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- Brigette B. Ma (Sha Tin, Hong Kong PRC)
- Paolo Bossi (Brescia, Italy)
650O - A phase II study of nivolumab for high-risk oral leukoplakia
- Glenn J. Hanna (Boston, United States of America)
Abstract
Background
Oral proliferative leukoplakia (PL) is an aggressive precancerous disease characterized by multifocal lesions and a high-risk of transformation to oral squamous cell carcinoma (OSCC). There are no effective therapies that prevent progression to oral cancer. PL demonstrates a rich immune microenvironment, providing strong rationale to evaluate PD-1 blockade as preventative immunotherapy.
Methods
This single-arm, phase 2 trial investigated nivolumab (N) among patients (pts) with PL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of epithelial dysplasia); a history of previously treated early-stage OSCC was permitted. Pts underwent pre-treatment biopsy of 1-3 sites then received 4 doses of N (480 mg IV) every 28-days, followed by re-biopsy. Intraoral photographs and bidirectional measurements occurred at each visit. Primary endpoint: change in composite score (size and degree of dysplasia) pre- to post-treatment (CR: >80% decrease in score; PR: 40-80% decrease; PD: ≥10% increase in composite score or new OSCC). Secondary endpoints: safety, cancer-free survival (CFS). Exploratory aims: PD-L1 status, genomic and immune profiling parameters.
Results
Between 1/2019 and 12/2021, 33 pts enrolled; 30 evaluable to date. Median age: 64 (range: 32-80), mostly women (18, 60%), 16 (53%) former/current smokers; oral tongue (13, 43%) was the main disease subsite; 8 (27%) had prior OSCC. A decrease of ≥40% in composite score was observed in 37% of pts (3 CRs and 8 PRs); 14 (47%) had stable disease, 4 experienced PD. 26 (86%) completed all 4 doses of N; 2 (7%) discontinued for toxicity, 2 (7%) for PD. Grade 3-4 irAEs were noted among 7 (23%) pts (hyperglycemia, colitis, hepatitis). At median follow-up of 16.3 mos (4.1-34.3+), median CFS was not reached, with 7 (23%) cancer events observed (3 among prior responders); 1-year CFS: 76.5% (95%CI 54.5-88.8). All pts are alive at last follow-up. Baseline median PD-L1 CPS trended higher among responders (15 vs. 5, p=0.10).
Conclusions
Nivolumab yielded a best response of PL regression among 37% of pts with a favorable overall CFS. This is the first study to demonstrate evidence of efficacy using preventative immunotherapy for high-risk oral precancerous disease.
Clinical trial identification
NCT03692325.
Legal entity responsible for the study
G.J. Hanna, MD and BMS.
Funding
Bristol-Myers Squibb.
Disclosure
G.J. Hanna: Financial Interests, Institutional, Sponsor/Funding: BMS; Financial Interests, Institutional, Research Grant: Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme; Financial Interests, Personal, Advisory Board: Coherus, Maverick, Merck. A. Villa: Financial Interests, Institutional, Research Grant: PCCA, Merck. N.S. Treister: Financial Interests, Personal, Advisory Role: MuReva Phototherapy; Financial Interests, Institutional, Research Grant: THOR Photomedicine Ltd; Financial Interests, Personal, Advisory Board: Alosa Health. R. Uppaluri: Financial Interests, Personal and Institutional, Research Grant, Advisory Board: Merck. R. Haddad: Non-Financial Interests, Personal, Member: NCCN; Financial Interests, Personal and Institutional, Advisory Role: Celgene, Merck, BMS, AstraZeneca, Pfizer, Genentech, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Eisai, Loxo, Immunomic Therapeutics, GSK, Gilead, Vaccinex, EMD Serono, BioNTech AG, Achilles Therapeutics, Bayer, Coherus, MIRATI; Financial Interests, Institutional, Research Grant: Kura. All other authors have declared no conflicts of interest.
651O - Pembrolizumab (pembro) + carboplatin (carbo) + paclitaxel (pacli) as first-line (1L) therapy in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Phase VI KEYNOTE-B10 study
- Marcin R. Dzienis (Southport, Australia)
Abstract
Background
Based on the phase 3 KEYNOTE-048 trial, 1L SOC treatment (tx) for R/M HNSCC, regardless of PD-L1 status, is pembro + platinum + 5-FU. 5-FU alternatives are needed because of associated cardiovascular, dihydropyrimidine dehydrogenase deficiency–related toxicities and patient (pt) inconvenience, costs, and complications associated with continuous 4-day infusion. In clinical studies, platinum + pacli was no less efficacious than platinum + 5-FU in R/M HNSCC. We present initial results of the first global prospective trial of pembro + carbo + pacli in 1L R/M HNSCC.
Methods
In the ongoing phase 4 KEYNOTE-B10 trial (NCT04489888), pts with previously untreated, R/M HNSCC regardless of tumor PD-L1 status and ECOG PS 0/1 received pembro 200 mg IV Q3W, carbo AUC 5 mg/mL/min IV Q3W, and pacli 175 mg/m2 IV Q3W or 100 mg/m2 IV Q1W on days 1 and 8. Tx continued for ≤35 cycles of pembro, ≤6 cycles of carbo and pacli, or until PD, unacceptable toxicity, or pt withdrawal. Primary end point: ORR per RECIST v1.1 by BICR. Secondary end points: DOR and PFS by BICR, OS, safety and tolerability. Efficacy analysis was based on first 82 treated pts to ensure sufficient follow-up. Safety was analyzed in all treated pts.
Results
At March 16, 2022, data cutoff, 92 of 100 planned pts were enrolled; 41 remained on tx and 51 discontinued, most because of PD (31 of 51 pts). Median follow-up was 8.2 mo (range, 0.3-15.8). Confirmed ORR was 43% (95% CI, 32-54). Median OS was 12.1 mo (95% CI, 10-NR). For all treated pts (n = 92), any-grade TRAEs occurred in 96%, most commonly decreased neutrophil count (57%), anemia (43%), and fatigue (40%). Grade 3-5 TRAEs occurred in 71% of pts; 2 were grade 5 (sepsis; hypersensitivity reaction). BICR, blinded independent central review; NR, not reached."+" indicates there is no progressive disease by the time of last disease assessment
pembro + carbo + pacli 43 (35) [32-54] 5 (4) 38 (31) 68 38 (27-51) 35 34 (19-52) 5.5 (1.1+ - 9.8+) 5.6 (4-7) 12.1 (10-NR) 73 (61-82) 58 (42-71)
Conclusions
Pembro + carbo + pacli showed antitumor activity with a manageable safety profile, suggesting this 5-FU-free regimen may be comparable to historical 1L SOC and may expand tx options for 1L R/M HNSCC.
Clinical trial identification
NCT04489888, release date July 28, 2020.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Mallory Campbell, PhD and Matthew Grzywacz, PhD, of ApotheCom (Yardley, PA, USA).
Legal entity responsible for the study
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Funding
Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Disclosure
M.R. Dzienis: Financial Interests, Personal, Advisory Board: MSD, Novartis; Financial Interests, Personal, Other, Honoraria: BMS, Novartis; Financial Interests, Personal, Other, Educational support: Novartis, Roche. A.R. Hansen: Financial Interests, Institutional, Principal Investigator: Novartis, BMS, Pfizer, Boehringer Ingelheim, Roche, Genentech, AstraZeneca, MedImmune, Merck, GSK; Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, GSK; Financial Interests, Institutional, Research Grant: Karyopharm. A.J. Joshi: Non-Financial Interests, Personal, Invited Speaker: Ipsen; Non-Financial Interests, Personal, Advisory Board: Ipsen, Amgen; Non-Financial Interests, Personal, Sponsor/Funding: MSD-Australia, Roche, Janssen-Cilag. J.S. Mccarthy: Financial Interests, Personal, Advisory Board: Merck, Pfizer, Ipsen, BMS. N. Naicker: Financial Interests, Personal, Full or part-time Employment: MSD. Y. Sidi, B. Gumuscu: Financial Interests, Personal, Full or part-time Employment: Merck; Financial Interests, Personal, Stocks/Shares: Merck. G. De Castro Jr.: Financial Interests, Personal and Institutional, Speaker’s Bureau: Merck Serono, Roche, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board: Merck Serono, Roche, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, GSK; Financial Interests, Personal and Institutional, Other: Merck Serono; Financial Interests, Personal and Institutional, Principal Investigator: Merck Sharp & Dohme, AstraZeneca, GSK. All other authors have declared no conflicts of interest.
Invited Discussant 650O and 651O
- Amanda Psyrri (Haidari, Greece)
Q&A
- All Speakers (Lugano, Switzerland)
652O - Randomized phase III VANCE study: Gemcitabine and carboplatin (GC) followed by Epstein Barr virus-specific autologous cytotoxic T lymphocytes (EBV-CTL) versus the same chemotherapy as first-line treatment for advanced nasopharyngeal carcinoma (NPC)
- Han Chong Toh (Singapore, Singapore)
Abstract
Background
The VANCE trial (NCT 20578641) is the largest clinical trial of adoptive T cell therapy in solid tumors. This phase III, multicenter, randomized, open-label study evaluates the efficacy of GC followed by EBV-CTL versus GC alone as first-line treatment for locally recurrent but incurable and metastatic NPC (R/M). EBV-CTL is an autologous T-cell immunotherapy generated from blood of the patient and manufactured without genetic modification. Thirty clinical trial sites involved were from USA, Singapore, Malaysia, Taiwan and Thailand.
Methods
Patients with R/M NPC were randomized to Arm A (GC x 4 cycles and EBV-CTL x up to 6 cycles) or Arm B (GC x 6 cycles) in a 1:1 ratio. Primary Objective is to assess Overall Survival (OS) of EBV-CTL following GC compared to GC.
Results
Of 330 randomized patients, 164 were enrolled in Arm A and 166 in Arm B. 325 patients were treated including 133 patients treated with EBV-CTL. The central Good Manufacturing Practice (GMP) facility was able to produce sufficient EBV-CTL for 94% of Arm A patients. Demographics and baseline characteristics were balanced. Median age was 54 (21-80) years, 75.2% were male, 97% were Asian, 43.6% had an ECOG PS of 1. 65.2% of Arm A and 66.3% in Arm B had prior radiation/chemoRT for earlier locoregional NPC. Patients who completed 4 cycles of GC were 82.3 % in Arm A, and 82.5 % in Arm B (58.4% completed 6 cycles). 80.5% of patients in Arm A received at least two infusions of EBV-CTL. Median dose per cycle was 4.5 × 108 cells/m2. The median OS was 25.0 months (19.7-31.8) in Arm A and 24.9 months (19.7-32.8) in Arm B (hazard ratio [HR] 1.19; p = 0.1942). Secondary endpoints of PFS and ORR will be available at time of ESMO Congress 2022. 87.7% of patients had grade 3 or higher adverse events (AE) (85.0% in Arm A, 89.6% in Arm B). Thirteen out of 133 patients treated with EBV-CTL (9.8%) experienced EBV-CTL related AEs, all grade 1 and 2, except two grade 3 events of anemia and leukopenia that occurred in one patient.
Conclusions
EBV-CTL as first-line treatment in patients with R/M NPC had a favorable safety profile but did not demonstrate a longer OS vs standard of care (SOC) chemotherapy.
Clinical trial identification
Protocol number: FF01; latest protocol release date: 1 May 2020 and 31 Jul 2020.
Editorial acknowledgement
Authors on behalf of VANCE trial investigators.
Legal entity responsible for the study
Tessa Therapeutics Ltd.
Funding
Tessa Therapeutics Ltd.
Disclosure
H.C. Toh: Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Advisory Board, Liver Cancer Global SAB in 2022: AstraZeneca; Financial Interests, Personal, Full or part-time Employment, I am a consultant for this biotech: Tessa Therapeutics Ltd; Financial Interests, Personal, Stocks/Shares: Tessa Therapeutics Ltd; Financial Interests, Institutional, Stocks/Shares, I am on the SAB and have stock options: Biosceptre Ltd; Financial Interests, Institutional, Invited Speaker, I am PI of an investigator initiated trial supported by: MSD Merck; Financial Interests, Personal and Institutional, Invited Speaker, I am coordinating PI for an investigator initiated trial supported by: BMS. E. Sirachainan: Financial Interests, Personal, Advisory Board: Merck, Roche, Taiho, MSD, Novartis. G.F. Ho: Financial Interests, Personal, Invited Speaker: MSD, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Pfizer; Financial Interests, Personal, Advisory Board: MSD, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Pfizer; Financial Interests, Personal and Institutional, Full or part-time Employment: University Malaya Medical Centre, UM Specialist Centre; Financial Interests, Institutional, Research Grant: Eli Lily, Regeneron, MSD, AB Science, Astellas, Tessa Therapeutics, Roche, Arcus Bioscience, AstraZeneca; Financial Interests, Institutional, Principal Investigator: Eli Lilly, Regeneron, MSD, AB Science, Astellas, Tessa Therapeutics, Roche, Arcus Bioscience, AstraZeneca, Pfizer; Financial Interests, Personal, Advisory Role: MSD, Novartis, Roche, Boehringer Ingelheim, AstraZeneca; Financial Interests, Personal, Other, Honoraria: MSD, Novartis, Roche, Boehringer Ingelheim, AstraZeneca. C. Tan: Financial Interests, Personal, Full or part-time Employment: Tessa Therapeutics Ltd. C. Ding: Financial Interests, Personal, Full or part-time Employment: Tessa Therapeutics, Pte. Ltd.; Financial Interests, Personal, Stocks/Shares: Tessa Therapeutics, Pte. Ltd.; Non-Financial Interests, Project Lead: Tessa Therapeutics, Pte. Ltd. A. Myo: Financial Interests, Personal, Full or part-time Employment: Tessa Therapeutics Ltd. All other authors have declared no conflicts of interest.
653O - Neoadjuvant nivolumab (N) before chemoradiation (CRT) in high-risk HPV driven oropharynx cancer (OPC) - IMMUNEBOOST-HPV: A multicenter randomized phase II trial
- Haitham Mirghani (Paris, France)
Abstract
Background
Some patients (pts) with HPV-driven OPC have a less favorable prognosis. We aimed to evaluate the feasibility of N prior to CRT in this population.
Methods
HPV driven OPC pts (p16+ & HPV-DNA+) with advanced disease (T4, N2/N3) or a smoking history >10 p/y were randomly allocated 1:2 to receive cisplatin (Cis)-based CRT or 2 cycles of N 240 mg followed by same CRT. Primary Endpoint is the rate of pts who receive Full Treatment in Due Time (FTDT) defined as: a) 2 N cycles (day 1, day 14-16) b) CRT started between days 28-37 after the 1st N cycle c) No RT break ≥1 week d) RT dose >95% of theoretical dose e) Cis dose ≥200 mg/m2 In the Experimental Arm (EA), the trial was designed with FTDT rate of 88% considered as inacceptable versus an alternative of 98%, type I error of 0.10, and type 2 error of 0.08. HPV16 circulating DNA was quantitatively monitored at baseline and after CRT.
Results
From 07/2019 to 09/2021, 61 pts were randomized: 41 in the EA, 20 in the Control Arm (CA). Median age was 60 years, 77% men, 72% current or former smokers, 57% stage III disease (TNM8). In the EA, 4 pts received < 200mg/m2 Cis (2 kidney failures, 2 ototoxicity) and 1 pt had RT-delay (day 38, logistical issues). All pts received the planned RT dose. One pt in the CA had a 9-day RT break (hemorrhage). In total, 36 pts (88%, 95% confidence interval (CI) [74; 96]) of the EA met FTDT criteria, which is < the lower limit of 39 pts set by the protocol. In the CA, 19 pts (95%, 95%CI [75; 99.9]) met FTDT criteria. 14 N-related Adverse Events (AE) occurred in 8 pts including 5 serious AE (ankylosing spondylitis flare-up, hepatic cytolysis, 2 colitis, diabetic ketoacidosis). Two pts in the EA had a partial response after N. Three months after CRT, rates of complete and partial responses were 53% and 45% in the EA and 65% and 35% in the CA. One pt of the EA had a doubtful new lesion (node), not confirmed later. At baseline, HPV16ctDNA was positive in 34 of 47 tested pts. Among them, DNA ranged from 33 to 38275 cp/mL and 21 pts were tested after CRT and all had complete clearance.
Conclusions
N prior to CRT did not reach the expected feasibility aim, due to decreased Cis dose (renal/ototoxicity), potentially related to N. Progression-free and overall survival will be evaluated in both arms.
Clinical trial identification
NCT03838263.
Legal entity responsible for the study
Unicancer.
Funding
Partial funding from BMS - study CA209-970.
Disclosure
H. Mirghani: Financial Interests, Institutional, Advisory Role: MSD; Financial Interests, Institutional, Other, Travel, acommodation exepenses: BMS. C. Even: Financial Interests, Personal, Advisory Board: BMS, MSD, Innate Pharma, Merck Serono; Financial Interests, Institutional, Advisory Board: F Star Therapeutics; Financial Interests, Institutional, Invited Speaker: BMS, AstraZeneca, ISA pharmaceutics, MSD, DebioPharma, Ayala, Novartis. H. Pere: Financial Interests, Institutional, Invited Speaker: MSD, Janssen; Financial Interests, Institutional, Advisory Role: Seegen. J. Fayette: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Innate Pharma, Merck Serono, Roche; Financial Interests, Institutional, Other, research funding: Seagen; Non-Financial Interests, Principal Investigator: AstraZeneca. L. Geoffrois: Financial Interests, Personal, Advisory Board, Ad Board RCC: Ipsen; Financial Interests, Personal, Invited Speaker: Ipsen, BMS, Merck Serono, MSD; Financial Interests, Personal, Advisory Board, Ad Board Bladder Cancer: Merck Serono; Financial Interests, Personal, Advisory Board, Melanoma: Novartis; Financial Interests, Personal, Advisory Board, Head and Neck/RCC: MSD; Financial Interests, Personal, Advisory Board, Bladder cancer: Pfizer; Financial Interests, Institutional, Invited Speaker: MSD, BMS, Roche; Financial Interests, Institutional, Research Grant: Novartis. F. Clatot: Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Advisory Role: Merck Serono, MSD, BMS, Roche, Lilly, AstraZeneca. Y. Tao: Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Other, travel: MSD, Merck Serono. C. Badoual: Financial Interests, Personal, Invited Speaker: Merck. A. Auperin: Financial Interests, Personal, Funding: F. Hoffmann-La Roche. All other authors have declared no conflicts of interest.
Invited Discussant 652O and 653O
- Lisa F. Licitra (Milan, Italy)
Q&A
- All Speakers (Lugano, Switzerland)