Clinical trial NCT03669523: Denosumab and Nivolumab Combination As 2d-line Therapy in Stage IV NSC Lung Cancer with Bone Metastases (DENIVOS)
Official title: A Multicenter Phase II Study Evaluating Denosumab (XGEVA®) in Combination with Nivolumab (OPDIVO®) As Second-line Therapy for Patients with Stage IV Non-small-cell Lung Cancer (squamous and Non-squamous) with Bone Metastases: DENIVOS STUDY
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Bone Metastases
Lead sponsor: Centre Hospitalier Annecy Genevois
Sponsor class: OTHER
Collaborators: name: French Lung Cancer Group
First posted: 2018-09-13
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: National (French), multicenter, prospective, open, single-arm phase II study
Primary purpose: TREATMENT

Brief summary: Bone metastases are common in Non-Small Cell Lung Cancer (NSCLC). They most often occur during disease progression. It is thought that more than half of the patients with bone metastases will have at least 1 skeletal-related event (SRE, i.e. pathological fractures, medullary compression, analgesic radiotherapy, preventive and/or analgesic surgery and hypercalcemia).

Expert and medical Society guidelines, notably European Society for Medical Oncology in 2014, then in 2016, recommended using anti-resorptive agents (bisphosphonates or denosumab) to prevent SREs, attenuate pain and improve the quality of life, and decrease the medical-economic impact of this major metastatic site. Denosumab was accorded marketing authorization in France in 2011 as an anti-resorptive agent for bone metastases to delay the occurrence of SREs in lung-cancer patients.

Immunotherapy, notably immune-checkpoint inhibitors, like nivolumab (anti-programed death-1), has recently become an integral part of the therapeutic arsenal against NSCLCs. Nivolumab was accorded marketing authorization based on the phase III CHECKMATE 017 (squamous cell NSCLCs) and CHECKMATE 057 (non-squamous cell NSCLCs) trials versus docetaxel, after the phase II CHECKMATE 063 trial.

The denosumab-nivolumab combination is commonly used in current practice but has not been evaluated prospectively. The aim of this trial is to evaluate the combination of denosumab and nivolumab in second line of NSCLC with bone metastases.

Detailed description: Bone metastases are common in Non-Small Cell Lung Cancer (NSCLC), affecting 30-65% of the patients, depending on the series. They most often occur during disease progression (59.7% in the French Lung Cancer Group trial). The frequency of skeletal-related events (SREs) (pathological fractures, medullary compression, analgesic radiotherapy, preventive and/or analgesic surgery and hypercalcemia) is high. It is thought that more than half of the patients with bone metastases will have at least 1 SRE, with rates ranging from 55% to 62%.

Expert and medical Society guidelines, notably European Society for Medical Oncology in 2014, then in 2016, recommended using anti-resorptive agents (bisphosphonates or denosumab) to prevent SREs, attenuate pain and improve the quality of life, and decrease the medical-economic impact of this major metastatic site.

Denosumab is a humanized monoclonal antibody. It mimics the action of osteoprotegerin (OPG), thereby inhibiting osteoclastogenesis by blocking the binding of the receptor activator of nuclear factor-kappaB (RANK) to its ligand (RANKL), and thus interrupts the vicious circle between tumor cells and bone. RANK is a transmembrane protein expressed on osteoclasts, and its ligand, RANKL, is soluble and secreted by osteoblasts. Denosumab was accorded marketing authorization in France in 2011 as an anti-resorptive agent for bone metastases to delay the occurrence of SREs in lung-cancer patients. The results of 3 phase III studies evaluating the place of denosumab versus zoledronic acid have been published. Lung cancers were included in the trial examining solid tumors (other than breast and prostate) and multiple myeloma, and represented 40% of the population. In a non-inferiority analysis, the primary objective was reached with denosumab prolonging by approximately 4 months the time to the first SRE (20.6 versus 16.3 months, hazard ratio 0.84 \[95% confidence interval 0.71-0.98\] p=0.0007). In the lung-cancer subgroup, this difference did not reach significance (hazard ratio 0.85 \[95% confidence interval 0.65-1.12\]). In contrast, the exploratory analysis of that subgroup showed overall survival prolonged by 1.2 months for the denosumab arm versus zoledronic acid (8.9 versus 7.7 months, hazard ratio 0.8 \[95% confidence interval 0.67-0.95\] p=0.01).

Immunotherapy, notably immune-checkpoint inhibitors (ICPIs), like nivolumab (anti-programed death-1 (PD-1)), has recently become an integral part of the therapeutic arsenal against NSCLCs. Nivolumab was accorded marketing authorization based on the phase III CHECKMATE 017 (squamous cell NSCLCs) and CHECKMATE 057 (non-squamous cell NSCLCs) trials versus docetaxel, after the phase II CHECKMATE 063 trial. The search for a biomarker predictive of the response to immunotherapy is becoming more-and-more crucial, so as not to expose patients who risk early cancer hyper-progression. Immunohistochemical labeling of PD-1 ligand (PD-L1) on tumor cells (± infiltrating the stroma) is the most studied and reliable biomarker. Knowing its status has become indispensable in immunotherapy trials because an elevated PD-L1 has been correlated to a better response. Prescribing second-line nivolumab is not conditioned by the PD-L1 status because those trials had not foreseen stratification according to this criterion's status. However, post-hoc analysis of PD-L1 in the CHECKMATE 057 trial on non-squamous cell NSCLCs showed prolonged overall survival for patients with PD-L1-positive tumors, whether the positivity threshold was 1%, 5% or 10%. Thus, knowing the PD-L1 status is necessary to interpret the results of immunotherapy trials.

The RANK-RANKL system was studied in preclinical osteoimmunology models. It is expressed by certain cells, notably antigen-presenting cells, such as dendritic cells or lymphocytes, essential for the adaptive immunity function solicited by immunotherapy. It is part of the tumor necrosis factor receptor (TNF-R) family and is implicated in the interactions between dendritic cells and lymphocytes. The RANK-RANKL role in the development and function of regulatory T cells (Tregs) remains poorly elucidated. Information on the interaction of the RANK-RANKL system and adaptive immunity obtained with the preclinical models is discordant and rare. A case report on a patient with melanoma bone metastases treated with denosumab and ipilimumab (ICPI of the anti-cytotoxic T-lymphocyte antigen 4 type) obtained a promising carcinological outcome, without any sign of deleterious interaction.

The aim of this trial is to evaluate the combination of denosumab and nivolumab in second line of NSCLC with bone metastases.

Eligibility criteria: Inclusion Criteria:

* Cytologically or histologically proven stage IV NSCLC
* Patients who had received first-line platin salt-based chemotherapy and will be given second-line nivolumab;
* Patients with bone metastases, symptomatic or not, confirmed by X-rays, CT scan, MRI, PET-CT scan or technetium bone scintigraphy
* Presence of at least 1 measurable target lesion, according to RECIST criteria 1.1, in a non-irradiated site
* For non-squamous cell NSCLC, patients without known activating epidermal growth factor receptor mutation, anaplastic lymphoma kinase (ALK) or reactive oxygen species (ROS)-1 translocation, or B-Raf proto-oncogene, serine/threonine kinase (BRAF V600) mutation
* PD-L1 status known and expressed as a percentage of tumor cells; assessed at the diagnosis or the more recent PD-L1 expression status available.
* Eastern Cooperative Oncology Group Performance Status 0/1
* Estimated life-expectancy ≥12 weeks
* No prior malignant tumor during the previous 5 years, except for in situ carcinomas of the cervix or basal or squamous cell carcinomas of the skin adequately treated;
* Adequate organ function determined by laboratory analyses less than 7 days before inclusion:

  * Normal hepatic function: bilirubin \< 1.5× normal (N), alanine aminotransferase and aspartate aminotransferase \<2.5× N or \<5× N if hepatic metastases are present
  * Renal function (renal clearance of creatinine at least ≥45 mL/min)
  * Hematological function: absolute number of neutrophils ≥1.5×109/L and/or platelets ≥100×109/L, hemoglobin ≥8 g/dL
* Women of child-bearing age must use an effective contraceptive method and mechanical contraception during and up to 6 months after the end of treatment;
* Men must use effective contraception during and up to 6 months after the treatment period
* Patient with asymptomatic brain metastases (treated or not) OR symptomatic brain metastases but adequately treated and controlled at the time of enrolment (without or with corticotherapy ≤ 10mg/day), can be included. Carcinomatous meningitis is excluded regardless of clinical stability
* Subjects must have signed and dated an approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
* Patient affiliated or benefitting from the French national health insurance program

Exclusion Criteria:

* Patients previously treated with immunotherapy
* Patients with symptomatic cerebral metastases not treated and not controlled
* Contraindication to nivolumab use:

  * Prior autoimmune disease(s), define as disease required systemic treatment in the past (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  * Prior diffuse interstitial pneumopathy
  * Systemic immunosuppressive therapy; define as steroid medication at a dose greater than prednisone 10 mg/day or equivalent. For patients with mismatch repair-deficient high-grade gliomas, concurrent steroid medication at a dose greater than prednisone 20mg/day or equivalent
* Contraindication for denosumab use:

  * Poor dental status requiring immediate specialized management, like oral surgery
  * Prior or current signs of osteonecrosis of the jaw/osteomyelitis
  * Invasive dental intervention schedule during the study or not yet healed
* Patient with known sensitivity to any of the products to be administered during the study
* Concomitant administration of bisphosphonates
* Hypocalcemia or severe uncorrected hypercalcemia
* Medical or psychological condition preventing informed consent
* Pregnant or breastfeeding woman
* PD-L1-status results unavailable
* Simultaneous participation of the patient in another clinical research trial

Primary outcomes:
measure: Overall Response Rate (ORR) according to the PD-L1-expression rate (threshold set at 1%)
timeFrame: At 24 months
Secondary outcomes:
measure: Disease-control rate (DCR)
timeFrame: up to 24 months
measure: Overall survival
timeFrame: over 24 months
measure: Progression-free survival
timeFrame: over 24 months
measure: Overall Response Rate for the entire population
timeFrame: At 24 months
measure: Overall Response Rate according to the histological type (adenocarcinoma versus squamous cell)
timeFrame: At 24 months
measure: Time to the first Skeletal-Related Event in months
timeFrame: Over 24 months
measure: Incidence of adverse events, serious adverse events, deaths and biological abnormalities
timeFrame: up to 24 months
Other outcomes:
Locations:
city: Aix-en-Provence
country: France
facility: CH du Pays d'Aix
city: Angers
country: France
facility: Chu Angers
city: Beauvais
country: France
facility: Centre Hospitalier de Beauvais
city: Bourg-en-Bresse
country: France
facility: Centre Hospitalier Fleyriat
city: Brest
country: France
facility: CHU Morvan - Institut de Cancérologie et d'Hématologie
city: Créteil
country: France
facility: CH Intercommunal
city: Elbeuf
country: France
facility: Ch Intercommunal Elbeuf Louvier Val de Reuil
city: Gap
country: France
facility: CH Intercommunal des Alpes du Sud
city: Libourne
country: France
facility: Hôpital Robert Boulin
city: Limoges
country: France
facility: Chu Dupuytren
city: Marne-La-Vallée
country: France
facility: CH Marne La Vallée
city: Marseille
country: France
facility: Hopital Européen
city: Marseille
country: France
facility: Hopital Nord APHM
city: Meaux
country: France
facility: CH Meaux
city: Perpignan
country: France
facility: Centre Catalan d'Oncologie
city: Pringy
country: France
facility: CH Annecy-Genevois
city: Rennes
country: France
facility: CHU Hôpital Pontchailloux
city: Rouen
country: France
facility: CHU Rouen
city: Saint-Denis
country: France
facility: CHU La Réunion - Site de Bellepierre
city: Saint-Pierre
country: France
facility: Groupe Hospitalier Sud Réunion - CHU de la Réunion
city: Saint-Priest-en-Jarez
country: France
facility: Institut de Cancérologie de la Loire
city: Strasbourg
country: France
facility: CLCC Paul Strauss
city: Tarbes
country: France
facility: Centre Hospitalier de Bigorre
city: Toulon
country: France
facility: Hôpital d'Instruction des Armées Saint-Anne
city: Toulon
country: France
facility: CHITS Toulon Sainte-Musse
city: Versailles
country: France
facility: Hôpital André Mignot Centre Hospitalier de Versailles
city: Villefranche-sur-Saône
country: France
facility: CH Villefranche sur Saone
Study officials:
affiliation: CH Annecy Genevois
name: Chantal Decroisette, MD
role: PRINCIPAL_INVESTIGATOR
References: