All times are listed in CEST (Central European Summer Time)
- Ana Martins Ferreira Varges Gomes (Faro, Portugal)
- Sandra Schmitz (Woluwe-Saint-Lambert, Belgium)
- Sjoukje Oosting (Groningen, Netherlands)
655MO - Quality of life in patients with p16+ oropharyngeal cancer receiving accelerated radiotherapy (RT) with either cisplatin or cetuximab in NRG/RTOG 1016
- Jolie Ringash (Toronto, Canada)
Abstract
Background
This phase 3 randomized non-inferiority de-escalation trial compared cetuximab (cetux) vs cisplatin (cis), concurrent with accelerated RT 70 Gy/6 weeks, in p16+ oropharyngeal cancer (OPC). Quality of life (QOL) was an important secondary endpoint.
Methods
EORTC QLQ-C30/HN35 was completed at baseline, end of treatment, 3, 6, and 12 months post. The substudy aimed for 400 eligible patients. We report completion rates and compare by arm for change from baseline in each domain (0.05 two-sided alpha and MID of 10 points) using linear mixed models.
Results
Consent was 91% (381/419 offered substudy); 6 protocol deviations excluded (n=375). No significant differences in patient/tumor characteristics were found by participation status. Completion rates (%) at the 5 times did not differ by arm (cis/cetux): 92/94, 74/77, 76/81, 76/81, and 73/74. The swallowing domain of HN35 (previously reported) did not differ significantly by arm. No significant difference was seen by arm for the 6-mo change from baseline on any domain. At end of RT (only), dry mouth was significantly worse for RT+cetux. At end of treatment, all domains showed statistically and clinically significant mean worsening across both arms except Emotional Functioning, Dyspnea, Diarrhea, and Teeth. Most domains returned within 10 points of baseline by 6 mo, with the following maintaining significant impairment: Senses (taste/smell), Social Eating, Opening Mouth, Dry Mouth, Sticky Saliva. At 12 mo post-treatment, worsening from baseline persisted for Senses, Dry Mouth, Sticky Saliva, and Weight Gain. Pain Killer use improved significantly from baseline to 3, 6, and 12 mo.
Conclusions
Although replacing RT+cis with RT+cetux did not benefit QOL, this study has confirmed the responsiveness of EORTC QLQ-C30/HN35 to the effects of concurrent systemic/RT for OPC. Dry Mouth, Sticky Saliva, and Senses showed large, significant, and persistent impairments, and remain worthwhile targets for future de-escalation efforts. Domains related to eating (Swallowing, Appetite, Nutritional Supplements, Social Eating, Weight Loss) did not show sustained significant impairment on this instrument in this study.
Clinical trial identification
NCT01302834.
Legal entity responsible for the study
NRG Oncology.
Funding
This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology).
Disclosure
M.L. Gillison: Financial Interests, Personal, Funding, Consulting: Istari Oncology Inc, LLX Solutions, Llc, Kura Oncology, Mirati Therapeutics, BioNtech AG, Shattuck Labs, INC, EMD Serono, INC, Depiopharm, Merck & Co, Ipsen Biopharmaceuticals Inc, Gilead Sciences, Inc, Bristol-Myers Squibb, Bicara Therapeutics, Bayer Healthcare Pharmaceutics, Genocea Biosciences, Inc, Coherus; Financial Interests, Personal, Invited Speaker: OncLive, Roche; Financial Interests, Personal, Advisory Board: Seagen, Sensei Biotherapeutics, Inc; Financial Interests, Personal and Institutional, Research Grant: Genocea Biosciences, Inc, Bristol-Myers Squibb, Genentech, Kura, Cullinan Labs, Agenus; Financial Interests, Personal, Advisory Board, DSMB: SQZBiotech, BioMimetix, Kura. E.M. Sturgis: Non-Financial Interests, Personal, Member of the Board of Directors, also Exec committee of Board: The Immunization Partnership; Non-Financial Interests, Personal, Research Grant: Trinity, Roche Diagnostics. E.M. Basch: Non-Financial Interests, Personal, Member of the Board of Directors: ASCO; Financial Interests, Institutional, Research Grant: NCI, PCORI; Financial Interests, Personal, Funding, consulting: AstraZeneca, Resilience, Sivan, N-Power, Carevive. S.A. Koyfman: Financial Interests, Personal, Advisory Role, consulting: Merck, Regeneron; Financial Interests, Personal, Invited Speaker: Varian; Financial Interests, Personal, Funding, travel expenses: Castle Biosciences; Financial Interests, Personal, Advisory Board, DSMB: Alpha Tau; Financial Interests, Personal and Institutional, Research Grant: BMS, Merck. J.E. Bates: Financial Interests, Personal, Advisory Board: Castle Biosciences, Galera Therapeutics . P. Torres-Saavedra: Non-Financial Interests, Institutional, Research Grant, NRG Oncology SDMC Grant: US NCI. Q. Le: Financial Interests, Personal and Institutional, Funding, support for group related travel (to NRG retreats): RTOG Foundation; Non-Financial Interests, Personal, Leadership Role, RTOG Group Chair: NRG Oncology. B. Movsas: Financial Interests, Personal, Research Grant: Varian, Philips, ViewRay. All other authors have declared no conflicts of interest.
656MO - Phase I study of M6620 (VX-970, berzosertib) in combination with cisplatin and XRT in patients with locally advanced head and neck squamous cell carcinoma
- Aarti Bhatia (New Haven, United States of America)
Abstract
Background
M6620 is a highly potent and selective ATP-competitive ATR inhibitor. It showed strong synergy with cisplatin and radiation in preclinical cancer models. The significant vulnerability to ATR inhibition by cancer cells harboring inactivating p53 mutations provided a rationale to test the safety of M6620 along with definitive chemoradiation in Head and Neck Squamous Cell Carcinoma (HNSCC) where such alterations are common.
Methods
Eligible patients with stage III or IV HNSCC not amenable to surgical resection were enrolled in defined dose cohorts using the Escalation with Overdose Control (EWOC) design. The optimal dose of cisplatin (40 or 30mg/m2 weekly) to combine with standard radiation (70Gy) and biologically relevant dose of M6620 (120mg/m2) was tested in stage I. The safety of escalating doses of M6620 across a range of 160 to 280mg/2 along with fixed dose cisplatin and XRT (70Gy) was planned in stage II of the study.
Results
We enrolled 43 patients; median age 60 years (range 45-76); 11.6% Black; 37.2% females. The most common treatment emergent adverse events (TEAE) in 39 evaluable patients were: Anemia (74%), Nausea (72%), Fatigue (69%), Dysphagia (69%), Lymphopenia (69%) and Leukopenia (67%) while the most frequent grade ≥3 TEAE occurring in ≥ 20% of patients were Lymphopenia (31%), Leukopenia (28%), Anemia (26%), Dysphagia (21%), and Neutropenia (21%). Dose limiting toxicities recorded on study included Dysphagia, neutropenia, thrombocytopenia, febrile neutropenia, intestinal hemorrhage, pseudogout and hypomagnesemia. M6620 was safely combined with cisplatin (40mg/m2) and XRT (70Gy) at doses of 120, 160 and 200mg/m2. The highest dose of 200mg/m2 plus standard chemoradiation was declared the recommended phase 2 dose. Unconfirmed best response in 20 evaluable patients by RECIST were complete response (30%), partial response (40%), stable disease (15%) and progressive disease (10%). Ongoing PK and tissue-based biomarker analysis will be presented at the meeting.
Conclusions
M6620 at the dose of 200mg/m2 was safe and was declared the RP2D in combination with weekly cisplatin (40mg/m2) and standard XRT (70Gy) in locally advanced HNSCC with encouraging initial efficacy.
Clinical trial identification
NCT02567422.
Legal entity responsible for the study
NCI CTEP.
Funding
US National Institutes of Health.
Disclosure
J.W. Riess, T.K. Owonikoko: Financial Interests, Personal, Advisory Board: EMD Serono. All other authors have declared no conflicts of interest.
657MO - Effectiveness of geriatric assessment-driven interventions on quality of life for 2 years in older patients with head and neck cancer: Results from the EGeSOR trial
- Charlotte Lafont (Paris, France)
Abstract
Background
About 30% of Head and Neck Cancer (HNC) cases are diagnosed in patients aged 70 years and older. Due to their location, HNC and the toxicity of associated treatments may have consequences on quality of life. The aim of this study was to assess the effectiveness of Geriatric Assessment (GA)-driven interventions on quality of life for 2 years in older patients with HNC.
Methods
The EGeSOR study was a two parallel group, multicenter, randomized, controlled and open-label trial, including HNC patients aged 65 years and over between 2013 and 2018. Patients were randomized 1 :1 to receive either a pre-therapeutic GA, a standardized geriatric intervention and follow-up (intervention group) or standard of care (control group). The main outcome was quality of life measures through the European Organisation for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30/100) and HNC questionnaire (QLQ-HN35/100) at 6, 12 and 24 months. Linear mixed models were performed.
Results
Among the 475 patients included (238 in the intervention group and 237 in the control group), the median age was 75.3 years, 31% were women, 44% with oral cancer and 21% metastasis. At baseline, the median score of global health status was 66.7 [50-83.3]. There were no statistically significant differences in evolution between the two groups in either the QLQ-C30 (15 dimensions) or HN35 scores (18 dimensions) over the 24-month period. The evolution of global health status followed a J-shape between M0 and M24 (median gain : 8 points). In the intervention group, 74% of patients did not receive the complete intervention as planned. Statistical analyses regarding age, tumor site and metastasis status are ongoing.
Conclusions
Baseline GA did not improve quality of life for 2 years in older patients with HNC. Difficulties in implementation of complete interventions may have contributed to this result. Alternative models to implement GA-driven interventions could be explored.
Clinical trial identification
NCT02025062.
Legal entity responsible for the study
Assistance Publique des Hôpitaux de Paris - APHP.
Funding
The EGeSOR study was supported by grants from the French National Cancer Institute [INCa] [RAFC1202] and the platform for clinical research in older cancer patients (PACAN, Ligue Nationale contre le Cancer).
Disclosure
E. Paillaud: Financial Interests, Invited Speaker, Honoraria for presentation during an educational Symposium: Amgen, Servier; Financial Interests, Advisory Board: Pfizer, BMS; Financial Interests, Other, Supports for participation to congress, travel and inscription from Nutricia. P. Caillet: Non-Financial Interests, Other, Contract as expert in geriatric oncology for an observational prospective cohort (phase IV). No fees: Pfizer; Financial Interests, Invited Speaker, Honoraria for presentation during an educational Symposium: Amgen; Financial Interests, Advisory Board: Pfizer. A. Raynaud-Simon: Financial Interests, Other: Nestlé, Nutricia, Lactalis, Fresenius, Entreprises de la Nutrition Clinique. A. Anota: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Sandoz, Amgen, Ipsen; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Other, Travel fees: BMS, AstraZeneca, Novartis; Financial Interests, Personal, Invited Speaker, Travel fees: AstraZeneca. All other authors have declared no conflicts of interest.
Invited Discussant 655MO, 656MO and 657MO
- Sjoukje Oosting (Groningen, Netherlands)
658MO - Pembrolizumab (pembro) vs standard-of-care (SOC) in previously treated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): 6-year follow-up of KEYNOTE-040
- Denis Soulieres (Montreal, Canada)
Abstract
Background
Pembro monotherapy is a SOC for R/M HNSCC that has progressed following platinum-containing chemo. In the phase 3 KEYNOTE-040 trial (NCT02252042), pembro had clinically meaningful prolonged OS and a favorable safety profile compared with SOC at the time (HR, 0.80; 95% CI, 0.65-0.98) in platinum-refractory R/M HNSCC. OS benefit was greater in patients (pts) with higher PD-L1 expression. Results of KEYNOTE-040 are presented after 6 years of follow-up.
Methods
Pts with incurable R/M HNSCC that progressed on or after platinum-containing chemo or ≤6 mo of prior platinum-containing multimodal therapy were randomized 1:1 to receive pembro 200 mg Q3W or investigator’s choice of methotrexate, docetaxel, or cetuximab. Primary end point was OS. Secondary end points were OS (PD-L1 CPS ≥1), ORR, DOR, PFS, and safety. Efficacy end points were evaluated in the ITT, PD-L1 TPS ≥50%, and PD-L1 CPS ≥1 populations.
Results
Of 495 pts, 15 (6.1%) and 5 (2.0%) were still being followed up in the pembro and SOC arms, respectively, as of the February 3, 2022, data cutoff date. Median follow-up was 74.8 mo (range, 68.8-85.4). Efficacy data are shown in the table. The 6-year OS rate for pembro vs SOC was 6.5% vs 2.4% for ITT, 8.9% vs 6.3% for TPS ≥50%, and 7.1% vs 2.1% for CPS ≥1 populations. Median OS for pembro vs SOC was 8.4 mo vs 7.1 mo (HR, 0.79; 95% CI, 0.66-0.94) for ITT, 11.6 mo vs 7.9 mo (HR, 0.62; 95% CI, 0.43-0.90) for TPS ≥50%, and 8.7 mo vs 7.1 mo (HR, 0.72; 95% CI, 0.59-0.89) for CPS ≥1 populations. Any-grade treatment-related AEs (TRAEs) occurred in 64.2% of pts in the pembro arm and 83.3% of pts in the SOC arm. Grade 3-5 TRAEs occurred in 13.4% of pts in the pembro arm and 36.8% in the SOC arm. “+” indicates response is ongoing
Pembro SOC 247 248 OS, median, mo 8.4 7.1 HR (95% CI) 0.79 (0.66-0.94) – 6-y OS rate, % 6.5 2.4 6-y PFS rate, % 3.3 0.4 ORR, % 15.4 8.9 DOR, median (range), mo 18.4 (0.0+ to 65.8+) 3.6 (0.0+ to 18.8) 64 65 OS, median, mo 11.6 7.9 HR (95% CI) 0.62 (0.43-0.90) – 6-y OS rate, % 8.9 6.3 6-y PFS rate, % 4.7 1.6 ORR, % 28.1 9.2 DOR, median (range), mo 15.1 (0.0+ to 65.1+) 4.2 (0.8-18.8) 196 191 OS, median, mo 8.7 7.1 HR (95% CI) 0.72 (0.59-0.89) – 6-y OS rate, % 7.1 2.1 6-y PFS rate, % 3.7 0.5 ORR, % 18.4 8.9 DOR, median (range), mo 18.4 (0.0+ to 65.8+) 4.2 (0.7-18.8)
Conclusions
Pembro continued to show OS benefit compared with SOC in R/M HNSCC, regardless of PD-L1 expression, after long-term follow-up. OS hazard ratios were similar over time. These results further support the use of pembro as second-line treatment in R/M HNSCC.
Clinical trial identification
NCT02252042, release date: September 29, 2014.
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
D. Soulieres: Financial Interests, Institutional, Research Grant: Adlai-Nortye, BMS, GSK; Financial Interests, Institutional, Leadership Role: Adlai-Nortye. K.J. Harrington: Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, MSD, Replimune; Financial Interests, Institutional, Other, Consulting fees: AstraZeneca, Boehringer Ingelheim, BMS, Codiak, Idera, Inzen, ISA Pharmaceuticals, MSD, Merck-Serono, Pfizer, Replimune; Financial Interests, Institutional, Other, Honoraria: BMS, Merck-Serono, MSD. C. Le Tourneau: Financial Interests, Personal and Institutional, Advisory Board: MSD, BMS, Merck Serono, Roche, Celgene, Seattle Genetics, Nanobiotix, AstraZeneca. J.D. Silva: Financial Interests, Personal, Advisory Board: Roche, PharmaMar, BMS, Merck-Serono, MSD; Financial Interests, Personal, Principal Investigator: Roche, Boehringer Ingelheim, MSD; Financial Interests, Personal, Other, Travel expenses, including accommodation and congress fee: PharmaMar. L.F. Licitra: Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis inc, Debiopharm International SA, Hoffmann-La Roche ltd, IRX Therapeutics inc, Medpace inc, Merck–Serono, MSD, Novartis, Pfizer, Roche Spa, Buran; Financial Interests, Personal, Other, Honoraria for public speaking/teaching in medical meetings and or for expert opinion in advisory boards: AstraZeneca, Bayer, BMS, Eisai, MSD, Merck–Serono, Merck Healthcare KGaA, Boehringer Ingelheim, Hoffmann-La Roche Ltd, Novartis, Roche, Debiopharm International SA, Sobi, Incyte Biosciences Italy srl, Doxa Pharma srl, Amgen, Nanobiotics Sa, GSK; Financial Interests, Personal, Other, Honoraria for public speaking/teaching from research companies & commercial education providers: AccMed, Medical Science Fundation G. Lorenzini, Associazione Sinapsi, Think 2 IT, Aiom Servizi, Prime Oncology, WMA Congress Education, Fasi, DueCi promotion Srl, MI&T, Net Congress & Education, PRMA Consulting, Kura Oncology, Health & Life srl, Ipsen Inn; Financial Interests, Personal, Other, Travel expenses: AstraZeneca, BMS, Eisai, MSD, Merck Serono. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Merck, Takeda, Daiichi Sankyo, Lilly, Roche, YUHAN, Amgen, Pfizer, Alpha Pharmaceuticals; Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Amgen, Merck, Takeda, Lilly, YUHAN. A. Soria: Financial Interests, Institutional, Invited Speaker: Merck Sharp & Dohme, Bristol Myers Squibb, Novartis Pharma, Merck-Serono, Sanofi Aventis; Financial Interests, Institutional, Expert Testimony: Merck Sharpe & Dohme, Bristol Myers Squibb, Novartis Pharma, Merck-Serono, Sanofi Aventis; Financial Interests, Institutional, Advisory Board: Merck Sharp & Dohme, Bristol Myers Squibb, Novartis Pharma, Merck Serono, Sanofi Aventis; Financial Interests, Institutional, Writing Engagements: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Sanofi Aventis. J. Machiels: Financial Interests, Institutional, Advisory Board, Advisory board member or speaker with honoraria (managed by my institution): Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boerhinger, BMS, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, Nektar; Financial Interests, Personal, Other, Travel expenses: Amgen, BMS, Pfizer, MSD; Financial Interests, Personal, Other, Data safety monitoring board with honoraria: Psioxus; Financial Interests, Institutional, Research Grant: Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boerhinger, BMS, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, eTheRNA, Nektar, Amgen, BMS, Psioxus; Non-Financial Interests, Personal, Advisory Role, Uncompensated: MSD. N. Mach: Financial Interests, Personal, Stocks/Shares: MaxiVAX. R. Mehra: Non-Financial Interests, Personal, Advisory Board: AstraZeneca; Non-Financial Interests, Personal, Advisory Role: AstraZeneca; Other, Personal, Other: AstraZeneca; Financial Interests, Personal, Advisory Board: Coherus; Financial Interests, Personal, Advisory Role: Coherus; Other, Institutional, Research Grant: Merck; Other, Institutional, Principal Investigator: Merck. B. Burtness: Financial Interests, Personal, Advisory Board: Merck, Vaccinex, Coherus; Financial Interests, Personal, Invited Speaker: Genentech. J. Lin: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.. N. Lerman: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. B. Gumuscu: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.. E.E..W. Cohen: Non-Financial Interests, Personal, Advisory Role: Axelia, Cel Sci, Eisai, Hoopika, ImmunoSensor, Istari, Janssen, Kahr Medical, Mana Therapeutics, Merck, Mirati, MSD, Nectin Tx, Pangea Therapeutics, Roche; Non-Financial Interests, Personal, Member of the Board of Directors: Therapeutics, NCCN; Financial Interests, Personal, Stocks/Shares: Kinnate Biopharma, Primmune Therapeutics; Non-Financial Interests, Personal, Leadership Role: Ayala, Kura, Kinnate Biopharma.
659MO - Pembrolizumab with or without chemotherapy for first-line treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): 5-year results from KEYNOTE-048
- Makoto Tahara (Kashiwa, Japan)
Abstract
Background
Long-term follow-up (4 years) of the phase 3 KEYNOTE-048 (NCT02358031) study continued to demonstrate survival benefit with pembrolizumab monotherapy and pembrolizumab + chemotherapy vs EXTREME in first-line R/M HNSCC. Pembrolizumab showed significantly longer OS vs EXTREME in PD-L1 CPS ≥1. Given that pembrolizumab + chemotherapy or pembrolizumab for CPS ≥1 is standard of care for first-line R/M HNSCC in the United States, outcomes with extended follow-up are of interest. We present 5 years of follow-up in all patients (pts) from KEYNOTE-048.
Methods
Pts with incurable R/M HNSCC of the oropharynx, oral cavity, hypopharynx, or larynx were randomly assigned 1:1:1 to pembrolizumab 200 mg Q3W, pembrolizumab + chemotherapy, or EXTREME. OS, PFS, ORR, and DOR were assessed in the ITT population and analyzed in PD-L1 CPS ≥1, PD-L1 CPS ≥20, and total populations.
Results
As of the February 21, 2022, data cutoff date, median follow-up was 69.2 mo (range, 61.2-81.6 mo) for pembrolizumab vs EXTREME and 68.6 mo (range, 61.2-82.1 mo) for pembrolizumab + chemotherapy vs EXTREME. The 5-year OS rate for pembrolizumab vs EXTREME was, respectively, 19.9% vs 7.4% in CPS ≥20, 15.4% vs 5.5% in CPS ≥1, and 14.4% vs 6.5% in total populations. The 5-year OS rate for pembrolizumab + chemotherapy vs EXTREME was, respectively, 23.9% vs 6.4% in CPS ≥20, 18.2% vs 4.3% in CPS ≥1, and 16.0% vs 5.2% in total populations. 5-yr OS and PFS rates, ORR, and DOR are shown in the table. Grade 3-5 treatment-related AEs were 17.0% for pembrolizumab, 71.7% for pembrolizumab + chemotherapy, and 69.3% for EXTREME.
Conclusions
With an extended follow-up of 5 years, first-line pembrolizumab and pembrolizumab + chemotherapy continued to show durable antitumor activity and manageable safety in R/M HNSCC. These results further support pembrolizumab and pembrolizumab + chemotherapy as first-line standard of care in R/M HNSCC. P, pembro; E, EXTREME; C, chemo
P vs E P vs E P + C vs E P + C vs E P E P + C E 133 122 126 110 5-yr OS, % 19.9 7.4 23.9 6.4 5-yr PFS, % 9.6 1.2 9.7 - ORR, % 23.3 36.1 45.2 38.2 DOR, median (range), mo 23.4 (2.7-75.5+) 4.3 (1.2+- 38.2+) 7.1 (2.1+-73.8+) 4.2 (1.2+- 38.2+) 257 255 242 235 5-yr OS, % 15.4 5.5 18.2 4.3 5-yr PFS, % 6.0 2.0 6.3 1.0 ORR, % 19.1 34.9 38.0 35.7 DOR, median (range), mo 23.4 (1.5+-75.5+) 4.5 (1.2+- 73.9+) 6.7 (1.6+-73.8+) 4.3 (1.2+- 66.5+) 301 300 281 278 5-yr OS, % 14.4 6.5 16.0 5.2 5-yr PFS, % 5.1 1.7 5.6 0.8 ORR, % 16.9 36.0 37.0 36.3 DOR, median (range), mo 22.6 (1.5+-75.5+) 4.5 (1.2+-73.9+) 6.7 (1.6+- 73.8+) 4.3 (1.2+- 66.5)
Clinical trial identification
NCT02358031, release date: February 6, 2015.
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. Tahara: Financial Interests, Personal and Institutional, Advisory Board: Ono Pharmaceutical, MSD, Bayer, BMS, Merck Biopharma, Eisai, Pfizer, Loxo, Celgene, Rakuten Medical, Amgen, Novartis; Financial Interests, Personal and Institutional, Principal Investigator: Ono Pharmaceutical, MSD, Bayer, BMS, Merck Biopharma, Eisai, Pfizer, Loxo, Rakuten Medical, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Ono Pharmaceutical, MSD, BMS, Merck Biopharma, Eisai, Rakuten Medical; Financial Interests, Personal and Institutional, Research Grant: Bayer. R. Greil: Financial Interests, Personal, Invited Speaker: 3rd Medical Dep., Uniklinikum Salzburg; Financial Interests, Personal, Advisory Board: 3rd Medical Dep., Uniklinikum Salzburg; Financial Interests, Personal, Research Grant: 3rd Medical Dep., Uniklinikum Salzburg; Financial Interests, Personal, Advisory Role: 3rd Medical Dep., Uniklinikum Salzburg. D. Rischin: Financial Interests, Institutional, Invited Speaker: MSD, Regeneron, BMS, Replimune, GSK, Kura oncology, and Roche; Other, Personal, Advisory Board: MSD, GSK, Regeneron, and Sanofi . K.J. Harrington: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer-Ingelheim, MSD, Replimune, Arch Oncology, BMS, Codiak Biosciences, Inzen Therapeutics, Pfizer. B. Burtness: Financial Interests, Personal, Advisory Board: Merck, Vaccinex, Coherus; Financial Interests, Personal, Invited Speaker: Genentech. G. De Castro Jr.: Financial Interests, Personal and Institutional, Speaker’s Bureau: Merck Serono, Roche, MSD, Bristol Myers Squibb, AstraZeneca, GSK; Financial Interests, Personal and Institutional, Advisory Board: Merck Serono, Roche, MSD, Bristol Myers Squibb, AstraZeneca. A. Psyrri: Financial Interests, Personal, Invited Speaker: Attikon Hospital, MSD, Merck Serono,; Financial Interests, Personal and Institutional, Research Grant: Attikon, BMS, Roche, Kura Oncology; Financial Interests, Personal and Institutional, Advisory Role: Attikon, Merck Serono, BMS. I. Brana: Financial Interests, Personal, Advisory Board: Achilles Therapeutics, Bristol Myers Squibb, eTheRNA Immunotherapies, Merck Sharp & Dohme (MSD), Rakuten Pharma, PCI Biotech; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme (MSD), Roche; Financial Interests, Personal, Expert Testimony: Cancer Expert Now, Merck Serono, Boehringer Ingellheim; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Gliknik, Incyte, ISA pharmaceuticals, Debiopharm, Janssen Oncology, Kura, Merck Serono, Merck Sharp & Dohme (MSD), Nanobiotix, Novartis, Northern Biologics, Regeneron, Pfizer, Seattle Genetics, Shattuck Labs, VCN Biosciences, Roche, Immutep, MacroGenics, Sanofi, PharmaMar, Odonate Therapeutics, Bicycle Therapeutics, Dragonfly therapeutics; Non-Financial Interests, Member: SEOM, ASCO; Non-Financial Interests, Principal Investigator, Basket of baskets: Cancer Core Europe; Non-Financial Interests, Member, Head and Neck Group: EORTC. Å. Bratland: Financial Interests, Personal and Institutional, Invited Speaker: MSD, BMS, Sanofi; Financial Interests, Personal and Institutional, Advisory Board: MSD, BMS, Sanofi; Financial Interests, Personal and Institutional, Advisory Role: MSD, BMS, Sanofi. T. Fuereder: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Roche; Pfizer; Boehringer Ingelheim; Sanofi, Merck KGaA; Amgen; Bristol Myers Squibb, Janssen; Financial Interests, Personal, Invited Speaker: Merck Sharp & Dohme; Roche; Pfizer; Boehringer Ingelheim; Sanofi, Merck KGaA; Amgen; Bristol Myers Squibb, Janssen; Financial Interests, Personal and Institutional, Funding: Merck Sharp & Dohme; Roche, Merck KGaA; Amgen; Bristol Myers Squibb; Financial Interests, Personal and Institutional, Invited Speaker: Merck Sharp & Dohme; Roche, Merck KGaA; Amgen; Bristol Myers Squibb; Financial Interests, Personal and Institutional, Research Grant: Merck Sharp & Dohme; Roche, Merck KGaA; Amgen; Bristol Myers Squibb. B.G.M. Hughes: Non-Financial Interests, Personal, Advisory Board: MSD, BMS, Sanofi, Eisai; Financial Interests, Institutional, Research Grant: Amgen. R. Mesia Nin: Financial Interests, Personal, Advisory Role: Merck, MSD, BMS, Roche, Amgen, AstraZeneca, Nanobiotix, Seattle Genetics, Boehringer; Financial Interests, Personal, Principal Investigator: Merck, BMS; Financial Interests, Personal, Advisory Board: Merck, MSD, BMS; Financial Interests, Personal, Speaker’s Bureau: Merck, MSD, BMS. N. Ngamphaiboon: Financial Interests, Personal, Principal Investigator: MSD, Roche, Exelixis, RAPT Therapeutics, BeiGene, Boehringer Ingelheim Pharmaceuticals, Pfizer; Financial Interests, Personal, Project Lead: Pfizer; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Advisory Board: MSD, Novartis, Bayer, AstraZeneca, Eli Lilly; Financial Interests, Personal, Invited Speaker: Roche, MSD, Novartis, Merck. W.Z. Wan Ishak: Other, Institutional, Full or part-time Employment: University of Malaya; Financial Interests, Personal and Institutional, Invited Speaker: Merck; Financial Interests, Personal and Institutional, Writing Engagements: Merck; Financial Interests, Personal and Institutional, Speaker’s Bureau: Merck; Financial Interests, Personal and Institutional, Advisory Board: Merck; Financial Interests, Personal and Institutional, Research Grant: Merck; Financial Interests, Personal and Institutional, Funding: Merck; Financial Interests, Personal and Institutional, Sponsor/Funding: Merck; Financial Interests, Personal and Institutional, Advisory Role: Merck; Financial Interests, Personal, Invited Speaker: Amgen, Roche, AstraZeneca, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Amgen, Roche; Financial Interests, Personal, Advisory Board: Amgen, Roche, AstraZeneca, Eisai; Financial Interests, Personal, Sponsor/Funding: Amgen, Roche, AstraZeneca, Eisai; Financial Interests, Personal, Advisory Role: Amgen, Roche, AstraZeneca, Eisai; Financial Interests, Personal, Writing Engagements: Roche; Financial Interests, Personal, Expert Testimony: Roche. B. Gumuscu: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. ; Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc. N. Lerman: Financial Interests, Personal, Full or part-time Employment: Merck, Sharp, and Dohme Corp. ; Financial Interests, Personal, Stocks/Shares: Merck, Sharp, and Dohme Corp. D. Soulieres: Financial Interests, Institutional, Research Grant: Merck, BMS, GSK, Adlai-Nortye; Financial Interests, Institutional, Leadership Role: Adlai-Nortye; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Advisory Board: Merck. All other authors have declared no conflicts of interest.
LBA33 - 5-year overall survival (OS) in patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) treated with xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in a randomized, phase II study
- Jean Bourhis (Lausanne, Switzerland)
Abstract
Background
In a double-blind, randomized, phase 2 study of pts with unresected LA SCCHN (NCT02022098), xevinapant + standard-of-care (SOC) CRT significantly improved locoregional control at 18 months after end of CRT (primary endpoint) and 3-year progression-free survival vs placebo + CRT, without increasing toxicity. Here we report updated data on duration of response (DoR) after 3 years and OS after 5 years.
Methods
Pts with unresected LA SCCHN, stratified by node involvement, primary tumor site, and HPV-16 status in pts with oropharyngeal tumors, were randomized (1:1) to receive xevinapant 200 mg once daily (days 1-14 of a 3-week cycle every 3 weeks [Q3W]) for 3 cycles + CRT (cisplatin 100 mg/m2 on day 2 Q3W for 3 cycles; intensity-modulated radiotherapy 70 Gy [2 Gy/day, 5 days/week for 7 weeks]) or placebo + CRT for 3 cycles.
Results
Between January 2016 and April 2017, 96 pts were randomized and followed up for disease progression until July 2020; survival data were collected until April 2022 (5 years after last patient randomized). The risk of death or disease progression after initial response was reduced by 79% in the xevinapant vs placebo arm (DoR; adjusted HR, 0.21; 95% CI, 0.08-0.54, p=0.0011). For long-term OS, median follow-up was 60.1 months (range, 7.1-70.5 months) in the xevinapant arm and 39.2 months (range, 4.8-71.2 months) in the placebo arm. The risk of death was more than halved in the xevinapant vs placebo arm (adjusted HR, 0.47 [95% CI, 0.27-0.84]; p=0.0101). OS was prolonged with xevinapant + CRT vs placebo + CRT; median OS was not reached (95% CI, 40.3 months-not evaluable) vs 36.1 months (95% CI, 21.8-46.7 months), and the probability of survival 5 years after randomization was 53% (95% CI, 37-66%) vs 28% (95% CI, 15-42%), respectively.
Conclusions
Adding xevinapant to SOC CRT improved 5-year OS in pts with unresected LA SCCHN vs placebo + CRT, with a marked improvement in 3-year DoR also observed. A pivotal phase 3 study of xevinapant + CRT in pts with unresected LA SCCHN (Trilynx; NCT04459715) is ongoing.
Clinical trial identification
NCT02022098.
Editorial acknowledgement
Medical writing support was provided by Sophie Saunders of ClinicalThinking, which was funded by Merck in accordance with Good Publication Practice guidelines. (http://www.ismpp.org/gpp3).
Legal entity responsible for the study
Debiopharm.
Funding
Debiopharm.
Disclosure
J. Bourhis: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Debiopharm, Merck, MSD, Nanobiotix, Roche. C. Le Tourneau: Financial Interests, Personal and Institutional, Advisory Role: MSD, BMS, AstraZeneca, Nanobiotix, Celgene, Seattle Genetics, MaxiVac, Roche, PCI BioTech, Onxeo, ALX Oncology. Y. Pointreau: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Role: Merck. J. Delord: Financial Interests, Institutional, Advisory Board: Roche, MSD, BMS, Pierre Fabre; Financial Interests, Institutional, Invited Speaker: Merck Serono; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Amgen, Genentech, Transgene, MSD. F. Clatot: Financial Interests, Institutional, Research Grant: Roche diagnostics, AstraZeneca; Financial Interests, Personal, Advisory Role: Merck, MSD, BMS, Roche, Eli Lilly, AstraZeneca. O. Elicin: Financial Interests, Personal, Advisory Role: AstraZeneca, Merck, MSD. L. Damstrup: Financial Interests, Personal, Full or part-time Employment: Debiopharm International SA. K. Gollmer: Financial Interests, Personal, Full or part-time Employment: Debiopharm International SA. P. Crompton: Financial Interests, Personal, Full or part-time Employment: Debiopharm International SA. Y. Tao: Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Other, Travel: MSD, Merck. All other authors have declared no conflicts of interest.
Invited Discussant 658MO, 659MO and LBA33
- Ana Martins Ferreira Varges Gomes (Faro, Portugal)
660MO - Molecular targets in salivary gland cancers: A comprehensive genomic analysis of 1,666 cases
- Abirami Sivapiragasam (Syracuse, United States of America)
Abstract
Background
Next Generation Sequencing (NGS) to identify key molecular targets is an important aspect of management in advanced Salivary Gland Carcinomas (SGC).
Methods
DNA was extracted from tissues of advanced SGC and Comprehensive Genomic Profiling (CGP) was done to evaluate for base substitutions, short insertions, deletions, copy number changes, gene fusions and rearrangements. Tumor Mutation Burden (TMB) was calculated on up to 1.25 Mb.
Results
The table shows the descriptive analysis of 1,666 SGC with clinically relevant Genomic Alterations (GA). Adenoid Cystic Carcinoma (ACC) (28.3%) was the commonest subtype.
N=1,666 GA (%) TMB > 10 PD-L1 High ACC 471 3.8 2.4 1 3.1 8.6 0.2/0 1.2 4.1 0 0.2 0 AcCC 195 59 37.4 3.6 9.7 2.1 0.5/0 0 0.5 0.5 1.5 3 MEC 118 52.5 30.5 1.7 7.6 16.9 5.9/0 5.1 0 0 16.9 4.2 Myoepi-thelial Carcinoma 55 32.7 23.6 1.8 1.8 9.1 0/0 5.5 7.3 0 7.3 6.3 Ductal Ca 337 24 15.4 5.6 18.1 32.6 16.3/3.6 2.1 1.8 1.2 9.4 3 AdenoCa NOS 152 26.3 19.1 2 7.9 20.4 10.5/2.6 0.7 2 0 5.9 4.4 High Grade Ca NOS 240 22.9 14.6 2.9 10.8 21.3 15.8/2.1 4.2 2.1 0.4 18.3 8.9 Ca ex PA 51 13.7 9.8 2 19.6 11.8 17.6/9.8 11.8 7.8 0 11.8 0 Basaloid Ca 47 10.6 8.5 0 2.1 10.6 0/0 2.1 8.5 0 8.5 0
Conclusions
This large dataset reveals many opportunities for IO and targeted therapy contributing to the continuing increased precision in the selection of treatment for these patients.
Legal entity responsible for the study
The authors.
Funding
Foundation Medicine Inc.
Disclosure
A. Sivapiragasam: Financial Interests, Personal, Advisory Role: Pfizer, Puma Oncology, Blueprint Medicines, Immunomedics. N.A. Danziger: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Personal, Stocks/Shares: F. Hoffman La-Roche LTd. J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. All other authors have declared no conflicts of interest.
654MO - High dimensional immuno-phenotyping of immunotherapy response in head and neck cancer
- Kenneth J. O'Byrne (Woolloongabba, Australia)
Abstract
Background
Immunotherapies, in particular immune check point inhibitors (ICI), have proven to be game changing treatments of mucosal head and neck squamous cell cancer (HNSCC). Emerging successes with anti-PD-1/PD-L1 ICI therapy have lead to durable responses and prolonged survival in human papillomavirus positive (HPV+) and negative (HPV-) patients, and there is now an urgent need for predictive biomarkers to guide patient selection for highly targeted ICI therapies. There are currently no means by which to determine whether a patient would respond to anti PD-1/PD-L1 immunotherapy. Studies in the tumour microenvironment (TME) have demonstrated that a high degree of T-cell infiltration provides fertile grounds for effective ICI.
Methods
In this project, we used high dimensional spatial biomarker profiling to characterise the TME using targeted (region of interest) and unbiased (whole slide imaging) of metastatic/recurrent HNSCC tumours from a cohort of patients (n=40) treated with Pembrolizumab/Nivolumab. The discovery cohort consisted of patients who had complete/partial/stable/progressive response to ICI therapy. We first analysed tissues using targeted panel, GeoMx digital spatial profiling (Nanostring Technologies) of 80 protein targets simultaneously across immune cell profiles, immune-modulatory targets and IO-drug targets. We then expanded this to ultra-high plex antibody imaging with the Phenocylcer Fusion platform (Akoya Biosciences) of over 50 antibodies to derive single cell phenotypic signatures that could offer cues as to which treatment matches best with certain outcome groups.
Results
Our study identified stromal tissue signatures, specifically, VISTA, CD44, CD127 associated with resistance to immunotherapy. Most notably, high expression of VISTA within the stromal compartment was associated with a worse overall survival (p=0.0062). Using whole slide tissue imaging of single cell proteomic readouts, we were able to co-localise this signature to cell types within the tumour microenvironment.
Conclusions
Our study demonstrates the complementarity of targeted proteomic discovery and whole tissue imaging to identify biomarkers associated with response to ICI therapy in HNSCC.
Legal entity responsible for the study
The University of Queensland.
Funding
The Passe and Williams Foundation.
Disclosure
N. Ma, N. Jhaveri, A. Pratapa: Other, Institutional, Full or part-time Employment: Akoya Biosciences; Financial Interests, Institutional, Stocks/Shares: Akoya Biosciences. B. Ben Cheikh, O. Braubach: Non-Financial Interests, Institutional, Full or part-time Employment: Akoya Biosciences; Financial Interests, Institutional, Stocks/Shares: Akoya Biosciences. All other authors have declared no conflicts of interest.
661MO - Evaluation of the DNA damage response (DDR) network as predictor of nivolumab efficacy in head and neck squamous cell carcinoma (HNSCC)
- Panagiota Economopoulou (Haidari, Greece)
Abstract
Background
We have previously shown that Peripheral Blood Mononuclear Cells (PBMCs) from HNSCC patients, at diagnosis, exhibit deregulated DDR-related parameters and higher levels of oxidative stress compared to healthy individuals. Herein, we tested the hypothesis that aberrations in DDR signals of the patients' PBMCs may predict therapeutic benefit from PD-1 checkpoint blockade in HNSCC.
Methods
Oxidative stress, DDR associated parameters, including endogenous DNA damage and basal DNA repair mechanisms, namely nucleotide excision repair (NER) and double-strand breaks (DSBs) repair, were evaluated in PBMCs from 50 recurrent/metastatic HNSCC patients who participated in a phase II nivolumab trial (NCT03652142) and 26 healthy controls (HC). PBMCs were obtained at baseline, after 4 weeks of nivolumab treatment, and at progression.
Results
Per our previous findings, we verified that PBMCs from patients at baseline showed significantly higher levels of endogenous DNA damage compared with HC. Using alkaline comet assay measuring single-strand breaks and/or double-strand breaks, we found that lower endogenous DNA damage was associated with longer PFS (P=0.006), OS (P=0.002), and higher likelihood for response (P=0.03) and clinical benefit from nivolumab (P=0.015). Using γH2AX immunofluorescence staining for the evaluation of DSBs, we found that lower DSBs burden at baseline was also associated with statistically significant improvement of PFS, OS, and higher likelihood for response and clinical benefit (all p < 0.002). Moreover, PBMCs which exhibited lower levels of oxidative stress were correlated with a better clinical benefit (P=0.011). More importantly, lower NER and DSBs repair capacities of patients’ PBMCs were associated with better PFS and OS and a higher likelihood for response and clinical benefit (all P<0.004).
Conclusions
Oxidative stress and DDR-related aberrations, measured in PBMCs from HNSCC patients correlated with the response to PD-1 immune checkpoint blockade. These results provide a proof of concept that DDR-based measurements could be used as a potential non-invasive biomarker to select HNSCC patients for treatment with PD-1 checkpoint inhibitors.
Legal entity responsible for the study
The authors.
Funding
Hellenic Society of Medical Oncology.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 660MO, 654MO and 661MO
- Sandra Schmitz (Woluwe-Saint-Lambert, Belgium)