Background

Based on the hypothesis of a potential synergistic effect of the anti-PD1 pembrolizumab when combined with RT, this new combination was tested in a randomized trial against the well-established standard of care (SOC) cetuximab-RT in LA-HNSCC.

Methods

In this phase II randomized trial, patients with non operated stage III-IVa-b SCC of oral cavity, oropharynx, hypopharynx and larynx and unfit for receiving high dose of cisplatin were enrolled. Patients received once-daily IMRT up to 69,96 Gy concomitant with cetuximab (Cetux-RT arm: 400 mg/m² loading dose and 250 mg/m² weekly) or pembrolizumab (Pembro-RT arm: 200 mg Q3W during RT). The primary endpoint was 15-month Loco-Regional Control (LRC) rate and secondary endpoints included Progression-free survival (PFS), Overall Survival (OS) and tolerance. To detect a difference between arms of 60% to 80% in 15-month LRC, inclusion of 66 patients per arm was required to achieve a power of at least 0.85 at 2-sided significance level of 0.20.

Results

Between May 2016 and October 2017, 131 patients were randomized and treated by 27 centers: 65 patients in Cetux-RT arm and 66 patients in Pembro-RT arm. The median age was 65 years, 92% were smokers, 60% of oropharynx (46% p16+), 41% of N2c-N3 with 25%, 56% and 19% of stage III, IVa and IVb respectively. Median follow-up was 25 months in both arms. Acute toxicity was lower in Pembro-RT arm than Cetux-RT arm: 74% vs 92% patients with at least one grade ≥ 3 acute adverse events (p=0.006), mainly due to dermatitis in radiation field, mucositis and cutaneous rash. LRC at 15 months were 59% in Cetux-RT arm and 60% in Pembro-RT arm, not significantly different: OR=1.05 (95%CI: 0.43-2.59, p=0.91). 2-year PFS rate was 40% in the Cetux-RT arm vs 42% in the Pembro-RT arm. There was no significant difference between arms for PFS: HR=0.83 (95%CI 0.53-1.29, p=0.41). 2-year OS rate was 55% in the Cetux-RT arm vs 62% in the Pembro-RT arm. OS was not significantly different between arms: HR=0.83 (95%CI: 0.49-1.40, p=0.49).

Conclusions

Compared to the SOC cetuximab-RT, the anti-PD1 pembrolizumab concomitant with RT did not improve carcinologic outcomes but appeared less toxic.

Clinical trial identification

NCT 02707588.

Legal entity responsible for the study

GORTEC.

Funding

GORTEC.

Disclosure

J. Bourhis: Advisory/Consultancy: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Merck. All other authors have declared no conflicts of interest.

Background

Despite high-dose, cisplatin-containing, multimodality therapy, LA SCCHN ultimately recurs in many patients. This trial investigated whether avelumab, a human anti–PD-L1 antibody, improved progression-free survival (PFS) when combined with concurrent CRT followed by avelumab maintenance.

Methods

This randomized, double-blind, placebo-controlled phase III trial (JAVELIN Head and Neck 100; NCT02952586) included patients with histologically confirmed, previously untreated LA SCCHN of the oropharynx, hypopharynx, larynx, or oral cavity eligible for definitive CRT with curative intent. Patients were required to have stage III, IVa, or IVb disease per AJCC (7th edition) except for HPV+ oropharyngeal patients, for whom only T4 or N2c or N3 status was allowed. Patients were randomized 1:1 to receive avelumab 10 mg/kg IV Q2W + CRT (cisplatin 100 mg/m² Q3W + standard fractionation of 70 Gy in 35 fractions over 7 weeks) or placebo + CRT. This was preceded by a lead-in dose and followed by avelumab or placebo maintenance therapy for up to 1 year. The primary endpoint was PFS by investigator assessment per modified RECIST v1.1; interim analysis was planned at ≈ 217 events.

Results

697 patients were randomized (avelumab arm, n=350; placebo arm, n=347); baseline characteristics were similar in both arms. At interim analysis, the hazard ratios for PFS per modified RECIST v1.1 (based on 224 events) and overall survival (OS; based on 131 deaths) were 1.21 (95% CI: 0.93-1.57; p=0.920) and 1.31 (95% CI: 0.93-1.85; p=0.937), respectively, both in favor of placebo + CRT. Median PFS and OS were not reached in either arm. Grade ≥3 adverse events (AEs) were more frequent with avelumab + CRT vs placebo + CRT (88% vs 82%); fatal AEs occurred in 6% and 5%, respectively. Rates of AEs leading to discontinuation of any study drug were similar in both arms (33% vs 32% in the avelumab vs placebo arms).

Conclusions

Tolerability was similar in both arms; however, the study did not demonstrate statistically significant improvement in PFS with avelumab + CRT vs placebo + CRT. These results may inform future trial design.

Clinical trial identification

NCT02952586.

Editorial acknowledgement

Medical writing assistance was provided by Eleanor Green of ClinicalThinking and funded by Pfizer and Merck KGaA, Darmstadt, Germany.

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany and Pfizer.

Funding

Pfizer, as part of an alliance between Merck KGaA, Darmstadt, Germany, and Pfizer.

Disclosure

E.E. Cohen: Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Incyte; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Merck KGaA, Darmstadt, Germany. R.L. Ferris: Advisory/Consultancy: Aduro Biotech, Inc; Advisory/Consultancy: Amgen; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca/MedImmune; Advisory/Consultancy: Bain Capital Life Sciences; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: EMD Serono; Advisory/Consultancy: GlaxoSmithKline; Advisory/Consultancy: Iovance Biotherapeutics, Inc; Advisory/Consultancy: Lilly; Advisory/Consultancy: MacroGenics, Inc.; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Nanobiotix; Advisory/Consultancy: Numab Therapeutics AG; Advisory/Consultancy: Oncorus, Inc.; Advisory/Consultancy: Ono Pharmaceutical Co. Ltd; Advisory/Consultancy: Pfizer; Advisory/Consultancy: PPD; Advisory/Consultancy: Regeneron Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): Tesaro; Advisory/Consultancy: Torque Therapeutics Inc; Advisory/Consultancy, Research grant/Funding (institution): TTMS; Research grant/Funding (institution): VentiRx Pharmaceuticals. A. Psyrri: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Merck Serono; Honoraria (self), Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (self): KURA; Research grant/Funding (self): Genesis; Research grant/Funding (self): DEMO; Travel/Accommodation/Expenses: Ipsen. R. Haddad: Advisory/Consultancy, Research grant/Funding (self): Merck; Advisory/Consultancy, Research grant/Funding (self): BMS; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Research grant/Funding (self): Genentech; Advisory/Consultancy, Research grant/Funding (self): GSK; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca. M. Tahara: Honoraria (self): Eisai; Honoraria (self): Merck Serono; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Ono; Honoraria (self): BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): MSD; Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Research grant/Funding (self): Rakuten Medical; Advisory/Consultancy: Celgene; Advisory/Consultancy: Amgen; Research grant/Funding (self): Novartis. K.J. Harrington: Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Honoraria (institution), Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck-Serono; Honoraria (institution), Advisory/Consultancy: Pfizer; Honoraria (institution), Research grant/Funding (institution): Regimmune; Advisory/Consultancy, Research grant/Funding (institution): BI. J-C. Lin: Travel/Accommodation/Expenses: Taiwan Merck; Travel/Accommodation/Expenses: ONO; Travel/Accommodation/Expenses: MSD. M. Razaq: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Merck; Advisory/Consultancy: Aspyrian; Speaker Bureau/Expert testimony, Shareholder/Stockholder/Stock options: Merck & co; Shareholder/Stockholder/Stock options: AbbVie. J. Lovey: Honoraria (self): Nutricia; Honoraria (self): Merck. J. Chamois: Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: MSD. A. Rueda Dominguez: Advisory/Consultancy, Speaker Bureau/Expert testimony: Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Takeda. S. De Beukelaer, H. Thurm: Full/Part-time employment: Pfizer. D. Pavlov: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. N. Lee: Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Research grant/Funding (self): Merck; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Lilly; Research grant/Funding (self): AstraZeneca. All other authors have declared no conflicts of interest.

Background

This was a double-blind, randomized phase 2 study of 96 patients with poor prognosis locally advanced, squamous cell carcinoma of the head and neck (LA-SCCHN). Previously reported data showed significant improvements of xevinapant (Debio 1143) versus placebo in addition to chemoradiation (CRT) for the primary endpoint of locoregional control (LRC) rate at 18 months, and demonstrated that addition of Debio 1143 was feasible, safe and did not compromise backbone therapy. Here we report up-dated data on PFS and overall survival (OS).

Methods

Patients, stratified by node involvement, tumor localization and HPV-16 status, were randomized (1:1) to receive Debio 1143 or matching placebo at 200 mg/day, oral once daily D1–14 q3w (3 cycles) when added to standard high-dose cisplatin CRT. PFS and OS were analyzed using a Cox model in the intention-to-treat population. Median and survival rates at 36 months were estimated by the Kaplan-Meier method.

Results

As of 21 Jul 2020, the median follow-up was 33 months. Debio 1143 combined with CRT showed a statistically significant improvement in OS vs placebo by reducing the risk of mortality by 51% (HR=0.49, [95%CI: 0.26-0.92], P=0.0261). The 3 years OS rate was 66% (95% CI: 49–78) in the Debio 1143 arm versus 51% (95% CI: 34–65) in the placebo arm; the median OS is not reached with Debio 1143 vs. 36.1 months with placebo (95%CI: 21.8-46.7). Statistically significant improvement in PFS was demonstrated, reducing the risk of disease progression or death by 66% (HR=0.34 [95%CI, 0.17-0.68], p=0.0023) and improving probability of PFS at 36 months to 72% in the Debio 1143 arm compared to 36% in the placebo arm. The predictable and manageable safety profile observed with Debio 1143 + CRT after 2 years remained unchanged after 3 years.

Conclusions

These results with extended follow-up confirm those previously reported, showing now in addition a statistically and clinically significant OS benefit by adding Debio 1143 to standard CRT. The confirmatory phase III Trilynx study (EudraCT Number: 2020-000377-25) is ongoing.

Clinical trial identification

EudraCT: 2013-000044-25; NCT02022098.

Legal entity responsible for the study

Debiopharm.

Funding

Debiopharm.

Disclosure

J. Bourhis: Advisory/Consultancy: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: Merck; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Debiopharm. C. Le Tourneau: Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Merck Serono; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self): Rakuten; Honoraria (self), Advisory/Consultancy: Nanobiotix; Honoraria (self), Advisory/Consultancy: GSK; Honoraria (self), Advisory/Consultancy: Roche. Y. Pointreau: Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: BMS. M-C. Kaminsky-Forrett: Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Novartis; Advisory/Consultancy: EMD Serono. P. Boisselier: Honoraria (institution), Advisory/Consultancy: Merck; Advisory/Consultancy: BMS; Advisory/Consultancy: Roche. J-P. Delord: Advisory/Consultancy: BMS; Advisory/Consultancy: Roche; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Merck. F. Clatot: Advisory/Consultancy: Merck; Advisory/Consultancy: BMS; Advisory/Consultancy: Lilly. F. Rolland: Advisory/Consultancy: BMS; Advisory/Consultancy: Novartis; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Merck. K. Gollmer: Full/Part-time employment: Debiopharm. S.A. Szyldergemajn: Full/Part-time employment: Debiopharm. C. Even: Advisory/Consultancy: BMS; Advisory/Consultancy: Merck; Advisory/Consultancy: MSD; Advisory/Consultancy: Innate Pharma. All other authors have declared no conflicts of interest.

Background

Nivolumab (NIVO) alone or with ipilimumab (COMBO) immune checkpoint blockade (ICB) prior to curative surgery has shown promising results in multiple tumor types. We completed a phase Ib/II study with neoadjuvant NIVO or COMBO in resectable head and neck squamous cell carcinoma (HNSCC) and show safety, efficacy and correlative biomarker results.

Methods

32 stage II-IVB HNSCC patients indicated for curative (salvage) surgery were treated with NIVO (240mg, weeks 1&3, N=6) or NIVO (240mg, weeks 1&3) + IPI (1mg/kg, week 1, N=26) prior to surgery in week 5. Imaging was performed at baseline and week 4. AEs were reported in terms of CTCAE. Pathological response (pR) was defined as % change in viable tumor cells from baseline to on-treatment; ≥90% pR was considered (near-) complete response (pCR). WES and RNAseq were performed on paired tumor biopsies.

Results

32 (31 HPV-negative) patients started treatment (stage II n=3, III n=8, IVA-B n=11, recurrent disease n=10). 6 patients included with recurrent disease had had previous (C)RT. 1 patient discontinued ICB after one course due to patient’s preference. Surgery was not postponed in any patient. 3/32 patients did not undergo surgery: 1 due to unresectable PD and 2 due to reasons unrelated to ICB or disease. Grade 3-4 irAEs in 11/32 patients were well manageable. (Near-)pCR in the primary tumor was seen in 9/29 evaluable patients (31%). Another 31% of patients had 20-89% pR. At 14 months median FU, RFS for patients with (near-)pCR was 100%, significantly better than patients with <90% pR (p=<0.05). Metabolic response assessment with FDG-PET (week 4) was able to identify (near-)pCRs. A baseline AID/APOBEC-associated tumor mutational profile was correlated with (near)pCR (p=<0.05). Finally, (near)pCR tumors were characterized by a decrease in hypoxia gene expression after ICB.

Conclusions

Neoadjuvant ICB was feasible in HNSCC and induced (near)pCR in 31% of evaluable patients at time of surgery, which was accompanied by 100% RFS. Baseline AID/APOBEC-related mutations, on-treatment FDG-PET and resolution of hypoxia need future validation to discover their potential role as biomarkers for (near)pCR after ICB in HNSCC.

Clinical trial identification

NCT03003637.

Legal entity responsible for the study

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital.

Funding

Bristol Myers-Squibb.

Disclosure

L. Zuur: Spouse/Financial dependant: Mosadex U.A.; Spouse/Financial dependant: Obvious Pharmaceuticals BV. M.W. van den Brekel: Research grant/Funding (institution), Travel/Accommodation/Expenses: ATOS Medical. S.M. Willems: Research grant/Funding (institution): Roche; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): MSD; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): BMS; Research grant/Funding (institution): Nextcure. T.N. Schumacher: Full/Part-time employment: Kite Pharma; Leadership role: Kite Pharma; Shareholder/Stockholder/Stock options: AIMM Therapeutics; Shareholder/Stockholder/Stock options: Allogene; Shareholder/Stockholder/Stock options: Merus; Shareholder/Stockholder/Stock options: Kite Pharma; Shareholder/Stockholder/Stock options: Neon Therapeutics; Shareholder/Stockholder/Stock options: Neogene Therapeutics; Shareholder/Stockholder/Stock options: Scenic Biotech; Advisory/Consultancy: AIMM Therapeutics; Advisory/Consultancy: Allogene; Advisory/Consultancy: Merus; Advisory/Consultancy: Neon Therapeutics; Advisory/Consultancy: Neogene Therapeutics; Advisory/Consultancy: Scenic Biotech; Research grant/Funding (self): Merck KgGA; Research grant/Funding (self): MSD; Licensing/Royalties: Kite Pharma; Licensing/Royalties: Neon Therapeutics; Licensing/Royalties: Scenic Biotech; Licensing/Royalties: Immatics. C.U. Blank: Honoraria (self), Paid to the institute: BMS; Honoraria (self), Paid to the institute: MSD; Honoraria (self), Paid to the institute: Roche; Honoraria (self), Paid to the institute: Novartis; Honoraria (self), Paid to the institute: GSK; Honoraria (self), Paid to the institute: AZ; Honoraria (self), Paid to the institute: Pfizer; Honoraria (self), Paid to the institute: Lilly; Honoraria (self), Paid to the institute: Genmab; Honoraria (self), Paid to the institute: Pierre Fabre; Honoraria (self), Paid to CUB: Third Rock Ventures; Shareholder/Stockholder/Stock options: Uniti Cars; Shareholder/Stockholder/Stock options: Immagene BV; Research grant/Funding (self), Paid to the institute: BMS; Research grant/Funding (self), Paid to the institute: Novartis; Research grant/Funding (self), Paid to the institute: NanoString. J.P. de Boer: Advisory/Consultancy: MSD; Research grant/Funding (self), Paid to the institute: Merck KgGa; Travel/Accommodation/Expenses: MSD. J.B.A.G. Haanen: Shareholder/Stockholder/Stock options: Neogene Therapeutics; Research grant/Funding (institution): BMS; Research grant/Funding (institution): MSD; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Neon. All other authors have declared no conflicts of interest.

Background

p16^INK4a (p16) immunostaining is the most widely implemented technique in clinical settings for determining HPV causation and HPV-related prognosis biomarker of oropharyngeal cancer (OPC). A subset of p16+ OPC are HPV-; and their prognosis is still unclear. The aim of this study is to clearly define the proportion, determinants and prognosis of OPC patients who are p16+/HPV-.

Methods

We established an international consortium comprising 13 cohorts of OPC patients with data on p16, HPV, demographics, tobacco/alcohol use and clinical data. A centralized individual patient data reanalysis was performed. Multivariate models were used to evaluate factors associated with HPV status as defined by different HPV-assessment methods. Proportional-hazards models were used to compare the risk of death (OS) among HPV-related and un-related OPC.

Results

In total 7702 patients from 9 different countries were included. The percentage of positive cases was 49.7%, 47.9% and 44.3% for p16+, HPV+ and p16+/HPV+, respectively. Among p16+ cases, 10.9% were HPV-. This proportion differed significantly by cohorts and geographic areas (p-value<0.001) and was lowest in the highest prevalence areas (Table). Compared to p16-/HPV- tumors, p16+/HPV+was the biomarker with strongest prognostic value (aHR 0.28, 95%CI 0.25-0.31), followed by p16+/HPV- (aHR=0.65, 95%CI 0.56-0.76), and p16-/HPV+ (HR=0.72, 95%CI 0.60-0.86). Disease-free/OPC-specific survival analyses will be presented at the congress. Table: 911O

p16+/HPV- by region and cohort from the EPIC-OPC study

Conclusions

p16+/HPV+ tumors showed the highest OS magnitude of association compared with other biomarkers combinations. Using p16 immunostaining alone, 11% OPC patients would be incorrectly classified as HPV-related OPC according to TNM-8 staging, and with risk of misclassification for de-escalation in clinical trials, particularly in regions with lower attributable fractions of HPV.

Legal entity responsible for the study

Catalan Institute of Oncology.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.