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Treatment plan:

* Part 1: induction with durvalumab plus histology-based chemotherapy regimen.
* Part 2: patients with a sufficient tumor shrinkage to be considered eligible for part 2 and they will be treated concomitantly with durvalumab and radiotherapy.
* Part 3: patients with partial response or stable disease after part 2 will be eligible for durvalumab maintenance, for up to 2 years or until disease progression or unacceptable toxicity.

Induction therapy: durvalumab plus histology-based chemotherapy regimen (cisplatin or carboplatin plus vinorelbine for squamous histology and pemetrexed for non-squamous histology).

durvalumab plus platinum-based chemotherapy (cisplatin or carboplatin plus vinorelbine or pemetrexed)

Durvalumab plus radiotherapy

durvalumab

Valter Torri

Roberto Ferrara

Standard treatment for stage III Non-Small Cells Lung Cancer (NSCLC) not eligibile for surgery is concomitant chemoradiotherapy. However median progression free survival and overall survival is still poor with only 15% of patients alive at 5 years. The addition of maintenance therapy with durvalumab after chemoradiation showed a significant benefit in PFS and OS, with good tolerability and no concerns in terms of safety. However, about 30% of patients with stage III are not eligible to concurrent chemoradiotherapy because of large volumes of the tumor. To date, these patients are initially treated with chemotherapy with the aim of reducing tumor volumes and allowing sequential radiotherapy. Response rate ranges between 25-30% and majority of patients will not become suitable for radiotherapy.

The combination of immunotherapy plus standard chemotherapy in advanced stages doubles response rates and provides major tumor shrinkage compared to standard chemotherapy alone. For these reasons, the investigators want to exploit the synergistic effect of immunotherapy combined with chemotherapy in the induction phase, in order to render suitable for radiotherapy a larger number of patients, and in a second phase the synergistic effect with radiotherapy.

Based on these premises the investigators designed a single arm, phase 2 trial to determine the efficacy and safety of combining immunotherapy with the drug durvalumab in association with standard chemotherapy and subsequently with standard radiotherapy, followed by a treatment of maintenance with only durvalumab.

The study population includes patients with NSCLC not eligible for surgery or concurrent chemoradiation at diagnosis because of large tumor volumes.

BRIDGE trial aims to evaluate the proportion of patients who did not progress and who achieved a mean lung dose \<20 Gy and/or a lung V20\<35% (response) after part 1. The primary objective of the study is to increase the proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy, in comparison with historical controls.

This study will last approximately 60 months and will include approximately 65 eligible patients in 3 international cancer centres of excellence.

Standard treatment for stage III Non-Small Cells Lung Cancer (NSCLC) not eligibile for surgery is concomitant chemoradiotherapy. However median progression free survival and overall survival is still poor with only 15% of patients alive at 5 years. The addition of maintenance therapy with durvalumab after chemoradiation showed a significant benefit in PFS and OS, with good tolerability and no concerns in terms of safety. However, about 30% of patients with stage III are not eligible to concurrent chemoradiotherapy because of large volumes of the tumor. To date, these patients are initially treated with chemotherapy with the aim of reducing tumor volumes and allowing sequential radiotherapy. Response rate ranges between 25-30% and majority of patients will not become suitable for radiotherapy.

The combination of immunotherapy plus standard chemotherapy in advanced stages doubles response rates and provides major tumor shrinkage compared to standard chemotherapy alone. For these reasons, the investigators want to exploit the synergistic effect of immunotherapy combined with chemotherapy in the induction phase, in order to render suitable for radiotherapy a larger number of patients, and in a second phase the synergistic effect with radiotherapy.

Based on these premises the investigators designed a single arm, phase 2 trial to determine the efficacy and safety of combining immunotherapy with the drug durvalumab in association with standard chemotherapy and subsequently with standard radiotherapy, followed by a treatment of maintenance with only durvalumab.

The study population includes patients with NSCLC not eligible for surgery or concurrent chemoradiation at diagnosis because of large tumor volumes.

The study consists of 3 parts:

* Part 1: induction with durvalumab plus chemotherapy.
* Part 2: patients with a sufficient tumor shrinkage to be considered eligible for part 2 and they will be treated concomitantly with durvalumab and radiotherapy.
* Part 3: patients with partial response or stable disease after part 2 will be eligible for durvalumab maintenance, for up to 2 years or until disease progression or unacceptable toxicity.

BRIDGE trial aims to evaluate the proportion of patients who did not progress and who achieved a mean lung dose \<20 Gy and/or a lung V20\<35% (response) after part 1. The primary objective of the study is to increase the proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy, in comparison with historical controls.

This study will last approximately 60 months and will include approximately 65 eligible patients in 3 international cancer centres of excellence.

multicentric, open label, single arm, minimax Simon 2 stages, phase 2 trial

Durvalumab and Chemotherapy Induction Followed by Durvalumab and Radiotherapy in Large Volume Stage III NSCLC

BRIDGE Trial: Phase II Trial of durvalumaB and chemotheRapy Induction Followed by Durvalumab and Radiotherapy in larGe volumE Stage III NSCLC

To evaluate the concordance between patients who reach the primary endpoint and patients who are included in part 2 after the evaluation of the multidisciplinary team

To evaluate correlation of clinical outcome with PD-L1 expression (in percentage %).

Plasma for cfDNA will be analyzed through whole exome sequencing (considering coding region only) to assess correlation with response.

To assess the dynamic changes of the tumor mutational profile upon different treatment time points.

The primary objective of the study is to increase the proportion of patients eligible for immunotherapy plus radiotherapy after induction with durvalumab and chemotherapy, in comparison to historical controls.

PFS is defined as the time from the date of start of induction treatment until the date of objective disease progression or death to any cause whichever comes first. PFS will be evaluated using RECIST 1.1 criteria according to investigators and blinded central review (BCR).

To evaluate Objective Response Rate (ORR) of each phase of treatment and the overall response rate. ORR is defined as the proportion of patients with complete or partial response (as best response) according to RECIST 1.1 as assessed by Investigators and BCR.

OS is defined as the time from the date of start of induction treatment until death due to any cause. Patients alive at the time of statistical analysis will be censored at their last information on vital status.

The assessment of safety will be mainly based on adverse reactions (ARs) and the frequency and nature of SAEs. Toxicity and safety will be evaluated during each part of the program, throughout study duration.

Spots Global Cancer Trial Database for durvalumab plus radiotherapy