On October 21, 2023 Immunocore Holdings plc (Nasdaq: IMCR), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, infectious diseases and autoimmune conditions, reported that the three-year overall survival (OS) data from the KIMMTRAK (tebentafusp-tebn) Phase 3 trial in previously untreated HLA-A*02:01 positive patients with metastatic uveal melanoma has been published in The New England Journal of Medicine, and presented as a late breaking abstract in a mini oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (Press release, Immunocore, OCT 21, 2023, View Source [SID1234636209]).
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"These long-term overall survival results further solidify KIMMTRAK as the first-line standard of care for HLA-A*02:01 positive patients with metastatic uveal melanoma," said Mohammed Dar, Immunocore Chief Medical Officer. "The survival benefit appears early, within the first six weeks, and the survival curve remains separated from the control arm; this long-term survival benefit is a hallmark of cancer immunotherapy."
In the Phase 3 trial follow up – the longest of any randomized trial for metastatic uveal melanoma – the three-year OS rate was 27% in the KIMMTRAK arm, versus 18% in the control arm (investigator’s choice, predominantly [82%] single agent pembrolizumab). The median OS was 21.6 months on KIMMTRAK, versus 16.9 months on investigator’s choice. The OS Hazard Ratio (HR) favored KIMMTRAK, HR=0.68 (95% CI: 0.54 to 0.87), over investigator’s choice.
Overall response rate remained in favor of KIMMTRAK when compared with the control arm (11% vs 5%) and the median duration of response for KIMMTRAK patients was 11.1 months. The rate of disease control (complete response, partial response, or stable disease for ≥12 weeks) was also higher in the KIMMTRAK arm (46% vs 27%) versus the control arm. Over half (57%; n=139) of all patients treated with KIMMTRAK were treated beyond initial radiographic progression.
The trial evaluated circulating tumor DNA (ctDNA) clearance as a predictor of overall survival. ctDNA clearance on KIMMTRAK occurred in 37% of evaluable patients (compared with previously reported 13% in second-line patients1) and was associated with longer OS.
No new adverse events (AEs) related to long-term KIMMTRAK treatment were observed. The rate of discontinuation due to treatment-related AEs continued to be lower (2%) in the KIMMTRAK arm than for the control arm (5%). There were no treatment-related deaths.
In a separate poster at the Congress, an analysis of the role of subsequent therapy from the Phase 3 trial in first-line mUM patients confirmed that the survival benefit mostly comes from KIMMTRAK treatment rather than subsequent therapy.
A further poster included an analysis from the Phase 1b study in previously treated metastatic cutaneous melanoma patients, demonstrating the safety and activity of KIMMTRAK by BRAF mutation status. A third poster investigated the reprogramming effect of KIMMTRAK on immunosuppressive M2 macrophages from Phase 2 unresectable or metastatic uveal melanoma patients, as well as in vitro.
Presentation and poster details
Title: Three-year survival with tebentafusp in previously untreated metastatic uveal melanoma in a phase 3 trial
Presenting author: Sophie Piperno-Neumann
Session: Mini oral session – Melanoma and other skin tumours, Saturday 21 October, 2023
Title: Tebentafusp reprograms immunosuppressive tumor-associated M2 macrophages towards anti-tumoral M1 macrophages
Presenting author: Josep M. Piulats
Session: Poster display, Saturday 21 October, 2023
Title: BRAF mutation status does not impact outcomes with tebentafusp in advanced cutaneous melanoma
Presenting author: Alexander N. Shoushtari
Session: Poster display, Sunday 22 October, 2023
Title: Effect of subsequent therapies including checkpoint inhibitors on overall survival in a phase 3 randomized trial of tebentafusp in first line metastatic uveal melanoma: long-term follow up
Presenting author: Marcus Butler
Session: Poster display, Sunday 22 October, 2023
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About ImmTAC molecules for cancer
Immunocore’s proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognize and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognize intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumors, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumors, regardless of mutational burden or immune infiltration, including immune "cold" low mutation rate tumors.
About KIMMTRAK
KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognize and kill tumor cells. KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom.
About Phase 3 IMCgp100-202 Trial
IMCgp100-202 (NCT03070392) is a randomized pivotal trial that evaluated overall survival (OS) of KIMMTRAK compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in HLA-A*02:01-positive adult patients with previously untreated mUM. KIMMTRAK demonstrated an unprecedented OS benefit with a Hazard Ratio (HR) in the intent-to-treat population favoring KIMMTRAK, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine).
IMPORTANT SAFETY INFORMATION
Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS occurred in 89% of patients who received KIMMTRAK with 0.8% being grade 3 or 4. Ensure immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS.
Skin Reactions
Skin reactions, including rash, pruritus, and cutaneous edema occurred in 91% of patients treated with KIMMTRAK. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions.
Elevated Liver Enzymes
Elevations in liver enzymes occurred in 65% of patients treated with KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity.
Embryo-Fetal Toxicity
KIMMTRAK may cause fetal harm. Advise pregnant patients of potential risk to the fetus and patients of reproductive potential to use effective contraception during treatment with KIMMTRAK and 1 week after the last dose.
The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate.
For more information, please see full Summary of Product Characteristics (SmPC) or full U.S. Prescribing Information (including BOXED WARNING for CRS).