This is a Phase II, randomized, blinded, active-controlled, global, multicenter study designed to evaluate the safety and efficacy of RO7121661 and RO7247669, 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.

The purpose of this study is to find out what effects, good or bad, RO7121661 and RO7247669, have on ESCC patients as compared to nivolumab.

RO7121661, RO7247669, and nivolumab belong to a group of medicines called cancer immunotherapeutics. They are designed to recognize and kill tumor cells in the body by activating the body’s own immune system, in particular, T-cells (a type of immune cell) against the tumor.

More precisely, RO7121661, RO7247669, and nivolumab are antibodies, which block proteins on T-cells, which help keep the body’s immune responses in check. These proteins are called PD1, TIM3, and LAG3. PD1, TIM3, and LAG3 are involved in regulating the body's natural immune response. Tumors can take advantage of this regulation to partially resist or evade the immune system. RO7121661 blocks PD1 and TIM3, RO7247669 blocks PD1 and LAG3, and nivolumab blocks PD1. By blocking these proteins, RO7121661, RO7247669, and nivolumab may help your immune system stop or reverse the growth of tumors.

RO7121661 and RO7247669 are experimental drugs, which means Health Authorities have not approved RO7121661 and RO7247669 for the treatment of esophageal cancer. Nivolumab is approved in some countries for the treatment of cancer including esophageal cancer.

Approximately 255 participants will take part in this study. The participants will be divided into three groups, receiving either RO7121661, RO7247669, or nivolumab. Each group will consist of 85 participants.

The primary study objective is To evaluate the efficacy of RO7121661 and RO7247669 compared with nivolumab and the primary endpoint is overall survival (OS) defined as the time from randomization to death from any cause.

The duration in each period of the study for each participant will be as follows:

• Screening: Days -28 to -1.
• Treatment Period: Cycle 1 Day 1 up to a maximum of 24 months.
• Survival follow-up: 90 (±7) days after last treatment with study drug; then every 3 months (± 14 days) until death, loss to follow-up, or study termination by the Sponsor.

The end of the study will occur when all of the following criteria have been met:

• The required number of deaths for the primary analysis of OS has been observed.
• The last participant, last visit has occurred.

PROTOCOL TITLE: A 3-ARM, RANDOMIZED, BLINDED, ACTIVE-CONTROLLED, PHASE II STUDY OF RO7121661, A PD1-TIM3 BISPECIFIC ANTIBODY AND RO7247669, A PD1-LAG3 BISPECIFIC ANTIBODY, COMPARED WITH NIVOLUMAB IN PARTICIPANTS WITH ADVANCED OR METASTATIC SQUAMOUS CELL CARCINOMA OF THE ESOPHAGUS

PROTOCOL NUMBER: BP42772

TEST PRODUCT: RO7121661, RO7247669, Nivolumab

PHASE: II

RATIONALE

Cancer remains a major cause of death worldwide despite several new agents providing survival

benefits to patients. Many cancer indications have a poor prognosis and the management of

most advanced solid tumors remains challenging because of the high rate of tumor recurrence or

the development of distant metastases.

Despite the effectiveness of PD1/L1 checkpoint inhibitor (CPI) therapy in various tumor types

including esophageal squamous-cell carcinoma (ESCC), additional treatment options targeting

immune checkpoints are needed, because the majority of patients eventually progress after an

initial response or fail to respond to PD1/L1 checkpoint blockade.

By targeting both PD1 and TIM3 or LAG3 on dysfunctional tumor-specific T lymphocytes, the

PD1-TIM3 and PD1-LAG3 bispecific antibodies aim to restore an effective anti-tumor

immune-response and provide survival benefit to more patients with cancer than currently

available agents do. PDL1 expression in ESCC ranges from 15% to 83% in tumor cells and from

13% to 31% in tumor-infiltrated immune cells. Studies with nivolumab, pembrolizumab, and other

PD1 inhibitors demonstrated benefit over chemotherapy in the second-line (2L) ESCC

population leading to market authorizations in that setting (e.g. in the U.S., EU, Japan, South

Korea, and other jurisdictions). Both TIM3 and LAG3 have been shown to be expressed on

tumor-infiltrating lymphocytes in patients with ESCC. RO7121661 and RO7247669 may

therefore have the potential to be a therapeutic option for patients with ESCC.

The purpose of this study is to assess the efficacy of RO7121661 and RO7247669 compared

with nivolumab to address a significant unmet medical need in patients with unresectable

advanced or recurrent ESCC who are refractory or intolerant to one prior line of chemotherapy.

OBJECTIVES AND ENDPOINTS

Primary Objective: To evaluate the efficacy of RO7121661 and RO7247669 compared with nivolumab.

Primary Endpoint: OS, defined as the time from randomization to death from any cause

Secondary Objectives:

• To evaluate the safety and tolerability of RO7121661and RO7247669 compared with nivolumab.
• To evaluate the efficacy of RO7121661 and RO7247669 compared with nivolumab.
• To investigate the pharmacokinetics (PK) of RO7121661, RO7247669, and nivolumab.
• To evaluate the immune response after administration of RO7121661, RO7247669, and nivolumab.
• To assess treatment-induced pharmacodynamic changes (PD Biomarkers) in peripheral blood and tumor microenvironment
• To assess baseline characteristics in the tumor microenvironment as predictive biomarkers of response

OVERALL DESIGN

Study Design

This is a Phase II, randomized, blinded, active-controlled, global, multicenter study designed to evaluate the safety and efficacy of RO7121661 and RO7247669, compared with nivolumab in patients with advanced or metastatic ESCC refractory or intolerant to fluoropyrimidine- or taxane- and platinum-based regimen. The study will enroll approximately 255 participants aged ³ 18 years with Eastern Cooperative Oncology Group Performance Status of 0 or 1. Participants will be randomized in a 1:1:1 ratio to receive RO7121661, RO7247669, or nivolumab. Participants will be stratified by previous (neo-)adjuvant chemotherapy, chemoradiotherapy or definitive chemoradiotherapy in curative intention (yes versus no), expression of PDL1 (< 1% versus ³ 1%), and geographic region of the enrolling site (Asia versus Rest of World). Randomization should occur on Day -1 or Day 1after the patient’s eligibility (i.e., inclusion/exclusion criteria) has been confirmed. In the experimental arms, participants will receive RO7121661 or RO7247669 at a fixed dose of 2100 mg administered by IV infusion every 2 weeks (Q2W) on Day 1 of each 14-day cycle. In the active comparator arm, participants will receive nivolumab at a fixed dose of 240 mg administered by IV infusion Q2W on Day 1 of each 14-day cycle. Treatment may be continued as long as participants are experiencing clinical benefit, as assessed by the Investigator, in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease progression after an integrated assessment of radiographic data, biopsy results (if available), and clinical status for a maximum of 24 months. Participants who meet the criteria for disease progression per RECIST v1.1 will be permitted to continue study treatment if they meet all criteria for treatment beyond progression.

Participants will undergo tumor assessments at screening and every 6 weeks (± 7 days) for

48 weeks following Day 1 of Cycle 1 (D1C1), regardless of treatment delays. After completion of the Week 48 tumor assessment, tumor assessments will be required every 12 weeks (± 7 days) regardless of treatment delays until radiographic disease progression per RECIST v1.1, initiation of a new anti-cancer therapy, withdrawal of consent, death, or study termination by the Sponsor, whichever occurs first. Thus, tumor assessments are to continue according to the schedule in participants who discontinue treatment for reasons other than disease progression or loss of clinical benefit. For participants who continue treatment after progressive disease, tumor assessments are to continue according to schedule until study treatment is discontinued. At the Investigator’s discretion, tumor assessments may be repeated at any time if progressive disease is suspected. Response will be assessed according to RECIST v1.1 and modified RECIST v1.1 for immune-based therapeutics (iRECIST). Objective response at a single timepoint will be determined by the Investigator according to RECIST v1.1. Objective response per iRECIST will be calculated programmatically by the Sponsor based on Investigator assessments of individual lesions at each specified timepoint. All primary imaging data used for tumor assessments may

be collected by the Sponsor; centralized, blinded independent review of response endpoints by an independent review facility may be conducted. The primary comparison of interest are the hazard ratio of OS of each experimental arm compared to nivolumab, assessing the superiority of the experimental arms over the active comparator treatment. The primary comparison of OS will be made regardless of whether participants withdraw from treatment or receive new anti-cancer therapy prior to disease progression. In order not to confound the OS endpoint, crossover from any of the treatment arms to another arm will not be allowed.

During the study, participants will be asked to complete patient-reported outcome (PRO) questionnaires at the beginning of the study, during study treatment, at treatment discontinuation, and during survival follow-up. These will assess disease and treatment-related symptoms, as well as functioning and overall health-related quality of life.

During the study, serum samples will be collected to monitor RO7121661, RO7247669, and nivolumab pharmacokinetics (PK) and to detect the presence of antibodies to RO7121661, RO7247669, or nivolumab. Blood samples for PK analysis may be collected at the participant’s home. This specifically applies to days where no other hospital assessments are required—i.e., C1D8 and C5D8.

Participant samples, including archival and fresh tumor tissue, serum, plasma, and blood samples, will also be collected for biomarker assessments. Safety assessments will include the incidence, nature, and severity of AEs, and other protocol-specified tests such as laboratory abnormalities that are deemed critical to the safety evaluation of the study.

After study treatment discontinuation and disease progression per RECIST v1.1, survival follow-up information will be collected by means of telephone calls, participant medical records, and/or clinic visits approximately every 3 months until death, lost to follow-up, or study termination by the Sponsor, whichever occurs first. All participants will be periodically contacted for survival and new anti-cancer therapy information unless the participant requests to be withdrawn from follow-up (this request must be documented in the source documents and signed by the Investigator). If the participant withdraws from the study, study staff may use a public information source (e.g., county records) when permissible to obtain information about survival status.

The IMPs are: RO7121661 (2100 mg Q2W IV), RO7247669 (2100 mg Q2W IV), and nivolumab (240 mg Q2W IV).

Length of Study

The duration in each period of the study for each participant will be as follows:

· Screening: Days -28 to -1.

· Treatment Period: Cycle 1 Day 1 up to a maximum of 24 months.

· Survival follow-up: 90 (± 7) days after last treatment with study drug; then every

3 months (± 14 days) until death, loss to follow-up, or study termination by the Sponsor.

End of Study

The end of the study will occur when all of the following criteria have been met:

· The required number of deaths for the primary analysis of OS has been observed.

· The last participant, last visit has occurred.

Data Monitoring Committee

A Joint Monitoring Committee (JMC) will review available safety data periodically and make

recommendations regarding study conduct to ensure the safety of patients enrolled in the study.

The JMC will consist of designated Sponsor personnel and independent clinical expert(s) (i.e., expert[s] independent from the Sponsor). The JMC Chair will be a medical oncologist who is neither the Medical Monitor nor associated with the study. Other JMC members will include, but not be limited to, a drug-safety scientist and biostatistician. The responsibility, membership, and communication flow of the JMC is further described in the JMC Charter.

PARTICIPANT POPULATION

The study population consists of male and female participants with advanced or metastatic

ESCC who are not indicated for radical resection and who are refractory or intolerant to

fluoropyrimidine- or taxane- and platinum-based regimen.

Key Inclusion Criteria

· Participants whose major lesion was histologically confirmed ESCC.

· Patients who are not indicated for radical resection and have previously received 1 line of treatment in non-curative intention prior to randomization. The prior line must be either a fluoropyrimidine- and platinum- or a taxane- and platinum-based regimen and patients must have experienced progressive disease after at least 3 cycles or are intolerable to the treatment. Patients who received treatment with curative intent, i.e. patients who underwent a radical resection (R0 resection confirmed) in conjunction with chemotherapy with fluoropyrimidine-/taxane- and platinum-based drugs including neo-adjuvant/adjuvant therapy (± radiotherapy) or patients who were treated with chemo-radiation (including patients who underwent chemo-radiation followed by salvage surgery) are allowed.

· If recurrence was confirmed by imaging or by pathological assessment of a biopsy within 24 weeks after the last dose of the treatment, patients are eligible and do not require an additional line of therapy in the non-curative setting.

· If recurrence occurred later than 24 weeks after the last dose of the treatment, patients need to be exposed to an additional line of fluoropyrimidine-/taxane- and platinum-based drugs in the non-curative setting to be eligible for the study—unless the Investigator considers the patient not eligible for the re-exposure with fluoropyrimidine/taxane and platinum-based drugs.

· The last dose of chemotherapy or the last radiation treatment (whichever occurs later) should be considered for the determination of the timepoint of recurrence after chemo-radiation.

· 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 Performance Status 0-1.

· A life expectancy of ³ 12 weeks.

· Tissue samples must be provided for analysis of PD-L1 tumor positivity using the PDL1 IHC 28-8 pharmDx assay. Testing will be done centrally and results must be obtained prior to stratification.

· Adequate visceral organ functions

· AEs 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 contraception

Key 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 ³ 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).

· 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 ³ 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.

· Patients with an active second malignancy.

· Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results.

· 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 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 (with the exception of participants with indwelling catheters, e.g., PleurXâ), 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 HIV test at screening.

· Positive hepatitis B surface antigen (HBsAg) or positive total hepatitis B core antibody (HBcAb) test at screening. Participants with a positive HBsAg or total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening are eligible.

· Positive hepatitis C virus (HCV) antibody test at screening. Participants with a positive

HCV antibody test followed by a negative HCV RNA test at screening are eligible.

· Prior cancer therapy with any immunomodulatory agents including 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 CAR-T therapies.

NUMBER OF PARTICIPANTS

The planned number of enrolled participants is 255, randomized 1:1:1 into 3 arms.

CONCOMITANT MEDICATIONS

As a general rule, no concomitant medication will be permitted, with the exception of medications to treat AEs, unless the rationale for exception is discussed and clearly documented between the Investigator and the Sponsor. Use of the following therapies is prohibited during the study and for at least 28 days or

5 half-lives of the drug, whichever is shorter, prior to randomization and during study treatment, unless otherwise specified below:

· Investigational or unlicensed/unapproved agents.

· Therapy intended for the treatment of cancer (including, but not limited to, chemotherapy, hormonal therapy, immunotherapy, and radiotherapy [with the exception of limited palliative radiotherapy], as well as herbal therapy or traditional Chinese medicines with anti-cancer activity in the label), whether Health Authority approved or experimental.

· Chronic use of steroids (inhaled and topical steroids are permitted) at baseline of > 10 mg of prednisone/day (or equivalent). Concurrent high doses of systemic corticosteroids.

· Administration of a live, attenuated vaccine or anticipation that such a live attenuated vaccine will be required during the study.

· Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) because these agents could potentially increase the risk for autoimmune conditions when given in combination with CPIs.

· Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide) because these agents could potentially alter the efficacy and safety of the study drug.

· Adoptive cell therapies, such as CAR-T therapies.