A Phase 1/2 interventional study of Nivolumab and Ipilimumab in Melanoma, sponsored by Hoffmann-La Roche. Completed at 14 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-07-18.
Sponsored by Hoffmann-La Roche · Phase 1/2, Interventional, and Treatment
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.
3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.
This study's enrollment of 110 is above the median of 38 across 2,351 interventional studies indexed under Melanoma.
Browse Melanoma studies →Hoffmann-La Roche is the lead sponsor of 2,061 studies on the registry; 85 are open to participants now.
Of its 319 completed or terminated interventional studies of FDA-regulated products, 239 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Inclusion Criteria for Cohort 1:
Exclusion Criteria for Cohort 1:
Inclusion Criteria for Cohort 2:
Exclusion Criteria for Cohort 2:
Cohort 1 participants in the nivolumab plus ipilimumab arm will receive treatment for 2 cycles (6 weeks) on Day 1 of each cycle (cycle length 21 days) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.
Drug: Nivolumab · Drug: Ipilimumab
Cohort 1 participants in the RO7247669 arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.
Drug: RO7247669 2100 mg
Cohort 1 participants in the atezolizumab plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.
Drug: Atezolizumab · Drug: Tiragolumab
Cohort 1 participants in the RO7247669 plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.
Drug: RO7247669 2100 mg · Drug: Tiragolumab
Cohort 2 participants in RO7247669 plus tiragolumab arm will receive treatment 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.
Drug: RO7247669 2100 mg · Drug: Tiragolumab
Cohort 1 participants in the RO7247669 arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.
Drug: RO7247669 600 mg
Cohort 1 participants in the RO7247669 plus tiragolumab arm will receive treatment for 2 cycles (6 weeks) until surgery, or until unacceptable toxicity or loss of clinical benefit, whichever occurs first.
Drug: Tiragolumab · Drug: RO7247669 600 mg
Nivolumab will be administered at a dose of 3 mg/kg IV on Day 1 of each 21 day cycle.
Ipilimumab will be administered at a dose of 1 mg/kg by IV on Day 1 of each 21 day cycle.
RO7247669 will be administered at a dose of 2100 mg by IV infusion on Day 1 of each 21 day cycle.
Atezolizumab will be administered at a dose of 1200 mg IV on Day 1 of each 21 day cycle.
Also known as: Tecentriq, RO5541267
Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle.
Also known as: RO7092284
RO7247669 will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.
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)
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
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)
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)
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)
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)
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)
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)
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)
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
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
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)
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)
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)
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
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)
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
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)
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.
| Milestone | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|---|---|---|---|
| Started | 22 | 40 | 20 | 20 | 8 |
| Completed | 0 | 0 | 0 | 0 | 0 |
| Not completed | 22 | 40 | 20 | 20 | 8 |
| Withdrew: Study terminated by sponsor | 21 | 38 | 17 | 18 | 0 |
| Withdrew: Withdrawal by subject | 0 | 1 | 1 | 1 | 1 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 0 | 2 |
| Withdrew: Death | 1 | 1 | 2 | 1 | 5 |
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.
| percentage of participants | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review | 77.3 (54.63 to 92.18) | 80.0 (64.35 to 90.95) | 45.0 (23.06 to 68.47) | 60.0 (36.05 to 80.88) |
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.
| percentage of participants | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|
| Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator | 0 (0 to 36.94) |
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.
| percentage of participants | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| pRR for Cohort 1 as Determined by Local Pathologic Assessment | 81.8 (59.72 to 94.81) | 75.0 (58.80 to 87.31) | 50.0 (27.20 to 72.80) | 60.0 (36.05 to 80.88) |
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.
| months | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| Event-free Survival (EFS) for Cohort 1 | 19.55 (19.55 to NA) | NA (14.09 to NA) | 22.51 (6.08 to NA) | NA (6.51 to NA) |
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.
| months | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| Relapse-free Survival (RFS) for Cohort 1 | 17.91 (17.91 to NA) | 17.08 (11.79 to NA) | 20.90 (4.40 to NA) | NA (NA to NA) |
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.
| months | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| Overall Survival (OS) for Cohort 1 | NA (NA to NA) | NA (NA to NA) | NA (NA to NA) | NA (NA to NA) |
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.
| percentage of participants | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| ORR for Cohort 1 | 59.1 (36.35 to 79.29) | 37.5 (22.73 to 54.20) | 35.0 (15.39 to 59.22) | 60.0 (36.05 to 80.88) |
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.
| Participants | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| AE, Any Grade | 19 | 36 | 19 | 18 |
| Worst Grade, Grade 1 AE | 4 | 13 | 9 | 4 |
| Worst Grade, Grade 2 AE | 9 | 15 | 9 | 8 |
| Worst Grade, Grade 3 AE | 4 | 5 | 1 | 6 |
| Worst Grade, Grade 4 AE | 2 | 3 | 0 | 0 |
| Worst Grade, Grade 5 AE | 0 | 0 | 0 | 0 |
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.
| Participants | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1 | 5 | 1 | 0 | 3 |
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.
| percentage of participants | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| Rate of Delayed Surgery Due to Treatment-related AEs | 13.6 | 2.5 | 0 | 5.0 |
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.
| weeks | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| Duration of Surgery Delay Due to Treatment-related AEs | 17.0 ± 14.8 | 5.1 ± NA | — | 3.0 ± NA |
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.
| percentage of participants | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab |
|---|---|---|---|---|
| Treatment Discontinuation Visit: Grade 0 | 0 | 0 | 5.55 | 5.26 |
| Treatment Discontinuation Visit: Grade I | 18.18 | 5.26 | 22.22 | 0 |
| Treatment Discontinuation Visit: Grade II | 13.63 | 18.42 | 16.66 | 10.52 |
| Treatment Discontinuation Visit: Grade IIIa | 0 | 7.89 | 0 | 5.26 |
| Treatment Discontinuation Visit: Grade IIIb | 0 | 2.63 | 0 | 10.52 |
| Treatment Discontinuation Visit: Grade IVa | 0 | 2.63 | 0 | 0 |
| Long-term Follow-up Month 6: Grade 0 | 0 | 0 | 5.88 | 0 |
| Long-term Follow-up Month 6: Grade I | 13.63 | 8.11 | 17.64 | 0 |
| Long-term Follow-up Month 6: Grade II | 4.54 | 10.81 | 5.88 | 0 |
| Long-term Follow-up Month 6: Grade IIIa | 0 | 13.51 | 5.88 | 0 |
| Long-term Follow-up Month 6: Grade IIIb | 0 | 0 | 0 | 11.76 |
| Long-term Follow-up Month 6: Grade IVa | 0 | 2.7 | 0 | 0 |
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.
| months | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|
| Progression-Free Survival (PFS) for Cohort 2 | 2.07 (1.68 to 2.37) |
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.
| months | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|
| OS for Cohort 2 | 8.94 (4.17 to NA) |
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.
| percentage of participants | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|
| 3 months | 100.0 (100.0 to 100.0) |
| 6 months | 71.43 (37.96 to 100.0) |
| 12 months | 47.62 (3.47 to 91.77) |
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.
No measurements were reported for this outcome.
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.
| percentage of participants | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|
| Disease Control Rate (DCR) for Cohort 2 | 0 (0.00 to 36.94) |
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.
| Participants | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|
| AE, Any Grade | 7 |
| Worst Grade, Grade 1 AE | 0 |
| Worst Grade, Grade 2 AE | 6 |
| Worst Grade, Grade 3 AE | 1 |
| Worst Grade, Grade 4 AE | 0 |
| Worst Grade, Grade 5 AE | 0 |
Collected over 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 for Cohort 1 and 10 months for Cohort 2); All-cause Mortality: Randomization up to the end of long-term follow-up (Up to approximately 25 months for Cohort 1 and 24.2 months for Cohort 2). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Cohort 1: Nivolumab + Ipilimumab (Control) | 1/22 (4.5%) | 4/22 (18.2%) | 18/22 (81.8%) |
| Cohort 1: Tobemstomig 2100 mg | 1/40 (2.5%) | 9/40 (22.5%) | 34/40 (85%) |
| Cohort 1: Atezolizumab + Tiragolumab | 2/20 (10%) | 3/20 (15%) | 18/20 (90%) |
| Cohort 1: Tobemstomig + Tiragolumab | 1/20 (5%) | 6/20 (30%) | 18/20 (90%) |
| Cohort 2: Tobemstomig + Tiragolumab | 5/8 (62.5%) | 1/8 (12.5%) | 7/8 (87.5%) |
| Event | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|---|---|---|---|
| EnteritisGastrointestinal disorders | 0/22 | 0/40 | 0/20 | 0/20 | 1/8 |
| MyocarditisCardiac disorders | 0/22 | 0/40 | 0/20 | 1/20 | 0/8 |
| CellulitisInfections and infestations | 1/22 | 1/40 | 0/20 | 1/20 | 0/8 |
| Postoperative wound infectionInfections and infestations | 0/22 | 0/40 | 1/20 | 0/20 | 0/8 |
| Infusion related reactionInjury, poisoning and procedural complications | 0/22 | 0/40 | 0/20 | 1/20 | 0/8 |
| Wound dehiscenceInjury, poisoning and procedural complications | 1/22 | 1/40 | 0/20 | 1/20 | 0/8 |
| Troponin increasedInvestigations | 0/22 | 0/40 | 1/20 | 0/20 | 0/8 |
| Diabetic ketoacidosisMetabolism and nutrition disorders | 0/22 | 0/40 | 0/20 | 1/20 | 0/8 |
| PneumonitisRespiratory, thoracic and mediastinal disorders | 1/22 | 0/40 | 1/20 | 0/20 | 0/8 |
| HaematomaVascular disorders | 0/22 | 0/40 | 0/20 | 1/20 | 0/8 |
| Event | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab | Cohort 2: Tobemstomig + Tiragolumab |
|---|---|---|---|---|---|
| FatigueGeneral disorders | 7/22 | 15/40 | 3/20 | 6/20 | 4/8 |
| DiarrhoeaGastrointestinal disorders | 2/22 | 3/40 | 1/20 | 3/20 | 3/8 |
| PruritusSkin and subcutaneous tissue disorders | 8/22 | 6/40 | 2/20 | 5/20 | 2/8 |
| HyperthyroidismEndocrine disorders | 4/22 | 7/40 | 3/20 | 6/20 | 1/8 |
| RashSkin and subcutaneous tissue disorders | 6/22 | 7/40 | 1/20 | 3/20 | 2/8 |
| AnaemiaBlood and lymphatic system disorders | 1/22 | 2/40 | 0/20 | 0/20 | 2/8 |
| Abdominal painGastrointestinal disorders | 1/22 | 1/40 | 0/20 | 0/20 | 2/8 |
| PyrexiaGeneral disorders | 1/22 | 0/40 | 2/20 | 1/20 | 2/8 |
| COVID-19Infections and infestations | 1/22 | 0/40 | 0/20 | 1/20 | 2/8 |
| HeadacheNervous system disorders | 2/22 | 1/40 | 0/20 | 1/20 | 2/8 |
Intent-to-treat (ITT) population included all participants who were enrolled in the study.
| Age, Continuous(years) | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab | Cohort 2: Tobemstomig + Tiragolumab | Total |
|---|---|---|---|---|---|---|
| Mean | 55.05 ± 16.03 | 64.10 ± 10.97 | 58.90 ± 14.10 | 59.15 ± 10.69 | 52.63 ± 14.22 | 59.6 ± 13.3 |
| Sex: Female, Male(Participants) | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab | Cohort 2: Tobemstomig + Tiragolumab | Total |
|---|---|---|---|---|---|---|
| Female | 11 | 9 | 8 | 6 | 3 | 37 |
| Male | 11 | 31 | 12 | 14 | 5 | 73 |
| Ethnicity (NIH/OMB)(Participants) | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab | Cohort 2: Tobemstomig + Tiragolumab | Total |
|---|---|---|---|---|---|---|
| Hispanic or Latino | 1 | 0 | 0 | 0 | 0 | 1 |
| Not Hispanic or Latino | 13 | 29 | 10 | 16 | 8 | 76 |
| Unknown or Not Reported | 8 | 11 | 10 | 4 | 0 | 33 |
| Race (NIH/OMB)(Participants) | Cohort 1: Nivolumab + Ipilimumab (Control) | Cohort 1: Tobemstomig 2100 mg | Cohort 1: Atezolizumab + Tiragolumab | Cohort 1: Tobemstomig + Tiragolumab | Cohort 2: Tobemstomig + Tiragolumab | Total |
|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 | 1 | 0 | 1 |
| White | 15 | 35 | 14 | 14 | 8 | 86 |
| More than one race | 0 | 0 | 0 | 0 | 0 | 0 |
| Unknown or Not Reported | 7 | 5 | 6 | 4 | 0 | 22 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here ( https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research\_and\_development/who\_we\_are\_how\_we\_work/clinical\_trials/our\_commitment\_to\_data\_sharing.htm).
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