PRAME Shows Promise as a Treatment Avenue in Melanoma, Other Solid Tumors

Omid Hamid, MD

As investigators continue to refine and carve out a role for targeted therapies in the treatment paradigm across tumor types, preferentially expressed antigen in melanoma (PRAME) has emerged as an intriguing treatment target in multiple solid tumors.

PRAME encodes the HLA-A24 antigen and is a member of the cancer testis antigen family of genes that can act as an oncogene or a tumor suppressor gene in multiple cancer types; high expression of PRAME is observed in 88% of primary and 95% of metastatic melanoma tissues. PRAME expression is regulated by SOX17, MZF1, miR-211, and miR-421, and overexpression affects several cellular processes via downstream regulation of targets such as p21, p53, RAR, TRAIL, S100A4, and HSP27.¹

PRAME is not present in healthy tissue aside from the testes and limited expression in the ovaries, adrenals, and endometrium. Preclinical findings have shown that the antigen is key in the immunotherapy response and thus it has been identified as an attractive target for the development of these agents.¹

“PRAME is attractive as a pan-tumor target due to its overexpression in multiple solid tumors,” Omid Hamid, MD, director of immuno-oncology and the codirector of the Melanoma Program at The Angeles Clinic and Research Institute, a Cedars-Sinai affiliate, in Los Angeles, California, said in an interview with OncologyLive. “High PRAME levels are associated with poor prognosis. It’s interesting that we’ve found this and have been able to target PRAME now in a way that we can evaluate PRAME-targeted therapies that are showing some promise in multiple solid tumors. Melanoma has the lead indication, [but] PRAME is overexpressed in a whole host of solid tumors, [such as] ocular melanoma, non–small cell lung cancer [NSCLC], serous ovarian cancer, endometrial cancer, and synovial sarcoma. You can develop a therapeutic that can be the backbone or combinatorial [partner] that works for multiple solid tumors.”

PRAME-Directed Agents Display Preliminary Efficacy in Multiple Solid Tumor Types

One approach that has displayed promise in effectively targeting PRAME-expressing solid tumors is the use of T-cell receptor-redirecting agents. During the European Society for Medical Oncology Congress 2022, investigators presented findings from the first-in-human phase 1/2 study (NCT04262466) of the novel bispecific protein IMC-F106C, which targets HLA-A2–presented peptide from PRAME, in patients with advanced solid tumors who were positive for HLA-A*02:01.² The primary end point was determining the maximum tolerated dose (MTD).

“IMC-F106C [contains] an immune-mobilizing monoclonal T-cell receptor on a platform similar to tebentafusp-tebn [Kimmtrak],” Hamid explained. “One side targets CD3, which brings the T cells in, and the other side targets PRAME like tebentafusp targets Gp-100. It brings T cells into PRAMEpositive tumors.”

Findings from the study demonstrated that efficacy- evaluable patients (n = 31) experienced an overall response rate (ORR) of 22.6%, all of which were partial responses (PRs); 2 PRs were ongoing for at least 7 months. Patients with serous ovarian cancer (n = 2/4), cutaneous melanoma (n = 2/6), and tebentafusp-naive uveal melanoma (n = 3/6) experienced PRs. Notably, patients in the efficacy population were heavily pretreated: all patients with ovarian cancer were platinum resistant, all of those with cutaneous melanoma had received prior anti–PD-1 and anti-CTLA4 therapy, all of those with NSCLC had received a prior anti–PD-1 agent, and those with triple-negative breast cancer or endometrial cancer had received 2 to 5 lines of previous treatment.²

Moreover, treatment with IMC-F106C led to a reduction in circulating tumor DNA (ctDNA) in 90% of evaluable patients across tumor types (n = 20). Thirteen patients experienced a 50% reduction in ctDNA and 25% achieved ctDNA clearance, despite 2 of these patients having a best response of disease progression.²

In terms of safety, any-grade adverse effects (AEs) in the safety population (n = 55) occurred at a rate of 95%, including pyrexia (56%), cytokine release syndrome (CRS; 49%), and fatigue (35%). Investigators noted that the CRS events were all manageable, with 77% occurring within the first 3 doses of IMC-F106C, 71% being grade 1, and the remaining 29% being grade 2. Grade 3 or higher AEs were reported in 35% of patients. The MTD was not reached and there were no treatmentrelated discontinuations and no grade 5 AEs.²

“The major toxicity to be aware of is CRS,” Hamid noted. “[However], what is good here is that there isn’t a lot of overlap in toxicities with these PRAME-directed agents and our anti–PD-1 therapies, which are standard in multiple indications. This allows us to have combinatorial trials.”

Study authors concluded that IMC-F106C activates T cells with a tolerable safety profile, producing durable responses per RECIST 1.1 criteria across multiple tumor types. At the time of the data presentation, expansion cohorts were open in cutaneous melanoma, NSCLC, and endometrial and ovarian cancer. Dose escalation was still in progress and combination regimens with chemotherapy and checkpoint inhibitors were being planned.²

Following the promising early-phase results, IMC-F106C is set to be evaluated in patients with previously untreated advanced melanoma in the phase 3 PRISM-MEL-301 trial (NCT06112314). The study will compare the safety and efficacy of nivolumab (Opdivo) plus low-dose or high-dose IMC-F106C with nivolumab monotherapy and nivolumab plus relatlimab-rmbw. The study will be initiated in quarter 1 of 2024, according to an investor presentation by Immunocore, the manufacturer of IMC-F106C.^3,4

“These novel approaches past checkpoint inhibition are really cementing the role of immunotherapeutics in multiple solid tumors,” Hamid said. “Our initial checkpoint inhibitor experience has shown that we can benefit with combinations, we can manage toxicity, and we can have durable responses, and we’re seeing the same here. These [novel] therapies are helpful because they do something that checkpoint inhibition has lacked for an extended period––being able to turn cold tumors hot by initiating T-cell infiltration into tumors.”

Another T-cell receptor-based agent that targets PRAME and is under evaluation in advanced solid tumors is the personalized cell therapy IMA203. IMA203 is being developed by Immatics and is composed of the patient’s T cells, which are engineered to express a T-cell receptor directed against PRAME. The agent is being examined as monotherapy or in combination with nivolumab in the phase 1 ACTengine trial (NCT03686124) enrolling patients with recurrent or refractory solid tumors.^5,6

In May 2023, the manufacturer of IMA203 reported updated findings from cohort A, the IMA203 monotherapy cohort, of the phase 1b dose-expansion portion of the study. The agent displayed a confirmed ORR of 67% (n = 6/9) across all tumor types, cutaneous melanoma, ovarian cancer, uveal melanoma, head and neck cancer, and synovial sarcoma. Two confirmed PRs were ongoing at over 9 months following treatment and 3 PRs were ongoing at the April 4, 2023, data cutoff.⁵

At the data cutoff, 5 of the 7 responses remained ongoing, including 2 confirmed PRs in cutaneous and uveal melanoma ongoing at 9 months, 1 confirmed PR in cutaneous melanoma at 6 months, 1 confirmed PR in ovarian cancer at 3 months, and 1 PR in synovial sarcoma at 6 weeks. At a median follow-up of 8.5 months, the median duration of response was not reached (range, 1.3+ to 8.8+). The initial ORR at week 6 was 64% (n = 7/11), all of which were PRs.⁵

The patient population was heavily pretreated, with a mean of approximately 4 prior lines of treatment, and had exhausted all available standard- of-care therapies. Patients with cutaneous melanoma were refractory to treatment with checkpoint inhibitors, and all patients with ovarian cancer were platinum resistant.

Safety findings showed that IMA203 monotherapy displayed a manageable tolerability profile with no dose-limiting toxicities observed in cohort A since the initial phase 1a dose escalation. Ninety-one percent (n = 10/11) of patients experienced grade 1 or 2 CRS and no instances of immune effector cell–associated neurotoxicity syndrome were reported.⁵

“The future is bright for PRAME-targeted agents,” Hamid said. “We are building this bank of information that’s helping us to understand how to give these drugs, how to manage toxicity, which subgroups are benefiting, and which ones need to go into combination therapies. Early on, we’re seeing responses in heavily pretreated tumors. This makes us push harder for these types of therapies, not only in melanoma or cutaneous melanoma but in multiple solid tumors.”