“It is great to see successful proof-of-concept data on two new promising immunotherapy targets at ESMO Virtual Congress 2020,” says Dr Christophe Massard from the Institute Gustave Roussy, Villejuif, France, commenting on two early trials exploring innovative new approaches. “Immunotherapy has had a major impact on cancer therapy, but it is very important to identify and test novel ways to interrupt immune tolerance pathways,” he continues.
Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule predominantly expressed by myeloid cells, which is enriched in the tumour microenvironment of various malignancies and may promote immune escape. Preliminary efficacy data for the first-in-human phase I dose-escalation trial of MK-4830, a first-in-class human ILT4-targeting monoclonal antibody, showed 9 objective responses among patients with advanced solid tumours receiving MK-4830 alone (n=50) or in combination with pembrolizumab (n=34) (Abstract 524O). There was one complete response (CR) and eight partial responses (PRs) among these often heavily pretreated patients, with five responses occurring in patients who had not had a response to prior anti-PD-1 therapy. Importantly, one response was observed in a patient receiving MK-4830 monotherapy. No dose-limiting toxicities were observed and the maximum-tolerated dose was not reached.
“The responses with combination therapy are pleasing, but it is difficult to differentiate the effects of each agent with combination therapy,” says Massard. “To me, the objective response in the patient on MK-4830 monotherapy provides evidence that ILT4 inhibition has the potential to affect myeloid cells in a clinically relevant way.” Final results are eagerly awaited, and in terms of next steps, Massard thinks it would be useful to test MK-4830 in patents with primary PD-1 refractory disease.
Results were also presented from a phase I study of PRS-343, a HER2/4-1BB bispecific molecule (Abstract 525O). 4-1BB is a key costimulatory immunoreceptor that plays a key role in the regulation of immune responses. In the phase I trial, 74 patients with HER2+ advanced or metastatic solid tumours (including gastric and gastroesophageal junction adenocarcinoma; n=27; breast, n=16; colorectal cancer, n=10; gynaecological cancer, n=9) were treated with PRS-343 monotherapy in sequential dose cohorts every week, 2 weeks or 3 weeks. There were no major toxicity issues and adverse events were as expected for immunotherapy agents.
Thirty-three patients treated at active dose levels were evaluable for response – the objective response rate (ORR) was 12% and the disease control rate (DCR) was 52% (CR, 3%; PR, 9%; stable disease [SD], 40%). At/above doses of 8 mg/kg every 2 weeks, the ORR was 40% (CR, 10%; PR, 30%) and DCR was 70%.
PRS-343 binds both 4-1BB and HER2, and was generated by the recombinant fusion of a 4-1BB–specific Anticalin protein, an engineered variant of lipocalins, to a HER2-specific antibody. As such, PRS-343 was designed to facilitate T-cell co-stimulation by tumour localised HER2-dependent 4-1BB clustering and activation. Providing evidence of a pharmacodynamic effect, the post-treatment expansion of CD8+ T cells observed in the study with active doses of PRS-343 was more pronounced in patients with a confirmed response.
Massard thinks the combination of HER2 inhibition with immune response regulation that PRS-343 appears to offer is a valuable alternative therapeutic strategy to trastuzumab, trastuzumab emtansine or newer agents, such as trastuzumab deruxtecan. According to the authors, a phase II trial is planned in patients with gastric and gastroesophageal junction adenocarcinoma in combination with ramucirumab and paclitaxel. Massard also hopes to see PRS-343 evaluated in other HER2-positive indications including breast cancer and colon cancer.
Abstracts and sessions details:
- Siu LL et al. Initial results of a phase I study of MK-4830, a first-in-class anti–immunoglobulin-like transcript 4 (ILT4) myeloid-specific antibody in patients (pts) with advanced solid tumours. ESMO Virtual Congress 2020, Abstract 524O
Proffered Paper - Developmental therapeutics, 20.09.2020, h. 16:20 – 18:00, Channel 3 - Ku G et al. A phase I dose escalation study of PRS-343, a HER2/4-1BB bispecific molecule, in patients with HER2-positive malignancies. ESMO Virtual Congress 2020, Abstract 525O
Proffered Paper - Developmental therapeutics, 20.09.2020, h. 16:20 – 18:00, Channel 3
