Neoplasms

All Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Ear, Nose, and Throat Diseases

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Laryngeal Diseases

Laryngeal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Respiratory Tract Diseases

Otorhinolaryngologic Diseases

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Respiratory Tract Neoplasms

Laryngeal Cancer

Hypopharyngeal Cancer

Antineoplastic Agents

All Drugs and Chemicals

Dermatologic Agents

Pembrolizumab

Docetaxel

Immune Checkpoint Inhibitors

Cisplatin

Benzoyl Peroxide

Antineoplastic Agents, Immunological

Standard-Arm:

Short Induction (IC-1):

T = Docetaxel 75 mg/m\^2 i.v. day 1 P = Cisplatin 75 mg/m\^2 i.v. day 1 Response evaluation will be performed in week 4 after IC-1 by endoscopic estimation of tumor-surface shrinkage (ETSS) to select nonresponders for early total laryngectomy (TL). Responders receive further 2 cycles TP followed by radiotherapy (RT) starting week 11.

ETSS \< 30% (Nonresponder):

- TL + adjuvant RT or chemo-radiotherapy (CRT) according the decision of the tumor board

ETSS \>=30% (Responder):

2 further TP cycles (IC-2 in week 5-7 and IC-3 in week 8-10; same doses as IC-1) Radiotherapy (RT) is accelerated IMRT with concomitant boost with total dose of 69.6 Gy applied over 5.5 weeks to all tumor localizations; clinically non-affected neck levels receive 51.6 Gy.

\* protocol is according exactly to the DeLOS-II protocol arm A in Dietz et al. Ann Oncol. 2018 Oct 1;29(10):2105-2114

Intervention arm aka Experimental-Arm:

Treatment same as for patients randomized into the standard arm A + application of KEYTRUDA® (pembrolizumab), i.v., in 3-week cycle (q3w) 200 mg, starting day 1; for 17 cycles (12 months). Treatment with pembrolizumab will continue in the experimental arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent from subsequent decision on adjuvant therapy after TL.

200 mg KEYTRUDA® i. v. in 3-week cycle (q3w)

KEYTRUDA®

Andreas Dietz, MD PhD

Susanne Wiegand, MD PhD

ELOS is a prospective, randomized, open-label, controlled, two-armed parallel group, phase II multicentre trial in local advanced stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHNSCC) with PD-L1-expression within tumor tissue biopsy, calculated as CPS ≥ 1 curable by total laryngectomy. Induction chemotherapy (IC) with Docetaxel and Cisplatin (TP) followed by radiation will be compared to additional PD-1 inhibition. Patients will be selected after short induction early response evaluation after the first cycle IC (IC-1) aiming on larynx organ-preservation by additional 2 cycles IC followed by radiotherapy (69.6 Gy) for responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥ 30%. Nonresponders (ETSS \< 30% or progressing disease) will receive total laryngectomy and selective neck dissection followed by postoperative radiation or chemoradiation according to the recommendation of the clinics multidisciplinary tumor board. However, Patients randomized into the intervention arm starting day 1 will receive 200 mg Pembrolizumab (MK-3475) i.v. in 3-week cycle (q3w) for 17 cycles (12 months). Treatment with pembrolizumab will continue in the experimental arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent from subsequent decision on adjuvant therapy after TL.

ELOS is a prospective, randomized, open-label, controlled, two-armed parallel group, phase II multicentre trial in local advanced stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHNSCC) with PD-L1-expression within tumor tissue biopsy, calculated as CPS ≥ 1 curable by total laryngectomy. Induction chemotherapy (IC) with Docetaxel and Cisplatin (TP) followed by radiation will be compared to additional PD-1 inhibition. Patients will be selected after short induction early response evaluation after the first cycle IC (IC-1) aiming on larynx organ-preservation by additional 2 cycles IC followed by radiotherapy (69.6 Gy) for responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥ 30%. Nonresponders (ETSS \< 30% or progressing disease) will receive total laryngectomy and selective neck dissection followed by postoperative radiation or chemoradiation according to the recommendation of the clinics multidisciplinary tumor board. However, Patients randomized into the intervention arm starting day 1 will receive 200 mg Pembrolizumab (MK-3475) i.v. in 3-week cycle (q3w) for 17 cycles (12 months). Treatment with pembrolizumab will continue in the experimental arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent from subsequent decision on adjuvant therapy after TL.

The primary objective of ELOS is to compare laryngectomy-free survival (LFS) achieved by adding KEYTRUDA® (pembrolizumab) to standard treatment and LFS after standard treatment according to the DeLOS-II protocol in advanced LHNSCC curable by laryngectomy.

Hypothesis: Adding PD-1 inhibition by pembrolizumab to organ-preservation chemoradiation treatment improves laryngectomy-free survival (LFS) compared to standard treatment according to the DeLOS-II protocol.

The secondary objectives are to compare Quality of Swallowing (QoS) assessed by FEES, event free survival (EFS) and overall survival (OS) achieved by adding KEYTRUDA® (pembrolizumab) to standard treatment and QoS, EFS and OS after standard treatment according to the DeLOS-II protocol in advanced LHNSCC. In general, the main interest in trials focusing on improving quality and degree of larynx organ preservation is late functional (in particular "swallowing") outcome. Current instruments assessing hrQoL are less meaningful than direct objective assessment of swallowing utilizing physical examination like FEES. FEES is a well approved and reliable method and allows clear scoring of quality of swallowing for instance by applying the Rosenbek Scale. Therefore, the investigators decided to avoid any questionnaires for this assessment including those approved for use in head and neck cancer, as they fail to specifically address the main study outcome, functional larynx organ preservation.

Hypothesis: Adding PD-1 inhibition by KEYTRUDA® (pembrolizumab) to organ-preservation chemoradiation treatment improves QoS, EFS and OS compared to standard treatment according to the DeLOS-II protocol. EFS events are defined as any event either in interfering with proper larynx organ function (independent of the cause, tumor- or treatment related), relapse (local, loco-regional, or distant), or death.

Prospective, randomized, open-label, controlled, two-armed parallel group, phase II multicenter larynx organ-preservation trial with randomization in a 1:1 ratio into standard arm vs. investigational arm with a flexible follow-up of 24-48 months

European Larynx Organ Preservation Study (ELOS) [MK-3475-C44]

ELOS - Induction Chemotherapy With Docetaxel and Cisplatin Followed by Radiation Compared to Additional PD-1 Inhibition in CPS ≥1 Advanced Laryngeal/Hypopharyngeal Cancer Suitable for Laryngectomy Selected After Early Response Evaluation

Laryngectomy-free survival (LFS) is the survival of the patient with larynx at place aka survival without laryngectomy, in the intent-to-treat population (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Laryngectomy or death from any cause count as event.

We measure LFS in the intent-to-treat population as the survival time of patients with larynx at place, which is the time interval from date of randomization until date of LFS event (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Laryngectomy or death from any cause count as LFS event. Patients lost to follow-up will be censored at date of last visit with larynx at place. Recruitment will be over 2 years and all patients will be followed up for at least 2 years, resulting in a maximum follow-up time of 4 years.

Overall survival (OS) is the survival of the patient without death from any cause, in the intent-to-treat population (follow-up of the total cohort until 24 months after randomization of the last patient accrued).

We measure OS in the intent-to-treat population as the survival time of patients as the time interval from date of randomization until date of death from any cause (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Patients lost to follow-up will be censored at date of last visit. Recruitment will be over 2 years and all patients will be followed up for at least 2 years, resulting in a maximum follow-up time of 4 years.

QoS will be assessed by fiber-endoscopic estimation of swallowing (FEES) at time of randomization and 6 and 24 months after first cycle induction chemo using the Rosenbek Scale (RS). De novo dysphagia (RS for aspiration and airway invasion/penetration \>1) or exacerbation of existing dysphagia RS 2-5 to RS ≥6 (aspiration), is loss of freedom from laryngo-esophageal dysfunction (FFLED; event). An event might also be persistence of either tracheostoma or gastric tube at 24 months (event at 24 months) or total laryngectomy or death from any cause.

We measure FFLED in the intent-to-treat population as time interval from date of randomization until date of event (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Patients lost to follow-up will be censored at date of last visit without event. Recruitment will be over 2 years and all patients will be followed up for at least 2 years, resulting in maximum follow-up of 4 years.

Event-free survival (EFS) is the survival of the patient without any event. Total laryngectomy (TL), progressing disease, occurrence of new lesions, local or nodal relapse, distant metastases or death from any cause count as event.

We measure EFS in the intent-to-treat population as the time interval from date of randomization until date of any event (follow-up of the total cohort until 24 months after randomization of the last patient accrued). Patients lost to follow-up will be censored at date of last visit without event. Recruitment will be over 2 years and all patients will be followed up for at least 2 years, resulting in a maximum follow-up time of 4 years.

Event-free survival (EFS) is the survival of the patient without any event. As early total laryngectomy (TL) of nonresponders with ETSS \<30% assessed by early response evaluation in week 4 is per-protocol therapy of LHSCC patients, which according to insufficient response to IC-1 cannot be selected for further 2 cycles TP followed by RT to achieve larynx organ-preservation, the alternative analysis of EFS will not consider early TL of nonresponders as event. However, progressing disease, occurrence of new lesions, local or nodal relapse, distant metastases or death from any cause and TL \>2 months after IC-1 or loss of FFLED count as event.

We measure EFS in the intent-to-treat population as the time interval from date of randomization until date of event. Patients lost to follow-up will be censored at date of last visit without event. Recruitment will be over 2 years and all patients will be followed up for at least 2 years, resulting in a maximum follow-up time of 4 years.

University of Göttingen

University of Jena

University of Cologne

University of Ulm

University of Regensburg

Wuerzburg University Hospital

Technical University of Munich

Ernst von Bergmann Hospital

Universitätsmedizin Mannheim

University of Kiel

University of Leipzig

Univ.-Prof. Dr. med. Andreas Dietz, Chairman, Clinic of Otolaryngology, Head and Neck Surgery & Dept. Head Medicine and Oral Health

Spots Global Cancer Trial Database for larynx organ preservation