654P - Peripheral neuropathy (PN) following treatment (tx) with bicycle toxin conjugates (BTCs) BT8009 or BT5528 monotherapy in patients (pts) with advanced solid tumors

Background

BT8009 and BT5528 are BTC® molecules comprising bicyclic peptides that target Nectin-4 and EphA2, respectively, linked to monomethyl auristatin E (MMAE) via a cleavable linker. Nectin-4 and EphA2 are overexpressed in many tumors. PN is a known adverse event in up to ∼65% (7% Grade [Gr] 3/4) of pts treated with MMAE-based antibody-drug conjugates. Owing to short plasma half-lives and high selectivity, BTCs have potential to limit toxicity by reducing non-tumor tissue exposure. Here we report on tx-related PN (TRPN) from two ongoing, phase 1/2 studies of BT8009 (NCT04561362) and BT5528 (NCT04180371) in adults with locally advanced/metastatic solid tumors.

Methods

Pts with tumors associated with Nectin-4 or EphA2 expression who had progressed on ≥1 prior therapy were eligible. Pts with ongoing Gr ≥2 PN from prior therapy were excluded (BT8009 only). Pts received the recommended phase 2 monotherapy dose: 5 mg/m² QW BT8009 or 6.5 mg/m² Q2W BT5528. Dose interruptions were required for new/worsening Gr 2 (BT8009/BT5528) or Gr 3 (BT5528) PN; tx was withdrawn for Gr 3 (BT8009) or Gr 4 (BT5528) PN. PN was reported using Standardized MedDRA Queries (broad) and graded per CTCAE v5.0.

Results

As of 14-22 Mar 2024, median time on tx was 10 wks for BT8009 and 8.5 wks for BT5528. TRPN was reported in 42/149 (28%, including <1% motor and 1% sensorimotor) pts treated with BT8009 (1% Gr ≥3) and 14/74 (19%, including 0 motor or sensorimotor) pts treated with BT5528 (0 Gr ≥3). Of pts with TRPN, 7/42 (16% BT8009) and 5/14 (36% BT5528) had ongoing Gr 1 PN at baseline. TRPN resulted in dose interruption in 9% (BT8009) and 1% (BT5528) of pts; dose reduction in 4% and 1%, respectively, and no drug withdrawals were necessary for either BTC. TRPN had resolved in 14% (BT8009) and 21% (BT5528) of pts, and 26% and 21%, respectively, had some resolution or improvement at time of reporting, though post-tx follow up was limited. Median time to resolution or improvement was 2 wks (BT8009) and 1.7 wks (BT5528).

Conclusions

Frequency and severity of TRPN were low following BT8009 or BT5528 monotherapy. Most events were mild to moderate, even in pts with baseline PN, required no withdrawals, and pts were often able to continue tx without modification.

Clinical trial identification

NCT04561362; NCT04180371.

Editorial acknowledgement

Writing assistance was provided by Rebecca L. Crepeau, PhD of Fishawack Communications Ltd.

Legal entity responsible for the study

BicycleTx Ltd.

Funding

BicycleTx Ltd.

Disclosure

M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, IQVIA, Merck, Moderna, Pfizer, Castle Biosciences, Moderna; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, Ideaya Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, Tmunity Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Arvinas, ASCO, Astellas, Bayer, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio, Aulos Bioscienc, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, InconVir, Jazz Pharmaceutical, Krystal Biotech, NucMito Pharmaceuticals, OnKure, Remix Therapeutics, Acentage, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentec, GSK, Ideaya Biosciences, lkena, Infinity Pharmaceuticals, Jacobio Pharma, Moderna, NBE-Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regenero, Sapience, Seattle Genetics, Tizona Therapeutics, Tmunity, Top Alliance Biosciences, Aadi Bioscience, Alpine Immune Sciences, Arch Bioscience, Arvinas, ASCO, Astellas, Bayer, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono Inc, Erasca, Foghorn, G1 Therapeutics, Gilead Sciences, ImmVira, KeChow Pharmaceuticals, Kezar Life, Kinnate Biopharma, MedImmune, Mereo BioPharma Group, Metabom, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceutical Company, Teneobio, Tempest Therapeutics, Xilio, Aulos Bioscience, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, lnconVir, Jazz Pharmaceuticals, Krystal Biotech, NucMito, OnKure, Remix Therapeutics. C. Baldini: Financial Interests, Institutional, Advisory Board: BMS, MSD; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Coordinating PI: iTeos, Janssen, Seattle Genetics, Taiho, Pyramid Bioscience; Financial Interests, Institutional, Local PI: AZ, Amgen, Bicycle Therapeutics, MSD, Tango, Roche Genentech; Non-Financial Interests, Member: ASCO, SIOG, SOFOG, AACR, ESMO. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. O. Reig Torras: Financial Interests, Personal, Invited Speaker: Pfizer, BMS, Ipsen. E. Fontana: Financial Interests, Personal, Invited Speaker: Caris Life Science, Repair Therapeutics; Financial Interests, Personal, Other, Conference attendance: Sapience Pharma; Financial Interests, Personal, Invited Speaker, Conference Attendance: Bicycles Therapeutics; Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International; Financial Interests, Personal, Officer: EORTC; Financial Interests, Institutional, Coordinating PI: Repair Therapeutics, Amgen, Taiho Pharmaceutical; Financial Interests, Institutional, Local PI: Bicycle Therapeutics, Artios Pharma, Seagen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Pfizer, Roche, Daiichi Sankyo, Gilead Science, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, Hutchmed, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma, Arcus Bioscience, Exelixis, Nerviano Medica, Elipsees, Deciphera, Ribon Therapeutics. L. Verlingue: Financial Interests, Personal, Stocks/Shares, CEO of Resolved dedicated to treatment approval prediction: Resolved; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Funding, Contract for bioinformatic analysis: Pierre Fabre, Servier; Non-Financial Interests, Advisory Role: Klineo; Non-Financial Interests, Institutional, Proprietary Information, As part of the Drug Development Department (DITEP) of Gustave Roussy and of the Phase 1 Unit of Centre Léon Bérard, as medical doctor, LV report being: Principal/sub-Investigator of Clinical Trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, GSK, H3 Biomedicine, F. Hoffmann-La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut de Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma A: Pharmas. B. Bashir: Financial Interests, Personal, Advisory Board: Merck/Eisai, Fate/Ono Therapeutics, Kahr Medical; Financial Interests, Personal, Other, Scientific reviewer: Department of Defense, United States; Financial Interests, Institutional, Local PI: Amgen Inc., Avenzo Therapeutics, Bicycle Therapeutics, Boehringer Ingelheim, Elucida Oncology, Gritstone Bio, Jazz Pharmaceuticals, Kahr Medical, Lyell Immunopharma, Merck, Ikena Oncology, Pionyr Immunopharma, Rascal Therapeutics, Syros Pharmaceuticals, Tarveda Therapeutics; Financial Interests, Personal and Institutional, Steering Committee Member: Fate Therapeutics. J.S. Wang: Financial Interests, Personal, Invited Speaker, Previous Member of Speaker's Bureau for Tagrisso and Imfinzi, stopped speaking engagements in 2021: AstraZeneca; Financial Interests, Personal, Advisory Board, Single consultancy engagement, 4/28/22: Kanaph Therapeutics; Financial Interests, Personal, Invited Speaker, Speaker for Speaker's Bureau for Levatinib, stopped in 7/2022: Eisai; Financial Interests, Personal, Advisory Board, on Safety Advisory Board, single engagement 6/22/23: Fusion Pharma; Financial Interests, Institutional, Funding, Clinical Trial PI/Sub-I: 7,8 Pharma, Accutar, Adagene, Artios Pharma, Astellas, AstraZeneca, Bayer Healthcare, BeiGene, Bicycle Therapeutics, BioNTech, BioTheryX, Blueprint, Boehringer Ingelheim, Celgene/BMS, Cullinan, Cyteir, Daiichi Sankyo, Erasca, Forty Seven, Genentech/Roche, GSK, H3 Biomedicine, Hotspot, IGM Biosciences, Immuno-Gen, ImmunoOnc, Janssen, Jazz Pharma, Klus Pharma, Kymab, LSK BioPartners, MabSpace, Macrogenics, Medikine, Moderna, NGM Bio, Novartis, Nurix, ORIC, Olema Therapeutics, Phoenix Molecular Designs, Pionyr, Prelude Therapeutics, PureTech Health, Pyxis, Qilu Pugent Sound, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Sanofi, StingThera, Syndax, Teneobio, TopAlliance, Treadwell Therapeutics, Xencor, Zymeworks, Compass, OnCusp, Tango, Vividion, Allorion, Kura, Georgimmune, Conjupro, Duality Bio, Ellipses, Compugen, Biostar, Centessa, Kineta, C4 Therapeutics. L. DeMars, X. Gu, C. Xu, K. Josephs: Financial Interests, Personal, Stocks/Shares: Bicycle Tx, Mersana Therapeutics. W.I. Ortuzar Feliu: Financial Interests, Personal, Full or part-time Employment, full time Employee: Bicycle Inc.; Financial Interests, Personal, Stocks/Shares, No longer employed: Agenus. A. De: Financial Interests, Institutional, Full or part-time Employment: Bicycle Therapeutics. M. Li: Financial Interests, Institutional, Full or part-time Employment: Bicycle Therapeutics; Financial Interests, Institutional, Stocks/Shares: Bicycle Therapeutics. L. Carter: Financial Interests, Personal, Other, Consultancy: Bicycle Therapeutics, Boehringer Ingelheim, Athenex; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: Cancer research UK Centre for Drug Development; Financial Interests, Institutional, Local PI: Boehringer Ingelheim, Cellcentric, Eli Lilly, Repare Therapeutics, EMD Serono/Merck KGaA, Sierra Oncology, Nurix Therapeutics, Takeda; Financial Interests, Institutional, Coordinating PI: Bicycle Therapeutics, Athenex, Lupin Limited, Cytomx therapeutics, ADC Therapeutics; Financial Interests, Institutional, Local PI, Funding for delivering commercial trial activity: Genmab. All other authors have declared no conflicts of interest.