Date: 2018-04-17
Type of
information: Presentation of results at a congress
phase: 1b-2
Announcement: presentation of results at the American Association for Cancer Research (AACR) Annual Meeting
Company: AstraZeneca (UK) Innate Pharma (France)
Product: monalizumab (IPH2201) and cetuximab
Action
mechanism:
- monoclonal antibody/immune checkpoint inhibitor.
- Monalizumab (IPH2201/anti-NKG2A) is a first-in-class humanized IgG4 antibody. NKG2A is a checkpoint receptor that inhibits anti-cancer functions of cytotoxic NK and T lymphocytes. NKG2A recognises HLA-E ligands, and by expressing HLA-E cancer cells can protect themselves from killing by CD94/NKG2A-positive NK-, NKT-, and T-cells (a/b and g/d). HLA-E is frequently up-regulated on cancer cells and this occurs in patients with different types of solid tumours or haematological malignancies. In some types of cancers, high-levels of HLA-E appear to confer poorer prognosis. IPH2201 blocks the inhibitory function of CD94/NKG2A, thereby unleashing NK and T cells to kill cancer cells, despite expression of HLA-E. IPH2201 enhances NK and T cell killing of a variety of cancer cell types. Hence, IPH2201 may potentially re-establish a broad anti-tumour response mediated by NK and T cells. Anti-NKG2A mAb may also enhance the cytotoxic potential of other therapeutic antibodies. In an ongoing single- and multiple-dose Phase I dose-escalation safety trial in patients with rheumatoid arthritis, IPH2201 appears to have a safe and well-tolerated profile at all doses tested.
- Cetuximab is an anti-EGFR monoclonal antibody acting through blocking oncogenic signaling and by antibody dependent cellular cytotoxicity (ADCC), a mechanism mediated by NK cells.
Disease: relapsed or metastatic squamous cell cancer of the head and neck (SCCHN)
Therapeutic
area: Cancer - Oncology
Country: Europe, USA
Trial
details:
- This Phase Ib/II study is a multicenter open label trial of the combination of monalizumab and cetuximab in patients with recurrent or metastatic SCCHN. Both HPV positive and negative patients will be included. The study objectives are to assess the safety and antitumor activity of the combination of monalizumab and cetuximab. The primary endpoint for efficacy is overall response rate. The trial will be performed in Europe and in the United States. Seventy patients maximum are planned to be enrolled. The trial will be conducted in two parts:
- - In the first part of the study, up to 30 patients will receive a combination of cetuximab and monalizumab; 5 dose levels of monalizumab up to 10 mg/kg will be explored. Based on previous experience with monalizumab, these dosages are expected to induce full saturation of the NKG2A receptor;
- - In the second part of the study, monalizumab will be assessed at the dose selected in the dose-escalating part, in combination with cetuximab, in 40 patients who received up to 2 prior systemic regimens. Treatment will be continued until progression or unacceptable toxicity.
- The rationale of this trial is based on the observation that HLA-E is expressed on tumor cells in 78% to 86% of patients with SCCHN. Among 150 patients with tonsillar SCC, overexpression of HLA-E was found in 99/119 (83%) of those with HPV- tumors and 30/31 (97%) with HPV+ tumors. HLA-E is a ligand of the inhibitory CD94/NKG2A receptors that are found on Natural Killer (NK) cells and intratumoral CD8+ T cells in a variety of tumor types, including SCCHN. Upon binding to NGK2A, monalizumab restores the capability of those cells to destroy tumor cells.
- This trial is part of a global co-development and commercialization agreement with AstraZeneca for monalizumab. Within this framework, four Phase I/II trials are ongoing: the cetuximab combination trial in SCCHN, two single agent trials respectively in SCCHN and in ovarian cancer, and a combination trial with ibrutinib in chronic lymphocytic leukemia. The codevelopment
plan also includes a combination clinical trial with monalizumab and durvalumab (MEDI4736), a PD-L1 immune checkpoint inhibitor, in solid tumors, which will be performed by AstraZeneca/MedImmune.
Latest
news:
- • On April 17, 2018, Innate Pharma announced that
first clinical activity data of the ongoing Phase I/II trial for the combination of monalizumab and cetuximab in recurrent and/or metastatic SCCHN have been presented at the American Association for Cancer Research (AACR) Annual Meeting, April 14-18, in Chicago.
- The highest dose tested for monalizumab in the dose-escalation portion of the study (10 mg/kg every 2 weeks) was given in combination with the approved dose and schedule of cetuximab (400 mg/m² load, then 250 mg/m² weekly) in the Phase II cohort expansion. Patients could be either HPV (-) or HPV (+) and had progressed after platinum-based therapy with a maximum of 2 prior systemic treatment regimens for R/M disease. Prior cetuximab treatment (when used for the definitive treatment of locally advanced disease in combination with radiation) and prior immuno-oncology (IO) therapy were allowed.
- Among the 31 patients enrolled in the expansion part, the combination was well tolerated, consistent with previously presented data at AACR 2017, with no additional safety concerns compared to monalizumab or cetuximab given alone. The majority of adverse events (AE) were of Grade 1-2 severity, rapidly reversible and easily manageable. No infusion-related reactions or treatment-related deaths occurred. The most frequent AEs (skin disorders) described with cetuximab were not potentiated by the combination with monalizumab.
- Among the patients enrolled, as per study design, all had been previously treated with platin-containing regimens. In addition, 14 patients had been previously treated with PD-1 antibodies and 3 with prior cetuximab.
- Twenty-six patients were evaluable for efficacy; the other 5 patients are too early on study to have had a post-baseline assessment. At the cut-off date of March 9, 2018, there were 8 confirmed RECIST partial responses (31%) with median time to follow-up of 129 days, achieving the predefined number of 8 responses needed to declare the trial positive. 14 patients (54%) had stable disease. Median duration of response has not yet been reached; six responders are still on treatment. The trial has now enrolled all planned patients (n=40). Further follow-up is needed to evaluate the duration of response, progression-free survival (PFS) and overall survival (OS).
- • On December 17, 2015, Innate Pharma announced the opening of the Phase Ib/II trial of monalizumab (previously IPH2201), a first-in-class NKG2A checkpoint inhibitor, in combination with cetuximab in patients with relapsed or metastatic squamous cell cancer of the head and neck (SCCHN). This multicentric trial, which will include up to 70 patients, will be performed in Europe and the United States. It is the second trial testing monalizumab in head and neck cancer, after the monotherapy neoadjuvant trial opened in 2014. Pierre Dodion, MD, Chief Medical Officer at Innate Pharma, said: “HLA-E is frequently expressed by head and neck cancer cells. Monalizumab is a new checkpoint inhibitor targeting both T and NK cells and preventing their inhibition by HLA-E on tumor cells. Furthermore, monalizumab enhances antibody dependent cellular cytotoxicity (ADCC), one of the mechanisms of action of cetuximab, setting a sound rationale for their combination”.
- Dr. Roger Cohen, Associate Director of Clinical Research at the Abramson Cancer Center and Professor of Medicine at the Hospital of the University of Pennsylvania, and lead investigator for the study, said: “Cetuximab is the only targeted therapy approved in recurrent/metastatic head and neck cancer. However, its response rate of about 13% and response duration of less than 6 months leave a significant unmet medical need for this patient population. Immunooncology could play a key role in the treatment of head and neck cancer, as demonstrated by a variety of emerging and very promising data. The combination of monalizumab and cetuximab could enhance the efficacy of cetuximab by activating the immune system. This is a very appealing dual mechanism rationale”.
Is
general: Yes
