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| Name | Class |
|---|---|
| Bristol-Myers Squibb | INDUSTRY |
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Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 on activated immune cells and disrupts engagement of the receptor with its ligands PD-L1 (B7 H1/CD274) and PD-L2 (B7-DC/CD273), thereby abrogating inhibitory signals and augmenting the host antitumor response. In early clinical trials, nivolumab has demonstrated activity in several tumor types, including melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC).
Nivolumab is in clinical development for the treatment of patients with NSCLC, RCC, melanoma, squamous cell carcinoma of the head and neck (SCCHN) and other tumors (eg, glioblastoma multiforme, mesothelioma, small cell lung cancer, gastric).
Nivolumab is approved in the United States (US), European Union, and other countries for the treatment of patients with unresectable or metastatic melanoma, advanced NSCLC with progression on or after platinum-based chemotherapy, advanced RCC whose disease progressed on an antiangiogenic therapy, classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin treatment, and recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy.
The proposed study will evaluate the efficacy and safety of preoperative administration of Nivolumab or Nivolumab combined with nab-paclitaxel and carboplatin in neoadjuvant setting and administration of Nivolumab in adjuvant setting in patients with high-risk resectable NSCLC, and will facilitate a comprehensive exploratory characterization of the tumor immune microenvironment and circulating immune cells in these patients. Data obtained in this study will provide valuable information for planning further prospective clinical trials of anti-PD-1 and other immunotherapies in NSCLC, both in the peri-operative and advanced disease setting. Ultimately, it is highly desirable to discover prospective biomarkers of response and toxicity to allow patients with NSCLC who are most likely to derive benefit to receive anti-PD-1 treatment, and conversely to minimize the risk of toxicity and ineffective treatment for patients who are unlikely to benefit.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1: Nivolumab Mono | Experimental | In arm A, 24 participants will be enrolled into this arm according to PD-L1 expressing level (≥50%).Arm A consists of 3 cycles of neoadjuvant nivolumab (360mg every 3 weeks), and adjuvant nivolumab (360mg IV, every 3 weeks) up to 12 months |
|
| Part 1: Nivolumab Plus Chemo | Experimental | In arm B, up to 12 participants will be enrolled into each subgroup according to PD-L1 expressing level (<1% and 1%-49%).arm B consists of 3 cycles of neoadjuvant nivolumab (360mg every 3 weeks) with nab-paclitaxel and carboplatin(nab-paclitaxel 135 mg/m2, d1, 8 and carboplatin AUC 5, d1 every three weeks ), and adjuvant nivolumab (360mg IV, every 3 weeks) up to 12 months |
|
| Part:2: Exploratory cohort | Experimental | In part 2，the treatment regimen consists of three cycles of neoadjuvant nivolumab (360 mg every 3 weeks) in combination with nab-paclitaxel and carboplatin (nab-paclitaxel 135 mg/m² on days 1 and 8, and carboplatin AUC 5 on day 1, every 3 weeks), followed by adjuvant nivolumab (360 mg every 3 weeks, administered via IV infusion over at least 30 minutes) for up to 12 months. A total of 53 subjects will be enrolled in this study, regardless of PD-L1 expression. |
|
| Part 3: Real-world cohort |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nivolumab | Biological | Nivolumab 360 mg IV (administered intravenously for more than 30 minutes) every 3 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| MPR (Major Pathological Response) rate | As the primary outcome in part 1. MPR rate, defined as the number of participants with <10% residual tumor in lung and lymph nodes, divided by the number of treated participants for each arm. Viable tumors in situ carcinoma should not be included in the MPR calculation. | The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks |
| EFS | Primary Outcome for Part 2. Outcome Measure Definition: Event-Free Survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: Disease progression that precludes surgical treatment; Local or distant recurrence; Death from any cause. Progression and recurrence will be assessed by the investigator according to RECIST 1.1. Subjects who die without documented disease progression or recurrence will be considered to have experienced an EFS event on the date of death. | Since the last patient was enrolled for follow-up for 36 months |
| 18 months EFS rate | Primary Outcome for Part 3. Outcome Measure Definition: 18months Event-Free Survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: Disease progression that precludes surgical treatment; Local or distant recurrence; Death from any cause. Progression and recurrence will be assessed by the investigator according to RECIST 1.1. Subjects who die without documented disease progression or recurrence will be considered to have experienced an EFS event on the date of death. | The patient was followed up for 18 months after frist cycle neoajuvant treatment. |
| Surgical Conversion Rate | The primary endpoint of Part 3 is the surgical conversion rate, defined as the proportion of patients who successfully undergo definitive surgery following neoadjuvant chemoimmunotherapy, relative to the total enrolled population (Intent-to-Treat [ITT] analysis set). Statistical Analysis: The surgical conversion rate will be summarized descriptively using frequencies and percentages. The two-sided 95% exact confidence interval (CI) for the proportion will be calculated using the Clopper-Pearson method. |
| Measure | Description | Time Frame |
|---|---|---|
| MPR (Major Pathological response) rate in 2 subgroups patients (PD-L1 <1%, and 1-49%) in Arm B | In part 1 | The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks |
| Proportion of resection without delay |
| Measure | Description | Time Frame |
|---|---|---|
| pCR rate | The pCR (complete pathological response) rate is defined as the number of subjects with no residual tumor cells in the lungs and lymph nodes divided by the number of subjects receiving treatment. | The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks |
Inclusion Criteria:
Exclusion Criteria:
Other protocol defined inclusion/exclusion criteria could apply
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences | Guangzhou | Guangdong | 510080 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38057314 | Derived | Liu SY, Dong S, Yang XN, Liao RQ, Jiang BY, Wang Q, Ben XS, Qiao GB, Lin JT, Yan HH, Yan LX, Nie Q, Tu HY, Wang BC, Yang JJ, Zhou Q, Li HR, Liu K, Wu W, Liu SM, Zhong WZ, Wu YL. Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC (CTONG1804): a multicenter open-label phase II study. Signal Transduct Target Ther. 2023 Dec 6;8(1):442. doi: 10.1038/s41392-023-01700-4. |
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Part 3 aims to evaluate the real-world effectiveness of neoadjuvant chemoimmunotherapy in patients with EGFR/ALK wild-type, potentially resectable or unresectable Stage III NSCLC. Treatment Paradigm: Eligible subjects will receive 3 cycles of neoadjuvant chemoimmunotherapy. Subsequently, a Multidisciplinary Team (MDT) will evaluate and determine the optimal definitive local therapy, triage patients to either radical resection or concurrent chemoradiotherapy (CCRT). Following the completion of local therapy, patients will receive adjuvant or consolidation immunotherapy for a duration of 1 year, administered every 3 weeks (Q3W). Sample Size: The planned enrollment for Part 3 is 215 patients. |
|
| carboplatin | Drug | AUC 5, d1 every three weeks |
|
| nab-paclitaxel | Drug | 135 mg/m2, d1, 8 |
|
| Radical resection for lung cancer | Procedure | Including lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. Segmentectomy and wedge resection are not permitted. |
|
| Radical radiation therapy | Radiation | In Part 3, for patients who are assessed by a Multidisciplinary Team (MDT) as unable to achieve R0 resection following neoadjuvant chemo-immunotherapy induction, the recommended radiotherapy regimen is: 60 Gy in 30 fractions (5 fractions per week) to 95% of the planning target volume (PTV). |
|
| Chemotherapy (Cisplatin) | Drug | Part 3: For patients who are determined by a Multidisciplinary Team (MDT) to be ineligible for R0 resection following neoadjuvant chemo-immunotherapy induction and require definitive radiotherapy, concurrent chemotherapy will be administered. The regimen consists of cisplatin 30 mg/m² administered once weekly |
|
| Nivolumab | Biological | Within 6 weeks after definitive surgery, subjects in each cohort who are assessed to have benefited from neoadjuvant therapy (CR, PR, or SD) and have adequately recovered from surgery may receive adjuvant nivolumab (360 mg via IV infusion over at least 30 minutes, every 3 weeks) for up to 12 months, or until disease recurrence or unacceptable toxicity. |
|
| Perioperative/Periprocedural |
In part 1and 2 |
| The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks |
| Number of Participants with Adverse Events | In parts 1 and 2 Safety and tolerability will be measured by incidence of AE, SAE, immune related AEs, deaths, and laboratory abnormalities | During the treatment period, within at least 100 days after the cessation of neoadjuvant therapy, within 90 days after surgery, and within 30 days after adjuvant therapy. |
| MRP rate | Also, as the primary outcome in part 1. MPR rate, defined as number participants with <10% residual tumor in lung and lymph nodes, divided by the number of treated participants for each arm Viable tumors in situ carcinoma should not be included in MPR calculation. | The patients considered to be technically resectable will undergo resection，an expected average of 13 weeks |
| The EFS rates of all subjects with different PD-L1 expression statuses (PD-L1 < 1%, 1-49% and ≥ 50%) | In parts 1 and 2. Outcome Measure Definition: Event-Free Survival (EFS) is defined as the time from randomization to the first occurrence of any of the following events: Disease progression that precludes surgical treatment; Local or distant recurrence; Death from any cause. Progression and recurrence will be assessed by the investigator according to RECIST 1.1. Subjects who die without documented disease progression or recurrence will be considered to have experienced an EFS event on the date of death. | From date of enrollment up to the end of study, 5 years. |
| 12 months EFS rate | In part 3, the 12-month EFS rate is the proportion of subjects who are alive and event-free at 12 months after the start of treatment. | After 12 months of enrollment for all patientsAfter 12 months of enrollment for all patients |
| OS | In part 3, OS is defined as the time from the start of treatment to death for any reason | From the date of enrollment until the date of death, assessed up to 100 months |
| TDDM (Time to Death or Distant Metastasis) | In part 3, TDDM is defined as the start of the first treatment to distant metastasis, or death from any cause, whichever occurs first | From the date of the first dose of study treatment until the date of first documented distant metastasis or death from any cause, whichever occurs first, assessed up to approximately 60 months. |
| OS rate |
OS is defined as the time since the treatment date and the death date, with the deletion date being the last known date when the subject was still alive |
| From date of enrollment up to the end of study, 5 years. |
| ORR | ORR is defined as the optimal objective tumor response rate between neoadjuvant therapy and surgery (according to RECIST 1.1 criteria). All subjects will have their ORR calculated. | Within 4 to 6 weeks after the patient completes the neoadjuvant treatment |
| Safty | Descriptive statistical analysis of safety data was conducted based on the 4th edition of NCI CTCAE. According to the most severe level determined by NCI CTCAE V4, all AE/ SAEs that occur after treatment and treatment-related AE/ SAEs will be summarized by systemic organ classification and standard terms. | From the time of enrollment until the completion of adjuvant therapy, which lasted for 13 weeks |
| 18m-DFS rate | Disease-Free Survival (DFS) is defined as the time from the date of surgery to any of the following events: disease progression, recurrence, or death from any cause. Disease progression and recurrence will be assessed according to RECIST 1.1 criteria. For subjects who do not experience a DFS event, the date of censoring will be the date of the last evaluable tumor assessment after surgery. For subjects who do not experience a DFS event but start subsequent anti-cancer therapy, the date of censoring will be the date of the last evaluable tumor assessment prior to receiving the subsequent anti-cancer therapy. | The 18-month DFS rate refers to the probability of being event-free at 18 months calculated from the date of surgery. |
| Landmark MRD positive rate | In part 3, the Landmark MRD positive rate is defined as the proportion of patients who were MRD positive at the Landmark time point among the total study population. Furthermore, the comparison is made between the proportion of patients with MRD positivity among those who underwent surgery and the proportion of patients with MRD positivity among those who received radiotherapy. | One month after local therapy |
| ID | Term |
|---|---|
| D002289 | Carcinoma, Non-Small-Cell Lung |
| ID | Term |
|---|---|
| D002283 | Carcinoma, Bronchogenic |
| D001984 | Bronchial Neoplasms |
| D008175 | Lung Neoplasms |
| D012142 | Respiratory Tract Neoplasms |
| D013899 | Thoracic Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D000077594 | Nivolumab |
| D016190 | Carboplatin |
| C520255 | 130-nm albumin-bound paclitaxel |
| D004358 | Drug Therapy |
| D002945 | Cisplatin |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |
| D013812 | Therapeutics |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017672 | Nitrogen Compounds |
| D017671 | Platinum Compounds |
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