NF1 Associated with More Cancer Types Than Previously Known

Melanoma Recurrence Risk Cut By 49% By New Vaccine/existing Drug Combo

According to the Melanoma Research Alliance, the number of new invasive melanoma cases diagnosed annually in the US increased by 27% in the 10 years since 2013. Advanced melanoma can be very hard to treat, and survival very much depends on when the cancer is detected.

From diagnosis, the five-year relative survival rate for localized, early melanoma is over 99%; for melanoma that has spread regionally to nearby lymph nodes and vessels (stage III), it's 68%; and for melanoma that has spread to distant sites like the brain, lungs, and gut (stage IV), it's 30%.

Biopharmaceutical companies Moderna, Inc. And Merck – known as MSD outside of the US and Canada – have announced the results of Phase IIb of the KEYNOTE-942 study, a clinical trial evaluating the longer-term effectiveness of combining a new melanoma vaccine with an existing anti-cancer immunotherapy drug.

The vaccine, developed by Moderna and called mRNA-4157 (V940), was given in combination with Keytruda (pembrolizumab), Merck's anti-PD-1 therapy, to 157 patients with high-risk (stage III-IV) melanoma that had been surgically removed. Both boost the immune system's cancer-fighting abilities. The vaccine is an individualized neoantigen therapy (INT), meaning that it uses the unique DNA signature of a person's tumor to create a treatment that helps their immune system produce an anti-tumor response. Keytruda blocks the PD-1 pathway that cancer uses to hide in the body, helping the immune system detect and fight cancer cells.

Individualized neoantigen therapies: Exploring one medicine for one patient

After a follow-up of almost three years (median follow-up 34.9 months), the combination treatment reduced the risk of cancer recurrence or death by 49%, compared to treatment with Keytruda alone. Further, compared to Keytruda alone, treatment with both drugs reduced the risk of developing distant metastases or death by 62%.

"The sustained improvements in recurrence-free survival and distant metastasis-free survival observed at approximately three years in the KEYNOTE-942/mRNA-4157-P201 study provide further support of the potential of mRNA-4157 (V940) in combination with Keytruda to help patients with resected high-risk melanoma," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development at Merck. "We look forward to building on our legacy of turning breakthrough science into medicines that may have a meaningful impact on patient's lives as we continue advancing our broad clinical development program evaluating this novel approach with Moderna."

The most common adverse effects attributed to the combination of mRNA-4157 (V940) and Keytruda were fatigue (60.6%), injection site pain (56.7%), and chills (49%).

The current Phase IIb trial could be considered a 'mini-Phase III' trial designed to provide data on the treatment's effectiveness. Merck and Moderna have now commenced Phase III randomized clinical trials proper to evaluate the mRNA-4157 (V940) vaccine in combination with Keytruda in patients with resected high-risk melanoma and non-small cell lung cancer, the most common type of lung cancer. The companies also, in 2024, began Phase II trials of the combination treatment in patients with renal cell carcinoma, a type of kidney cancer, and bladder cancer.

The researchers presented their trial results at the 2024 American Society of Oncology (ASCO) annual scientific meeting, currently being held in Chicago.

Source: Moderna

ASCO: Moderna May File Melanoma Vaccine On Phase 2b Data

News

Moderna

New data from a phase 2b trial of Moderna and MSD's neoantigen melanoma vaccine may be strong enough to consider filing for accelerated approval before a phase 3 programme.

The new results from the KEYNOTE-942 study, presented at ASCO, come after a median follow-up period of nearly three years after adjuvant treatment with mRNA-4157 (V940) given in combination with MSD's immunotherapy Keytruda (pembrolizumab) for high-risk stage III/IV melanoma that has been removed with surgery.

At 34.9 months, the vaccine/Keytruda combination reduced the risk of recurrence or death by 49% – from around 50% to 25% – while the risk of distant metastasis or death fell 62% compared to Keytruda alone, with very little addition to the side-effect burden.

Crucially, the difference between the groups seems to be getting better over time, with a separation in the curves on the efficacy plot. At the two-and-a-half-year endpoint, the recurrence-free survival rate was 74.8% with the combination versus 55.6% for Keytruda.

Moderna's head of development for therapeutics and oncology, Kyle Holen, said it was particularly encouraging that the benefit was observed "across various patient exploratory subgroups, reflecting the potential of mRNA-4157…for a broad range of these patients."

mRNA-4157 is a personalised vaccine targeting 34 cancer neoantigens, derived from a biopsy of a patient's tumour, and uses the same underlying technology as Moderna's SpikeVax COVID-19 vaccine. It is designed to prime the immune system to attack the tumour cells, while Keytruda blocks an immunological 'brake' that protects the cancer.

The primary endpoint of the trial is disease-free survival (DFS) with an overall follow-up period of up to 78 months, so the strong efficacy signal point at this point is impressive and points to the potential of Moderna's neoantigen vaccination approach in oncology. An early filing would of course depend on the outcome of discussions with the FDA. 

In the meantime, Moderna and MSD – known as Merck & Co in the US and Canada – have already started phase 3 trials in patients with high-risk melanoma and non-small cell lung cancer (NSCLC). They are also running a phase 2/3 study in cutaneous squamous cell carcinoma (CSCC), another form of skin cancer and midstage studies in renal cell carcinoma (RCC) and urothelial carcinoma (UC).

The two companies are meanwhile working on additional cancer vaccines and recently started dosing patients in a phase 1/2 trial of mRNA-4359 – designed to generate antibodies against PD-L1 and IDO1 – in advanced solid tumours.

A Shot In The Arm That Can Help Fight Cancer? How Vaccine Trials Are Showing Promise.

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