Unveiled by Oxfordshire, U.K.-based Immunocore Ltd. at the November meeting of the Society for Immunotherapy of Cancer (SITC) in National Harbor, Md., were encouraging new findings from the phase I/II study with tebentafusp (also known as IMC-gp100), a bispecific protein in the pivotal works for metastatic uveal melanoma (MUM). The results showed a correlation between treatment-induced immune response and improvement in overall survival (OS) and tumor shrinkage in advanced uveal as well as cutaneous melanoma.

Tebentafusp is composed of a soluble T-cell receptor fused to an anti-CD3 immune-effector function, and is engineered to specifically target gp100, a lineage antigen expressed in melanocytes and melanoma. It’s the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognize and kill tumor cells.

The goal of the analysis of two experiments was to increase understanding of the biological effects of tebentafusp and association with rash that turns up during treatment, serum CXCL10 and clinical outcomes in uveal disease. Researchers focused on the first, 42-patient cohort enrolled in IMCgp100-102, the phase I/II study in patients with HLA-A2-positive advanced conditions. Patients were treated using a weekly intrapatient dose-escalation regimen, and the occurrence of rash within 21 days following treatment initiation was evaluated as a predictor of OS.

Investigators measured a transient increase in peripheral cytokines after treatment with tebentafusp, reaching maximal changes at eight to 24 hours post-therapy, with CXCL10 having the greatest increment between 12-24 hours. Patients treated with tebentafusp experienced induced type 1/2 IFN pathways and neutrophil, eosinophil signatures and reduced CD4, CD8 and NK cell signatures in the blood, the company noted at SITC. Tebentafusp-treated patients with rash and those with a greater increase in serum CXCL10 following the first treatment dose appeared to be associated with improved OS; in a multivariate Cox proportional hazards model, both rash (p<0.001) and CXCL10 induction (p=0.01) were independent predictors.

Sometimes called ocular melanoma, the disease is the most common primary cancer of the eye in adults, diagnosed in about 2,000 every year in the U.S. and occurring most often in lightly pigmented people with a median age of 55 years, though it can occur in all races at any age, according the Ocular Melanoma Foundation. It’s the second most common type of melanoma after cutaneous.

In the first part of December, Immunocore started the first-in-human trial with IMC-C103C, the third bispecific developed using ImmTAC. IMC-C103C is focused on targeting tumors that express the protein MAGE-A4 (melanoma-associated antigen A4) and is being developed in partnership with Genentech, part of Basel, Switzerland-based Roche Holding AG.

Immunocore is hardly alone in the MUM space, and another firm drawing attention lately is Ideaya Biosciences Inc., of South San Francisco, which also in November offered upbeat data from an ongoing phase I/II effort with IDE-196 at the Congress for the Society for Melanoma Research SMR Congress in Salt Lake City. The study is testing the tolerability and preliminary clinical activity of the compound, a small-molecule inhibitor of PKC, a protein kinase that functions downstream of the GTPases GNAQ and GNA11 (GNAQ/11), against MUM as well as other solid tumors harboring GNAQ/11 mutations.

Accelerated approval?

Ideaya reported robust enrollment, with 27 total patients enrolled in the phase I dose-escalation portion, including 12 patients in MUM dose-limiting toxicity (DLT) cohorts, 14 patients in the MUM overflow cohort, and one GNA11 cutaneous melanoma patient in the non-MUM GNAQ/11 cohort. All 12 patients in the DLT cohorts remained on therapy with duration of treatment ranging from 1.3 to four months as of the Oct. 28 data cut-off. No DLTs turned up and no adverse events above grade 3 were reported in any patients. The company said it’s on track for phase II dose-selection and expansion into what could be the registration-enabling portion of the trial for MUM in December. Also ahead are interim data with efficacy for GNAQ/11 phase I/II tissue type-agnostic basket trial, expected in the second or third quarter of next year. Previous estimates placed results unavailable until the fourth quarter of 2020.

Among those who like the Ideaya story is Jefferies analyst Maury Raycroft, who noted in a Nov. 4 report that the aim of the basket attempt is to reveal the compound’s targeted-oncology potential with a tumor-impartial regulatory path for the GNAQ/11 therapy that would expand market opportunity beyond MUM. The strategy would follow examples such as those of Roche, which acquired Ignyta Inc., of San Diego, for $1.7 billion in late 2017. The deal focused on Ignyta’s entrectinib, a selective central nervous system-active tyrosine-kinase inhibitor being developed for tumors that harbor ROS1 or neurotrophic tyrosine receptor kinase (NTRK) fusions. In the summer of this year, the FDA cleared the drug under the brand name Rozlytrek for adults and pediatric patients 12 and older with solid tumors that have a NTRK fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy.

Ideaya boasts a Swiss big pharma connection, too, having last October exclusively licensed IDE-196, then known as LXS-196, from Basel, Switzerland-based Novartis AG. The candidate in MUM represents the “tip of the spear,” Raycroft said, pointing out that proof-of-concept data generated by Novartis as well as Ideaya show activity and durability. Talks with the FDA suggest that next steps “could consist of a favorable single-arm design that may be registration-enabling,” possibly with accelerated approval. “Though we estimate MUM to be a small opportunity, getting an initial approval of IDE-196 should facilitate label expansion strategies,” in his view. The phase II effort would aim to enroll 60 MUM patients, and the primary endpoint will be overall response rate (ORR) with duration of response (DoR) as a secondary goal. “We caught up with management and they mentioned that ultimately the FDA’s views on ORR and DoR will be a review issue, but with high unmet need they aim for double digits, and they ultimately want an ORR and confidence interval that enables them to rule out that ORR can be lower than 10%,” he wrote. The single-arm phase II trial with IDE-196 was on track to start by the end of the year.

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