Rationale:~Tumor immunotherapy has demonstrated that therapies focused on enhancing T cell responses against cancer can result in a significant survival benefit in subjects with advanced stages of cancer. The most frequently used immunotherapy drugs bind to the Programmed death-ligand 1 (PD-L1) or programmed death protein 1 (PD-1). This binding interrupts the PD-L1/PD-1 pathway which inhibits an anti-tumor response of the immune system. Not all patients respond to anti-PD-1 or anti-PD-L1 treatment and therefore, combinations of immunotherapy drugs have been investigated and proven more effective than single-agent immunotherapy. These combinations, however, also increase the chance of immune toxicity. Possible strategies to overcome this problem are to develop less toxic combinations of immunotherapy drugs.~The T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) protein is also a target for immunotherapy. TIGIT is overexpressed in several malignancies including, melanoma, head and neck squamous cell carcinoma (HNSCC), and microsatellite instability high (MSI-H) colorectal cancer. The combination of the anti-TIGIT drug tiragolumab with the anti-PD-L1 drug atezolizumab increased the overall response rate by 15.1% compared to atezolizumab alone in a study with non-small cell lung cancer patients (NSCLC), without increasing toxicity.~In this trial, we will assess anti-tumor activity, safety, and tolerability of atezolizumab in combination with tiragolumab in subjects with cancer. We will also investigate proteins in the tumor to determine if we can predict which patients will respond to the atezolizumab and tiragolumab treatment. Patients will be included in one of four cohorts, namely: cohort 1, patients with localized HNSCC who will be treated with atezolizumab and tiragolumab followed by tumor resection, cohort 2, patients with metastatic MSI-H tumors, cohort 3, patients with irresectable or metastatic melanoma who progressed after PD-1 treatment, or cohort 4, with patients with a locally advanced or metastatic solid tumor for whom, based on available clinical data, treatment with anti-PD-L1 immunotherapy may be beneficial. Acquired data could lead to improved, more patient-tailored immune checkpoint inhibition.~Objective:~The main objective of the trial is to determine the pathological response rate in cohort 1 and the radiological response rates in cohort 2, 3 and 4. The secondary objectives of the trial are the safety of atezolizumab and tiragolumab, the response rates measured by overall response rate, disease free survival rate, duration of response and the last secondary objective is to determine the correlation between the protein expression of different proteins involved in the immune response of cancer to immunotherapy and the different response rates as mentioned before.~Main trial endpoints:~Pathologic response of the primary tumor in patients with HNSCC and objective response rate according to RECIST 1.1 and iRECIST in patients with advanced or metastatic MSI-H cancer, metastatic melanoma, and patients with a locally advanced or metastatic solid tumor whom, in the opinion of the investigator, based on available clinical data, may benefit from treatment with anti-PD-L1 immunotherapy.~Secondary trial endpoints:~The secondary endpoints are toxicity scored according to the common criteria for adverse events version 5.0, disease free survival in patients with HNSCC, overall response rate, progression free survival and duration of response in the patients in cohort 2, 3 and 4 as well as The correlation between the expression of the proteins TIGIT, PD-1, PD-L1 and CD8 on tumor tissue and pathologic and radiographic response rate.~Trial design:~Open label phase 2 basket trial with atezolizumab and tiragolumab in patients with localized HNSCC who will undergo surgery, and advanced or metastatic MSI-H cancer, PD-1 resistant metastatic melanoma, and patients with a locally advanced or metastatic solid tumor who, in the opinion of the investigator, based on available clinical data, may benefit from treatment with anti-PD-L1 and anti-TIGIT immunotherapy.~Trial population:~Subjects with localized HNSCC who will undergo surgery, and advanced or metastatic MSI-H cancer, PD-1 resistant metastatic melanoma, and patients with a locally advanced or metastatic solid tumor who, in the opinion of the investigator, based on available clinical data, may benefit from treatment with anti-PD-L1 and anti-TIGIT immunotherapy.~Interventions:~Subjects will receive atezolizumab and tiragolumab every 3-weeks until 1) resection as scheduled for HNSCC after 2 courses, 2) resectable disease for the MSI-H tumors, 3) progressive disease or side effects requiring treatment termination or 4) a maximum of 2 years. At baseline archival tissue or a tumor biopsy will be obtained and tissue will be collected once during the trial and when lesions are surgically resected. Blood samples will be collected during the trial to measure circulating tumor DNA. During the trial regular CT or MRI scans will be made to monitor the response to the treatment.
In this open label phase II trial combination therapy with the anti-PD-L1 antibody atezolizumab and the anti-TIGIT antibody tiragolumab will be investigated in patients with localized HNSCC who will undergo surgery, advanced or metastatic MSI-H cancer, PD-1 resistant metastatic melanoma, and patients with a locally advanced or metastatic solid tumor who, in the opinion of the investigator, based on available clinical data, may benefit from treatment with anti-PD-L1 and anti-TIGIT immunotherapy.