Novel bispecific T-cell receptor therapy shows early promise in advanced solid tumors
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An off-the-shelf T-cell receptor therapy has shown promising early results in multiple solid tumor types, according to initial data from a phase 1 dose-escalation trial presented at ESMO Congress.
Treatment with IMC-F106C produced durable responses or disease stabilization in most patients and appeared well-tolerated, the researchers noted.
Background
IMC-F106C (Immunocore) is an investigational bispecific fusion protein comprising a soluble T-cell receptor that targets HLA-A*02:01 PRAME-derived peptides and an anti-CD3 chain that binds to and activates a patient’s endogenous T cells.
Previous development of tebentafusp (Kimmtrak, Immunocore) for uveal melanoma led the investigators to evaluate use of another T-cell-engaging bispecific fusion protein, this time for a wider array of solid tumors known to express the PRAME antigen, according to HemOnc Today Editorial Board member Omid Hamid, MD, chief of translational research and immunotherapy and co-director of melanoma therapeutics at Cedars-Sinai Cancer at the Angeles Clinic and Research Institute.
"T-cell therapeutics are gaining a greater foothold in the treatment of solid tumors,” Hamid told Healio, adding this is especially true among those who have experienced disease progression on standard chemotherapy and other immunotherapy, including immune checkpoint inhibitors.
“This population of patients has relatively few options for treatment, but surprisingly many benefited from this new therapy,” Hamid said.
Methodology
Hamid and colleagues conducted the phase 1 study of IMC-F106C to determine its safety, preliminary efficacy and the recommended phase 2 dose in patients who are HLA-A*02:01-positive with solid tumors known to express the cancer-testis antigen PRAME.
The study included 55 patients (median age, 60 years; range 26-79) divided into 10 cohorts receiving weekly IV doses of IMC-F106C ranging from 0.3 to 320 µg, with intra-patient dose-escalation for the first 3 weeks to reach the targeted dose for each cohort.
Diseases evaluated in the study included uveal melanoma (47%), ovarian carcinoma (18%), cutaneous melanoma (15%), non-small cell lung cancer (7%), endometrial cancer (7%) and triple-negative breast cancer (5%).
Safety and determination of recommended phase 2 dose served as the study’s primary objectives. Secondary objectives included efficacy, biomarkers and circulating tumor DNA (ctDNA) response.
The study population eligible for safety analysis included 31 patients (median age, 61 years; range, 36-79) in cohorts who received the clinically active dose of at least 20 µg of IMC-F106C.
Key findings
A maximum tolerated dose was not reached during the study. In addition, no treatment discontinuation due to treatment-related adverse events or treatment-related deaths occurred.
The most common grade 3 or greater treatment-related adverse events included lymphopenia (15%), increase in aspartate aminotransferase (7%) and anemia (5%).
Nearly half of patients (49%) experienced cytokine release syndrome, but none had grade 3 or higher CRS. Most cases of CRS (77%) occurred within the first three doses of the study drug.
Investigators observed partial responses to therapy in three of six patients (50%) with uveal melanoma who were tebentafusp-naive, whereas none of the five patients with uveal melanoma who previously received tebentafusp responded to therapy.
Two of six patients (33%) with cutaneous melanoma showed a response to therapy. Other partial responders included two of four patients (50%) with serous ovarian cancer.
Six of the seven partial responders continued to respond to therapy as of the data cutoff date of July 18, with two partial responses lasting 7 or more months.
Among 20 patients eligible for ctDNA analysis, 90% showed evidence of ctDNA reduction. Thirteen (65%) had a greater than 50% reduction in ctDNA, including five with ctDNA clearance.
Clinical implications
Hamid said the results show “interesting initial response rates in multiple solid tumors” in a group of heavily pretreated patients who have exhausted all standard treatment options.
"We saw significant clinical benefit and responses among those treated with 20 µg and above,” he added.
“The treatment was very tolerable and able to be given without the development of significant toxicities,” Hamid said. “This treatment represents a significant option for our patients.”
The trial will move into dose-expansion phases for patients with cutaneous melanoma, NSCLC, endometrial cancer and ovarian carcinoma. Other plans include expansion into combination therapy cohorts, including combination with chemotherapy and immune checkpoint inhibitors, Hamid said.
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Hamid O, et al. Abstract 728O. Presented at: European Society for Medical Oncology Congress. Sept. 9-13, 2022; Paris.
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