Bispecific PSMAxCD3 Antibody CC-1 in Patients With Squamous Cell Carcinoma of the Lung

SCC of the lung is an aggressive malignant disease with poor prognosis after failure of established therapies. Any drug employed after second-line treatment is associated with only limited clinical benefit. Therefore, there is a high medical need for new therapeutic approaches in this patient population. The clinical effects of immune checkpoint inhibitors in NSCLC have proven the potential of T-cell based immunotherapy in this entity. The rationale for the therapeutic use of CC-1 is based on its proposed mode of action as a bsAb being specifically designed to direct T cells via its CD3 binding part towards tumor target cells via its PSMA binding part. Furthermore, CC-1 also reacts with tumor vessels of NSCLC thereby allowing for a dual mode of anti-cancer action by also attacking tumor blood supply and allowing for improved influx of immune effector cells. Due to its unique ability to redirect T cells via CD3 for PSMA-expressing tumor cell lysis, CC-1 can elicit repeated target cell elimination by cytotoxic T cells and a polyclonal response of previously primed CD4+ and CD8+ T cells. Compared to other immunotherapeutics presently being approved or in development (bsAbs with alternative formats like the authorised bsAb blinatumomab or other antibodies or CAR T cells), CC-1 is expected to offer the following major advantages:

(i) Reduction of off-target T cell activation and thus reduction of side effects due to its optimized format (ii) The possibility to tightly steer anti-target activity via serum level-controlled antibody application which, in contrast to CAR T cells, allows for termination of activity if desired.

On the background of the poor prognosis of patients with SCC of the lung after second-line therapy, the bsAb CC-1 holds promise as a new treatment option of immunotherapy for these patients.

The planned study will include patients with SCC of the lung with detectable PSMA expression on tumor cells after second line treatment. PSMA expression is to be determined by central immunohistochemical assessment of fresh or kryopreserved tumor samples. Only patients with proven PSMA expression on tumor cells as defined by ≥10% positivity of tumor cells can be included. The requirement of ≥10% positivity of tumor cells for PSMA expression cells is in line with definitions of positivity for target antigen expression employed for other antibodies used in cancer treatment, for example the human epidermal receptor protein-2 (HER2)-specific antibodies trastuzumab and pertuzumab. Both antibodies are approved for the treatment of HER2-positive breast cancer, and HER2 positivity is given if ≥10% of tumor cells show staining for HER2 as assessed by immunohistochemistry .

PSMA-positivity is estimated for about 50% of screened patients with SCC of the lung.

Further as a translational research program the investigators implemented PSMA-PET CTs at different time points. PSMA positivity in PSMA-PET CT has been described on several tumor entities including tumors of the lung. In line, PSMA expression has been described on tumor cells and neovasculature of tumor in lung cancer, especially SCC of the lung. However, a correlation of PSMA-PET positive tumors with immunhistochemical PSMA evaluation has so far not been described.

The implementation of PSMA-PET as additional imaging to routine CT, will further improve treatment for patients with SCC of the lung as results of PSMA-PET may replace biopsy in future patients. A maximum of three PSMA-PET CTs may be performed.

Study rationale with regard to objectives and further development of CC-1

In nonclinical studies, in vitro and in vivo, proof of concept, preliminary PK and PK/PD effects as well as toxicology have been evaluated. However, due to differences between animal models and the human situation, some aspects have to be assessed and further characterised in humans. For example, the target mediated drug disposition (TMDD), an effect that largely influences the serum half-life of antibody molecules particularly at low concentrations, cannot be properly addressed in mice. Furthermore, non-human primates (NHP) and rodents have several limitations as predictive models for toxicity and immunogenicity evaluation of CC-1. The CD3 binding part of CC-1 does not cross-react with CD3 of macaques and thus it is not possible to evaluate in these NHPs dose limiting side effects. Likewise, although CC-1 is cross-reactive with macaque-PSMA, PSMA distribution in macaques significantly differs from that in humans. The same holds true for rodents.

Due to the high medical need for patients with SCC of the lung after second-line treatment, the planned phase I trial is designed to confirm and further explore the safety and tolerability of the PSMAxCD3 bsAb CC-1 in adult patients with SCC of the lung. The primary objective is incidence and severity of adverse events (AEs) under therapy with CC-1. Furthermore, the trial aims to expand experience on pharmacokinetics, pharmacodynamics and toxicology of CC-1 from nonclinical studies to the human situation in relation to the PK, expected efficacy and safety. A focus will be on the following specific aspects/parameters:

• Pharmacokinetics and pharmacodynamics of CC-1 in humans
• Immunogenicity of CC-1 in humans based on both absolute (number and percentage of subjects who develop human anti-human antibody (HAHA).
• Absolute changes from baseline in laboratory parameters
• Change in cytokines from baseline
• Assessment of response rate by RECIST on routine imaging
• Evaluation of PSMA PET CT in a translational research program
• Overall and progression free survival

Rationale for preemptive IL-6R blockade by Tocilizumab

As described above, in the planned study the investigators exploit the strategy to use tocilizumab rather to prevent development of CRS in the first place than to treat CRS once it has arisen.

This strategy holds promise to increase the safety of study patients and timely study conduct. By starting the study treatment with CC-1 directly with prophylactic tocilizumab, all study patients will benefit from the expected advantage of this combination with regard to safety and can be treated with sufficiently high doses of CC-1 to achieve dose levels high enough to hopefully result in efficacy effects.

The rationale for preemptive IL-6R blockade by tocilizumab treatment is based on i. The firmly established efficiency and safety of tocilizumab for the treatment of CRS

ii. Lack of clear evidence for increased tumor growth as potential drawback of IL-6R blockage iii. Observations that IL-6 activity, while being responsible for the undesirable sequelae of CRS, appears not to be required for the therapeutic activity of CC-1 CRS that was induced by therapy with the approved bsAb blinatumomab was reported to be successfully treated by tocilizumab. Most importantly, despite rapid disappearance of clinical CRS symptoms, the therapeutic activity of the bsAb blinatumomab was maintained. Furthermore, tocilizumab was also used in the very recent FIH study with the REGN1917 (CD20xCD3) antibody.

Our own nonclinical studies demonstrate that tocilizumab does not impair the therapeutic activity of CC-1, neither in vitro nor in vivo. This is in contrast to steroids which are currently recommended and used as pre- and concomitant treatment to prevent CRS upon blinatumomab therapy.

Due to the mechanism of action of tocilizumab, there is a theoretical risk of tumor development or tumor progression due to immune modulation. On the basis of the current literature derived from large studies conducted in Japan, the USA and Europe, however, there is no evidence for an increased tumor risk upon application of tocilizumab. Only one Japanese study described a minimally increased risk of de novo lymphoma development. However, this could not be confirmed in any other study. Especially for lung cancer, there is no evidence for an increased incidence rate. Interestingly, high systemic IL-6 levels are associated with dismal prognosis in NSCLC. Furthermore, tocilizumab is currently being investigated in several Phase I/II studies for the treatment of solid and hematological neoplasia without evidence for an influence on tumor pathophysiology. Based on these findings, no relevant negative effects of tocilizumab on the efficacy and safety of CC-1 are expected.