1967MO - Preliminary efficacy and safety of disitamab vedotin (DV) with pembrolizumab (P) in treatment (Tx)-naive HER2-expressing, locally advanced or metastatic urothelial carcinoma (la/mUC): RC48G001 cohort C

Background

Vedotin-based, antibody-drug conjugates (ADCs) combined with P have changed 1L tx of la/mUC; however, ∼50% of pts with la/mUC express HER2 (IHC ≥1+), making HER2 an attractive target. DV is an investigational ADC comprising a fully humanized HER2-directed monoclonal antibody, disitamab, conjugated to MMAE via a protease-cleavable mc-vc linker. We report preliminary data on DV+P in HER2-expressing la/mUC from RC48G001 (NCT04879329), a phase 2, single-arm, multicohort, open-label, multicenter, global study.

Methods

RC48G001 Cohort C enrolled tx-naive pts with HER2-expressing la/mUC (IHC ≥1+). Part 1 was planned to enroll 20 pts to receive DV IV Q2W + P IV day 1 Q6W (cycle length = 6 weeks [W]). The primary endpoint is confirmed ORR (cORR) per blinded independent central review (BICR). Secondary endpoints include investigator-assessed (INV) cORR and safety. While INV-cORR is reported here, BICR-ORR will be reported in the final presentation.

Results

At data cutoff (Mar 4, 2024), all 20 pts in Part 1 received DV+P; 9 (45%) remain on tx. Median age was 75 y (range 58-86), 7 (35%) were cisplatin-ineligible, 30% (6/20) were HER2-high (IHC 3+ or IHC 2+/amplified). 12 (60%) pts had primary bladder cancer, 14 (70%) had visceral metastases, and 5 (25%) had lymph node-only disease. 8 pts (40%) were ECOG 0 and 12 pts (60%) were ECOG 1. Median duration of exposure was 18.1 W (range 10-48) for DV and 18.0 W (range 6-58) for P. Efficacy was evaluable in 18 pts; INV-cORR was 61.1% (95% CI, 35.7-82.7; CR: 16.7%; PR: 44.4%) in all pts and 76.9% (95% CI, 46.2-95.0; CR: 23.1%; PR: 53.8%) in HER2-low pts (IHC 1+ or IHC2+/non-amplified). DCR was 94.4% (95% CI, 72.7-99.9) in all pts and 92.3% (95% CI, 64.0-99.8) in HER2-low pts. TRAEs occurred in 20 (100%) pts, the most common being fatigue (DV, 50%; P, 40%) and diarrhoea (DV, 45%).

Conclusions

DV+P demonstrated encouraging preliminary activity in pts with HER2-expressing la/mUC with a manageable safety profile and supports further evaluation of this regimen. RC48G001 Cohort C Part 2 (DV vs DV+P) and DV001 (DV+P vs platinum-based chemo; phase 3 study; NCT05911295) are ongoing.

Clinical trial identification

NCT04879329.

Editorial acknowledgement

Medical writing support was provided by Kiran Verma, of Nucleus Global, an Inizio Company, and was funded by Pfizer.

Legal entity responsible for the study

Seagen Inc., Bothell, WA, USA, which was acquired by Pfizer in December 2023.

Funding

Seagen Inc., Bothell, WA, USA, which was acquired by Pfizer in December 2023.

Disclosure

M.D. Galsky: Financial Interests, Personal, Advisory Board: Janssen, Merck, GSK, Eli Lilly, Astellas, Genentech, Bristol Myers Squibb, Pfizer, EMD Serono, AstraZeneca, Seagen, Incyte, Alligator, AbbVie, Asieris, Bicycle, Gilead, Curis, Fujifilm; Financial Interests, Personal, Other, Consultant: Rappta Therapeutics; Financial Interests, Personal, Invited Speaker: Veracyte; Financial Interests, Institutional, Steering Committee Member: Merck, Genentech, Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Jazz; Financial Interests, Institutional, Local PI: Seagen. V.S. Koshkin: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Pfizer, EMD Serono; Financial Interests, Personal, Other, Consulting: GLG, ExpertConnect, Guidepoint; Financial Interests, Personal, Advisory Board, Advisory Board Participation: MSD, Bicycle Therapeutics; Financial Interests, Institutional, Local PI: Merck, Taiho, Eli Lilly, Clovis, Novartis, Nektar, Curium, Gilead; Financial Interests, Institutional, Steering Committee Member: Seagen; Financial Interests, Personal and Institutional, Research Grant: Prostate Cancer Foundation. M.T. Campbell: Financial Interests, Personal, Advisory Board: Exelixis, Pfizer, Seagen, AstraZeneca, Curio Science, Eisai; Financial Interests, Institutional, Local PI: Pfizer, Aravive, Seagen; Financial Interests, Institutional, Coordinating PI: Exelixis, Janssen. A. Drakaki: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Seagen, Janssen, PACT Pharma, Merck, Exelixis, Roche Genentech, Emd Serono, Infinity; Financial Interests, Personal, Stocks/Shares: Athos Therapeutics; Financial Interests, Institutional, Local PI: Roche, Merck, AstraZeneca, Seattle Genetics, Kite Pharma, Bms, Infinity, Adcentrix, Acrivon. I. Bowman: Financial Interests, Personal, Advisory Board: Aveo; Financial Interests, Personal, Invited Speaker: Caris, Natera. A.A..N. Rose: Financial Interests, Personal, Advisory Board: Pfizer, EMD Serrono; Financial Interests, Personal, Invited Speaker: Advanced Accelerator Applications, Pfizer; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Local PI: Pfizer, AstraZeneca, Advanced Accelerator Applications/Novartis, Merck. J.R. Brown: Financial Interests, Personal, Invited Speaker, Speaker's Bureau for Avelumab: EMD Serono; Financial Interests, Personal, Invited Speaker, Speaker for MSL Training: AstraZeneca; Financial Interests, Institutional, Local PI: Jounce Pharmaceuticals, Seattle Genetics, Novita, Bicycle Therapeutics, Roche. J.B. Aragon-Ching: Financial Interests, Personal, Advisory Board: Pfizer, Astellas/Seagen, Bayer, Merck, Novartis, EMD Serono; Financial Interests, Personal, Invited Speaker: EMD Serono, BMS; Financial Interests, Personal, Advisory Board, One -time only: Immunomedics; Financial Interests, Personal, Advisory Board, One-time only: AZD; Financial Interests, Personal, Advisory Board, One-time only; related to prostate cancer: Pfizer/Myovant. S. Gadde: Financial Interests, Personal, Invited Speaker: Exelixis; Financial Interests, Personal, Advisory Board: Taiho Oncology. J.E. Rosenberg: Financial Interests, Personal, Advisory Board: Aadi Biosciences, Alligator Biosciences, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, EMD-Serono, Genentech, Gilead, IMVax, Janssen, Lilly Oncology, Merck, Mirati, NCCN, Pfizer, Tyra Biosciences, Aktis, Samsung Bioepis, Century Therapeutics, Bayer, Kalivir; Financial Interests, Personal, Invited Speaker, Medical Education: Clinical Care Options, Peer Direct; Financial Interests, Personal, Invited Speaker, Medical education: MJH Associates, Physicians Education Resource, Research to Practice; Financial Interests, Personal, Invited Speaker: Pfizer, Medscape, Mashup Media; Financial Interests, Personal, Advisory Board, + travel funding to attend meeting: Seagen; Financial Interests, Personal, Royalties: Wolters Kluyer/Uptodate; Financial Interests, Institutional, Coordinating PI, Coordinating PI of rogaratinib/atezolizumab trial; consultant: Bayer; Financial Interests, Personal and Institutional, Steering Committee Member, EV-201, EV- 103; consultant, trial open at my institution: Seagen; Financial Interests, Personal and Institutional, Steering Committee Member, EV-301, consultant, trial open at my institution: Astellas; Financial Interests, Personal and Institutional, Coordinating PI, Consultant, PI of trial: AstraZeneca; Financial Interests, Institutional, Coordinating PI, PI of IMVIGOR210 (still open at my institution): Genentech; Financial Interests, Institutional, Coordinating PI, PI of trial, consultant to company: Loxo Oncology; Non-Financial Interests, Leadership Role, Genitourinary Committee Chair: Alliance for Clinical Trials in Oncology. N. Matsubara: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Coordinating PI: Janssen, Roche, MSD, Taiho, Pfizer, Chugai; Financial Interests, Institutional, Local PI: AstraZeneca, Bayer, Astellas, Amgen, Eisai, Eli Lilly, AbbVie. K.M. Sokolowski: Financial Interests, Institutional, Full or part-time Employment: Pfizer, Inc; Financial Interests, Institutional, Stocks/Shares: Pfizer, Inc. M. Ichimaru: Financial Interests, Personal, Full or part-time Employment: Pfizer/L-Seagen. S. Chan: Financial Interests, Personal, Full or part-time Employment: Pfizer. S. Franco: Financial Interests, Personal, Full or part-time Employment, I am a full-time employee at Merck in the Philadelphia office, in the US. My role is Clinical Director in the Bladder team in Oncology at the Merck Research Laboratories (MRL): Merck; Financial Interests, Personal, Stocks/Shares, As a Merck employee, I receive Restricted Stock Units (RSUs) as part of my compensation (long-term incentives): Merck. T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd; Financial Interests, Institutional, Other, honoraria: Gilead; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai; Financial Interests, Institutional, Other, Honoraria: Gilead. All other authors have declared no conflicts of interest.