PD-1 Inhibitor and Chemotherapy With Concurrent Irradiation at Varied Tumour Sites in Advanced Non-small Cell Lung Cancer
Overall survival (OS) of patients with advanced (stage IIIB/IV) non-small-cell lung cancer (NSCLC) remains short after the first line of treatment with a median OS of 12.2 months in non squamous NSCLC and 9.2 months in squamous NSCLC . In this setting the programmed death 1/ligand 1 (PD-1/-L1) were targeted with nivolumab (IgG4) in advanced squamous and nonsquamous NSCLC leading to an increase of the 1-year OS rate of approximately 10-15% in both histologies. Nivolumab, pembrolizumab and atezolizumab are now considered a standard of care in 2nd line advanced NSCLC and in 1st line for pembrolizumab but but prognosis still remains poor in advanced NSCLC. Overall survival (OS) of patients with advanced (stage III/IV) NSCLC remains limited with a median OS of 12.2 months in non-squamous NSCLC and 9.2 months in squamous NSCLC if anti-PD1 alone. It is of around 16 months if pembrolizumab is combined with chemotherapy. Preclinical data indicates that anti-tumor efficacy is increased when anti-PD-1/-L1 are combined with irradiation (IR). Radiotherapy alone can elicit tumor cell death which can increase tumor antigen in the blood stream, favoring recognition by the immune system and its activation against tumor cells outside of the radiation field (=abscopal effect). IR may also reverse acquired resistance to PD-1 blockade immunotherapy by limiting T-cell exhaustion. Because of these preclinical and clinical data several studies analysing the combination of IR and anti-PD1 in NSCLC are ongoing. Among them, two studies are testing the administration of IR and nivolumab in stage III NSCLC: the NCT02768558 phase III trial (RTOG), and the NCT02434081 phase II trial (ETOP). Antonia et al \[2017\] tested the use of anti-PD-L1 after chemoradiotherapy in unresectable stage III NSCLC. Median time to distant metastasis was increased (23.2 months vs. 14.6 months, p\<0.001). An increase of OS is consequently expected. However, no study involving concurrent RT and pembrolizumab combined with chemotherapy in advanced NSCLC is ongoing, which is the purpose of the present study, NIRVANA-Lung.
• Patient must have signed a written informed consent form prior to any study specific procedures
• Histologically or cytologically confirmed advanced (stage IIIB/IIIC/IV), squamous or non-squamous NSCLC
• NSCLC patients eligible for treatment with pembrolizumab and chemotherapy according to the European Marketing Authorization:
∙ squamous: in combination with carboplatin and either paclitaxel or nab-paclitaxel
‣ non squamous with no EGFR or ALK positive mutations: in combination with pemetrexed and a platinum based chemotherapy
• Patient ≥18 of age
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1
• Life expectancy \>3 months
• Measurable lesion as assessed by RECIST version 1.1
• Metastases and/or primary tumour eligible for 3 dimensional conventional radiotherapy (3D-CRT) or stereotactic ablative radiotherapy (SABR) in terms of dose constraints at organ at risk (according to QUANTEC review)
• Patients must have adequate organ function defined by the following laboratory results obtained within 14 days prior to the first study treatment:
∙ absolute neutrophil count of ≥1 500 /mm³
‣ platelets ≥ 100 000/mm³
‣ haemoglobin \>9 g/dL (transfusions allowed)
‣ creatinine clearance \>60 mL/min
‣ bilirubin ≤1.5 X upper limit of normal (ULN) (unless Gilbert's syndrome where 3 X ULN is permitted)
‣ serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 X ULN (unless documented liver metastasis where ≤5 X ULN is permitted)
‣ Alkaline phosphatase (ALP) ≤2.5 X ULN (unless documented bone or liver metastasis where ≤5 X ULN is permitted)
‣ International normalized ratio (INR), prothrombin (PT), and prothrombin time (PTT) ≤1.5 X ULN (unless the subject is receiving anticoagulant therapy)
⁃ Woman of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 6 months after completing treatment/therapy
⁃ Patients affiliated to the social security system (or equivalent)
⁃ Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations including follow-up