Melanoma
Conditions
Brief summary
This study will evaluate the efficacy, safety, and pharmacokinetics of treatment combinations in cancer immunotherapy (CIT)-naive participants with resectable Stage III melanoma (Cohort 1) and in participants with Stage IV melanoma (Cohort 2). The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, and modify the participant population.
Interventions
DRUGNivolumab
Nivolumab will be administered at a dose of 3 mg/kg IV on Day 1 of each 21 day cycle.
DRUGIpilimumab
Ipilimumab will be administered at a dose of 1 mg/kg by IV on Day 1 of each 21 day cycle.
DRUGRO7247669 2100 mg
RO7247669 will be administered at a dose of 2100 mg by IV infusion on Day 1 of each 21 day cycle.
DRUGAtezolizumab
Atezolizumab will be administered at a dose of 1200 mg IV on Day 1 of each 21 day cycle.
DRUGTiragolumab
Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle.
DRUGRO7247669 600 mg
RO7247669 will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.
Sponsors
Hoffmann-La Roche
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
for Cohort 1: * ECOG performance status (PS) of 0 or 1 * Histologically confirmed resectable Stage III melanoma according to AJCC-8 and no history of in-transit metastases within the last 6 months * Fit and planned for CLND * Measurable disease according to RECIST v1.1 * Availability of a representative tumor specimen * Adequate hematologic and end-organ function * For patients receiving therapeutic anticoagulation: stable anticoagulant regimen * Negative HIV test, negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test, and negative hepatitis C virus (HCV) at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count \>= 200/μL, and have an undetectable viral load.
Exclusion criteria
for Cohort 1: * Mucosal, uveal and acral lentiginous melanoma * Distantly metastasized melanoma * History of in-transit metastases within the last 6 months * Prior radiotherapy * Prior immunotherapy, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, and other systemic therapy for melanoma * Treatment with investigational therapy within 28 days prior to initiation of study treatment * Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment * Prior allogeneic stem cell or solid organ transplantation * Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication, or anticipation of need for systemic immunosuppressant medication during study treatment * Active or history of autoimmune disease or immune deficiency Inclusion Criteria for Cohort 2: * ECOG PS of 0 or 1 * Life expectancy \>= 3 months, as determined by the investigator * Histologically confirmed Stage IV (metastatic) cutaneous melanoma according to AJCC-8 * Disease progression during or following at least one but no more than two lines of treatment for metastatic disease * Measurable disease according to RECIST v1.1 * Availability of a representative tumor specimen * Adequate hematologic and end-organ function * For patients receiving therapeutic anticoagulation: stable anticoagulant regimen * Negative HIV test, negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test, and negative hepatitis C virus (HCV) at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count \>= 200/μL, and have an undetectable viral load.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review | Time of surgery (scheduled at Week 7) | pRR was defined as the percentage of participants with pathologic complete response (pCR), pathologic near complete response (pnCR), and pathologic partial response (pPR) as determined by an independent pathologic review. pCR was defined as a complete absence of viable tumor cells, pnCR as \> 0 to ≤ 10% of viable tumor cells, and pPR was defined as \> 10 to ≤ 50% of viable tumor cells in the dissected lymph node. Participants with missing or no pathologic response assessment, including participants who did not proceed to complete lymph node dissection (CLND), were classified as non-responders. pRR was calculated for each arm along with 95% confidence intervals (CIs) using Clopper-Pearson method. The difference in pRR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction. |
| Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator | From randomization up to approximately 3.6 months | ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. ORR was calculated for each arm, along with 95% CIs using Clopper-Pearson method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse-free Survival (RFS) for Cohort 1 | From surgery (scheduled at Week 7) to first documented disease recurrence or death or last tumor assessment (up to 20.9 months) | RFS was defined as the time from surgery to the first documented recurrence of disease or death from any cause. Recurrent disease includes local, regional, or distant recurrence: local recurrence was defined as tumor regrowth within 2 cm of the primary lesion's tumor bed; regional recurrence as any nodal or non-nodal tumor lesions that are more than 2 cm from the primary lesion but are not beyond the regional nodal basin; distant recurrence as any non-local/non-regional recurrence. Participants without disease recurrence or death at the time of analysis were censored at the last tumor assessment. Kaplan-Meier method was used to estimate the median for RFS, and 95% CIs were constructed using the Brookmeyer and Crowley method. |
| Overall Survival (OS) for Cohort 1 | From randomization to death from any cause or last known to be alive (Up to 25 months) | OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. Kaplan-Meier method was used to estimate the median for OS, 95% CIs were constructed using the Brookmeyer and Crowley method. |
| ORR for Cohort 1 | Prior to surgery (up to Week 6) | ORR was defined as the percentage of participants with a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. ORR was calculated for each arm, along with 95% CIs using the Clopper-Pearson method. The difference in ORR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction. |
| Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | From initiation of study treatment up to 135 days (Serious AEs and AESI) or 30 days (all other AEs) after the final dose of study treatment or until initiation of new systemic anti-cancer therapy (Up to 5.6 months) | An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Severity was determined per NCI CTCAE v5.0 Grade 1: Mild; asymptomatic or mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2:Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe or medically significant, but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling or limiting self-care ADL; Grade 4: Life-threatening consequences or urgent intervention indicated; Grade 5: Death related to AE. Multiple occurrences of AEs in the same category at the worst (highest) NCIC-CTCAE grade for an individual are counted only once. |
| Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1 | From initiation of study treatment up to 135 days after the final dose of study treatment (Up to 5.6 months) | An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. Participants with immune-related adverse events Grade ≥ 3 were reported. |
| Rate of Delayed Surgery Due to Treatment-related AEs | Time of surgery (scheduled at Week 7) up to 40.1 weeks | Rate of delayed surgery due to treatment related AEs was defined as the percentage of participants for whom surgery was delayed due to treatment-related AEs for more than 2 weeks. An AE was any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of the investigational product, whether considered related to the investigational product. |
| Duration of Surgery Delay Due to Treatment-related AEs | Time of surgery (scheduled at Week 7) up to 40.1 weeks | Duration of surgery delay due to treatment related AEs was calculated on the participants for whom surgery was delayed due to treatment-related AEs for more than 2 weeks. An AE was any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of the investigational product, whether considered related to the investigational product. |
| pRR for Cohort 1 as Determined by Local Pathologic Assessment | Time of surgery ( scheduled at Week 7) | pRR was defined as the percentage of participants with pCR, pnCR, and pPR as determined by a local pathologic review. pCR was defined as a complete absence of viable tumor cells, pnCR as \> 0 to ≤ 10% of viable tumor cells, and pPR was defined as \> 10 to ≤ 50% of viable tumor cells in the dissected lymph node. Participants with missing or no pathologic response assessment, including participants who did not proceed to CLND, were classified as non-responders. pRR was calculated for each arm along with 95% CIs using Clopper-Pearson method. The difference in pRR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction. |
| Progression-Free Survival (PFS) for Cohort 2 | From randomization/enrollment to first documented disease progression or death or last tumor assessment (up to 3.6 months) | PFS after randomization/enrollment was defined as the time from randomization/enrollment to the first occurrence of disease progression or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline) and/or unequivocal progression of a non-target lesion and/or any new lesion. Participants without documented disease progression or death at the time of analysis were censored at the day of the last tumor assessment. Kaplan-Meier method was used to estimate the median for PFS, with 95% CIs constructed by using the Brookmeyer and Crowley method. |
| OS for Cohort 2 | From randomization/enrollment to death from any cause or last known to be alive (Up to 24.2 months) | OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. Kaplan-Meier method was used to estimate the median for OS, with 95% CIs constructed by using the Brookmeyer and Crowley method. |
| OS Rates at Specific Timepoints for Cohort 2 | Months 3, 6 and 12 | OS was defined as the time from randomization to death from any cause. OS rate is percentage of participants who were event free for OS. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. OS rate at specific time points were estimated using the Kaplan-Meier method, with 95% CIs calculated based on Greenwood's estimate for the variance. |
| Duration of Response (DOR) for Cohort 2 | Time from the first occurrence of a documented OR to disease progression or death from any cause (up to 3.6 months) | DOR was defined as the time from the first occurrence of a documented objective response (OR) to disease progression or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. OR was defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. CR = disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR = at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline). Participants without PD or death at time of analysis were censored at time of last tumor assessment. Kaplan-Meier method was used to estimate median for DOR, with 95% CIs constructed using Brookmeyer & Crowley method. |
| Disease Control Rate (DCR) for Cohort 2 | From randomization up to 3.6 months | DCR was defined as the percentage of participants with stable disease for ≥ 12 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Stable disease was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline). DCR was calculated for each treatment arm, with 95% CIs estimated through use of Clopper-Pearson's exact method. |
| Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2 | From initiation of study treatment up to 135 days (Serious AEs and AESI) or 30 days (all other AEs) after the final dose of study treatment or until initiation of new systemic anti-cancer therapy (Up to 10 months) | An AE=any untoward medical occurrence in clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. AE can therefore be any unfavorable & unintended sign, symptom/disease temporally associated with using an investigational product, whether or not considered related to the investigational product. Severity was determined per NCI CTCAE v5.0 Grade 1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2: Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe/medically significant, but not immediately life-threatening: hospitalization/prolongation of hospitalization indicated; disabling/limiting self-care ADL; Grade 4: Life-threatening consequences/urgent intervention indicated; Grade 5: Death related to AE. Multiple occurrences of AEs in 1 individual are counted once at highest grade. |
| Surgical Complication Rates for Cohort 1 | At treatment discontinuation visit (Week 13) and Surgery Follow-Up (6 months after surgery) | Surgical complications were scored according to the Clavien-Dindo surgical classification. Complication rates for every grade were reported and scored for participants who underwent CLND. The Surgical complications according to Clavien-Dindo can be classified into the following grades: Grade I: Any complication that does not need pharmacological treatment or surgical, endoscopic, and radiological interventions. Grade II: Complications that require pharmacological treatment with drugs or blood transfusions and total parenteral nutrition. Grade III: Complications that require surgical, endoscopic, or radiological intervention with (Grade IIIb) or without (Grade IIIa) general anesthesia. Grade IV: Life-threatening complications requiring intensive care unit (ICU) management, which may be single organ (Grade IVa) or multiorgan (Grade IVb) dysfunction. Grade V: Complications that might cause the death of a participant. Values have been rounded off to 2 decimal digits. |
| Event-free Survival (EFS) for Cohort 1 | From randomization to disease progression, disease recurrence or death or last tumor assessment (up to 22.51 months) | EFS was defined as the time from randomization to any of the following events (whichever occurs first): documented disease progression (PD) that precludes surgery, as assessed by investigator per RECIST v1.1, local, regional, or distant disease recurrence, or death from any cause. PD = as at least a 20% increase in smallest sum of diameter (SOD) of target lesions, taking as reference the smallest SOD on study (including baseline). Local recurrence was defined as tumor regrowth within 2 cm of the primary lesion's tumor bed; regional recurrence as any nodal or non-nodal tumor lesions that are \> 2 cm from the primary lesion but not beyond the regional nodal basin; distant recurrence as any non-local/non-regional recurrence. Participants without disease recurrence, progression, or death at the time of analysis were censored at the time of the last tumor assessment. Kaplan-Meier method was used to estimate the median for EFS, and 95% CIs was constructed using Brookmeyer and Crowley method. |
Countries
Australia, France, Italy, Spain, United States
Participant flow
Recruitment details
Participants took part in the study across 14 investigative sites in 5 countries: the United States, Italy, France, Spain, and Australia. The study is considered Completed because all the pre-planned study activities and analyses have been performed.
Pre-assignment details
A total of 110 participants with resectable Stage III melanoma and Stage IV melanoma took part in Cohort 1 and Cohort 2, respectively. A total of 6 treatment arms were planned in Cohort 1 and 102 participants were enrolled in only 4 arms. The study was closed before the Cohort 1 arms tobemstomig 600 milligrams (mg), and tobemstomig 600 mg + tiragolumab were opened. 8 participants were enrolled in 1 arm in Cohort 2.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) Participants received nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13. | 22 |
| Cohort 1: Tobemstomig 2100 mg Participants received a fixed dose of tobemstomig 2100 mg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13. | 40 |
| Cohort 1: Atezolizumab + Tiragolumab Participants received atezolizumab 1200 mg IV and tiragolumab 600 mg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13. | 20 |
| Cohort 1: Tobemstomig + Tiragolumab Participants received tobemstomig 2100 mg IV and tiragolumab 600 mg IV on Day 1 of each 21-day cycle for 2 cycles (6 weeks) until surgery (Week 7) or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. Post-surgery at the discretion of the investigator, participants started either adjuvant therapy or an observation phase from Week 13. | 20 |
| Cohort 2: Tobemstomig + Tiragolumab Participants received tobemstomig 2100 mg IV and tiragolumab 600 mg IV on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. | 8 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 2 | 1 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Study Terminated by Sponsor | 21 | 38 | 17 | 18 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Cohort 1: Tobemstomig + Tiragolumab | Total | Cohort 2: Tobemstomig + Tiragolumab | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab |
|---|---|---|---|---|---|---|
| Age, Continuous | 59.15 years STANDARD_DEVIATION 10.69 | 59.6 years STANDARD_DEVIATION 13.3 | 52.63 years STANDARD_DEVIATION 14.22 | 55.05 years STANDARD_DEVIATION 16.03 | 64.10 years STANDARD_DEVIATION 10.97 | 58.90 years STANDARD_DEVIATION 14.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 76 Participants | 8 Participants | 13 Participants | 29 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 33 Participants | 0 Participants | 8 Participants | 11 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 22 Participants | 0 Participants | 7 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) White | 14 Participants | 86 Participants | 8 Participants | 15 Participants | 35 Participants | 14 Participants |
| Sex: Female, Male Female | 6 Participants | 37 Participants | 3 Participants | 11 Participants | 9 Participants | 8 Participants |
| Sex: Female, Male Male | 14 Participants | 73 Participants | 5 Participants | 11 Participants | 31 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 22 | 1 / 40 | 2 / 20 | 1 / 20 | 5 / 8 |
| other Total, other adverse events | 18 / 22 | 34 / 40 | 18 / 20 | 18 / 20 | 7 / 8 |
| serious Total, serious adverse events | 4 / 22 | 9 / 40 | 3 / 20 | 6 / 20 | 1 / 8 |
Outcome results
Primary
Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator
ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. ORR was calculated for each arm, along with 95% CIs using Clopper-Pearson method.
Time frame: From randomization up to approximately 3.6 months
Population: Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator | 0 percentage of participants |
Primary
Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review
pRR was defined as the percentage of participants with pathologic complete response (pCR), pathologic near complete response (pnCR), and pathologic partial response (pPR) as determined by an independent pathologic review. pCR was defined as a complete absence of viable tumor cells, pnCR as \> 0 to ≤ 10% of viable tumor cells, and pPR was defined as \> 10 to ≤ 50% of viable tumor cells in the dissected lymph node. Participants with missing or no pathologic response assessment, including participants who did not proceed to complete lymph node dissection (CLND), were classified as non-responders. pRR was calculated for each arm along with 95% confidence intervals (CIs) using Clopper-Pearson method. The difference in pRR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.
Time frame: Time of surgery (scheduled at Week 7)
Population: Efficacy-evaluable population included all participants in Cohort 1 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review | 77.3 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review | 80.0 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review | 45.0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review | 60.0 percentage of participants |
95% CI: [-22.25, 27.7]
95% CI: [-65.01, 0.46]
95% CI: [-49.75, 15.21]
Secondary
Disease Control Rate (DCR) for Cohort 2
DCR was defined as the percentage of participants with stable disease for ≥ 12 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Stable disease was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline). DCR was calculated for each treatment arm, with 95% CIs estimated through use of Clopper-Pearson's exact method.
Time frame: From randomization up to 3.6 months
Population: Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Disease Control Rate (DCR) for Cohort 2 | 0 percentage of participants |
Secondary
Duration of Response (DOR) for Cohort 2
DOR was defined as the time from the first occurrence of a documented objective response (OR) to disease progression or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. OR was defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. CR = disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR = at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline). Participants without PD or death at time of analysis were censored at time of last tumor assessment. Kaplan-Meier method was used to estimate median for DOR, with 95% CIs constructed using Brookmeyer & Crowley method.
Time frame: Time from the first occurrence of a documented OR to disease progression or death from any cause (up to 3.6 months)
Population: Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen.~DOR was only evaluated in participants who achieved an OR (CR or PR).
Secondary
Duration of Surgery Delay Due to Treatment-related AEs
Duration of surgery delay due to treatment related AEs was calculated on the participants for whom surgery was delayed due to treatment-related AEs for more than 2 weeks. An AE was any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of the investigational product, whether considered related to the investigational product.
Time frame: Time of surgery (scheduled at Week 7) up to 40.1 weeks
Population: Safety-evaluable population included all randomized participants in Cohort 1 who received any amount of the study treatment. Participants with a surgery delay of more than 2 weeks due to treatment-related AE were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Duration of Surgery Delay Due to Treatment-related AEs | 17.0 weeks | Standard Deviation 14.8 |
| Cohort 1: Tobemstomig 2100 mg | Duration of Surgery Delay Due to Treatment-related AEs | 5.1 weeks | — |
| Cohort 1: Tobemstomig + Tiragolumab | Duration of Surgery Delay Due to Treatment-related AEs | 3.0 weeks | — |
Secondary
Event-free Survival (EFS) for Cohort 1
EFS was defined as the time from randomization to any of the following events (whichever occurs first): documented disease progression (PD) that precludes surgery, as assessed by investigator per RECIST v1.1, local, regional, or distant disease recurrence, or death from any cause. PD = as at least a 20% increase in smallest sum of diameter (SOD) of target lesions, taking as reference the smallest SOD on study (including baseline). Local recurrence was defined as tumor regrowth within 2 cm of the primary lesion's tumor bed; regional recurrence as any nodal or non-nodal tumor lesions that are \> 2 cm from the primary lesion but not beyond the regional nodal basin; distant recurrence as any non-local/non-regional recurrence. Participants without disease recurrence, progression, or death at the time of analysis were censored at the time of the last tumor assessment. Kaplan-Meier method was used to estimate the median for EFS, and 95% CIs was constructed using Brookmeyer and Crowley method.
Time frame: From randomization to disease progression, disease recurrence or death or last tumor assessment (up to 22.51 months)
Population: Efficacy-evaluable population included all participants in Cohort 1 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Event-free Survival (EFS) for Cohort 1 | 19.55 months |
| Cohort 1: Tobemstomig 2100 mg | Event-free Survival (EFS) for Cohort 1 | NA months |
| Cohort 1: Atezolizumab + Tiragolumab | Event-free Survival (EFS) for Cohort 1 | 22.51 months |
| Cohort 1: Tobemstomig + Tiragolumab | Event-free Survival (EFS) for Cohort 1 | NA months |
95% CI: [0.42, 10.42]
95% CI: [0.79, 19.7]
95% CI: [0.73, 53.7]
Secondary
Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1
An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Severity was determined per NCI CTCAE v5.0 Grade 1: Mild; asymptomatic or mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2:Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe or medically significant, but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling or limiting self-care ADL; Grade 4: Life-threatening consequences or urgent intervention indicated; Grade 5: Death related to AE. Multiple occurrences of AEs in the same category at the worst (highest) NCIC-CTCAE grade for an individual are counted only once.
Time frame: From initiation of study treatment up to 135 days (Serious AEs and AESI) or 30 days (all other AEs) after the final dose of study treatment or until initiation of new systemic anti-cancer therapy (Up to 5.6 months)
Population: Safety-evaluable population included all randomized participants in Cohort 1 who received any amount of study treatment. All AEs were reported until 30 days after final dose or until initiation of new systemic anti-cancer therapy (whichever occurs first). Serious AEs and AEs of special interest (AESIs) and treatment-related non-serious AEs that lead to surgery delay were reported until 135 days after final dose or until initiation of new systemic anti-cancer therapy (whichever occurs first).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 5 AE | 0 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 2 AE | 9 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | AE, Any Grade | 19 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 4 AE | 2 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 3 AE | 4 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 1 AE | 4 Participants |
| Cohort 1: Tobemstomig 2100 mg | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | AE, Any Grade | 36 Participants |
| Cohort 1: Tobemstomig 2100 mg | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 1 AE | 13 Participants |
| Cohort 1: Tobemstomig 2100 mg | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 2 AE | 15 Participants |
| Cohort 1: Tobemstomig 2100 mg | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 3 AE | 5 Participants |
| Cohort 1: Tobemstomig 2100 mg | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 4 AE | 3 Participants |
| Cohort 1: Tobemstomig 2100 mg | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 5 AE | 0 Participants |
| Cohort 1: Atezolizumab + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 4 AE | 0 Participants |
| Cohort 1: Atezolizumab + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 3 AE | 1 Participants |
| Cohort 1: Atezolizumab + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 1 AE | 9 Participants |
| Cohort 1: Atezolizumab + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | AE, Any Grade | 19 Participants |
| Cohort 1: Atezolizumab + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 2 AE | 9 Participants |
| Cohort 1: Atezolizumab + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 5 AE | 0 Participants |
| Cohort 1: Tobemstomig + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 2 AE | 8 Participants |
| Cohort 1: Tobemstomig + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 5 AE | 0 Participants |
| Cohort 1: Tobemstomig + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 3 AE | 6 Participants |
| Cohort 1: Tobemstomig + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 4 AE | 0 Participants |
| Cohort 1: Tobemstomig + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | Worst Grade, Grade 1 AE | 4 Participants |
| Cohort 1: Tobemstomig + Tiragolumab | Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1 | AE, Any Grade | 18 Participants |
Secondary
Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2
An AE=any untoward medical occurrence in clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. AE can therefore be any unfavorable & unintended sign, symptom/disease temporally associated with using an investigational product, whether or not considered related to the investigational product. Severity was determined per NCI CTCAE v5.0 Grade 1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2: Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe/medically significant, but not immediately life-threatening: hospitalization/prolongation of hospitalization indicated; disabling/limiting self-care ADL; Grade 4: Life-threatening consequences/urgent intervention indicated; Grade 5: Death related to AE. Multiple occurrences of AEs in 1 individual are counted once at highest grade.
Time frame: From initiation of study treatment up to 135 days (Serious AEs and AESI) or 30 days (all other AEs) after the final dose of study treatment or until initiation of new systemic anti-cancer therapy (Up to 10 months)
Population: Safety-evaluable population included all randomized participants in Cohort 2 who received any amount of the study treatment. All AEs were reported until 30 days after the final dose or until initiation of new systemic anti-cancer therapy (whichever occurs first). Serious AEs and AESIs were reported until 135 days after the final dose or until initiation of new systemic anti-cancer therapy (whichever occurs first).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2 | AE, Any Grade | 7 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2 | Worst Grade, Grade 1 AE | 0 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2 | Worst Grade, Grade 2 AE | 6 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2 | Worst Grade, Grade 4 AE | 0 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2 | Worst Grade, Grade 5 AE | 0 Participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2 | Worst Grade, Grade 3 AE | 1 Participants |
Secondary
Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1
An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. Participants with immune-related adverse events Grade ≥ 3 were reported.
Time frame: From initiation of study treatment up to 135 days after the final dose of study treatment (Up to 5.6 months)
Population: Safety-evaluable population included all randomized participants in Cohort 1 who received any amount of the study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1 | 5 Participants |
| Cohort 1: Tobemstomig 2100 mg | Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1 | 1 Participants |
| Cohort 1: Atezolizumab + Tiragolumab | Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1 | 0 Participants |
| Cohort 1: Tobemstomig + Tiragolumab | Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1 | 3 Participants |
Secondary
ORR for Cohort 1
ORR was defined as the percentage of participants with a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. ORR was calculated for each arm, along with 95% CIs using the Clopper-Pearson method. The difference in ORR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.
Time frame: Prior to surgery (up to Week 6)
Population: Efficacy-evaluable population included all participants in Cohort 1 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | ORR for Cohort 1 | 59.1 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | ORR for Cohort 1 | 37.5 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | ORR for Cohort 1 | 35.0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | ORR for Cohort 1 | 60.0 percentage of participants |
95% CI: [-50.55, 7.37]
95% CI: [-58.17, 9.99]
95% CI: [-33.58, 35.4]
Secondary
OS for Cohort 2
OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. Kaplan-Meier method was used to estimate the median for OS, with 95% CIs constructed by using the Brookmeyer and Crowley method.
Time frame: From randomization/enrollment to death from any cause or last known to be alive (Up to 24.2 months)
Population: Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | OS for Cohort 2 | 8.94 months |
Secondary
OS Rates at Specific Timepoints for Cohort 2
OS was defined as the time from randomization to death from any cause. OS rate is percentage of participants who were event free for OS. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. OS rate at specific time points were estimated using the Kaplan-Meier method, with 95% CIs calculated based on Greenwood's estimate for the variance.
Time frame: Months 3, 6 and 12
Population: Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen. Number analyzed per timepoint are unique number of participants out of all the assessed participants who remain at risk for an OS event at that timepoint. Different participants may have contributed data for each timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | OS Rates at Specific Timepoints for Cohort 2 | 3 months | 100.0 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | OS Rates at Specific Timepoints for Cohort 2 | 6 months | 71.43 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | OS Rates at Specific Timepoints for Cohort 2 | 12 months | 47.62 percentage of participants |
Secondary
Overall Survival (OS) for Cohort 1
OS was defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. Kaplan-Meier method was used to estimate the median for OS, 95% CIs were constructed using the Brookmeyer and Crowley method.
Time frame: From randomization to death from any cause or last known to be alive (Up to 25 months)
Population: Efficacy-evaluable population included all participants in Cohort 1 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Overall Survival (OS) for Cohort 1 | NA months |
| Cohort 1: Tobemstomig 2100 mg | Overall Survival (OS) for Cohort 1 | NA months |
| Cohort 1: Atezolizumab + Tiragolumab | Overall Survival (OS) for Cohort 1 | NA months |
| Cohort 1: Tobemstomig + Tiragolumab | Overall Survival (OS) for Cohort 1 | NA months |
95% CI: [0.05, 12.39]
95% CI: [0.23, 28.65]
95% CI: [0.07, 18.58]
Secondary
Progression-Free Survival (PFS) for Cohort 2
PFS after randomization/enrollment was defined as the time from randomization/enrollment to the first occurrence of disease progression or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline) and/or unequivocal progression of a non-target lesion and/or any new lesion. Participants without documented disease progression or death at the time of analysis were censored at the day of the last tumor assessment. Kaplan-Meier method was used to estimate the median for PFS, with 95% CIs constructed by using the Brookmeyer and Crowley method.
Time frame: From randomization/enrollment to first documented disease progression or death or last tumor assessment (up to 3.6 months)
Population: Efficacy-evaluable population included all participants in Cohort 2 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Progression-Free Survival (PFS) for Cohort 2 | 2.07 months |
Secondary
pRR for Cohort 1 as Determined by Local Pathologic Assessment
pRR was defined as the percentage of participants with pCR, pnCR, and pPR as determined by a local pathologic review. pCR was defined as a complete absence of viable tumor cells, pnCR as \> 0 to ≤ 10% of viable tumor cells, and pPR was defined as \> 10 to ≤ 50% of viable tumor cells in the dissected lymph node. Participants with missing or no pathologic response assessment, including participants who did not proceed to CLND, were classified as non-responders. pRR was calculated for each arm along with 95% CIs using Clopper-Pearson method. The difference in pRR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.
Time frame: Time of surgery ( scheduled at Week 7)
Population: Efficacy-evaluable population included all participants in Cohort 1 who received at least one dose of each drug for their assigned treatment regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | pRR for Cohort 1 as Determined by Local Pathologic Assessment | 81.8 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | pRR for Cohort 1 as Determined by Local Pathologic Assessment | 75.0 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | pRR for Cohort 1 as Determined by Local Pathologic Assessment | 50.0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | pRR for Cohort 1 as Determined by Local Pathologic Assessment | 60.0 percentage of participants |
95% CI: [-31.31, 17.68]
95% CI: [-63.79, 0.16]
95% CI: [-53.44, 9.8]
Secondary
Rate of Delayed Surgery Due to Treatment-related AEs
Rate of delayed surgery due to treatment related AEs was defined as the percentage of participants for whom surgery was delayed due to treatment-related AEs for more than 2 weeks. An AE was any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of the investigational product, whether considered related to the investigational product.
Time frame: Time of surgery (scheduled at Week 7) up to 40.1 weeks
Population: Safety-evaluable population included all randomized participants in Cohort 1 who received any amount of the study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Rate of Delayed Surgery Due to Treatment-related AEs | 13.6 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Rate of Delayed Surgery Due to Treatment-related AEs | 2.5 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Rate of Delayed Surgery Due to Treatment-related AEs | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Rate of Delayed Surgery Due to Treatment-related AEs | 5.0 percentage of participants |
Secondary
Relapse-free Survival (RFS) for Cohort 1
RFS was defined as the time from surgery to the first documented recurrence of disease or death from any cause. Recurrent disease includes local, regional, or distant recurrence: local recurrence was defined as tumor regrowth within 2 cm of the primary lesion's tumor bed; regional recurrence as any nodal or non-nodal tumor lesions that are more than 2 cm from the primary lesion but are not beyond the regional nodal basin; distant recurrence as any non-local/non-regional recurrence. Participants without disease recurrence or death at the time of analysis were censored at the last tumor assessment. Kaplan-Meier method was used to estimate the median for RFS, and 95% CIs were constructed using the Brookmeyer and Crowley method.
Time frame: From surgery (scheduled at Week 7) to first documented disease recurrence or death or last tumor assessment (up to 20.9 months)
Population: Adjuvant evaluable population included participants in Cohort 1 who had completed surgery (CLND).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Relapse-free Survival (RFS) for Cohort 1 | 17.91 months |
| Cohort 1: Tobemstomig 2100 mg | Relapse-free Survival (RFS) for Cohort 1 | 17.08 months |
| Cohort 1: Atezolizumab + Tiragolumab | Relapse-free Survival (RFS) for Cohort 1 | 20.90 months |
| Cohort 1: Tobemstomig + Tiragolumab | Relapse-free Survival (RFS) for Cohort 1 | NA months |
95% CI: [0.25, 7.75]
95% CI: [0.35, 12.62]
95% CI: [0.22, 26.32]
Secondary
Surgical Complication Rates for Cohort 1
Surgical complications were scored according to the Clavien-Dindo surgical classification. Complication rates for every grade were reported and scored for participants who underwent CLND. The Surgical complications according to Clavien-Dindo can be classified into the following grades: Grade I: Any complication that does not need pharmacological treatment or surgical, endoscopic, and radiological interventions. Grade II: Complications that require pharmacological treatment with drugs or blood transfusions and total parenteral nutrition. Grade III: Complications that require surgical, endoscopic, or radiological intervention with (Grade IIIb) or without (Grade IIIa) general anesthesia. Grade IV: Life-threatening complications requiring intensive care unit (ICU) management, which may be single organ (Grade IVa) or multiorgan (Grade IVb) dysfunction. Grade V: Complications that might cause the death of a participant. Values have been rounded off to 2 decimal digits.
Time frame: At treatment discontinuation visit (Week 13) and Surgery Follow-Up (6 months after surgery)
Population: Safety-evaluable population included all randomized participants in Cohort 1 who received any amount of the study treatment. Overall number analyzed is the number of participants who underwent surgery. Number analyzed is the number of participants with surgical complication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IIIb | 0 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade II | 13.63 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade I | 13.63 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IIIb | 0 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade 0 | 0 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade 0 | 0 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade II | 4.54 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IVa | 0 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IIIa | 0 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade I | 18.18 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IIIa | 0 percentage of participants |
| Cohort 1: Nivolumab + Ipilimumab (Control) | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IVa | 0 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IIIa | 13.51 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade 0 | 0 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IIIb | 0 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IVa | 2.63 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IVa | 2.7 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade II | 18.42 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade 0 | 0 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IIIb | 2.63 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade I | 8.11 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IIIa | 7.89 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade I | 5.26 percentage of participants |
| Cohort 1: Tobemstomig 2100 mg | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade II | 10.81 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade 0 | 5.88 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IIIb | 0 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IVa | 0 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade I | 22.22 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade I | 17.64 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade II | 5.88 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IIIa | 5.88 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IIIb | 0 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade 0 | 5.55 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade II | 16.66 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IIIa | 0 percentage of participants |
| Cohort 1: Atezolizumab + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IVa | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade II | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade I | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade I | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade 0 | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IVa | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IVa | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade II | 10.52 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IIIb | 10.52 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IIIb | 11.76 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Long-term Follow-up Month 6: Grade IIIa | 0 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade IIIa | 5.26 percentage of participants |
| Cohort 1: Tobemstomig + Tiragolumab | Surgical Complication Rates for Cohort 1 | Treatment Discontinuation Visit: Grade 0 | 5.26 percentage of participants |