Non Small Cell Lung Cancer
Conditions
Brief summary
The purpose of this neoadjuvant study is to compare nivolumab plus chemotherapy and chemotherapy alone in terms of safety and effectiveness, and to describe nivolumab plus ipilimumab's safety and effectiveness in treating resectable NSCLC. This study has multiple primary endpoints.
Interventions
BIOLOGICALNivolumab
Specified dose on specified days
DRUGCisplatin
Specified dose on specified days
DRUGVinorelbine
Specified dose on specified days
DRUGGemcitabine
Specified dose on specified days
DRUGDocetaxel
Specified dose on specified days
DRUGPemetrexed
Specified dose on specified days
DRUGCarboplatin
Specified dose on specified days
DRUGPaclitaxel
Specified dose on specified days
BIOLOGICALIpilimumab
This arm is closed and no longer enrolling patients.
Sponsors
Ono Pharmaceutical Co. Ltd
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Early stage IB-IIIA, operable non-small cell lung cancer, confirmed in tissue * Lung function capacity capable of tolerating the proposed lung surgery * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 * Available tissue of primary lung tumor
Exclusion criteria
* Presence of locally advanced, inoperable or metastatic disease * Participants with active, known or suspected autoimmune disease * Prior treatment with any drug that targets T cell co-stimulations pathways (such as checkpoint inhibitors) Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | From randomization to disease progression, reoccurrence, or death due to any cause. (Up to a median of 30 months) | Event-free survival (EFS) is defined as the length of time from randomization to any of the following events: any progression of disease precluding surgery, progression or recurrence disease based on blinded independent central review (BICR) assessment per response evaluation criteria in solid tumors (RECIST) 1.1 after surgery, or death due to any cause. Participants who don't undergo surgery for reason other than progression will be considered to have an event at progression or death. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). |
| Pathologic Complete Response (pCR) Rate | From randomization up to a median of 30 months after randomization. | Pathologic complete response (pCR) rate is defined as the number of randomized participants with absence of residual tumor in lung and lymph nodes as evaluated by blinded independent pathological review (BIPR). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathologic Response (MPR) Rate | From randomization up to a median of 30 months after randomization. | Major pathologic response (MPR) rate is defined as number of randomized participants with \</= 10% residual tumor in lung and lymph nodes as evaluated by blinded independent pathological review (BIPR). Viable tumors in situ carcinoma should not be included in MPR calculation. |
| Overall Survival (OS) | From randomization to the date of death (Up to approximately 93 months) | Overall survival (OS) is defined as the time between the date of randomization and the date of death. OS will be censored on the last date a participant was known to be alive. |
| Time to Death or Distant Metastases (TTDM) | From randomization to the first date of distant metastasis or the date of death in the absence of distant metastasis (Up to approximately 84 months) | TTDM is defined as the time between the date of randomization and the first date of distant metastasis or the date of death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is outside of the thorax using blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST) 1.1. Patients who have not developed distant metastasis or died at the time of analysis will be censored on the date of their last evaluable tumor assessment. |
Countries
Argentina, Brazil, Canada, China, France, Greece, Hungary, Italy, Japan, Romania, South Korea, Spain, Taiwan, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
One participant randomized to Arm A (nivo+ipi) received the wrong treatment of chemo. This participant is counted in Arm A for baseline and efficacy analyses (analyses based on the randomized population) and is counted in Arm B (chemo) for exposure and safety analyses (based on the treated population). This participant was randomized prior to Revised Protocol 02 and is not included in the All Treated Participants from the Concurrently Randomized Arms B and C population.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Nivo 3 mg/kg + Ipi 1 mg/kg Participants received nivolumab 3 mg/kg IV over 30 minutes every 2 weeks for up to 3 doses (ie, 6 weeks of treatment; each cycle is 14 days). In Cycle 1 Day 1 only, nivolumab will be followed by a single dose of ipilimumab 1 mg/kg IV over 30 minutes.
Following definitive surgery, participants could receive up to 4 cycles of adjuvant chemotherapy and/or radiation at the discretion of the investigator. | 113 |
| Arm B: Platinum Doublet Chemo Participants receive investigator-choice of platinum doublet chemotherapy regimens in 3-week cycles up to a maximum of 3 cycles of IV chemotherapy (ie, 9 weeks of treatment; each cycle is 21 days).
Following definitive surgery, participants could receive up to 4 cycles of adjuvant chemotherapy and/or radiation at the discretion of the investigator. | 213 |
| Arm C: Nivo 360 mg + Platinum Doublet Chemo Participants receive nivolumab 360 mg IV + platinum doublet chemotherapy in 3-week cycles up to a maximum of 3 cycles of IV chemotherapy (ie, 9 weeks of treatment; each cycle is 21 days).
Following definitive surgery, participants could receive up to 4 cycles of adjuvant chemotherapy and/or radiation at the discretion of the investigator. | 179 |
| Total | 505 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Neoadjuvant Treatment Period | Adverse event unrelated to study treatment | 0 | 3 | 0 |
| Neoadjuvant Treatment Period | Death | 1 | 0 | 0 |
| Neoadjuvant Treatment Period | Disease progression | 3 | 2 | 1 |
| Neoadjuvant Treatment Period | Participant no longer meets study criteria | 0 | 1 | 0 |
| Neoadjuvant Treatment Period | Participant request to discontinue study treatment | 0 | 7 | 0 |
| Neoadjuvant Treatment Period | Participant withdrew consent | 0 | 4 | 0 |
| Neoadjuvant Treatment Period | Study drug toxicity | 6 | 14 | 10 |
| Randomization Period | Adverse event unrelated to study drug | 0 | 0 | 1 |
| Randomization Period | Participant no longer meets study criteria | 1 | 3 | 2 |
| Randomization Period | Participant withdrew consent | 0 | 3 | 0 |
| Systemic Adjuvant Treatment Period | Adverse event unrelated to study drug | 1 | 0 | 1 |
| Systemic Adjuvant Treatment Period | Disease progression | 1 | 0 | 0 |
| Systemic Adjuvant Treatment Period | Other reasons | 0 | 0 | 1 |
| Systemic Adjuvant Treatment Period | Participant request to discontinue treatment | 3 | 1 | 1 |
| Systemic Adjuvant Treatment Period | Study drug toxicity | 4 | 5 | 1 |
Baseline characteristics
| Characteristic | Arm A: Nivo 3 mg/kg + Ipi 1 mg/kg | Arm B: Platinum Doublet Chemo | Arm C: Nivo 360 mg + Platinum Doublet Chemo | Total |
|---|---|---|---|---|
| Age, Customized < 65 | 62 Participants | 99 Participants | 93 Participants | 254 Participants |
| Age, Customized >= 65 AND < 75 | 40 Participants | 96 Participants | 75 Participants | 211 Participants |
| Age, Customized >= 75 AND < 85 | 11 Participants | 17 Participants | 11 Participants | 39 Participants |
| Age, Customized >= 85 | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 0 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants | 105 Participants | 100 Participants | 258 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 58 Participants | 103 Participants | 79 Participants | 240 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 41 Participants | 96 Participants | 86 Participants | 223 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 4 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 4 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) White | 64 Participants | 108 Participants | 89 Participants | 261 Participants |
| Sex: Female, Male Female | 40 Participants | 65 Participants | 51 Participants | 156 Participants |
| Sex: Female, Male Male | 73 Participants | 148 Participants | 128 Participants | 349 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 46 / 112 | 105 / 214 | 66 / 179 |
| other Total, other adverse events | 102 / 111 | 202 / 208 | 160 / 176 |
| serious Total, serious adverse events | 30 / 111 | 58 / 208 | 53 / 176 |
Outcome results
Primary
Event-Free Survival (EFS)
Event-free survival (EFS) is defined as the length of time from randomization to any of the following events: any progression of disease precluding surgery, progression or recurrence disease based on blinded independent central review (BICR) assessment per response evaluation criteria in solid tumors (RECIST) 1.1 after surgery, or death due to any cause. Participants who don't undergo surgery for reason other than progression will be considered to have an event at progression or death. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: From randomization to disease progression, reoccurrence, or death due to any cause. (Up to a median of 30 months)
Population: All concurrently randomized participants in Arm C and Arm B
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B: Platinum Doublet Chemo | Event-Free Survival (EFS) | 20.80 Months |
| Arm C: Nivo 360 mg + Platinum Doublet Chemo | Event-Free Survival (EFS) | 31.57 Months |
p-value: 0.005297.38% CI: [0.43, 0.91]Log Rank
Primary
Pathologic Complete Response (pCR) Rate
Pathologic complete response (pCR) rate is defined as the number of randomized participants with absence of residual tumor in lung and lymph nodes as evaluated by blinded independent pathological review (BIPR).
Time frame: From randomization up to a median of 30 months after randomization.
Population: All concurrently randomized participants in Arm C and Arm B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm B: Platinum Doublet Chemo | Pathologic Complete Response (pCR) Rate | 4 Participants |
| Arm C: Nivo 360 mg + Platinum Doublet Chemo | Pathologic Complete Response (pCR) Rate | 43 Participants |
99% CI: [13, 30.3]
p-value: <0.000199% CI: [3.49, 55.75]Cochran-Mantel-Haenszel
Secondary
Major Pathologic Response (MPR) Rate
Major pathologic response (MPR) rate is defined as number of randomized participants with \</= 10% residual tumor in lung and lymph nodes as evaluated by blinded independent pathological review (BIPR). Viable tumors in situ carcinoma should not be included in MPR calculation.
Time frame: From randomization up to a median of 30 months after randomization.
Population: All concurrently randomized participants in Arm C and Arm B
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm B: Platinum Doublet Chemo | Major Pathologic Response (MPR) Rate | 16 Participants |
| Arm C: Nivo 360 mg + Platinum Doublet Chemo | Major Pathologic Response (MPR) Rate | 66 Participants |
95% CI: [19.6, 36.1]
95% CI: [3.16, 10.26]
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the time between the date of randomization and the date of death. OS will be censored on the last date a participant was known to be alive.
Time frame: From randomization to the date of death (Up to approximately 93 months)
Population: All concurrently randomized participants in Arm C and Arm B
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B: Platinum Doublet Chemo | Overall Survival (OS) | 73.72 Months |
| Arm C: Nivo 360 mg + Platinum Doublet Chemo | Overall Survival (OS) | NA Months |
Secondary
Time to Death or Distant Metastases (TTDM)
TTDM is defined as the time between the date of randomization and the first date of distant metastasis or the date of death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is outside of the thorax using blinded independent central review (BICR) according to response evaluation criteria in solid tumors (RECIST) 1.1. Patients who have not developed distant metastasis or died at the time of analysis will be censored on the date of their last evaluable tumor assessment.
Time frame: From randomization to the first date of distant metastasis or the date of death in the absence of distant metastasis (Up to approximately 84 months)
Population: All concurrently randomized participants in Arm C and Arm B
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B: Platinum Doublet Chemo | Time to Death or Distant Metastases (TTDM) | 36.76 Months |
| Arm C: Nivo 360 mg + Platinum Doublet Chemo | Time to Death or Distant Metastases (TTDM) | 64.66 Months |
95% CI: [0.49, 0.9]
Post Hoc
Event-Free Survival (EFS)
Event-free survival (EFS) is defined as the length of time from randomization to any of the following events: any progression of disease precluding surgery, progression or recurrence disease based on blinded independent central review (BICR) assessment per response evaluation criteria in solid tumors (RECIST) 1.1 after surgery, or death due to any cause. Participants who don't undergo surgery for reason other than progression will be considered to have an event at progression or death. Progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: From randomization to disease progression, reoccurrence, or death due to any cause. (Up to a median of 69 months)
Population: All concurrently randomized participants in Arm C and Arm B
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B: Platinum Doublet Chemo | Event-Free Survival (EFS) | 21.06 Months |
| Arm C: Nivo 360 mg + Platinum Doublet Chemo | Event-Free Survival (EFS) | 59.60 Months |
95% CI: [0.51, 0.91]