cirtociclib (BLU-222) / UT MD Anderson Cancer Center, Sanofi - LARVOL DELTA

CDK2 inhibitor BLU-222 synergizes with CDK4/6 inhibitors in drug resistant breast cancers through p21/p27 induction. (PubMed, Nat Commun) - "In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. CRISPR knockout of p21 or p27 in palbociclib-resistant cells eliminated this synergy. Further, RNA sequencing revealed that combination treatment upregulated senescence and interferon pathways, providing mechanistic insight into the observed therapeutic synergy."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDKN1A • HER-2

CDK2 inhibitor BLU-222 synergizes with CDK4/6 inhibitors in drug resistant breast cancers through p21/p27 induction (Nature) - "Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2− and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival."

Preclinical • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Triple Negative Breast Cancer

CDK2 inhibition enhances CDK4/6 inhibitor antitumor activity in comprehensive breast cancer PDX model screen. (PubMed, NPJ Breast Cancer) - "Early clinical data demonstrated activity of BLU-222, a potent and selective CDK2 inhibitor, both as monotherapy (CCNE1 amplified) and in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer. These findings provide evidence that CDK2i combined with CDK4/6i can address multiple known mechanisms of resistance to CDK4/6i, enhancing antitumor responses in preclinical breast cancer models."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCND1 • CCNE1 • CDKN2A • HER-2 • RB1

(VELA) Study of BLU-222 in Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=50 | Terminated | Sponsor: Blueprint Medicines Corporation | Phase classification: P1/2 ➔ P1 | N=366 ➔ 50 | Trial completion date: Sep 2026 ➔ Jul 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Nov 2025 ➔ Jul 2025; This trial was terminated prior to the initiation of Phase 2 for reasons not due to safety concerns.

Enrollment change • Phase classification • Platinum resistant • Trial completion date • Trial primary completion date • Trial termination • Breast Cancer • Carcinosarcoma • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor • CCNE1 • HER-2

Antitumor activity of potent and selective CDK2 inhibitors as monotherapy and in combination with chemotherapy in models of small cell lung cancer (AACR 2025) - P1/2 | "CDK2 inhibition represents a novel therapeutic approach in SCLC, an aggressive cancer with high unmet medical need. In pre-clinical models of SCLC, BLU-222 and BLU-956 demonstrated substantial anti-tumor activity as single agents, with enhanced effects in combination with cisplatin. These findings provide rationale for exploring targeting CDK2 in combination with cisplatin in SCLC and suggest that specific biomarkers could be useful to predict response."

Combination therapy • Monotherapy • Eye Cancer • Lung Cancer • Oncology • Retinoblastoma • Small Cell Lung Cancer • Solid Tumor • CCNE1 • CDK4 • CDKN2A • RB1 • SKP2

Profiling the Activity of the Potent and Highly Selective CDK2 Inhibitor BLU-222 Reveals Determinants of Response in CCNE1-Aberrant Ovarian and Endometrial Tumors. (PubMed, Cancer Res) - "BLU-222 demonstrated robust activity in combination with carboplatin or paclitaxel in CCNE1-aberrant models, rendering chemotherapy-resistant tumors strongly sensitive to the combination. These findings demonstrate that response to CDK2 inhibition by BLU-222 can be further predicted using a combinatorial biomarker signature that could refine patient selection criteria in CCNE1-high patients and support clinical development."

Journal • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1

Profiling the Activity of the Potent and Highly Selective CDK2 Inhibitor BLU-222 Reveals Determinants of Response in CCNE1-Aberrant Ovarian and Endometrial Tumors (Cancer Res) - "Rb and p16 expression were biomarkers that enriched for CDK2-dependency/BLU-222 sensitivity in CCNE1 overexpressed, non-amplified cells....BLU-222 demonstrated robust activity in combination with carboplatin or paclitaxel in CCNE1-aberrant models, rendering chemotherapy-resistant tumors strongly sensitive to the combination."

Preclinical • Endometrial Cancer • Ovarian Cancer

Tumor Suppressors Condition Differential Responses to the Selective CDK2 Inhibitor BLU-222 (Cancer Res) - "Unlike CDK4/6 inhibitors, BLU-222 was able to robustly inhibit proliferation through cell cycle inhibition in both G1 and G2 phases....Models that were exceptionally sensitive to CDK2 inhibition displayed coordinate expression of cyclin E1 and P16INK4A, an endogenous CDK4/6 inhibitor. Functional studies demonstrated that P16INK4A and CDK4/6 activity were key mediators of sensitivity to BLU-222."

Preclinical • Breast Cancer • Ovarian Cancer

(VELA) Study of BLU-222 in Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=366 | Active, not recruiting | Sponsor: Blueprint Medicines Corporation | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • Carcinosarcoma • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor • CCNE1 • HER-2

Blueprint Medicines Reports Third Quarter 2024 Results… (PRNewswire) - "Key Upcoming Milestones - Mast cell disorders: Initiate registration-enabling Part 2 of the HARBOR trial of elenestinib in ISM by the end of this year. Cell cycle inhibition: Continue strategic business development discussions. Complete Phase 1 combination dose escalation for BLU-222 by end of year to inform registration plans."

Trial status • Aggressive Systemic Mastocytosis • Oncology • Solid Tumor

BLU-222, an investigational, oral, potent, and highly selective CDK2 inhibitor (CDK2i), as monotherapy in patients (pts) with advanced solid tumors and in combination with ribociclib (RIBO) and fulvestrant (FUL) in HR+/HER2− breast cancer (BC). (ASCO 2024) - P1/2 | "BLU-222 monotherapy was generally well tolerated in unselected heavily pretreated pts. In addition to encouraging safety, markers of cell cycle modulation and antitumor activity were seen. The initial cohort of BLU-222 with RIBO + FUL exhibited no additional safety concerns."

Clinical • Combination therapy • Metastases • Monotherapy • Anemia • Breast Cancer • Fatigue • Gastrointestinal Disorder • Hematological Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CCNE1 • HER-2

Blueprint Medicines to Present the First Promising and Most Advanced Clinical Data for a CDK2 Inhibitor in Combination with an Approved CDK4/6 Inhibitor in HR+/HER2- Breast Cancer at the 2024 ASCO Annual Meeting (PRNewswire) - P1/2 | N=366 | VELA (NCT05252416) | Sponsor: Blueprint Medicines Corporation | "As of the data cutoff date, 19 patients with HR+/HER2- breast cancer who had progressed on prior CDK4/6 inhibitors were treated with 100 mg to 400 mg twice daily (BID) of BLU-222 plus 400 mg once daily (QD) of ribociclib and combined with fulvestrant...The combination of BLU-222, ribociclib, and fulvestrant was well-tolerated at all BLU-222 dose levels tested. No dose-limiting toxicities, treatment-related severe adverse events (SAEs), or BLU-222-related treatment discontinuations were reported. Treatment-related hematologic and gastrointestinal AEs were generally mild. The maximum tolerated combination dose has not been identified, and combination dose escalation is ongoing....Preliminary clinical activity showed compelling reductions in thymidine kinase 1 (TK1) and circulating tumor DNA (ctDNA), biomarkers that have been shown to be predictive of clinical benefit."

P1/2 data • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

Blueprint Medicines Reports Strong First Quarter 2024 Results and Raises AYVAKIT/AYVAKYT (avapritinib) Full Year Revenue Guidance (PRNewswire) - "Achieved AYVAKIT net product revenues of $92.5 million for first quarter of 2024, representing more than 135 percent growth year-over-year....Advanced the development of BLU-222, an oral, potent, and selective CDK2 inhibitor in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer, with plans to present the first positive combination safety data with signal of early clinical activity for a CDK2 inhibitor in combination with an approved CDK4/6 inhibitor at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting."

P1/2 data • Sales • Breast Cancer • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Anti-tumor activity of CDK2 inhibitor BLU-222 in combination with CDK4/6 inhibitors for overcoming resistance in HR positive and triple negative metastatic breast cancers models (AACR 2024) - " Palbociclib resistant (PR) HR+/HER2- (MCF7 and T47D) and TN (MDA-MB-231 and BT-20) breast cancer cell lines were generated by escalating palbociclib concentrations in culture. We found robust activity of the CDK2 inhibitor, BLU-222 when combined with CDK4/6is in resistant HR+/HER2- and TN breast cancer cell lines and in vivo models. These results support the potential clinical utility of BLU-222 in combination with CDK4/6is for the treatment of both subtypes of breast cancer."

Combination therapy • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDKN1A • HER-2

BLU-222, a potent and highly selective CDK2 inhibitor, demonstrates antitumor activity as monotherapy and as combination treatment in CCNE1-aberrant endometrial cancer models (AACR 2024) - "In preclinical models of CCNE1-aberrant endometrial cancer, BLU-222 demonstrated enhanced activity in combination with paclitaxel. Furthermore, Rb and p16 protein expression can be used in conjunction with CCNE1 copy number to predict response to both BLU-222 monotherapy and combination treatment. These data provide a rationale for using BLU-222 in combination with paclitaxel and demonstrate the potential benefit of using specific biomarkers to predict response."

Monotherapy • Preclinical • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1

Blueprint Medicines Highlights 2024 Corporate Strategy and Business Priorities at 42nd Annual J.P. Morgan Healthcare Conference (PRNewswire) - "Discontinue further investment in the early clinical-stage therapies BLU-945 and BLU-451 for EGFR-mutant NSCLC and explore strategic options, including potential out-licensing, based on the evolving external landscape and emerging clinical data....Present data for BLU-222 in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer in the first half of 2024. Provide update on BLU-222 registration plan in HR+/HER2- breast cancer in the second half of 2024."

Discontinued • P1/2 data • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Combination treatment with CDK2 inhibitor (BLU-222) and either palbociclib or ribociclib is synergistic in pre-clinical models of CDK4/6 inhibitor-resistant breast cancer (SABCS 2023) - "The efficacy of BLU-222 as a single agent or in combination with palbociclib or ribociclib was also assessed in two PDX models (PR 1 and 2) from patients with acquired resistance (i.e. progressed following >6 months of treatment) to palbociclib plus letrozole treatment, and another two PDX models (PR 3 and 4) from patients who were intrinsically resistant (i.e. progressed following < 3 months of treatment) to palbociclib plus fulvestrant or letrozole, respectively. These results show robust activity of BLU-222 in combination with CDK4/6 inhibitors in breast cancer cell lines and PDX models resistant to CDK4/6 inhibitors, providing a strong rationale for advancing BLU-222 plus CDK4/6 inhibitor treatment to clinical development in HR-positive/HER2-negative breast cancer patients who have progressed on CDK4/6 inhibitors."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDKN1A • HER-2

BLU-222: "Escalating monotherapy doses of BLU-222, a potent and selective CDK2 inhibitor, were generally well tolerated in an unselected population of heavily pretreated patients with advanced cancer"; Solid tumor (Blueprint Medicines) - ASCO 2023

P1/2 data • Oncology • Solid Tumor

Blueprint Medicines Highlights Clinical Progress Across Precision Oncology Pipeline at 2023 ASCO Annual Meeting (PRNewswire) - P1/2 | N=366 | VELA (NCT05252416) | Sponsor: Blueprint Medicines Corporation | "Results from the ongoing dose escalation part of the VELA trial of BLU-222 (n=27) showed encouraging safety and evidence of cell cycle pathway modulation consistent with the treatment's best-in-class preclinical profile...in patients with HR+/HER2- metastatic breast cancer. BLU-222 was generally well-tolerated with no discontinuations due to adverse events (AEs). Treatment-related hematologic AEs commonly seen with CDK4/6 inhibitors were generally mild and primarily reported in patients with a history of low blood cell counts. No cardiac AEs or QTc prolongation were observed. BLU-222 showed evidence of cell cycle pathway modulation as demonstrated by circulating and tumor tissue-based biomarker data."

P1/2 data • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • EGFR • HER-2

BLU-222, an oral, potent, and selective CDK2 inhibitor, in patients with advanced solid tumors: Phase 1 monotherapy dose escalation. (ASCO 2023) - P1/2 | "One partial response was seen in a pt with HR+/HER2− metastatic breast cancer previously treated with 5 lines of therapy, including palbociclib, abemaciclib, and capecitabine. As of the cutoff date, BLU-222 monotherapy was generally well tolerated in pts at the BID doses tested. Dose escalation is ongoing to determine the recommended phase 2 dose. Preliminary evidence of cell cycle pathway modulation and clinical activity have been observed."

Clinical • Metastases • Monotherapy • P1 data • Anemia • Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCNE1 • HER-2

Blueprint Medicines to Present New Clinical Data Across Broad Precision Therapy Pipeline at 2023 ASCO Annual Meeting (PRNewswire) - "Blueprint Medicines Corporation...announced the acceptance of clinical abstracts for multiple programs across its precision therapy portfolio at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, June 2 to 6...The datasets to be reported at the ASCO Annual Meeting include: Results from the ongoing dose escalation part of the VELA trial of BLU-222 in breast cancer and other cancers vulnerable to CDK2 inhibition, showing evidence of monotherapy safety and pathway modulation. Updated results from the dose escalation part of the SYMPHONY trial showing the safety and tolerability of BLU-945 as a monotherapy and in combination with osimertinib in patients with late-line, EGFR-mutant non-small cell lung cancer (NSCLC). Results from the ongoing dose escalation part of the CONCERTO trial of BLU-451 in EGFR exon 20 insertion-positive NSCLC showing early safety and clinical activity."

P1/2 data • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • CDK2 • EGFR

Blueprint Medicines Announces Lift of Partial Clinical Hold on Phase 1/2 VELA Trial of BLU-222 (PRNewswire) - "Blueprint Medicines Corporation...announced that the U.S. Food and Drug Administration (FDA) has lifted a partial clinical hold on the Phase 1/2 VELA trial of BLU-222....'We are confident in the potential of BLU-222 to improve outcomes in patients with cancers vulnerable to CDK2 inhibition, and we look forward to presenting initial dose escalation data from the VELA trial in the second quarter of 2023.'"

FDA event • P1/2 data • Oncology • Solid Tumor

BLU-222: Protection of composition-of-matter patent until 2042 (Blueprint Medicines) - Annual Report 2022

Patent • Oncology

Blueprint Medicines Announces Partial Clinical Hold for Phase 1/2 VELA Trial of BLU-222 (PRNewswire) - "Blueprint Medicines Corporation...announced that the U.S. Food and Drug Administration (FDA) verbally informed the company on February 8, 2023 that it has placed a partial clinical hold on the Phase 1/2 VELA trial of BLU-222 due to visual adverse events (AEs) observed in a limited number of patients. Patients currently enrolled in the trial are continuing on study drug at this time, and additional patients will not be enrolled until the partial clinical hold is resolved....Consistent with prior guidance, Blueprint Medicines plans to present initial dose escalation data from the VELA trial of BLU-222 in the first half of 2023."

P1/2 data • Trial suspension • Breast Cancer • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Estrogen Receptor Positive Breast Cancer • Gastric Cancer • Gastrointestinal Cancer • Gynecologic Cancers • HER2 Negative Breast Cancer • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor

Florida Cancer Specialists & Research Institute Contributing to Rapid Advancements in Breast Cancer Treatment (GlobeNewswire) - "Florida Cancer Specialists & Research Institute, LLC (FCS) hematologists and medical oncologists were contributors to several presentations at the San Antonio Breast Cancer Symposium (SABCS) this past week, sharing the findings of state-of-the-art breast cancer research conducted at FCS. These oncology experts join a diverse audience of academic and private physicians and researchers from over 90 countries with special interest in breast cancer, the most frequently diagnosed cancer among women in 140 of 184 countries worldwide....FCS hematologist and medical oncologist and FCS Director of Drug Development Manish R. Patel, MD is first author for the trial, VELA: A first-in-human phase 1/2 study of BLU-222...in patients with cyclin E1 gene (CCNE1)-amplified or CDK4/6 inhibitor-resistant advanced solid tumors."

P1/2 data • Oncology • Solid Tumor