A phase 1 study of LY3076226, a fibroblast growth factor receptor 3 (FGFR3) antibody–drug conjugate, in patients with advanced or metastatic cancer

Kollmannsberger, Christian; Britten, Carolyn D.; Olszanski, Anthony J.; Walker, Joan Andrews; Wei, Zang; Willard, Melinda D.; Radtke, David; Farrington, Daphne L.; Bell‐McGuinn, Katherine M.; Patnaik, Amita

doi:10.1007/s10637-021-01146-x

Cited by 14 publications

(11 citation statements)

References 19 publications

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“…Acceptable safety with no reported clinical activity. 85 52. Lysosome-associate membrane glycoprotein 1 (LAMP-1) SAR428926 Nonspecific Lys conj.Cleavable SPBD linkerDM4 payloadDAR~ UndisclosedImmunoGen, Inc.; Sanofi2015–2018 Phase 1 Monotherapy NCT02575781 Completed Solid Tumors n = 34, no published results.…”

Section: Adcs As a New Class Of Targeted Therapeuticsmentioning

confidence: 99%

Exploration of the antibody–drug conjugate clinical landscape

Maecker,

Jonnalagadda,

Bhakta

et al. 2023

mAbs

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The antibody–drug conjugate (ADC) field has undergone a renaissance, with substantial recent developmental investment and subsequent drug approvals over the past 6 y. In November 2022, Elahere TM became the latest ADC to be approved by the US Food and Drug Administration (FDA). To date, over 260 ADCs have been tested in the clinic against various oncology indications. Here, we review the clinical landscape of ADCs that are currently FDA approved (11), agents currently in clinical trials but not yet approved (164), and candidates discontinued following clinical testing (92). These clinically tested ADCs are further analyzed by their targeting tumor antigen(s), linker, payload choices, and highest clinical stage achieved, highlighting limitations associated with the discontinued drug candidates. Lastly, we discuss biologic engineering modifications preclinically demonstrated to improve the therapeutic index that if incorporated may increase the proportion of molecules that successfully transition to regulatory approval.

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Section: Adcs As a New Class Of Targeted Therapeuticsmentioning

confidence: 99%

Exploration of the antibody–drug conjugate clinical landscape

Maecker,

Jonnalagadda,

Bhakta

et al. 2023

mAbs

View full text Add to dashboard Cite

show abstract

“…For example, Fibroblast growth factor receptor 3 (FGRF3) is frequently overexpressed and sometimes activated in patients with the t(4;14) translocation [102]. However, the Phase I study of the FGFR3-targeted ADC LY3076226, which showed an acceptable safety profile, did not enroll any myeloma patients [103]. Thus, it could be of interest to revisit this agent which, if active, would be an especially exciting development considering that t(4;14) myeloma is considered a high-risk subtype with an inferior prognosis [104].…”

Section: Future Directions For Adcs In Myelomamentioning

confidence: 99%

Antibody–Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?

Ray

Orłowski

2023

Pharmaceuticals

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Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved in the advanced setting. Most recently, the bispecific anti-BCMA and T-cell-engaging antibody teclistamab has become available, again for patients with relapsed/refractory disease. Another format into which antibodies can be converted to exert anti-tumor efficacy is as antibody–drug conjugates (ADCs), and belantamab mafodotin, which also targets BCMA, represented the first such agent that gained a foothold in myeloma. Negative results from a recent Phase III study have prompted the initiation of a process for withdrawal of its marketing authorization. However, belantamab remains a drug with some promise, and many other ADCs targeting either BCMA or other plasma cell surface markers are in development and showing potential. This contribution will provide an overview of some of the current data supporting the possibility that ADCs will remain a part of our chemotherapeutic armamentarium against myeloma moving forward, and also highlight areas for future development.

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“…Irreversible inhibitors (such as erdafitinib and pemigatinib) are thought to have a better binding affinity and selectivity, but the early phases of clinical trials showed limited efficacy or demonstrated minimal clinical benefit 447,448 . Other molecules that have been developed as investigational agents targeting FGF/FGFR signaling include the FGF traps FP‐1039 (HGS1036), msFGFR2c, sFGFR3 sm27, and NSC12 449–451 ; the anti‐FGF2 mAbs 3F12E7 452 and H3L3 453 ; the anti‐FGFR2 mAb hFR2‐14 454 ; the anti‐FGFR4 mAb U3‐1784 455 ; and the anti‐FGFR1 antibody–drug conjugate (ADC) LY3076226 456 . The benefits of FGFR inhibitors have been proven in clinical trials in subsets of patients, including those with lung, breast, and gastric cancer.…”

Section: Targeting Oncofetal Reprogramming In Cancer Therapymentioning

confidence: 99%

“… 447 , 448 Other molecules that have been developed as investigational agents targeting FGF/FGFR signaling include the FGF traps FP‐1039 (HGS1036), msFGFR2c, sFGFR3 sm27, and NSC12 449 , 450 , 451 ; the anti‐FGF2 mAbs 3F12E7 452 and H3L3 453 ; the anti‐FGFR2 mAb hFR2‐14 454 ; the anti‐FGFR4 mAb U3‐1784 455 ; and the anti‐FGFR1 antibody–drug conjugate (ADC) LY3076226. 456 The benefits of FGFR inhibitors have been proven in clinical trials in subsets of patients, including those with lung, breast, and gastric cancer. However, the low response rates among patients with FGFR alterations and the existence of responders without detectable FGFR alterations still hamper treatment outcomes.…”

Section: Targeting Oncofetal Reprogramming In Cancer Therapymentioning

confidence: 99%

Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy

Cao,

Zhang,

Zhou

et al. 2023

MedComm

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Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP‐binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance‐associated protein 1 (MRP1), and breast cancer‐resistant protein (BCRP), in drug‐resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.

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A phase 1 study of LY3076226, a fibroblast growth factor receptor 3 (FGFR3) antibody–drug conjugate, in patients with advanced or metastatic cancer

Cited by 14 publications

References 19 publications

Exploration of the antibody–drug conjugate clinical landscape

Exploration of the antibody–drug conjugate clinical landscape

Antibody–Drug Conjugates for Multiple Myeloma: Just the Beginning, or the Beginning of the End?

Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy

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