Patient case: 57-year-old male with lung adenocarcinoma; genetic feature: KRAS (G12V), high tumor mutational burden

Clinical trial: Adjuvant Therapy of Completely Resected Merkel Cell Carcinoma With Immune Checkpoint Blocking Antibodies Versus Observation

Summary: Primary Objective:
  To estimate the efficacy of adjuvant nivolumab monotherapy in completely resected Merkel cell carcinoma (MCC) patients; i.e. the primary endpoint is disease-free survival (DFS) in arm A at 12 months, defined as the number of patients alive and free of disease at 12 months after randomization compared to DFS in arm B.
  Secondary Objectives:
  To assess safety and additional efficacy parameters of the ipilimumab or nivolumab treatment in MCC, as well as to characterize potential biomarkers; secondary endpoints are: (i) adverse events according to CTCAE (Common Terminology Criteria for Adverse Events), Version 4.0 criteria, that are definitely, probably, or possibly related to the administration of ipilimumab, (ii) Overall survival rate at 12 months, defined as the number of patients surviving at 12 months after randomization divided by the total number of patients randomized, (iii) DFS rate at 12 months, defined as the number of patients alive and free of disease at 12 months after randomization divided by the total number of patients randomized.

Detailed description: This is a national, open-label, randomized, multicenter phase II study to assess the efficacy of adjuvant therapy with immune checkpoint blocking antibodies in completely resected Merkel cell carcinoma (MCC) patients.
  MCC is a rare (incidence of 0.44 per 100,000), highly aggressive form of skin cancer. Indeed, MCC has a dramatically higher mortality rate after initial diagnosis than malignant melanoma (37 vs. 15 percent). Almost half of the patients with completely resected MCC will relapse with loco-regional or distant metastases within the first two years after initial diagnosis of this highly immunogenic cancer. This high mortality rate is largely due to the fact that to date there is no established adjuvant therapy for completely resected MCC, and none of the until recently available therapeutic interventions was able to improve overall survival of patients suffering from metastatic disease. Consequently, new therapeutic strategies both for the adjuvant as well as the palliative setting are needed.
  Recently, the European Commission granted a clinical trial for metastatic MCC within the FP7 HEALTH2011.2.4.1-1 call. The present proposal aims at using this newly established network to investigate an adjuvant immune therapy for MCC.
  Epidemiologic data suggest that there are approximately 2500 new MCC cases per year within the EU (European Union), more than 1000 of these patients will die from their disease. MCC usually affects the elderly. The median age at diagnosis is 70 years, and there is a 5- to 10-fold increase in incidence after age 70 as compared with an age less than 60 years. Thus, with an ageing European population the impact of this deadly cancer will increase.
  As compared to most cancers, MCC is particularly linked to immune suppression. Indeed, 7.8% of MCC patients are profoundly immune suppressed, with a 16-fold over-representation of MCC compared with the normal incidence. Notably, the impact of immune surveillance on the course of MCC is much more pronounced than on that of melanoma: while the ratio of melanoma to MCC is 60:1 in the normal population, it is 6:1 in the immune suppressed population. Moreover, there are more than 20 reported cases of complete spontaneous regressions of confirmed MCCs, which suggest the ability of the immune system to exert a sudden immune recognition and clearance of this tumor. Notably, regressions may also be induced by cessation of immune suppression. Another line of evidence for the immunogenicity of MCC is the observation, that a strong inflammatory infiltrate, particularly CD8+ T cells, within the tumor is associated with a favorable prognosis. The immunogenicity of MCC can be explained by the recently recognized viral pathogenesis of this tumor entity. Indeed, preliminary data from our MCC research network suggest that immune dominant T-cell epitopes derived from the oncogenic virus elicit spontaneous immune responses in MCC patients. Consequently, immune modulating strategies are particularly attractive for the therapy of MCC and may improve the disease-free survival as well as the overall survival of MCC patients if given in an adjuvant setting.
  The PD-1 immune checkpoint pathway, which comprises the PD-1 T-cell coinhibitory receptor and its ligands PD-L1 and PD-L2 expressed on tumor and immune cells in the tumor microenvironment, mediates local immune resistance. Monoclonal antibodies blocking this pathway are active against advanced tumors of several different types, providing a "common denominator" for cancer therapy. PD-L1 expression in pretreatment tumor specimens may identify patients and tumor types that are more likely to have a response to PD-1 pathway blockade. An elevated tumor mutational burden or association with viral carcinogenesis, creating new determinants for immune recognition, has also been associated with tumor regressions in individual patients and the responsiveness of tumor subtypes to anti-PD-1 therapy.
  In the initial trial design, the immune modulating treatment was based on CTLA-4 blockade by ipilimumab; however, the advent of PD-1/PD-L1 blockade in the palliative treatment of MCC (presented at AACR, ASCO and ESMO) dramatically changed the treatment environment to an extent that applying treatments other than by PD-1/PD-L1 blockade had become very difficult. Moreover, the side effects of PD-1/PD-L1 blocking are far less frequent than side effects of ipilimumab. Consequently, randomization into the previous Ipilimumab treatment arm A will be stopped. New patients will be randomized to nivolumab treatment instead. Patients randomized already into the Ipilimumab-arm will be evaluated descriptively. Patients randomized into the observation arm (arm B) will be evaluated together with the newly randomized arm B-patients.
  Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody (HuMAb), which binds to PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. It is authorized in the EU since 19.06.2015 for monotherapy of advanced (unresectable or metastatic) melanoma and after prior chemotherapy for the treatment of advanced renal cell carcinoma and locally advanced or metastatic non-small cell lung cancer. Clinical activity was noted across a range of doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg). The safety profile of nivolumab monotherapy is manageable and generally consistent across completed and ongoing clinical trials with no maximum tolerated dose (MTD) reached at any dose tested up to 10 mg/kg.
  Ipilimumab/Yervoy® is a new therapeutic strategy targeting an immune checkpoint (CTLA-4), which has provided significant benefit in overall survival in two phase III trials in patients with unresectable stage III or stage IV melanoma. In the adjuvant treatment of melanoma, ipilimumab at 10 mg/kg is currently being tested in patients of the clinical stages IIIA to IIIC (EORTC 18071; ECOG 1609). Although the 10 mg/kg dose regimen has been shown to be the most efficacious in phase II trials in stage IV melanoma patients (CA 184-022, CA184-008, CA184-007), the 3 mg/kg regimen also provides clinical responses with a much lower rate of severe adverse events. Indeed, the 3 mg/kg dosage was used in one of the two positive phase III trials on in metastatic melanoma. Due to its safer toxicity profile, 3 mg/kg ipilimumab is probably best suitable for an adjuvant use in patients with completely resected MCC.
  Both drugs have demonstrated a manageable safety profile, which however, is more preferable for nivolumab.
  Therefore new patients will be randomized in a 2:1 ratio to receive nivolumab instead of ipilimumab treatment versus observation.

Eligibility: Inclusion Criteria:
  1. The patient is willing and able to give written informed consent.
  2. Central histological confirmation of diagnosis of Merkel cell carcinoma (MCC).
  3. All MCC manifestations have been completely resected by surgery within 12 weeks before enrolment.
  4. No currently present metastases (as confirmed by standard imaging studies (e.g. suggested by S2k guidelines)).
  5. No previous systemic therapy for MCC.
  6. Required values for initial laboratory tests:
  -  WBC ≥ 2000/uL
  -  ANC ≥ 1000/uL
  -  Platelets ≥ 75 x 103/uL
  -  Hemoglobin ≥ 8 g/dL (≥ 80 g/L)
  -  Creatinine ≤ 2.0 x ULN
  -  AST/ALT ≤ 2.5 x ULN
  -  Total Bilirubin ≤ 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
  7. ECOG performance status 0 or 1.
  8. No active or chronic infection with HIV, Hepatitis B (HBV) or C (HCV).
  9. Men and women, ≥ 18 years of age.
  10. Women of childbearing potential (WOCBP) must be using an adequate method of contraception (Pearl-Index < 1) to avoid pregnancy for up to 12 weeks (for ipilimumab therapy) or for 5 months (for nivolumab therapy) after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab or nivolumab.
  11. Men of fathering potential must be using an adequate method of contraception to avoid conception for up to 12 weeks (for ipilimumab therapy) or for 7 months (for nivolumab therapy) after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.
  Exclusion Criteria:
  1. Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease requiring systemic steroids (e.g., rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus, autoimmune vasculitis); autoimmune motor neuropathy.
  2. Other serious illnesses, e.g., serious infections requiring i.v. antibiotics.
  3. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immune deficient condition.
  4. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab or nivolumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea.
  5. Any non-oncology vaccine therapy for up to 1 month before or after any dose of ipilimumab or nivolumab.
  6. A history of prior or current treatment with a T cell potentiating agent (e.g. IL-2, interferon, anti-CTLA-4, anti-CD137, anti-PD1, anti-PD-L1, or anti-OX40 antibody).
  7. Chronic use of immunosuppressive agents or systemic corticosteroids.
  8. Women of childbearing potential (WOCBP), defined above in Section 5.1, who:
  -  are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for up to 12 weeks (for ipilimumab therapy) or for 5 months (for nivolumab therapy) after the last dose of investigational product
  -  have a positive pregnancy test at baseline
  -  are pregnant or breastfeeding.
  9. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
  10. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.
  11. Men of reproductive potential unwilling to use an adequate method to avoid pregnancy for up to 12 weeks (for ipilimumab therapy) or for 7 months (for nivolumab therapy) after the last dose of investigational product.
  12. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment.

Relevance to patient case: not relevant