Study Comparing the Standard Administration of IO Versus the Same IO Administered Each 3 Months in Patients With Metastatic Cancer in Response After 6 Months of Standard IO

Overview

Immunotherapy (IO), such as treatment with anti-PD-1, PD-L1, or CTLA-4 inhibitors, is a rapidly expanding treatment for multiple metastatic cancers with improved survival for certain cancers. However, the optimal duration of immunotherapies is currently unknown. Our hypothesis is that a reduced dose intensity of IO could be as effective as the current standard treatment in term of prevention of the disease progression. If proved right, this study will have a positive medico-economic impact by reduction of the costs associated with the treatment and the toxicity, and an increase of the patients' quality of life.

Description

Immunotherapy (IO) is a rapidly expanding treatment for multiple metastatic cancers with improved survival for certain cancers. For currently approved immunotherapies such as PD-1 / PD-L1 inhibitors and anti-CTLA-4, the rhythm and duration of treatment are recommended until disease progression or unacceptable toxicity. However, the optimal duration of these treatments is currently unknown.

No major dose-dependent effect of anti-PD-1 have been observed and whether the frequency of infusion of IO could improve response or maintain efficacy. Moreover, phase I studies have shown that saturation of the target (PD-1 or PD-L1) can persist far beyond the serum half-life of the IO and 3-monthly infusions of an anti-PD-1 antibody could potentially generate the same level of activity as infusions administered every 2 weeks.

In silico modeling studies have suggested that alternate scheduling with IO couldn't compromise the efficacy of the treatment. Indeed, prolonged half-lives of IO drugs, time-varying clearance plus plasma concentrations far above the threshold associated with maximal target-engagement, suggest that the rhythm of administration of IO could be slowed down.

Without substantial international data for responding patients, apart metastatic melanoma in complete response, patients and physicians are afraid of stopping treatment, by fear of relapse. Over-treatment with IO may be toxic and inefficient. The rising cost of cancer care in the era of immunotherapy is of great concern for public and private payers around the world.

Chronic administration has important consequences for patients and health systems, with multiple medical visits and the risk of chronic, progressive and sometimes fatal toxicities induced by immunotherapy.

This is a pragmatic and strategic study challenging the routine practice which compares for the first time in a randomized phase III study, the standard administration of IO versus the same agent administered each three months in patients with metastatic cancer in partial or complete response after 6 months of standard IO ( except melanoma in CR).

If our hypothesis of non-inferiority of PFS with a reduced dose intensity of IO is verified, this could replace standard treatment and have a positive medico-economic impact, allowing, on the one hand, a reduction of the costs associated with the treatment and the toxicity, and on the other hand, an increase of the patients' quality of life.

Eligibility

Inclusion Criteria:

1. Patients must have signed a written informed consent form prior to any trial specific procedures.
2. Patient aged ≥18 years old.
3. Initial metastatic disease histologically confirmed including: lung cancer, renal cell cancer, head and neck cancer, bladder cancer, triple negative breast cancer, Merkel cancer, hepatocellular carcinoma, and melanoma.
4. Patients in partial or complete response after 6 months of standard immunotherapy (whatever the line of therapy) according to the RECIST (confirmed by local radiological assessment). For metastatic melanoma only patients in partial response.
5. Eligible to maintain the same standard IO treatment.
6. Patient with Eastern cooperative oncology group (ECOG) performance status ≤1.
7. Patients with brain metastases are allowed, provided they are stable according to the following definitions: treated with surgery or stereotactic radiosurgery and without evidence of progression prior to randomization and have no evidence of new or enlarging brain metastases.
8. Patients treated by IO previously combined with chemotherapy are allowed.
9. Patients with Tyrosine Kinase Inhibitor (TKI)-IO or pemetrexed-IO or bevacizumab-IO are allowed.
10. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for pre-menopausal patients.
11. Both sexually active women of childbearing potential and males (and their female partners) patients must agree to use adequate contraception method for the duration of the study treatment and after completing treatment according to the most recent version of the IO Summary of product characteristics (SmPC).
12. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.
13. Patient must be affiliated to a Social Security System.

Exclusion Criteria:

1. Metastatic melanoma in complete response.
2. Metastatic renal cell carcinoma with International Metastatic Renal Cell Carcinoma Database (IMDC) favourable-risk treated TKI/IO combination.
3. Hematologic malignancies (leukaemia, myeloma, lymphoma…)
4. Active infection requiring systemic therapy.
5. Patients enrolled in another therapeutic study within 30 days before the inclusion in and during MOIO study.
6. Patient unable to comply with study obligations for geographic, social, or physical reasons, or who is unable to understand the purpose and procedures of the study.
7. Person deprived of their liberty or under protective custody or guardianship.