Trial Outcomes & Findings for A Study of Lomvastomig (RO7121661) and Tobemstomig (RO7247669) Compared With Nivolumab in Participants With Advanced or Metastatic Squamous Cell Carcinoma of the Esophagus (NCT NCT04785820)

A total of 190 participants with advanced or metastatic esophageal squamous-cell carcinoma (ESCC) refractory or intolerant to fluoropyrimidine- or taxane- and platinum-based regimen took part in the study at 81 investigative sites across 21 countries from 25 June 2021 to 30 January 2025.

Participants were randomized in a 1:1:1 ratio to receive nivolumab, tobemstomig (RO7247669), or lomvastomig (RO7121661). From Protocol Version 3 onwards, recruitment into the lomvastomig arm was stopped and participants were randomized in a 1:1 ratio to receive either nivolumab or tobemstomig. Two participants did not receive any study treatment and were excluded from the safety analysis.

A Study of Lomvastomig (RO7121661) and Tobemstomig (RO7247669) Compared With Nivolumab in Participants With Advanced or Metastatic Squamous Cell Carcinoma of the Esophagus

OS was defined as the time from randomization to death from any cause. Kaplan-Meier (K-M) method was used to estimate median OS. 80% confidence interval (CI) for median was computed using the method of Brookmeyer and Crowley. IxRS=Interactive response system.

An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

ORR was defined as the percentage of participants who have achieved an objective response (OR), characterized by a complete response (CR) or partial response (PR), as per response evaluation criteria in solid tumors version 1.1 (RECIST v1.1). CR was defined as disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. 80% CI for rates were constructed using the Clopper-Pearson method. Percentages have been rounded off.

DCR was defined as ORR plus stable disease rate (SDR). ORR was defined as the percentage of participants who have achieved an OR, characterized by a CR or PR as per RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for 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 sum on study including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm and unequivocal progression of existing non-target lesions. 80% CI for rates were constructed using the Clopper-Pearson method. Percentages have been rounded off.

DoR for participants with ORR was defined as time from first occurrence of a documented OR to PD as per RECIST v1.1 or death from any cause, whichever occurs first. ORR was defined as the percentage of participants who have achieved an OR, chaacterized by a CR or PR as per RECIST v1.1. CR was defined as disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of target lesions, taking as reference the baseline SOD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm and unequivocal progression of existing non-target lesions. K-M method was used to estimate median DOR. 80% CI for median was computed using the method of Brookmeyer and Crowley.

PFS was defined as the time from randomization to the first occurrence of PD, as determined per RECIST v1.1, or death during the treatment period, or within 60 days of the last tumor assessment after treatment discontinuation from any cause, whichever occurs first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest sum on study including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm and unequivocal progression of existing non-target lesions. K-M method was used to estimate median PFS. 80% CI for median was computed using the method of Brookmeyer and Crowley.

EORTC QLQ-C30 is a cancer-specific instrument consisting of 30 questions to evaluate 5 aspects of participant functioning (physical, emotional, role, cognitive, \& social), 3 symptom scales (fatigue, nausea, vomiting, \& pain), global health status (GHS)/quality of life (QoL), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea \& financial difficulties). Functioning \& symptom items were scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. The GHS/QoL questions were scored on a 7-point scale with scores ranging from 1=Very poor to 7=Excellent. All EORTC scales \& single-item measures were linearly transformed to a score range of 0-100. High score for a functioning/GHS scale=high/healthy level of functioning/better HRQoL; however, high score for a symptom scale=high level of symptom severity. Clinically significant improvement=an increase of at least 10 points from baseline in GHS/QoL, emotional and social functioning.

EORTC QLQ-IL97, a reduced version of the QLQ-C30, is a cancer-specific instrument consisting of 17 questions to evaluate two aspects of participant functioning (emotional and social), GHS/QoL, and six symptoms (fatigue, nausea, vomiting, pain, appetite loss, \& diarrhoea), with a recall period of the previous week. The scoring for the IL97 followed the same pattern as the QLQ-C30. Functioning \& symptom items were scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. The GHS/QoL questions were scored on a 7-point scale with scores ranging from 1=Very poor to 7=Excellent. Scores were linearly transformed to a range of 0-100. High score for a functioning/GHS scale=high/healthy level of functioning/better HRQoL; however, high score for a symptom scale=high level of symptom severity. Clinically significant improvement=an increase of at least 10 points from baseline in GHS/QoL, emotional and social functioning.

EORTC QLQ-OES18, a modular supplement to the EORTC QLQ-C30, is a cancer-specific instrument, consisting of 4 multiple-item scales (dysphagia, eating, reflux, and pain) and 6 single items (trouble swallowing saliva, choked when swallowing, dry mouth, trouble with taste, trouble with coughing, and trouble talking), with a recall period of the previous week. The scoring for the OES18 followed the same pattern as the QLQ-C30. Each symptom item was scored on a 4-point scale: 1=Not at all, 2=A little, 3=Quite a bit, 4=Very much. Scores were linearly transformed to a range of 0-100, with a high score reflecting a high level of symptom severity. Clinically significant improvement=an increase of at least 10 points from baseline in GHS/QoL, emotional and social functioning.

day\*µg/mL=days-micrograms per milliliter.

Participants were considered to be ADA positive if they were ADA negative at baseline but developed an ADA response following nivolumab administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 0.60 titer unit (t.u.) greater than the baseline titer result (treatment-enhanced ADA response).

Participants were considered to be ADA positive if they were ADA negative at baseline but developed an ADA response following lomvastomig administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 0.60 t.u. greater than the baseline titer result (treatment-enhanced ADA response).

Participants were considered to be ADA positive if they were ADA negative at baseline but developed an ADA response following tobemstomig administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was greater than the titer of the baseline sample by a scientifically reasonable margin such as at least 0.60 t.u. greater than the baseline titer result (treatment-enhanced ADA response).

Biomarker analyses were performed on peripheral blood samples collected from participants and assessed by flow cytometry. Zeros are present when no valid samples for PD assessments were collected/available at the respective visits. As the number of participants in the lomvastomig arm was more limited, chances to observe zeros are higher in this arm vs the other arms.

Biomarker analyses were performed on peripheral blood samples collected from participants and assessed by flow cytometry. Zeros are present when no valid samples for PD assessments were collected/available at the respective visits. As the number of participants in the lomvastomig arm was more limited, chances to observe zeros are higher in this arm vs the other arms.

CD8 T-cell infiltration, poliferation (CD8A+ Ki67+) expression in the tumor microenvironment at baseline, was assessed from previously collected tumour samples (archival samples). For participants without an available archival tumor sample, a fresh tumor sample was collected during the screening. Both archival and screening samples were considered baseline samples to assess biomarkers within the tumor microenvironment.

Anti-PDL1 expression in the tumor microenvironment at baseline, was assessed from previously collected tumour samples (archival samples). For participants without an available archival tumor sample, a fresh tumor sample was collected during the screening. Both archival and screening samples were considered as baseline samples to assess biomarkers within the tumor microenvironment.

CD8A+ Anti-PD1+ expression in the tumor microenvironment at baseline, was assessed from previously collected tumour samples (archival samples). For participants without an available archival tumor sample, a fresh tumor sample was collected during the screening. Both archival and screening samples were considered as baseline samples to assess biomarkers within the tumor microenvironment.

CD8A+ TIM3+ expression in the tumor microenvironment at baseline, was assessed from previously collected tumour samples (archival samples). For participants without an available archival tumor sample, a fresh tumor sample was collected during the screening. Both archival and screening samples were considered as baseline samples to assess biomarkers within the tumor microenvironment.

CD8A+ LAG3+ expression in the tumor microenvironment at baseline, was assessed from previously collected tumour samples (archival samples). For participants without an available archival tumor sample, a fresh tumor sample was collected during the screening. Both archival and screening samples were considered as baseline samples to assess biomarkers within the tumor microenvironment.