First patients getting individualised risk-reducing therapy for melanoma

An international clinical trial testing a novel cancer immunotherapy which may prevent skin cancer from recurring has recruited its first patients at UCLH.

The mRNA-based technology in this study is aimed at people who have already had high-risk melanomas removed.

The new Phase 3 clinical trial is evaluating the combination of mRNA-4157 (V940) and Keytruda (pembrolizumab) versus a current standard of care (pembrolizumab) as a risk-reducing treatment option for patients with resected, high-risk, stage IIB to IV melanoma.

It follows a successful Phase 2 study which found that in patients with stage IIIB to IV resected melanoma this treatment option almost halved the risk of cancer recurrence or death after three years compared with treatment with Keytruda alone among patients with advanced melanomas following surgical removal of the cancer.

The personalised treatment works by instructing the body to make up to 34 proteins, each targeting ‘neoantigens’ identified by gene sequencing and thought to be driving the cancer in that particular patient. The neoantigens are proteins found only on the cancer cells, and the individualised neoantigen therapy is designed to prime the immune system to attack the tumour cells in each patient, while Keytruda blocks an immunological ‘brake’ that protects the cancer.

Medical oncologist Heather Shaw, the national coordinating investigator of this new trial, says: “The idea behind this immunotherapy is that, by prompting the body to make these proteins, it can prepare the immune system to quickly identify and attack any cancer cells bearing them, with the aim of preventing recurrence of melanoma.”

Melanoma, the most serious form of skin cancer, is characterised by the uncontrolled growth of pigment-producing cells. The rates of melanoma have been rising over the past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020. In the UK, melanoma is the fifth most common type of cancer, accounting for about 8,400 new cases every year.

The technology was developed by Moderna in conjunction with MSD. A lot of the learning came from Covid research development and is now contributing to new treatments for cancer patients.

Researchers are now hoping that the Phase 3 study, which is running in several sites across the UK, will confirm the findings of the earlier trial. The Phase 3 trial, named INTerpath-001, will enrol around 1,089 patients across the world.

The primary outcome measure is recurrence-free survival, with overall survival and metastasis-free survival as secondary outcomes.

One of the first patients to sign up to the clinical trial is musician Steve Young, 52, of Hertfordshire. He was diagnosed with a stage II melanoma which was removed. He is now a participant in the immunotherapy trial as he feels this is his best chance of trying to stop the cancer returning.

“I feel lucky to be part of this clinical trial. Of course, I did not feel so lucky when I was diagnosed with skin cancer, in fact it came as quite a shock, but now that I’ve had treatment, I’m keen to ensure it does not recur. This is my best chance at stopping the cancer in its tracks,’ Steve says.

V940-001 is a Phase 3 global, randomized, double-blind, placebo- and active-comparator-controlled study. This means Steve knows he is receiving Keytruda, but will not find out if he is getting the personalised cancer treatment or a placebo.

The Phase 2 study which reported in The Lancet in January found that the immunotherapy combination was effective.

The results from the KEYNOTE-942 study revealed that combining mRNA-4157 (also known as V940) with MSD’s PD-1 inhibitor Keytruda (pembrolizumab) resulted in a 49% reduction in the risk of recurrence or death after three years compared to Keytruda alone in patients with high-risk stage III-IV melanoma following complete resection.

Data reported at last year’s American Association of Cancer Research (AACR) congress showed that the regimen achieved a 44% reduction in recurrence or death at 18 months.

Two-year distant metastasis-free survival rates were also presented at AACR, showing a 65% reduction, and the new update indicates this has largely been maintained with a 62% difference at three years.