488P Phase I trial of PF-06821497, a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in follicular lymphoma (FL), small cell lung cancer (SCLC) and castration-resistant prostate cancer (CRPC)

Schweizer, Michael T.; Penkov, K.D.; Tolcher, A.W.; Choudhury, Atish D.; Doronin, Vadim; Aljumaily, Raid; Calvo, E.; Frank, Richard C.; Hamm, John; Moreno, Víctor; Vorobyev, Vladimir I.; Billotte, Stephane; Bowler, T.; Chen, J.; Lin, Tsung H.; Liu, LI; Maity, Arnab Kumar; Sharma, Sheena; Johnson, Melissa L.

doi:10.1016/j.annonc.2022.07.616

Cited by 3 publications

(1 citation statement)

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“…The addition of EZH2 inhibitors to cytotoxic chemotherapy prevented the emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant SCLC patient-derived models. Although a phase I trial of selective EZH2 inhibitor PF-06821497 monotherapy failed to show a treatment response in two SCLC patients [ 225 ], these preclinical findings provide a rationale for further development of epigenetic targeting strategies.…”

Section: Potent Molecular-targeted Therapy For Patients With Gep-necmentioning

confidence: 99%

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Ooki

Osumi

Fukuda

et al. 2023

Cancer Metastasis Rev

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Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.

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Section: Potent Molecular-targeted Therapy For Patients With Gep-necmentioning

confidence: 99%

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Ooki

Osumi

Fukuda

et al. 2023

Cancer Metastasis Rev

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Applications of oxetanes in drug discovery and medicinal chemistry

Huang,

Hucek,

Cierpicki

et al. 2023

European Journal of Medicinal Chemistry

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Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial

Mukohara,

Park,

Sommerhalder

et al. 2024

Nat Med

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Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2−) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3–4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144–fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2–46.1%) and the median PFS was 10.7 (5.3–not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2− mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446.

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488P Phase I trial of PF-06821497, a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in follicular lymphoma (FL), small cell lung cancer (SCLC) and castration-resistant prostate cancer (CRPC)

Cited by 3 publications

References 0 publications

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma

Applications of oxetanes in drug discovery and medicinal chemistry

Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial

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