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654MO - A phase II prospective trial of frontline cabozantinib in metastatic collecting ducts renal cell carcinoma: The BONSAI trial (Meeturo 2)
- Giuseppe Procopio (Milan, Italy)
Abstract
Background
Metastatic collecting ducts carcinoma (mCDC) is biologically poorly characterized and under-represented in prospective randomized trials.
Methods
This prospective, monocentric, phase II trial tested cabozantinib (cabo) 60 mg in treatment-naïve mCDC patients (pts). Primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints were progression-free survival (PFS), overall survival and safety profile. Exploratory objectives were: to identify somatic mutations by targeted DNA sequencing; to define molecular subtypes, signatures and transcript fusions genes by RNA sequencing. A central pathological review was mandatory. The study was based on a Simon’s two-stage optimal design.
Results
From January 2018 to November 2020, 25 pts were enrolled, of whom 23 started treatment. Median age was 66 years, 19 pts were male. The most common metastatic sites were lymph nodes and bone (15 and 13 pts), followed by lung and liver (10 and 4 pts). Median follow up was 8 months. ORR was 35% (1 CR and 7 PR). Median PFS was 6 months. All pts reported at least one grade (G) 1-2 adverse event (AE): the most common were fatigue (43%), hypothyroidism (28%), stomatitis (28%), anorexia (26%), hand-foot syndrome (13%), hypertension (17%), and diarrhea (13%). Five pts reported G3 AEs (2 thromboembolic events, 2 arterial hypertension, 1 fatigue), while no G4-5 AEs were reported. 17% of pts required dose reduction. DNA sequencing was successful in 21 (91%) patients. All tumors were microsatellite stable. No association between tumor mutational burden and response to cabo was observed. The most affected pathways were chromatin-modifying enzymes (46%) and adaptive immune system (23%). Responsive pts (PFS > 6 months) showed high frequency of mutations affecting deubiquitination, cell-cell communication, and TGF-b signaling. Non-responders were frequently mutated in chromatin remodeling, transcriptional regulation and WNT pathways.
Conclusions
The study met its primary endpoint showing promising efficacy and acceptable tolerability of cabo in mCDC pts. Mature results according to mutational profiles and gene signatures will be presented.
Clinical trial identification
NCT03354884.
Legal entity responsible for the study
The authors.
Funding
Ipsen Spa.
Disclosure
All authors have declared no conflicts of interest.
655MO - A prospective phase II trial of cabazitaxel in male patients with chemotherapy pre-treated metastatic germ-cell tumors: The CABA-GCT study
- Giulia Baciarello (Rome, CEDEX, Italy)
Abstract
Background
Men with advanced germ cell tumor (GCT) with cancer progression after 2-3 lines of chemotherapy have a poor prognosis with currently no standard treatment. Taxanes have established activity in GCT. Cabazitaxel (CABA) may cross the blood-brain barrier and has limited peripheral neuro-toxicity, two major potential advantages for these patients (pts).
Methods
In this multicentre phase II study, men with cancer progression after at least 2 chemotherapy regimen for advanced GCT received CABA 25 mg/m2 every 3 weeks, for a maximum of 6 cycles. The primary endpoint was the favorable response (FR) rate, defined as complete response (CR) or partial response (PR) with normalized tumor markers (m-). For each patient we retained his best response. Using a 1-step Fleming design, 34 pts were required to show an improvement from 5% to 20%, with a type I error of 5% and a type II error of 10%. If 4 favorable responses or more were observed, it would be concluded that CABA is active in this setting (exact type I error = 9%, exact type II error = 7%). Tumor response was assessed at W6 and at the end of treatment (EOT).
Results
From September 2014 to October 2019, 34 pts from 5 centres were included and received 2 (47.1%), 3 (35.3%), or ≥4 (17.6%) previous lines of chemotherapy, respectively (including n=11 (32.5%) with previous high-dose chemotherapy). Overall, 3/34 (8.8%, 95% CI: 2.3-24.8] achieved a FR. (1 at W6, 2 at EOT). Exploratory analyses included overall disease control rate (CR, PRm-, PRm+ or SD), observed in 9 (26.5%; 95%CI: 13.5-44.6) pts at EOT. The 6-month PFS rate was 20.6% (95% CI: 10.4 - 36.8) and the 6-month OS was was 58.8% (95% CI: 42.2-73.6). No evidence of local anticancer activity was shown in the 4 patients with brain metastases (1 progression, 3 NE). At W6, 10 pts (29.4%) and 6 pts (17.6%) had a ≥30% reduction in hCG and AFP, respectively. G3 adverse events were reported in 7 pts (20.6%). Febrile neutropenia occurred in 4/34 pts (11.8%); 1/4 did not receive G-CSF prophylaxis. Only 1/34 pt (2.9%) developed a G2 peripheral neuropathy after the 1st cycle.
Conclusions
CABA can be safely administered in men with refractory NSGCT and it has modest and similar activity to other drugs used in monotherapy in this setting.
Clinical trial identification
EudraCT 2013-000286-36.
Legal entity responsible for the study
Institut Gustave Roussy.
Funding
Sanofi.
Disclosure
G. Baciarello: Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Invited Speaker: Gensenta. G. Gravis: Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Speaker’s Bureau: BMS; Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Invited Speaker: Janssen; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Advisory Board: Alliance Merck-Pfizer; Financial Interests, Institutional, Advisory Board: AAA; Financial Interests, Institutional, Invited Speaker: Astellas; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: Sanofi. A. Fléchon: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Invited Speaker: AAA. E. Colomba: Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Tesaro; Financial Interests, Personal, Invited Speaker: GSK. R. Flippot: Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Pfizer. K. Fizazi: Financial Interests, Institutional, Advisory Board: AAA; Financial Interests, Institutional, Advisory Board: Astellas; Financial Interests, Institutional, Invited Speaker: Astellas; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Advisory Board: Curevac; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Invited Speaker: Janssen; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Advisory Board: Sanofi; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Orion; Financial Interests, Institutional, Research Grant: Pfizer. All other authors have declared no conflicts of interest.
656MO - Phase II study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, plus cabozantinib for treatment of advanced clear cell renal cell carcinoma (ccRCC)
- David F. McDermott (Boston, MA, United States of America)
Abstract
Background
Belzutifan monotherapy has shown antitumor activity and favorable safety in advanced ccRCC. This ongoing, open-label, phase II study (NCT03634540) investigates belzutifan plus cabozantinib for pts with advanced ccRCC who were either treatment naive (cohort 1) or previously treated with immunotherapy (cohort 2). This analysis presents data from cohort 2.
Methods
Pts had advanced ccRCC and had previously received immunotherapy and ≤2 systemic treatment regimens. Initially, a safety review committee evaluated the first 6 pts enrolled in either cohort for 21 days to determine the recommended phase II dose (RP2D). The primary end point was ORR (CR + PR) per RECIST v1.1 by investigator review. Secondary end points were DCR (CR + PR + SD), DOR, PFS, and OS. For this preliminary analysis, efficacy was evaluated in pts who received ≥1 dose of treatment and had an opportunity for ≥6 mo of follow-up. Safety was evaluated in all pts.
Results
In the first 6 pts enrolled, 1 had a DLT (hand–foot syndrome); belzutifan 120 mg plus cabozantinib 60 mg was determined to be the RP2D. Overall, 52 pts were enrolled in cohort 2 and were included in the safety analysis set. In all pts, 28 (54%) previously received 1 line therapy and 24 (46%) previously received 2 lines of therapy. Median time from enrollment to data cutoff was 8.9 mo (range, 2.2-24.0). In the efficacy analysis set (N = 41), ORR was 22% (9 PRs) and DCR was 90%; 88% of pts had tumor shrinkage. Median DOR was not reached (range, 3.7+ to 14.8+ mo); all responses were ongoing as of the data cutoff date. Median PFS was 16.8 mo (95% CI, 9.2 to not reached); PFS rate at 12 mo was 65%; OS rate at 12 mo was 81%. In all pts, 98% had a treatment-related adverse event (TRAE); most events (92%) were grade 1 or 2. Incidence of grade 3 TRAEs ≥10% were hypertension (23%), anemia (12%), and fatigue (12%). Two (4%) pts experienced grade 3 hypoxia. There were no grade 4 or 5 TRAEs. Discontinuations owing to TRAEs occurred in 6 pts (12%) for belzutifan and 8 pts (15%) for cabozantinib.
Conclusions
In this preliminary analysis, belzutifan plus cabozantinib had manageable safety and showed promising antitumor activity in previously treated pts with advanced ccRCC.
Clinical trial identification
NCT03634540, August 16, 2018.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
D.F. McDermott: Financial Interests, Personal, Other, Honoraria: BMS, Pfizer, Merck, Alkermes, Inc., EMD, Serono, Eli Lilly and Company, Iovance, Eisai Inc., Werewolf Therapeutics, Calithera Bioscience; Financial Interests, Institutional, Research Grant: BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes, Inc., Checkmate Pharmaceuticals. T.K. Choueiri: Financial Interests, Personal, Full or part-time Employment: Dana Farber Cancer Hospital; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis; Financial Interests, Personal, Leadership Role: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCO; Financial Interests, Personal, Other, Travel expenses, including accommodations: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis; Financial Interests, Personal, Other: Patent application PCT/US2018/058430; Financial Interests, Personal, Stocks/Shares: Pionyr, Tempest Therapeutics; Financial Interests, Personal, Other, Honoraria: NCCN, UpToDate, Michael J. Hennessey Associates, ASCO, Harborside Press, Analysis Group, Alexion Pharmaceuticals, Sanofi/Aventis, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Co; Financial Interests, Institutional, Research Grant: Pfizer, Novartis, Merck, Exelixis, TRACON Pharma, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Peloton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Pharmaceuticals, Cerulean Pharma, Seattle Genetics/Aste. T.M. Bauer: Financial Interests, Institutional, Research Grant: Medpacto, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Millennium, Phosplatin Therapeutics, Calithera Biosciences, Kolltan; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Lilly, Bayer; Financial Interests, Personal, Advisory Role: AstraZeneca, Lilly, Bristol Myers Squibb, Foundation Medicine, Pfizer, Loxo, Bayer, Guardant Health, Exelesis, Blueprint Medicines; Non-Financial Interests, Personal, Other, Expense reimbursement: Lilly, Bristol Myers Squibb, Foundation Medicine, Ignyta, Moderna Therapeutics, Loxo, Bayer, Guardant Health; Financial Interests, Institutional, Advisory Role: Leap Therapeutics, Ignyta, Moderna Therapeutics, Pfizer. E. Arrowsmith: Financial Interests, Institutional, Research Grant: AstraZeneca, Onyx, Sarah Cannon Research Institute, Exelixis, Incyte, Modra Pharmaceuticals, Bristol Myers Squibb, Cephalon, Eisai, Lilly, Infinity Pharmaceuticals, Calistoga Pharmaceuticals, Chorus, EMD Serono, Genentech, Cougar Biotechnology, Evelo Bios. A. Roy: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. R. Perini: Financial Interests, Personal, Full or part-time Employment: MSD; Financial Interests, Personal, Stocks/Shares: MSD. D. Vickery: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.; Financial Interests, Personal, Research Grant: Merck & Co., Inc.; Financial Interests, Personal, Other, Travel expenses: Merck & Co., Inc. S.S. Tykodi: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Merck, Intellisphere LLC, Natera, Bristol-Myers Squibb, Exelixis; Financial Interests, Institutional, Research Grant: Genentech, Bristol-Myers Squibb, Merck, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, Clinigen Group; Financial Interests, Personal, Other: Patent Pending - “Binding Proteins Specific for 5T4 and Uses Thereof”.
Discussion 654MO, 655MO and 656MO
- Samra Turajlic (London, United Kingdom)
657MO - Antibiotic (ATB) therapy and outcome from nivolumab (N) in metastatic renal cell carcinoma (mRCC) patients (pts): Results of the GETUG-AFU 26 NIVOREN multicentric phase II study
- Lisa Derosa (Villejuif, France)
Abstract
Background
Previous studies examined the impact of ATB on immune checkpoint inhibitor efficacy across a wide range of tumors, including genitourinary neoplasms. Perturbation of the gut microbiota has been indicated as a putative mechanism to explain this influence. We aimed to assess the impact of ATB in refractory mRCC pts.
Methods
The GETUG-AFU 26 NIVOREN phase II trial (NCT 0301335) assessed the activity and safety of N in metastatic ccRCC pts who failed anti-angiogenic regimen. Pts who received ATB between 60 days before until 42 days after N initiation were compared with those who did not. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and toxicities were assessed. Multivariate Cox analysis was used to adjust for established risk factors: sex, age, international Metastatic RCC Database Consortium (IMDC) score, number of previous lines, hypoalbuminemia, and brain, bone and liver metastasis.
Results
Among 707 pts included between February 2016 and June 2017, 104 (14.7%) received ATB. Characteristics were well balanced except for IMDC score: 12% vs 19% good, 49% vs 57% intermediate, 39% vs 24% poor in ATB users vs non-users, respectively. Median OS was 13.0 (95%CI 8.1-19.8; 67/104) months for ATB users vs 25.0 (95%CI 22.4-28.4; 284/603) months in non-users [HR 1.77 (95%CI 1.36-2.31), p<.0001]. In multivariate analysis, ATB was still associated with worse OS [HR 1.59 (1.22-2.09), p=0.0008]. Median PFS was 2.6 (95%CI 2.4-4.1; 90/104) months in ATB users vs 3.8 (95%CI 2.9-4.6; 504/603) months in non-users [HR 1.24 (0.99-1.55), p=0.0564]. ORR was 15.1% for ATB users vs 21.1% for non-users (p=0.176). Among ATB users, there was no complete response (CR) and 53 (57.0%) had progressive disease (PD), while 9 (1.5%) and 275 (47.3%) of non-users had CR and PD, respectively. The incidence of grades 3-5 toxicity leading to treatment stop was 26.9% among ATB vs 17.9% of non-users (p=0.031).
Conclusions
ATB severely compromise OS and PFS in N-treated mRCC pts. We confirm the potential deleterious effect for ATB in pts treated with anti-PD1, and the suspected impact of microbiota lay the ground for interventional study.
Clinical trial identification
NCT 0301335.
Legal entity responsible for the study
Unicancer.
Funding
Institut National du Cancer, Direction Générale de l’Offre de Soins, Bristol-Myers-Squibb.
Disclosure
E. Colomba: Financial Interests, Personal, Invited Speaker: Ipsen, Sanofi, BMS and Pfizer. B. Escudier: Financial Interests, Personal and Institutional, Invited Speaker: Bristol-Myers Squibb, Bristol-Myers Squibb, Ipsen, Roche , Pfizer, Oncorena, Aveo. L. Albiges: Financial Interests, Personal and Institutional, Advisory Role: declared consulting or Advisory Role: Novartis, Amgen (Inst), Bristol-Myers Squibb, Bristol-Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst). All other authors have declared no conflicts of interest.
658MO - Cisplatin (cis)-related immunomodulation and efficacy with atezolizumab (atezo) + cis- vs carboplatin (carbo)-based chemotherapy (chemo) in metastatic urothelial cancer (mUC)
- Matthew D. Galsky (New York, United States of America)
Abstract
Background
Cis- but not carbo-based chemo leads to durable disease control in a subset of pts with mUC, but the underlying mechanisms remain elusive. Exploratory data from the randomised Ph III IMvigor130 study suggested improved OS with the addition of atezo to cis- but not carbo-based chemo (Galsky AACR 2021). Here we tested the hypothesis that cis may induce immunomodulatory effects.
Methods
Single-cell RNA sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) obtained at Cycle (C) 1 Day (D) 1 and C3D1 from 70 IMvigor130 pts receiving atezo + platinum and gemcitabine (plt [cis or carbo]/gem; Arm A) or placebo + plt/gem (Arm C). Gene expression profiling of paired pre-/post- neoadjuvant gem + cis samples was used to study cis-related changes in the tumour microenvironment (TME; n=113).
Results
The impact of pre-treatment tumour PD-L1 immune cell expression on OS with cis vs carbo in Arms A and C is shown (Table). In IMvigor130 Arm C cis- vs carbo-treated pts, on-treatment enrichment of Hallmark TNFα signalling via NFKB and inflammatory response gene sets was observed across all immune cell clusters; trends were even more pronounced in Arm A. Among top-ranked genes enriched in PBMCs post-cis vs -carbo was PD-L1 expression on tumour-infiltrating immune cells assessed from archival pre-treatment tumour samples (VENTANA SP142 assay). CI, confidence interval; HR, hazard ratio; IC0/1, presence of programmed death-ligand 1 (PD-L1)–expressing immune cells on <5% of the tumour area; IC2/3, presence of PD-L1–expressing immune cells on ≥5% of the tumour area; OS, overall survival.
IMvigor130: treatment subgroups IC0/1 IC2/3 HR (95% CI) n Median OS, mo n Median OS, mo Arm A (atezo + cis/gem) 102 19.5 35 Not reached 0.46 (0.25, 0.83) Arm A (atezo + carbo/gem) 241 13.9 73 16.6 0.85 (0.61, 1.17) Arm C (placebo + cis/gem) 102 12.8 34 27.9 0.51 (0.30, 0.86) Arm C (placebo + carbo/gem) 207 13.0 57 14.0 1.00 (0.71, 1.42)
Conclusions
PD-L1 IC 2/3 status is associated with longer OS in cis- but not carbo-treated pts with mUC. Cis, vs carbo, is associated with increased TNFα-mediated proinflammatory signalling in circulating immune cells and the TME. Together these data suggest that cis/gem induces immunogenic cell death and enhances antitumour immunity, particularly when combined with atezo.
Clinical trial identification
NCT02807636.
Editorial acknowledgement
Medical writing assistance for this abstract was provided by Bena Lim, PhD, of Health Interactions, Inc., and funded by F. Hoffmann-La Roche Ltd.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
M.D. Galsky: Financial Interests, Advisory Role: Merck; Financial Interests, Advisory Role: Pfizer; Financial Interests, Advisory Role: EMD/Serono; Financial Interests, Advisory Role: BMS; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Seattle Genetics; Financial Interests, Advisory Role: Astellas; Financial Interests, Advisory Role: Genentech; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: AstraZeneca. X. Guan: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares, RSU: Genentech. R. Banchereau: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. L. Wang: Financial Interests, Personal, Full or part-time Employment: Sema4. J. Zhu: Financial Interests, Personal, Full or part-time Employment: Sema4. H. Yu: Financial Interests, Full or part-time Employment: Sema4. D. Rishipathak: Financial Interests, Personal, Full or part-time Employment: Genentech. E. Hajaj: Financial Interests, Personal, Full or part-time Employment: Immunai. R.H. Herbst: Financial Interests, Personal, Full or part-time Employment: Immunai. I.D. Davis: Non-Financial Interests, Member: IMvigor130 Steering Committee; Non-Financial Interests, Advisory Board: Roche; Non-Financial Interests, Advisory Board: Janssen; Non-Financial Interests, Advisory Board: Astellas; Non-Financial Interests, Advisory Board: AstraZeneca; Non-Financial Interests, Advisory Board: Bayer; Non-Financial Interests, Advisory Board: Eisai; Non-Financial Interests, Advisory Board: Ipsen; Non-Financial Interests, Advisory Board: Merck/Pfizer; Non-Financial Interests, Advisory Board: MSD. E. Grande: Financial Interests, Personal, Invited Speaker: Adacap; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board: Caris Life Sciences; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Invited Speaker: Eusa Pharma; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Merck KGa; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Oncodna (Biosequence); Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Sanofi-Genzyme; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant, No financial interest: AstraZeneca; Financial Interests, Institutional, Principal Investigator, Coordinating PI, No financial interest: Ipsen; Financial Interests, Institutional, Research Grant, No financial interest: Lexicon; Financial Interests, Institutional, Research Grant, No financial interest: MTEM/Threshold; Financial Interests, Institutional, Research Grant, No financial interest: Nanostring Technologies; Financial Interests, Institutional, Research Grant, No financial interest: Pfizer; Financial Interests, Institutional, Research Grant, No financial interest: Roche; Non-Financial Interests, Personal, Advisory Board: ENETS. A. Bamias: Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: BMS; Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: Ipsen; Financial Interests, Personal, Other, Honoraria: Debio; Financial Interests, Advisory Role: Roche; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: BMS; Financial Interests, Advisory Role: MSD; Financial Interests, Advisory Role: Ipsen; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Roche. M. De Santis: Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Amgen; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Astellas; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: AstraZeneca; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Basilea; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Bayer; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Bioclin; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: BMS; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Eisai; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: ESSA; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Ferring; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Immunomedics; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Ipsen; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Janssen; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: MSD; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Merck; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Novartis; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Pfizer; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Pierre Fabre Oncology; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Roche; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Sandoz; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: Sanofi; Financial Interests, Personal and Institutional, Other, Honoraria; Travel, Accommodations, Expenses: SeaGen; Financial Interests, Advisory Board: Amgen; Financial Interests, Advisory Board: Astellas; Financial Interests, Advisory Board: AstraZeneca; Financial Interests, Advisory Board: Basilea; Financial Interests, Advisory Board: Bayer; Financial Interests, Advisory Board: Bioclin; Financial Interests, Advisory Board: BMS; Financial Interests, Advisory Board: EISAI; Financial Interests, Advisory Board: ESSA; Financial Interests, Advisory Board: Ferring; Financial Interests, Advisory Board: Immunomedics; Financial Interests, Advisory Board: Ipsen; Financial Interests, Advisory Board: Janssen; Financial Interests, Advisory Board: MSD; Financial Interests, Advisory Board: Merck; Financial Interests, Advisory Board: Novartis; Financial Interests, Advisory Board: Pfizer; Financial Interests, Advisory Board: Pierre Fabre Oncology; Financial Interests, Advisory Board: Roche; Financial Interests, Advisory Board: Sandoz; Financial Interests, Advisory Board: Sanofi; Financial Interests, Advisory Board: SeaGen. J. Á. Arranz: Financial Interests, Advisory Role: BMS; Financial Interests, Advisory Role: Astellas; Financial Interests, Advisory Role: MSD; Financial Interests, Advisory Role: Pfizer; Financial Interests, Advisory Role: Merck; Financial Interests, Institutional, Research Grant: BMS (SOGUG). E. Kikuchi: Financial Interests, Other, Honoraria: Astellas; Financial Interests, Other, Honoraria: AstraZeneca; Financial Interests, Other, Honoraria: Bayer; Financial Interests, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Other, Honoraria: Chugai; Financial Interests, Other, Honoraria: Janssen; Financial Interests, Other, Honoraria: Kissei; Financial Interests, Other, Honoraria: Kyorin; Financial Interests, Other, Honoraria: Merck Biopharma; Financial Interests, Other, Honoraria: MSD; Financial Interests, Other, Honoraria: Nippon Kayaku; Financial Interests, Other, Honoraria: Nippon Shinyaku; Financial Interests, Other, Honoraria: Pfizer; Financial Interests, Other, Honoraria: Sanofi; Financial Interests, Other, Honoraria: Taiho; Financial Interests, Other, Honoraria: Takeda; Financial Interests, Advisory Role: Astellas; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Bristol Myers Squibb; Financial Interests, Advisory Role: Chugai; Financial Interests, Advisory Role: Merck Biopharma; Financial Interests, Advisory Role: MSD; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Chugai; Financial Interests, Institutional, Research Grant: Kissei; Financial Interests, Institutional, Research Grant: Kyorin; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Nippon Kayaku; Financial Interests, Institutional, Research Grant: Nippon Shinyaku. J. Zhang: Financial Interests, Personal, Full or part-time Employment: Hoffmann-La Roche Ltd. C. Lee: Financial Interests, Personal, Full or part-time Employment: Roche Products Limited. X. Shen: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. P.C. Black: Financial Interests, Advisory Role: AbbVie; Financial Interests, Advisory Role: AstraZeneca; Financial Interests, Advisory Role: Astellas; Financial Interests, Advisory Role: Bayer; Financial Interests, Advisory Role: Biosyent; Financial Interests, Advisory Role: BMS; Financial Interests, Advisory Role: EMD-Serono; Financial Interests, Advisory Role: Ferring; Financial Interests, Advisory Role: Fergene; Financial Interests, Advisory Role: TerSera; Financial Interests, Advisory Role: H3-Biomedicine; Financial Interests, Advisory Role: Janssen; Financial Interests, Advisory Role: Merck; Financial Interests, Advisory Role: Protara Therapeutics; Financial Interests, Advisory Role: QED Bioscience; Financial Interests, Advisory Role: Roche; Financial Interests, Advisory Role: Sanofi; Financial Interests, Advisory Role: Sesen Bio; Financial Interests, Speaker’s Bureau: AbbVie; Financial Interests, Speaker’s Bureau: Biosyent; Financial Interests, Speaker’s Bureau: Janssen; Financial Interests, Speaker’s Bureau: Ferring; Financial Interests, Speaker’s Bureau: TerSera; Financial Interests, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Research Grant: iProgen; Financial Interests, Other, Travel, Accommodations, Expenses: Sanofi; Financial Interests, Other, Travel, Accommodations, Expenses: Bayer; Financial Interests, Licensing Fees: Decipher Biosciences. S. Mariathasan: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech.
Discussion 657MO and 658MO
- Sumanta K. Pal (Duarte, CA, United States of America)
659MO - Avelumab (A) as the basis of neoadjuvant chemotherapy (NAC) regimen in platinum eligible and ineligible patients (pts) with non-metastatic muscle invasive bladder cancer (NM-MIBC)
- Nieves Martinez Chanza (Brussels, Belgium)
Abstract
Background
Cisplatin-based NAC is considered as standard of care for NM-MIBC pts based on a modest survival benefit correlated with pathological complete response (pCR). Avelumab, a monoclonal antibody directed against PD-L1, showed efficacy in advanced urothelial cancer. We report preliminary data from the AURA trial assessing preoperative avelumab associated with two cisplatin-based regimens in the cisplatin eligible cohort.
Methods
AURA is a prospective, multicenter, randomized, phase II trial for pts with cT2-4aN0-2M0 bladder carcinoma. Cisplatin-eligible pts received cisplatin-gemcitabine (CG) plus A or dose-dense MVAC (DD-MVAC) plus A (1:1). Primary endpoint was pCR (ypT0/isN0) with the objective, in each arm, to show pCR rate > 25% (90% power reached in case of pCR rate > 45%). Two-step design was used with planned interim analysis after 28 evaluable pts per arm. Secondary endpoints were pathologic downstaging rate (<ypT2N0) and safety.
Results
At interim analysis data cut-off, 56 cisplatin-eligible pts were evaluable. For CG + A arm (n=28): median age was 69 years (41-81), 64% male, 7% cT4 and 7% cN+. For DD-MVAC + A arm (n=28): median age was 62 years (51-77), 79% male, 7% cT4 and 7% cN+. Six pts did not undergo surgery but were included in intention to treat analysis. Efficacy outcomes according to treatment regimen are represented in the table. Most common grade 3/4 AEs were thrombocytopenia (29%), acute kidney injury (18%) neutropenia (14%), and anemia (13%). No patients required steroids for immune-related AEs. No treatment-related deaths were reported. The IDMC recommended stopping accrual in this cohort because the endpoint was reached.
CG + A N = 28 DD-MVAC + A N = 28 pCR 50% 54% <ypT2N0 57% 64% Median weeks from randomization to surgery 15.7 11.5
Conclusions
Interim results from the AURA phase II trial demonstrate a high pCR rate with neoadjuvant avelumab in combination with each cisplatin-based NAC regimen. Further results in cisplatin eligible/ineligible cohorts and correlative studies will be presented.
Clinical trial identification
NCT03674424.
Legal entity responsible for the study
CTSU - Jules Bordet Institute.
Funding
Merck N.V.-S.A., Belgium, an affiliate of Merck KGaA, Darmstadt, Germany, as part of an alliance between Merck KGaA and Pfizer.
Disclosure
All authors have declared no conflicts of interest.
LBA31 - High- vs low-dose pre-operative ipilimumab and nivolumab in locoregionally advanced urothelial cancer (NABUCCO cohort 2)
- Jeroen Van Dorp (Amsterdam, Netherlands)
Abstract
Background
Standard treatment for patients (pts) with stage III (cT3-4aN0M0 or cT1-4aN1-3M0) urothelial cancer (UC) is cisplatin (cis)-based chemotherapy followed by radical surgery. A substantial number of pts is unfit for cis-based chemotherapy. In NABUCCO cohort 1, 24 pts were treated with pre-operative day 1 ipilimumab 3 mg/kg (ipi 3), day 22 ipi 3 + nivolumab 1 mg/kg (nivo 1), and day 43 nivolumab 3 mg/kg (nivo 3), showing encouraging efficacy (46% pathological complete response (pCR, ypT0N0)). Recent data in pre-operative trials for other cancer types suggests that a lower dose of ipilimumab has equal activity and is better tolerated. In cohort 2, we set out to identify if this is also true in stage III UC, by testing two different dosing schedules for ipi + nivo.
Methods
NABUCCO is a multicentre, phase Ib/II, pre-operative trial. In cohort 2, thirty stage III, cis-ineligible (or refusal) UC pts were randomly assigned (1:1) to arm A: two cycles ipi 3 + nivo 1 (day 1, 22) and nivo 3 (day 43); or arm B: two cycles ipi 1 + nivo 3 (day 1, 22) and nivo 3 (day 43). The primary endpoint was pCR rate. Secondary endpoints include feasibility (resection within 12 weeks) and grade 3–4 immune-related adverse events (irAEs).
Results
Thirty pts were randomly assigned to arm A (n=15) or arm B (n=15). 26/30 (87%) pts received all 3 treatment cycles. Four pts missed one or more cycles of therapy due to irAEs. 26/30 pts underwent radical surgery, 24 within twelve weeks after start of treatment. One patient (arm B) progressed before surgery (evaluable, non-response) and three pts (1x arm A and 2x arm B) refused radical surgery while responding radiologically; one of these (arm B, baseline cT4aN3) had a lymph node dissection showing a micrometastasis (evaluable, non-response). Response was evaluable in 28 pts. In arm A, 6/14 (43%) pts had a pCR; 8/14 (57%) had a pCR or ypTisN0. In arm B, 1/14 (7%) had a pCR whereas 3/14 (21%) had a pCR or ypTisN0.
Conclusions
We observed a pCR in 6/14 (43%) evaluable pts treated with ipi 3 + nivo 1 (arm A). In contrast, a pCR was observed in 1/14 (7%) evaluable pts treated with ipi 1 + nivo 3 (arm B). Our data suggest that ipi 3 + nivo 1 is more efficacious than ipi 1 + nivo 3 as pre-operative treatment in stage III UC.
Clinical trial identification
NCT03387761.
Legal entity responsible for the study
The Netherlands Cancer Institute.
Funding
Bristol Myers Squibb.
Disclosure
B.B.M. Suelmann: Financial Interests, Personal and Institutional, Advisory Role: Pfizer, MSD, BMS, Novartis, Ipsen; Financial Interests, Institutional, Research Grant: Pfizer, Astellas, BMS. N. Mehra: Financial Interests, Personal and Institutional, Advisory Board: Roche; Financial Interests, Personal and Institutional, Advisory Board: MSD; Financial Interests, Personal and Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Board: Bayer; Financial Interests, Personal and Institutional, Advisory Board: Astellas; Financial Interests, Personal and Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Astellas; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Sanofi; Financial Interests, Institutional, Funding: Genzyme. J. de Feijter: Financial Interests, Personal and Institutional, Advisory Board: Janssen; Financial Interests, Personal and Institutional, Advisory Board: Merck; Financial Interests, Personal and Institutional, Advisory Board: Pfizer; Financial Interests, Personal and Institutional, Other, Travel expenses: Pfizer. C.U. Blank: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Bristol Meyers Squibb; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Genmab; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal and Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Research Grant: NanoString; Financial Interests, Personal and Institutional, Research Grant: Novartis. R. Meijer: Financial Interests, Institutional, Advisory Board: Merck; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Astellas; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Roche. T. van der Heijden: Financial Interests, Personal, Advisory Role: Merck, Pfizer, Janssen, Bristol Myers Squibb, Astellas, AstraZeneca, MSD. B.W.G. van Rhijn: Financial Interests, Personal, Advisory Board: AstraZeneca, Ferring and QED Therapeutics. M.S. van der Heijden: Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, AstraZeneca, 4SC, Roche; Financial Interests, Institutional, Advisory Role: Bristol Myers Squibb, Merck, Roche, AstraZeneca, Seattle Genetics, Pfizer, Janssen. All other authors have declared no conflicts of interest.
Discussion 659MO and LBA31
- Ignacio Duran (Cantabria, Spain)