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

Hoffmann-La Roche190 enrolled

Overview

This is a Phase II, randomized, blinded, active-controlled, global, multicenter study designed to evaluate the safety and efficacy of lomvastomig and tobemstomig, compared with nivolumab, in patients with advanced or metastatic esophageal squamous-cell carcinoma (ESCC) refractory or intolerant to fluoropyrimidine- or taxane- and platinum-based regimen. Following approval of the protocol amendment version 3, recruitment into the lomvastomig arm has been stopped. The decision to stop recruitment for lomvastomig was based on strategic considerations and not based on emerging safety and/or efficacy data. The benefit/risk assessment for lomvastomig remains unchanged. The study was planned to enroll participants randomized in a 1:1:1 ratio to receive lomvastomig, tobemstomig, or nivolumab. With version 3 of the protocol, recruitment into the lomvastomig arm has stopped, and moving forward, participants will be randomized in a 1:1 ratio to receive either tobemstomig or nivolumab.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

190

Conditions

Advanced or Metastatic Esophageal Squamous Cell Carcinoma

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Advanced or metastatic, histologically confirmed esophageal squamous-cell carcinoma (ESCC) * Patients who have previously received 1 line of treatment with either a fluoropyrimidine- and platinum- or a taxane- and platinum-based regimen in non-curative intention prior to randomization; or patients who received treatment with a fluoropyrimidine-/taxane- and platinum-based regimen in curative intention and had recurrence or progression within 24 weeks after the last dose of the treatment * Radiologically measurable disease according to RECIST v1.1. Previously irradiated lesions should not be counted as target lesions unless clearly progressed after the radiotherapy * Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 * A life expectancy of at least (≥)12 weeks * Tissue samples must be provided for analysis of anti-programmed death ligand-1 (PD-L1) tumor positivity * Adverse events from any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade ≤1, except alopecia (any grade), vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 peripheral neuropathy * Adequate cardiovascular, hematological, liver, and renal function * Serum albumin ≥25 grams per liter (g/L), * For participants not receiving therapeutic anticoagulation: prothrombin time (PT) and activated partial thromboplastin time ≤1.5 times (×) the upper limit of normal (ULN); for participants receiving therapeutic anticoagulation: stable anticoagulant regimen * A female participant is eligible to participate if she is not pregnant, not breastfeeding, not a woman of childbearing potential (WOCBP), or a WOCBP who agrees to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods during the treatment period and for at least 5 months after the final dose of study drug and have a negative pregnancy test (blood) within the 7 days prior to randomization. * A male participant must remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom plus an additional contraceptive method and refrain from donating sperm during the treatment period and for at least 5 months after the final dose of study drug Exclusion Criteria: * Pregnancy, lactation, or breastfeeding * Known hypersensitivity to any of the components of RO7121661, RO7247669, or nivolumab, including but not limited to, hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies * Patients with significant malnutrition. Patients whose nutrition has been well controlled for ≥28 days prior to randomization may be enrolled * Evidence of complete esophageal obstruction not amenable to treatment * Higher risk of bleeding or fistula caused by esophageal lesions invading adjacent organs (aorta or tracheobronchial tree). Patients with manageable fistula may be included at the Investigator's discretion. * Symptomatic central nervous system (CNS) metastases * Spinal cord compression not definitively treated with surgery and/or radiation or without evidence that disease has been clinically stable for ≥14 days prior to randomization * Active or history of carcinomatous meningitis/leptomeningeal disease * Asymptomatic CNS primary tumors or metastases if they have requirement for steroids or enzyme inducing anticonvulsants in the last 28 days prior to randomization * Uncontrolled tumor-related pain. Participants requiring pain medication must be on a stable regimen at study entry * Active second malignancy (with some exceptions) * Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders, known autoimmune diseases or immune deficiency, or other diseases with ongoing fibrosis (such as scleroderma, pulmonary fibrosis, emphysema, neurofibromatosis, palmar/plantar fibromatosis, etc.). * Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent * Significant cardiovascular/cerebrovascular disease within 6 months prior to randomization * Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not limited to tuberculosis \[TB\] and typical mycobacterial disease), parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with intravenous (IV) antibiotics or hospitalization (relating to the completion of the course of antibiotics, except if for tumor fever) within 28 days prior to randomization * Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and inherited liver disease. * Major surgical procedure or significant traumatic injury (excluding biopsies) within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study * Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk from treatment complications * Dementia or altered mental status that would prohibit informed consent * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (expected to occur once monthly or more frequently) * Active or history of autoimmune disease or immune deficiency * Positive human immunodeficiency virus (HIV) test at screening * Positive hepatitis B surface antigen (HBsAg) or positive total hepatitis B core antibody (HBcAb) test at screening * Positive hepatitis C virus (HCV) antibody test at screening * Prior cancer therapy with any immunomodulatory agents including checkpoint inhibitors (CPIs; such as anti-PDL1/PD1, anti-CTLA-4, anti-LAG3, anti-TIM3) * Vaccination with live vaccines within 28 days prior to randomization, or anticipation that a live attenuated vaccine will be required during the study * Treatment with therapeutic oral or IV antibiotics within 14 days prior to randomization * Concurrent therapy with any other investigational drug (defined as treatment for which there is currently no regulatory authority approved indication) 28 days or 5 half-lives of the drug (whichever is shorter) prior to randomization * Treatment with immune-modulating and immune suppressive agents/medication 5 half-lives or 28 days (whichever is shorter) prior to randomization * Regular immunosuppressive therapy (i.e., for organ transplantation, chronic rheumatologic disease) * Radiotherapy within the last 28 days before start of study drug treatment is not allowed, with the exception of limited palliative radiotherapy * Prior treatment with adoptive cell therapies, such as chimeric antigen receptor T cells (CAR-T) therapies

Outcomes

Primary Outcomes

Overall Survival (OS)

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.

Time frame: From randomization to death (up to approximately 38.7 months)

Secondary Outcomes

Number of Participants With Adverse Events (AEs)

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.

Time frame: Up to approximately 27 months

Objective Response Rate (ORR)

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.

Time frame: Up to approximately 38.7months

Disease Control Rate (DCR)

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.

Time frame: Up to approximately 38.7 months

Duration of Response (DoR)

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.

Time frame: Up to approximately 38.7 months

Progression-free Survival (PFS)

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.

Time frame: Up to approximately 38.7 months

Percentage of Participants Reporting Clinically Meaningful Improvement in GHS/QoL, Emotional and Social Functioning as Measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-life Questionnaire (QLQ)-C30

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.

Time frame: From baseline up to Week 12

Percentage of Participants Reporting Clinically Meaningful Improvement in GHS/QoL, Emotional and Social Functioning, as Measured by the EORTC QLQ - Item Library 97 (IL97)

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.

Time frame: From baseline up to Week 12

Percentage of Participants Reporting a Clinically Meaningful Improvement in Dysphagia, as Measured by the EORTC QLQ for Oesophageal Cancer-18 (OES-18)

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.

Time frame: From baseline up to Week 12

Serum Concentration of Nivolumab

Time frame: 4 hours (h) pre-dose, and 1 & 5 h post-dose on Day 1 of Cycle 1; pre-dose, and 0.5 & 4.5 h post-dose on Day 1 of Cycles 2 & 5; 168 h post-dose on Day 8 of Cycles 1 & 5; pre-dose, and 0.5 h post-dose on Day 1 of Cycles 3, 4 & 6 to 52 (1 Cycle=14 days)

Serum Concentration of Lomvastomig

Time frame: 4h pre-dose, and 1 & 5 h post-dose on Day 1 of Cycle 1; pre-dose, and 0.5 & 4.5 h post-dose on Day 1 of Cycles 2 & 5; 168 h post-dose on Day 8 of Cycles 1 & 5; pre-dose, and 0.5 h post-dose on Day 1 of Cycles 3, 4 & 6 to 19 (1 Cycle=14 days)

Serum Concentration of Tobemstomig

Maximum Observed Serum Concentration (Cmax) of Nivolumab