mg BID cohort (16 evaluable participants)....Results from the Part 1a dose escalation portion of the trial (data cut-off July 15, 2024) include: INCB123667 demonstrated a manageable safety profile (n=84)....Strong selective inhibition of CDK2 was observed resulting in circulating tumor DNA (ctDNA) reduction at all dose levels."

P1 data • Endometrial Cancer • Gastrointestinal Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Ovarian Cancer • Triple Negative Breast Cancer

Incyte to Present Late-Breaking Phase 3 Results for Retifanlimab (Zynyz) and Initial Data from Phase 1 CDK2 Inhibitor Program at the European Society of Medical Oncology (ESMO) Congress 2024 (Businesswire) - "Incyte...announced that the Company will present key data from its oncology portfolio at the upcoming European Society of Medical Oncology (ESMO) Congress 2024, to be held September 13-17 in Barcelona and virtually....'Notably, a Presidential Symposium will feature new, pivotal results from the Phase 3 POD1UM-303/InterAACT2 study of retifanlimab (Zynyz) for the treatment of squamous cell anal carcinoma (SCAC). The POD1UM-303 data will support the supplemental Biologics License Application (sBLA) filing for retifanlimab in SCAC planned by year end 2024'...We will also present new data on INCB123667, a potential first-in-class CDK2 inhibitor, which we believe has the potential to enhance outcomes and serve as a foundational treatment for platinum-resistant ovarian and other cancers.'"

FDA filing • P1 data • P3 data • Anal Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma

Incyte Reports 2023 Fourth Quarter and Year-End Financial Results, Provides 2024 Financial Guidance and Highlights R&D Priorities (Businesswire) - P1 | N=340 | NCT05238922 | Sponsor: Incyte Corporation | "JAK2V617Fi (INCB160058), a potent and selective JAK2 pseudokinase domain binder, cleared the Investigational New Drug (IND) process with the FDA and a Phase 1 study is anticipated to initiate in the first half of 2024. In January 2024, Incyte highlighted promising early clinical efficacy data for its selective small molecule inhibitor of CDK2 (INCB123667), which demonstrated its potential use as monotherapy or combination therapy for late-stage cancers. In a Phase 1 study of INCB123667, early clinical activity was observed with several partial responses (PR) achieved in patients with amplification/over expression of CCNE1, a cell cycle regulator and potential predictive biomarker. Tumor shrinkage was observed across multiple tumor types, including CCNE1+ patients with ovarian cancer. The safety profile of for INCB123667 aligns with the mechanism of action. Additional data is expected to be presented in 2024."

IND • New P1 trial • P1 data • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Incyte Highlights Growth Opportunities and Provides Business Updates at the 42nd Annual J.P. Morgan Healthcare Conference (Businesswire) - "Additionally, the Company will highlight progress across its Oncology pipeline and the research it is advancing in areas of high potential, including promising early clinical efficacy data for INCB123667, a potent and selective inhibitor of CDK2, demonstrating its potential use as monotherapy or combination therapy for late-stage cancers."

P1 data • Oncology • Solid Tumor

Study of INCB123667 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=340 | Recruiting | Sponsor: Incyte Corporation | N=250 ➔ 340

Enrollment change • Metastases • Monotherapy • Breast Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Incyte Reports 2023 First Quarter Financial Results and Provides Updates on Key Clinical Programs (Businesswire) - "At AACR, Incyte presented data demonstrating INCB123667 exhibited significant single-agent activity in vivo in CCNE1high breast cancer xenograft and patient-derived xenograft models....Preclinical in vivo data presented at AACR show that INCA33890 has a greater anti-tumor effect than either individual benchmark antibodies or a simple combination of these."

Preclinical • Breast Cancer • Oncology • Solid Tumor