A Phase 3, Randomized, Double blind Study of Neoadjuvant Chemotherapy plus Nivolumab versus Neoadjuvant Chemotherapy plus Placebo, followed by Surgical Resection and Adjuvant Treatment with Nivolumab or Placebo for Participants with Resectable Stage II-IIIB Non-small Cell Lung Cancer

Approximately 80% of lung cancer cases are NSCLC, with most patients presenting
with late stage disease. Of these patients with NSCLC, 20% present with stage I
or II disease, whereas 30% present with stage III disease and 50% with stage IV
disease. Patients with pathologic stage I NSCLC have a 5-year survival of
approximately 70%. Stage II to III NSCLC patients have a 5-year survival of
approximately 25% to 50%. The early-stage (II-IIIB) NSCLC represents a
population of high unmet need with poor 5-year survival. Surgical resection
remains the mainstay of treatment for Stage I and II patients and resectable
IIIB. Despite potential curative surgery, 50% of stage IIA-IIIB NSCLC patients
will relapse and eventually die of their disease. This study aims to improve
survival in these patients by eradicating micrometastatic disease and to
minimize the risk of relapse with adjuvant or neoadjuvant chemotherapy.

This study has been transitioned to CTIS with ID 2022-502658-15-00 check the CTIS register for the current data.

Primary Objective
• To compare the event-free survival (EFS) by blinded independent central
review (BICR) in Arm A (vs Arm B participants

Secondary Objectives
• To compare the overall survival (OS) in Arm A vs Arm B participants
• To assess the pathologic complete response (pCR) rate by blinded independent
pathology review (BIPR) in Arm A vs Arm B participants

This is a randomized, double blind, multicenter phase 3 study for participants
with early stage (Stage IIA [>= 4 cm] to IIIB [T3N2 only]) NSCLC evaluating Arm
A with the comparator arm (Arm B). This study will examine if periadjuvant
(neoadjuvant, then adjuvant) immunotherapy will prolong event free survival in
participants with early stage (Stage IIA [>= 4 cm] to IIIB [T3N2 only]) NSCLC.

Participants will be randomized (1:1 ratio) across 2 treatment arms:

) platinum-based doublet chemotherapy Q3W x 4 cycles as neoadjuvant treatment
followed by surgery; then post surgery nivolumab 480 mg Q4W adjuvant treatment
for up to 13 cycles (approximately 1 year) post surgery.

• Arm B: placebo Q3W + SOC platinum-based doublet chemotherapy Q3W x 4 cycles
as neoadjuvant treatment followed by surgery, then post-surgery placebo Q4W for
up to 13 cycles (approximately 1 year) post surgery.

The choice of platinum-based doublet regimens is dependent on NSCLC histology:
• Squamous histology: carboplatin (AUC 5 or AUC 6) + paclitaxel (175 mg/m2 or
200 mg/m2)
• Non-squamous histology:
- carboplatin (AUC 5 or AUC 6) + pemetrexed 500 mg/m2
- cisplatin 75 mg/m2 + pemetrexed 500 mg/m2

After completing treatment with protocol specified adjuvant study treatment,
participants will have follow-up assessments (FU1 and FU2) and disease
surveillance (Year 2 through year 5).

Participants will be randomized (1:1 ratio) across 2 treatment arms:

• Arm A: nivolumab 360 mg Q3W + SOC platinum-based doublet chemotherapy Q3W x 4
cycles as neoadjuvant treatment followed by surgery; then post surgery
nivolumab 480 mg
Q4W adjuvant treatment for up to 13 cycles (approximately 1 year) post surgery.

• Arm B: placebo Q3W + SOC platinum-based doublet chemotherapy Q3W x 4 cycles as
neoadjuvant treatment followed by surgery, then post-surgery placebo Q4W for up
to 13 cycles
(approximately 1 year) post surgery.

The choice of platinum-based doublet regimens is dependent on NSCLC histology:
• Squamous histology: carboplatin (AUC 5 or AUC 6) + paclitaxel (175 mg/m2 or
200 mg/m2)
• Non-squamous histology:
- carboplatin (AUC 5 or AUC 6) + pemetrexed 500 mg/m2
- cisplatin 75 mg/m2 + pemetrexed 500 mg/m2

All study drugs will be provided by the sponsor.

As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements,
blood tests for safety assessment, pregnancy testing (for females of child
bearing potential) and monitoring for adverse events & serious adverse events.
Patients will be asked to complete questionnaire*s (NSCLC-SAQ, PGIS, PROMIS PF
8c, FACT-L & EQ-5Q-3L) about their quality of life. Blood will also be
collected at certain visits for research purposes (PK, immunogenicity and
biomarker studies). If there is no archival tumour tissue (10 tumor slides)
available or the sample was taken too long ago (>= 3 months), patients need to
have a fresh tumor biopsy. Surgery will be performed on patients post
completion of neo-adjuvant therapy. A tumour biopsy will also be performed at
disease progression, if clinically possible. Patients will undergo radiographic
assessment of their tumors by CT and within 1 week prior to initiation of
adjuvant study treatment. PET-CT scans will be performed prior to start of the
study and 14 days prior to surgery. Subsequent imaging assessments will be
performed every 12 weeks for 2 years, then every 6 months for up to a maximum
of 5 years until disease recurrence or progression (confirmed by blinded
independent central review). Brain MRI will be performed prior to start of the
study and thereafter only if clinically indicated. The frequency of visits and
number of procedures carried out during this trial would be typically
considered over and above standard of care. The procedures are carried out by
trained medical professionals and every effort will be made to minimise any
risks or discomfort to the patient.
Treatment for cancer often has side effects, including some that are life
threatening. To assure an ongoing favourable risk/benefit assessment for
patients enrolled onto the study, an Independent Data Monitoring Committee
(DMC) will be established to provide oversight of safety and efficacy
considerations. Additionally, the DMC will provide advice to the sponsor
regarding actions the committee deems necessary for the continuing protection
of patients enrolled in the study.
BMS will conduct rigorous safety monitoring to ensure patients safety by
regularly & systematically reviewing safety data; the reported safety events
will be closely followed-up; sites and study investigators will receive
training on the implementation of nivolumab toxicity management strategies. New
immune system targeted therapy (immunotherapies) such as nivolumab could
potentially provide clinical benefit and improvements in the outcomes for
patients with this disease. However, with all experimental drugs and clinical
trials, there are known and unknown risks. Study medication and procedure
related risks are outlined in the patient information sheet in detail to ensure
the patients are fully informed before agreeing to take part in the study.