Moderna and Merck report 5‑year follow‑up for intismeran autogene plus pembrolizumab in resected high‑risk melanoma | iPharmaCenter
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- 6 days ago
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Moderna and Merck have released updated results from the phase 2b KEYNOTE‑942/mRNA‑4157‑P201 trial, providing the first median five‑year follow‑up for the personalised mRNA neoantigen therapy intismeran autogene given with pembrolizumab in patients with completely resected stage III/IV melanoma at high risk of relapse.
The adjuvant combination continued to deliver a sustained and clinically meaningful improvement in recurrence‑free survival compared with pembrolizumab alone, reinforcing the potential of this strategy in the post‑surgical setting.
In this pre‑specified analysis, adjuvant treatment with intismeran autogene plus pembrolizumab was associated with a 49% relative reduction in the risk of recurrence or death versus pembrolizumab monotherapy.
Expanding late‑stage development across tumour types
The long‑term KEYNOTE‑942 results support a broad development programme for intismeran autogene in partnership with Merck, spanning melanoma, lung, bladder and kidney cancers. A pivotal phase 3 trial in the adjuvant melanoma setting (INTerpath‑001; NCT05933577) evaluating intismeran autogene plus pembrolizumab versus pembrolizumab alone following complete resection is fully enrolled.
Two phase 3 studies in non‑small cell lung cancer are ongoing: one in patients with completely resected disease receiving adjuvant therapy, and another in patients with resectable disease who receive neoadjuvant pembrolizumab plus platinum‑based chemotherapy followed by postsurgical treatment. A randomized phase 2 trial testing adjuvant intismeran autogene plus pembrolizumab in renal cell carcinoma has completed enrolment, while separate phase 2 randomized studies in resected muscle‑invasive and resected non‑muscle‑invasive bladder cancer continue to enrol patients. In addition, phase 2 trials are underway assessing the combination as first‑line systemic treatment for metastatic melanoma and for metastatic squamous non‑small cell lung cancer.
Intismeran autogene: individualized mRNA neoantigen therapy
Intismeran autogene is an investigational individualized neoantigen therapy built on messenger RNA technology. For each patient, tumour DNA is sequenced to identify tumour‑specific mutations, and a bespoke synthetic mRNA is designed to encode up to 34 predicted neoantigens arising from that mutational profile. Once administered, the mRNA is translated inside the body to produce the encoded neoantigen peptides, which are processed and presented by antigen‑presenting cells, a critical step in initiating adaptive immune responses.
The goal of this individualized approach is to prime and expand tumour‑specific T‑cell populations capable of recognising and attacking cancer cells that carry the same neoantigens, thereby enhancing antitumour immunity when combined with checkpoint blockade. By tailoring the encoded antigens to each patient’s tumour, intismeran autogene aims to generate a focused immune response against malignant cells while sparing normal tissues.
Overview of the KEYNOTE‑942/mRNA‑4157‑P201 study
KEYNOTE‑942 is an ongoing, randomized, open‑label phase 2b study that enrolled 157 patients with high‑risk stage III or IV cutaneous melanoma who had undergone complete surgical resection. Participants were stratified by disease stage and assigned in a 2:1 ratio to receive intismeran autogene plus pembrolizumab or pembrolizumab alone as adjuvant therapy until recurrence, unacceptable toxicity, or completion of the planned treatment course.
In the combination arm, patients received intramuscular intismeran autogene at a dose of 1 mg every three weeks for up to nine doses, together with intravenous pembrolizumab 200 mg every three weeks for up to 18 cycles, corresponding to approximately one year of treatment. Patients in the control arm were treated with pembrolizumab alone on the same schedule for about one year, in line with standard adjuvant practice in this setting.
The primary endpoint of the trial is recurrence‑free survival, defined as the time from the first pembrolizumab dose to locoregional or distant melanoma recurrence, emergence of a new primary melanoma, or death from any cause in the intention‑to‑treat population. Key secondary endpoints include distant metastasis‑free survival and safety, while exploratory analyses are evaluating factors such as tumour mutational burden and their relationship to clinical outcomes.
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