NIvolumab COmbination With Standard First-line Chemotherapy and Radiotherapy in Locally Advanced Stage IIIA/B Non-Small Cell Lung Carcinoma

Over the past decade, concomitant chemotherapy and radiotherapy has become the first choice treatment for most patients with stage III non-small-cell lung carcinoma (NSCLC).

However, only about 30% of patients are alive 5 years after con¬comitant therapy. These figures remain approximately the same with the addition of surgery. After chemo-radiotherapy, at least 30-40% of the patients show local tumour progression on CT scans as first site of relapse. Also after surgery, about 30% of patients fail locally as a first site of recurrence. In addition, more than half of the patients eventually develop distant metastases that may have been present but undetected at the time of staging or that may have come from persistent or recurring local disease. It is thus obvious that new approaches that preferentially tackle both local and distant disease sites are needed to improve long-term survival and cure rates.

Attempts to improve the long-term survival include radiotherapy dose escalation/acceleration, new chemotherapy combinations, and adding biological agents and cancer vaccines to standard regimens. At present, none of these have demonstrated an improved outcome.

Improved understanding of the immune profile of NSCLC has led to immunotherapeutic strategies, including inhibitory molecules responsible for abrogating an anti-cancer immune response such as PD-1 and CTLA-4. Nivolumab, an investigational monoclonal antibody that inhibits the immune checkpoint receptor PD-1 expressed on activated T cells, has demonstrated positive results in several trials in previously treated patients with advanced NSCLC. However, rare cases of severe or fatal pneumonitis have been reported throughout clinical trials using anti-PD1 or anti-PDL1 compounds.

Pre-clinical data consistently show a clear beneficial effect by combining local radiotherapy and anti-PD-1. Not only was the local tumour control increased, but an "abscopal" effect on distant metastases could be observed. Radiotherapy clearly acted as an "in situ" tumour vaccination resulting in the induction of specific anti-tumour immunity in all sites of the body that could result in a clinical anti-tumour effect because of the combination with anti-PD-1.

In these models, the concurrent administration of anti-PD-1/PD-L1 antibodies was more efficient to provoke an anti-tumour immune response than the sequential approach.

While the role of immunotherapy is currently being evaluated as monotherapy or in combination with chemotherapy or tyrosine kinase inhibitors in all lines of treatment of advanced NSCLC, as monotherapy in early NSCLC adjuvant setting as well as monotherapy in consolidation after completion of definitive chemo-radiotherapy, it has not yet been assessed in combination with radiotherapy. Anecdotal data of concurrent treatment in the palliative setting suggest acceptable safety and a good tolerability of such combination.

The NICOLAS trial was initially developed to prospectively assess the safety of checkpoint inhibition concurrently with chemo-radiotherapy.

In summary, there is a definite unmet need in multi-disciplinary care to improve the prognosis of patients diagnosed with stage III NSCLC, with a strong rationale supporting the combination of chemo-radiotherapy with anti-PD-1. A major theoretical concern is the development of pneumonitis, a rare toxicity of both radiotherapy and checkpoint inhibitors. The main aim of the ongoing current trial is therefore to evaluate the pneumonitis rate in patients being treated with chemo-radiotherapy in combination with nivolumab treatment.

Rationale for protocol amendment 2:

Since the NICOLAS trial was initiated, the landscape of combining chemo-radiotherapy with immune-checkpoint inhibition, such as anti-PD-1 antibodies, has changed rapidly, opening a new window of opportunity.

There is a very strong interest of the multidisciplinary lung cancer community to investigate the optimal integration of anti-PD-1 treatment into chemo-radiotherapy. Currently, 11 sites from 5 countries are activated for the NICOLAS trial and recruiting strongly (ahead of schedule). Using this momentum will allow us to rapidly recruit additional patients in order to reach the power to not only determine the feasibility in terms of pneumonitis grade 2 and abouve, but also to evaluate the efficacy of the concurrent treatment.

So far, during the regular safety review, the ETOP IDMC did not observe any additional toxicity compared the chemo-radiotherapy alone.

A first planned analysis of the PACIFIC trial (stage III NSCLC treated with concurrent chemotherapy and radiotherapy, followed by the anti-PD-L1 durvalumab or observation, NCT02125461) showed an increased progression-free survival (PFS), which was co-primary endpoint together with overall survival (OS). The full details are not known, yet, but it appears that the pre-clinical rationales of combined chemo-radiotherapy and anti-PD-1 treatment can be successfully transferred into clinical trials, without serious toxicities.

A recent secondary analysis of the Keynote 001 trial indicates synergistic affects of radiotherapy and immunotherapy. This international, multicentre phase I trial assessed the effect of pembrolizumab monotherapy in patients with progressive locally advanced or metastatic NSCLC. Patients were assigned to multiple expansion cohorts to allow for the inclusion of patients who were naïve to systemic therapy and those who had progression after one or two previous regimens.

The results from this study showed that the effect of pembrolizumab was significantly higher in patients who received previous radiotherapy than in patients without previous radiotherapy.

These findings were well in line with pre-clinical studies that underlined the ability of radiotherapy to enhance antitumour immune response.

In the absence of of serious pulmonary toxicity, the apperant benefit of chemo-radiotherapy and anti-PD-1 and the high interest of the NICOLAS study group, we propose to amend the NICOLAS trial protocol to expand on the number of patients in order to reach sufficient power for an efficacy readout (progression-free survival).