mRNA therapy found to prevent recurrence of melanoma

Pharmaceutical companies Merck and Moderna have announced positive topline results from their Phase 3 trial of a personalised mRNA skin cancer therapy, indicating the potential to make a treatment designed specifically for an individual patient’s cancer.

The INTerpath-001 trial evaluated adjuvant treatment with intismeran autogene — an mRNA-based, individualised neoantigen therapy (INT) being jointly developed by Merck and Moderna — in combination with KEYTRUDA (pembrolizumab), Merck’s anti-programmed death receptor-1 (PD-1) therapy, in patients with completely resected (removed) stage IIB–IV melanoma. Patients with resected melanoma are at risk of disease recurrence, which most often occurs within the first two years.

Individualised neoantigen therapies such as intismeran are designed to train and activate an anti-tumour immune response based on the unique mutational signature of a patient’s tumour. Each therapy consists of a synthetic mRNA coding for up to 34 neoantigens and is tailored to the unique biology of an individual patient’s tumour. Upon administration, the RNA-encoded neoantigen sequences are translated in the body and presented to the immune system — a key step in generating specific T-cell responses against cancer cells.

KEYTRUDA, meanwhile, is, a standard-of-care immunotherapy that works by increasing the ability of the body’s immune system to help detect and fight tumour cells. There are currently more than 2800 trials studying KEYTRUDA across a wide variety of cancers and treatment settings.

This particular trial involved 1137 patients who, following complete surgical resection, were randomised 2:1 to receive intismeran (1 mg every three weeks for up to nine doses) and KEYTRUDA (400 mg every six weeks up to nine cycles) versus KEYTRUDA alone for approximately one year until disease recurrence or unacceptable toxicity, or for a total treatment duration of up to approximately 56 weeks, whichever was sooner. The primary endpoint was recurrence-free survival (RFS), defined as the time from randomisation to any disease recurrence as assessed by the investigator, or death due to any cause. Key secondary endpoints include distant metastasis-free survival (DMFS), overall survival (OS), safety, tolerability and quality of life.

“By intervening earlier in the course of disease, when many cancers are considered most treatable, the goal of adjuvant therapy given after surgery is to increase the possibility of cure for more patients,” explained Dr Dean Y Li, President of Merck Research Laboratories.

Interim analysis of intismeran in combination with KEYTRUDA demonstrated statistically significant and clinically meaningful improvements in RFS and DMFS compared to KEYTRUDA alone for patients with completely resected stage IIB, IIC, III or IV cutaneous melanoma who had not undergone prior treatment with systemic therapy; this means the trial met both its primary endpoint and a key secondary endpoint. Furthermore, it is understood to represent the first positive Phase 3 readout for an INT and for an mRNA-based cancer therapy, as well as the first Phase 3 study to demonstrate a clinically meaningful improvement over KEYTRUDA alone in the adjuvant setting for patients with resected melanoma.

“Today’s results represent a landmark moment for adjuvant melanoma treatment,” said principal investigator Professor Georgina Long, Medical Director of Melanoma Institute Australia and Chair of Melanoma Medical Oncology and Translational Research at The University of Sydney.

“Intismeran in combination with pembrolizumab has the potential to establish a new treatment paradigm in the adjuvant melanoma setting, helping patients remain cancer-free for longer.”

The work builds on previously reported Phase 2b results for intismeran in combination with KEYTRUDA, including five-year follow-up data in which the combination demonstrated a 49% reduction in the risk of recurrence or death and a 59% reduction in the risk of distant metastasis or death compared to KEYTRUDA alone. The safety profiles of intismeran and KEYTRUDA in this latest trial were consistent with those observed in previously reported studies for the combination, with no new safety signals observed.

“These first Phase 3 findings for intismeran in combination with KEYTRUDA as adjuvant therapy reinforce the promise of a more personalised approach to cancer treatment,” Li said. “We believe individualised neoantigen therapies have the potential to redefine how patients with completely resected stage IIB-IV melanoma are treated.”

Merck and Moderna are now advancing the INTerpath clinical development program evaluating the safety and efficacy of intismeran in combination with KEYTRUDA and other anti-cancer therapies, and as a monotherapy, across multiple tumour types and stages of disease. The INTerpath-001 trial will also continue in order to evaluate other key secondary endpoints, including OS, while the companies plan to share their data at an upcoming international medical meeting and to engage with regulatory authorities.

“For many years, the idea of creating an mRNA treatment designed specifically for an individual patient’s cancer was aspirational. We are now helping turn that vision into a reality,” concluded Stéphane Bancel, CEO of Moderna.

“Together with Merck, we have started to demonstrate the transformative potential of this technology to address critical unmet needs in the adjuvant melanoma setting. We are deeply grateful to the patients, investigators and study teams whose contributions make this progress possible.”

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