Dana-Farber Research Publication 02.15.2024

February 18, 2024

Welcome to Dana-Farber's Research News

February 15, 2024

This twice-monthly newsletter highlights the research endeavors at Dana-Farber Cancer Institute, noting recently published papers available from PubMed where Dana-Farber faculty are listed as first or senior authors.

Annals of Oncology

Is There a Role for Continuation of CDK4/6 Inhibition After Progression on a Prior CDK4/6 Inhibitor in HR+/HER2- Metastatic Breast Cancer?

Giordano A, Lin NU, Tolaney SM, Mayer EL

Cyclin-dependent kinase 4 (CDK4) and CDK6 interact with cyclin D1 to hyperphosphorylate the retinoblastoma (RB1 ) gene product pRb early in the G1 phase of the cell cycle. This results in pRb inactivation and release of transcription factors that allow progression to the S phase. Cyclin D1 and CDK4 play particularly important roles in mammary gland biology and breast cancer and numerous molecular features suggest that the cyclin D–CDK4/6 pathway can be hyperactivated in human hormone receptor (HR)-positive breast cancers. The CDK4/6 inhibitors (CDK4/6is) palbociclib (Pfizer, Collegeville, PA), ribociclib (Novartis East, Hanover, NJ), and abemaciclib (Eli Lilly, Indianapolis, IN) are currently approved by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) in either the first-line or pretreated setting in combination with endocrine therapy (ET; aromatase inhibitors or fulvestrant) for HR-positive, HER2-negative (HR+/HER2?) metastatic breast cancer (mBC). They all are ATP-competitive kinase inhibitors that bind to the hinge region of CDK4/6 and inhibit phosphorylation of downstream substrates. Recently, abemaciclib received EMA and FDA approval for node-positive, high-risk, early-stage breast cancer in combination with adjuvant aromatase inhibitor, and positive data for ribociclib in the adjuvant setting have been reported.

Annals of Oncology

The Double Antibody Drug Conjugate (DAD) Phase I Trial: Sacituzumab Govitecan Plus Enfortumab Vedotin for Metastatic Urothelial Carcinoma

McGregor BA, Sonpavde GP, Kwak L, Regan MM, Gao X, Hvidsten H, Mantia CM, Wei XX, Berchuck JE, Berg SA, Ravi PK, Michaelson MD, Choueiri TK, Bellmunt J

BACKGROUND: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018).

PATIENTS AND METHODS: Patients with mUC and Eastern Cooperative Oncology Group performance status ?1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints.

RESULTS: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ?3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ?3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months.

CONCLUSIONS: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.

Blood

Consensus Recommendations on the Management of Toxicity Associated with CD3xCD20 Bispecific Antibody Therapy

Crombie JL, Abramson JS, Armand P

Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in heavily pretreated patients, and at least three have so far received regulatory approvals in various countries. However, BsAbs can lead to potentially severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy have been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies. Yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3xCD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3xCD20 BsAb-related toxicities.

Blood

How We Use Genomics and BTK-Inhibitors in the Treatment of Waldenstrom Macroglobulinemia

Treon SP, Sarosiek S, Castillo JJ

Mutations in MYD88 (95-97%) and CXCR4 (30-40%) are common in Waldenstrom macroglobulinemia (WM). TP53 is also altered in 20-30% of WM patients, particularly those previously treated. Mutated MYD88 upregulates and activates HCK that drives BTK pro-survival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants such as CXCR4S338X show greater resistance to BTK-inhibitors. Covalent BTK-inhibitors (cBTK-i) produce major responses in 70-80% of WM patients. MYD88 and CXCR4 mutation status can impact time to major response, depth of response and/or progression-free survival (PFS) in WM patients treated with cBTK-i. The cBTK-i zanubrutinib shows greater response activity and/or improved PFS in wild-type MYD88, mutated CXCR4, or altered TP53 patients. Marked differences in adverse events have been observed between BTK-inhibitors in WM patients, including atrial fibrillation, bleeding diathesis and neutropenia. Intolerance is also common with c-BTKi, and dose reduction or switchover to another c-BTKi can be considered. For patients with acquired resistance to c-BTKi, newer options include the non-covalent BTK-inhibitor pirtobrutinib or the BCL2 antagonist venetoclax. Combinations of BTK-inhibitors with chemoimmunotherapy, CXCR4 and BCL2 antagonists have advanced and are discussed. Algorithms for positioning BTK-inhibitors in treatment-naïve and previously treated WM patients based on genomics, disease characteristics, and co-morbidities are presented.

Blood

PI3K? Maintains the Self-Renewal of Acute Myeloid Leukemia Stem Cells by Regulating the Pentose Phosphate Pathway

Gu H, Hou ZS, He XD, Xie S, Ni J, Qian C, Cheng X Dr, Jiang T Dr, Yang C, Roberts TM Dr, Armstrong SA, Zhao JJ

Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem/progenitor cells. AML prognosis remains poor, due to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The PI3K/AKT pathway is often dysregulated in AML. We found while that PI3K? is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3K?-AKT signaling promotes NRF2 nuclear accumulation, which induces PGD and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3K? impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3K? in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3K? pathway may therefore eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.

Cancer Discovery

Non-Invasive Detection of Neuroendocrine Prostate Cancer Through Targeted Cell-Free DNA Methylation

Mizuno K, Ku SY, Rothmann E, Freeman D, Beltran H

Cancer Discovery

Sotorasib is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers

Rubinson DA, Tanaka N, Fece de la Cruz F, Kapner KS, Rosenthal MH, Norden BL, Barnes H, Ehnstrom S, Morales-Giron AA, Brais LK, Lemke CT, Aguirre AJ, Corcoran RB

Cancer Discovery

TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Anti-Tumor Immunity

Tani T, Campisi M, Li ZH, Haratani K, Fahey CG, Ota K, Mahadevan NR, Shi Y, Saito S, Mizuno K, Thai TC, Yusuf CFB, Barbie TU, Paweletz CP, Gokhale PC, Liu D, Uppaluri R, Barbie DA

Cell

Inherited Blood Cancer Predisposition Through Altered Transcription Elongation

Zhao J, Cato LD, Arora UP, Bao EL, Bryant SC, Jia Y, Goldman SR, Armstrong SA, Sankaran VG