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Clinical Trial
. 2024 Aug;30(8):2242-2250.
doi: 10.1038/s41591-024-03060-0. Epub 2024 Jun 1.

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

Toru Mukohara  1 , Yeon Hee Park  2 , David Sommerhalder  3 , Kan Yonemori  4 , Erika Hamilton  5 , Sung-Bae Kim  6 , Jee Hyun Kim  7 , Hiroji Iwata  8 , Toshinari Yamashita  9 , Rachel M Layman  10 , Monica Mita  11 , Timothy Clay  12 , Yee Soo Chae  13 , Catherine Oakman  14 , Fengting Yan  15 , Gun Min Kim  16 , Seock-Ah Im  17 , Geoffrey J Lindeman  18 , Hope S Rugo  19 , Marlon Liyanage  20 , Michelle Saul  20 , Christophe Le Corre  20 , Athanasia Skoura  21 , Li Liu  20 , Meng Li  22 , Patricia M LoRusso  23
Affiliations
Clinical Trial

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

Toru Mukohara et al. Nat Med. 2024 Aug.

Erratum in

Abstract

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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Conflict of interest statement

T.M. received honoraria from AstraZeneca, Chugai Pharma, Eisai, Kyowa Kirin, Lilly Japan, Novartis, Pfizer and Taiho Pharmaceutical; had a consulting or advisory role at Eisai and Micin; and received research funding from AstraZeneca, Chugai Pharma, Daiichi Sankyo/AstraZeneca, Eisai, Gilead Sciences, MSD, Novartis, Ono Pharmaceutical, Pfizer, Sanofi and Sysmex. Y.H.P. received honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer and Roche; had a consulting or advisory role at AstraZeneca, Boryung, Daiichi Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer and Roche; received research funding from AstraZeneca, Pfizer, Gencurix, Genome Insight, NGeneBio and Roche; and received travel and accommodation expenses from Gilead. D.S. was employed at Texas Oncology; had stock and other ownership interests in Texas Oncology and NEXT Oncology; received honoraria from Syneos Health; had a consulting or advisory role at Guidepoint and Revolution Medicines; and received research funding from Abbvie, ADC Therapeutics, Ascentage Pharma, Biomea Fusion, BioNTech SE, BJ Bioscience, Boehringer Ingelheim, Fate Therapeutics, Gilead Sciences, Immuneering, Kura Oncology, MediLink, Mirati Therapeutics, Monopteros Therapeutics, Navire, NGM Biopharmaceuticals, Nimbus Therapeutics, OncoResponse Inc., Pfizer, Revolution Medicines, Symphoge, Tachyon Therapeutics, Teon Therapeutics and ZielBio. K.Y. received honoraria from AstraZeneca, Chugai Pharma, Daiichi Sankyo/AstraZeneca, Eisai, Fujifilm, Lilly Japan, MSD Oncology, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical and Takeda; had a consulting or advisory role at Chugai Pharma, Eisai, Henlius, Novartis, OncXerna Therapeutics and Ono Pharmaceutical; and received research funding from AstraZeneca/MedImmune, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo/AstraZeneca, Eisai, Genmab, Haihe Pharmaceutical, Kyowa Kirin, Lilly, MSD, Nihonkayaku, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, Seagen, Taiho Pharmaceutical and Takeda. E.H. had a consulting or advisory role at AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Genentech/Roche, Greenwich LifeSciences, ITeos Therapeutics, Janssen, Lilly, Loxo, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Pfizer, Relay Therapeutics, Seagen, Stemline Therapeutics, Theratechnologies, Tubulis GmbH and Verascity Science; and received research funding from Abbvie, Accutar Biotech, Acerta Pharma, ADC Therapeutics, Akeso Biopharma, Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond Therapeutics, Bliss Biopharmaceutical, Boehringer Ingelheim, Cascadian Therapeutics, Clovis Oncology, Compugen, Context Therapeutics, Cullinan Oncology, Curis, CytomX Therapeutics, Daiichi Sankyo, Dana Farber Cancer Hospital, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Ellipses Pharma, Elucida Oncology, EMD Serono, Fujifilm, G1 Therapeutics, Genentech/Roche, H3 Biomedicine, Harpoon, Hutchison MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, InventisBio, Jacobio, K-Group Beta, Karyopharm Therapeutics, Kind Pharmaceuticals, Leap Therapeutics, Lilly, Loxo, Lycera, MabSpace Biosciences, Macrogenics, MedImmune, Mersana, Merus, Millennium, Molecular Templates, Novartis, Nucana, Olema Pharmaceuticals, OncoMed, Onconova Therapeutics, Oncothyreon, ORIC Pharmaceuticals, Orinove, Orum Therapeutics, Pfizer, PharmaMar, Pieris Pharmaceuticals, Pionyr, Plexxikon, Prelude Therapeutics, ProfoundBio, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicines, Rgenix, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Stem CentRx, Sutro Biopharma, Syndax, Syros Pharmaceuticals, Taiho Pharmaceutical, TapImmune Inc, Tesaro, Tolmar, Torque, Treadwell Therapeutics, Verastem, Zenith Epigenetics and Zymeworks. S.-B.K. holds stock and other ownership Interests of Genopeaks; received honoraria from DAEHWA Pharmaceutical, Kalbe Farma and LegoChem Biosciences; had a consulting or advisory role at AstraZeneca, BeiGene, DAEHWA Pharmaceutical, Daiichi Sankyo/AstraZeneca, Ensol Biosciences, ISU Abxis, Lilly and OBI Pharma; and received research funding from Genzyme. J.H.K. received honoraria from Roche Korea, AstraZeneca Korea, Lilly Korea, Roche diagnostics and Roche; had a consulting or advisory role at Bixink, Eisai Korea, Roche, MSD Korea, Everest Medicine and Yuhan; and received research funding from Ono Pharma Korea, Roche and Eisai. H.I. received honoraria from AstraZeneca, Chugai, Daiichi Sankyo, Kyowa Kirin, Lilly, MSD, Pfizer and Taiho; had a consulting or advisory role at AstraZeneca, Chugai, Daichi Sankyo, Gilead, Lilly, MSD and Pfizer; and received research funding from AstraZeneca, Chugai and Daiichi Sankyo. T.Y. received honoraria from AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Kyowa Kirin, Lilly, Pfizer and Taiho Pharmaceutical; and received research funding from AstraZeneca, Chugai Pharma, Daiichi Sankyo, Kyowa Kirin, Lilly, MSD, Nihonkayaku, Pfizer, Seagen and Taiho Pharmaceutical. R.M.L. received honoraria from Pfizer; had a consulting or advisory role at Eli Lilly, Novartis, Pfizer, Celcuity, Gilead Sciences and Biotheryx; and received research funding to institution from Eli Lilly, Novartis, Pfizer, Puma, Zentalis, Celcuity, Arvinas and Accutar Biotechnology. T.D.C. received honoraria from Lilly, Specialised Therapeutics, Roche, MSD and The Limbic; had a consulting or advisory role for AstraZeneca/MedImmune, Merck KGaA, Takeda, Merck/Pfizer, Ipsen, AstraZeneca, Daiichi Sankyo, Janssen and Roche; was a member of Speakers’ Bureau of AstraZeneca/MedImmune; and received research funding from Abbvie, Amgen, Bayer, BeiGene, Clovis Oncology, Daiichi Sankyo/AstraZeneca, Exelixis, Immutep, Janssen Oncology, MSD Oncology, Pfizer, BridgeBio Pharma and Bristol Myers Squibb GmbH & Co. K.G. held stock and other ownership Interests of ClinicIQ; and received travel and accommodation expenses from AstraZeneca, Daiichi Sankyo/UCB Japan and Boehringer Ingelheim. F.Y. received honoraria from Daiichi Sankyo, Merck, AstraZeneca, Grail, Gilead, Stemline, Eli Lilly, SeaGen and GE; and received research funding from Pfizer, Gilead, Merck, Agendia and Genentech. S.-A.I. received honoraria from MSD Korea; had a consulting or advisory role at AstraZeneca, Bertis, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer and Roche; and received research funding from AstraZeneca, Daiichi Sankyo, Boryung Pharm, Daewoong Pharm, Eisai, Roche and Pfizer. G.J.L. received honoraria from Pfizer; had a consulting or advisory role at Pfizer and AbbVie; and received research funding from AbbVie, Amgen, Genentech and Pfizer (all study support to Institution for investigator-initiated studies) and Cooperative Research Centre for Cancer Therapeutic, Australia (laboratory funding). H.S.R. had a consulting or advisory role at Daiichi Sankyo, Eisai, Mylan, Napo Pharmaceuticals and Puma Biotechnology; and received research funding from Astellas Pharma, AstraZeneca, Daiichi Sankyo, Genentech/Roche, Gilead Sciences, GSK, Lilly, Merck, Novartis, OBI Pharma, Pfizer, Stemline Therapeutics, Taiho Oncology and Veru. P.M.L.R. received honoraria from Five Prime Therapeutics; had a consulting or advisory role at Abbvie, ABL Bio, Actuate Therapeutics, Agenus, Amgen, AstraZeneca, Atreca, BAKX Therapeutics, Boehringer Ingelheim, Compass Therapeutics, Cullinan Oncology, DAAN Biotherapeutics, EMD Serono, GSK, I-Mab, ImCheck therapeutics, IQvia, Kineta, Kyowa Kirin International, Mekanistic Therapeutics, Mersana, Molecular Templates, Neurotrials Research, Pfizer, QED Therapeutics, Qualigen Therapeutics, Quanta Therapeutics, Relay Therapeutics, Roche/Genentech, Roivant, Scenic Biotech, Schrodinger, Seagen, Sotio, ST Cube, Stemline Therapeutics, Takeda and Zentalis; received research funding from Genentech; and received travel and accommodation expenses from Genentech. M.L. has a patent royalty from the Johns Hopkins University; is employed at Pfizer; and owns stock and other ownership interests of Pfizer. M.L., C.L.C., A.S., L.L. and M.S. are employed at Pfizer; and own stock and other ownership interests of Pfizer. The other authors have no competing interests.

Figures

Fig. 1
Fig. 1. Patient disposition.
CONSORT diagram.
Fig. 2
Fig. 2. Waterfall plot of tumor size change from baseline.
a, Waterfall plot of patients in part 2A (PF-07248144 5 mg q.d.). b, Waterfall plot of patients in parts 1B and 2B (PF-07248144 5 mg q.d. + fulvestrant 500 mg). Largest decrease or smallest increase represents the best response to treatment. uPR, unconfirmed PR (considered as SD in Table 3). * indicates ongoing.
Fig. 3
Fig. 3. Kaplan–Meier plot of PFS based on investigator response.
a, Patients in parts 1B and 2B (PF-07248144 5 mg q.d. + fulvestrant 500 mg). b, Subgroup analysis by prior lines of therapies: 2L versus 3L+ in patients in parts 1B and 2B (PF-07248144 5 mg q.d. + fulvestrant 500 mg). c, Subgroup analysis by ESR1 mutation status: MT versus WT in patients in parts 1B and 2B (PF-07248144 5 mg q.d. + fulvestrant 500 mg). d, Subgroup analysis by PIK3CA/AKT1/PTEN mutation status: MT versus WT patients in parts 1B and 2B (PF-07248144 5 mg q.d. + fulvestrant 500 mg).
Extended Data Fig. 1
Extended Data Fig. 1. Study design and enrollment status.
*3L+ for patients enrolled in the Republic of Korea. 2L, with at least one prior line of treatment; 3L+, as third line and above; CRPC, castration-resistant prostate cancer; ER, estrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; mBC, locally advanced or metastatic breast cancer; NSCLC, non-small cell lung cancer; QD, once a day.
Extended Data Fig. 2
Extended Data Fig. 2. Pharmacokinetics and pharmacodynamics of PF-0728144 and tumor size change from baseline over time.
(a) Steady-state (C1D15) concentration-time profiles are provided as mean + standard deviation for each cohort. (b) H3K23Ac PD biomarker modulation in PBMC by single and multiple doses of PF-07248144 in part 1A (monotherapy) and part 1B (in combination with fulvestrant). Data are presented as median ± interquartile range (IQR). (c) H3K23Ac PD biomarker modulation by PF-07248144 after 14 days of treatment in tumor. High, medium, and low intensity H3K23Ac staining positive tumor cells from the entire tissue were evaluated from semi-quantitative image analysis. Percentage of high and medium intensity positive tumor cells were used for tumor H3K23Ac PD changes. Insert representative tumor area images of the IHC staining at 20X for the baseline (SCN) and on-treatment (C1D15) samples from patient #3: brown stain indicates the presence of H3K23AC antigen, while the blue counterstain highlights cell nuclei. The scale bar is 50 µm. (d) The patient had ER + /HER2– mBC and PIK3CA H1047R mutation and achieved confirmed PR (−39.72%) after PF-07248144 8 mg QD monotherapy with the duration of response of 15.7 months. (Images courtesy of Dr Toru Mukohara). BC, breast cancer; C, cycle; CRPC, castration-resistant prostate cancer; D, day; ER, estrogen receptor; Fulv, fulvestrant; HER2, human epidermal growth factor receptor 2; IQR, interquartile range; mBC, advanced/metastatic breast cancer; NA, not applicable; NE, not evaluable; PD, progressive disease; PF-8144, PF-07248144; PMBC, peripheral blood mononuclear cell; PR; partial response; pre, predose; Pt, patient; QD, once a day; SCN, screening; SD, stable disease.
Extended Data Fig. 3
Extended Data Fig. 3. Treatment duration.
(a) Part 1A dose escalation. (b) Part 2A PF-07248144 5 mg QD monotherapy. (c) Parts 1B and 2B PF-07248144 5 mg QD plus fulvestrant 500 mg. * All patients in part 2A who received PF-07248144 5 mg QD monotherapy and all patients in part 1B and 2B who received PF-07248144 5 mg QD plus fulvestrant 500 mg had ER + HER2− breast cancer. Patients with BC indicate patients with ER + HER2 − BC. BC, breast cancer; BOR, best of response; ER, estrogen receptor; Fulv, fulvestrant; HER2, human epidermal growth factor receptor 2; NE, not evaluable; NCSLC, non-small cell lung cancer; PC, prostate cancer; PD, progressive disease; PR, partial response; QD, once a day; SD, stable disease.
Extended Data Fig. 4
Extended Data Fig. 4. Waterfall plot of tumor size change from baseline of part 1A dose escalation.
All patients in part 1A received PF-07248144 monotherapy. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PD, progressive disease; PR, partial response; QD, once a day; SD, stable disease.
Extended Data Fig. 5
Extended Data Fig. 5. Spider plot of tumor size change from baseline over time in patients with target lesions at baseline and at least one adequate post-baseline assessment.
(a) Part 2A PF-07248144 5 mg QD monotherapy (n = 32). (b) Parts 1B and 2B PF-07248144 5 mg QD plus fulvestrant 500 mg (n = 40). NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.
Extended Data Fig. 6
Extended Data Fig. 6. PBMC H3K23AC from part 2A and part 2B.
Patients with ER + HER2− mBC. In part 2A, patients were treated with PF-07248144 5 mg QD monotherapy. In part 2B, patients were treated with PF-07248144 5 mg QD plus fulvestrant 500 mg. Data are presented as median (column) ± interquartile ranges (solid lines on each column). C, cycle; D, day; ER, estrogen receptor; Fulv, fulvestrant; HER2, human epidermal growth factor receptor 2; mBC, advanced/ metastatic breast cancer; PMBC, peripheral blood mononuclear cell; QD, once a day; SCR, screening; IQR, interquartile ranges.
Extended Data Fig. 7
Extended Data Fig. 7. ctDNA analysis of patients in part 1B and part 2B treated with PF-07248144 5 mg QD plus fulvestrant 500 mg.
* Changes of mean VAF of all detectable mutants. † Changes of single VAF of ESR1 mutants. Multiple mutants present from individual samples. VAF, variant allele frequency. Data are presented as median (middle line in the box) and interquartile ranges (top and bottom lines in the box).
See this image and copyright information in PMC

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