Dr. Lu Si
Department of Melanoma and Sarcoma, Peking University Cancer Hospital
PD-1 inhibitors have become the international standard for adjuvant treatment of stage IIB-IV melanoma after surgery. Research on the neoadjuvant use of PD-1 monotherapy (pembrolizumab) for resectable melanoma was just published in the New England Journal of Medicine in March of this year. With this, PD-1 inhibitors cover the two major treatment areas of neoadjuvant and adjuvant treatment of melanoma. Two studies presented at this year’s AACR conference have brought new breakthroughs to this field.
KEYNOTE-942 Study: Personalized Neoantigen mRNA Vaccine Combined with PD-1 Monoclonal Antibodies vs. PD-1 Monoclonal Antibodies as Adjuvant Treatment
Background:
KEYNOTE-942-054 and CheckMate-238 studies established the role of PD-1 monoclonal antibodies as adjuvant treatment in high-risk recurrent melanoma patients. For example, with pembrolizumab (compared to a placebo), the 5-year recurrence-free survival rates were 55% and 38%, respectively. mRNA-4157 is a personalized neoantigen-based therapeutic approach (vaccine therapy) that predicts new antigens by collecting patient tissue and blood samples, performing NGS sequencing, using a series of algorithms to select up to 34 new antigens, and synthesizing the corresponding mRNA. Finally, this mRNA is administered to patients to activate specific T-cell immunity. This study aims to compare mRNA vaccines combined with PD-1 monoclonal antibodies against PD-1 monoclonal antibodies alone for adjuvant treatment in high-risk patients.
Study Design: This is a phase II open-label clinical trial, randomized in a 2:1 ratio into the combination group and the PD-1 monotherapy group, as illustrated in the diagram. The primary endpoint of this study is recurrence-free survival (RFS), while the secondary endpoints include distant metastasis-free survival (DMFS), safety, and tolerability.
Study Results: The baseline characteristics of the patients are presented in the following figure. Most of the baseline characteristics were similar between the two groups, with the combination group having a higher proportion of patients who had undergone multiple prior surgeries.
The overall safety data for both groups are comparable (as shown in the first column of the figure). However, the combination group had a slightly higher incidence of treatment-related adverse events (TRAEs) of grade ≥3 compared to the monotherapy group (25% vs. 18%). The main TRAEs associated with the mRNA vaccine included fatigue, injection site pain/swelling, chills/fever, but most of these events were grade 1-2 (as shown in the second column of the figure). The combination of mRNA vaccine with pembrolizumab primarily increased the incidence of fatigue and diarrhea (as shown in the third column of the figure).
The RFS curves for both groups and the RFS curves stratified by PD-L1 are shown below. The combination group demonstrated a significant 44% reduction in the risk of recurrence (HR 0.561, 95% CI: 0.309~1.017, P=0.0266), with an increase in the 18-month RFS rate by 16.4% (78.6% vs 62.2%).
Study Conclusion: The 2-year follow-up data shows a 44% reduction in the risk of recurrence or death in the combination group. This is the first study to confirm the benefit of personalized neoantigen vaccines for RFS (Phase III international clinical trials have been initiated). Additionally, the combination group did not experience an increase in grade 3/4 adverse events. This therapy received FDA breakthrough therapy designation in February 2023 and is also being explored in other areas, including lung cancer.
Study Commentary: Vaccine therapy for melanoma has undergone numerous attempts in the past, primarily targeting tumor-associated antigens that can also be expressed in normal cells, such as MAGE-A3, GM2-KLH, and gp-100. These efforts in the adjuvant and advanced settings did not yield positive results and, in some cases, performed worse than the control groups.
In recent years, vaccine therapy targeting tumor neoantigens has garnered significant attention due to its ability to enhance the functionality of specific T cells. Neoantigens are unique to tumor cells and result from specific mutations that occur during tumor cell growth. However, not all mutations can serve as effective targets. Ideal targets not only need to appear on the surface of tumor cells but also must elicit a strong enough immune system response in patients. Only a small fraction of mutations is presented on the surface of tumor cells as neoantigens in practice, making new algorithms and mRNA synthesis platforms critical for this technology. Products like NEOVOX, NEO-PV-01, and samRNA are currently undergoing early clinical studies. Several domestic companies in China are also actively researching and clinically testing mRNA vaccines focused on predicting neoantigens. Our center is preparing to initiate related research in this field later this year.
KEYMAKER-U02 Study-02C Subgroup: PD-1 Monoclonal Antibodies + TIGIT Monoclonal Antibodies vs. PD-1 Monoclonal Antibodies + Small RNA Oncolytic Virus (V937) vs. PD-1 Monoclonal Antibodies as Neoadjuvant Therapy
Background: Oncolytic virus therapy, exemplified by T-VEC, has received FDA approval. V937 is another investigational small RNA oncolytic virus (wild-type coxsackievirus A21), and previous phase I studies have demonstrated promising antitumor activity when combined with anti-CTLA-4 therapy. There have been numerous studies reporting the combination of T-VEC with PD-1 inhibitors (click to read: Oncolytic Virus or Lag3 Monoclonal Antibodies? Who is the Perfect Match for PD-1 Monoclonal Antibodies?). This study aims to explore the differences between PD-1+TIGIT (Vibo) and PD-1+V937 (Geba) neoadjuvant therapies.
Study Design: As illustrated in the diagram, patients are randomized into three groups. The primary endpoints of this study are safety, tolerability, and pCR (pathologic complete response) rate.
Study Flowchart: As shown in the diagram, the number of patients entering each group at each stage is relatively balanced in the combination group. Not all patients completed the adjuvant treatment stage. The baseline characteristics of patients in all three groups are depicted in the figure, with the PD-1+oncolytic virus group having the highest proportion of BRAF mutations and the monotherapy group having the lowest.
Study Results: Adverse reactions are illustrated in the following figure. The TIGIT group experienced more severe side effects such as rash, vitiligo, itching, and fatigue. In contrast, the monotherapy group showed more pronounced joint pain and elevated creatine kinase (CK) levels. According to the RECIST 1.1 assessment, the TIGIT combination group had the highest objective response rate (ORR), reaching 50%.
From the figure below, it can be observed that the oncolytic virus group had the lowest pathological response rate (52%), while the TIGIT combination group had the highest response rate (83%).
From the 18-month survival curves, it appears that the combination group has better 18-month event-free survival (EFS) and recurrence-free survival (RFS) compared to the monotherapy group.
Summary: In the TIGIT combination group, 19% of patients experienced rash, while in the oncolytic virus group, 20% of patients had injection site pain. Efficacy and RFS data are depicted in the figure below. Additionally, an international Phase III clinical trial of TIGIT monoclonal antibodies + PD-1 monoclonal antibodies for adjuvant treatment has commenced, with China launching its study simultaneously later this year. Our center is the first hospital in China to initiate this trial.
Study Commentary: This study compared the neoadjuvant effects of three treatment regimens for cutaneous melanoma. Similar to the MASTERKRY study from the previous year, which showed that the combination of K+TVEC (an engineered herpes simplex virus oncolytic virus) did not outperform monotherapy with a PD-1 inhibitor in terms of efficacy and overall survival. Similarly, this study did not demonstrate a clear advantage of small RNA oncolytic virus in combination with PD-1 inhibitors compared to monotherapy. However, it’s worth noting that V937 is a wild-type coxsackievirus A21, a small RNA oncolytic virus, which is not the mainstream DNA virus used in current therapies. Its effectiveness may differ from other types of oncolytic viruses.
Furthermore, the significantly higher proportion of BRAF-V600 mutations in the oncolytic virus group might have influenced the results to some extent. Additionally, results from clinical trials in China using oncolytic viruses (engineered herpes simplex virus) in combination with PD-1 inhibitors for neoadjuvant treatment of acral melanoma showed a 70% pathologic response rate, which was far superior to PD-1 monotherapy. This suggests that different subtypes of melanoma and different types of oncolytic virus therapies can yield different outcomes.
In this study, the combination of TIGIT and PD-1 inhibitors showed superior results compared to previous reports on neoadjuvant dual immune therapy (PD-1+CTLA-4 inhibitors, PD-1 inhibitors+Lag3 inhibitors). This combination could potentially become the third approved dual immune therapy for melanoma treatment. Our center is currently conducting research on TIGIT+PD-1 inhibitors in advanced melanoma, and global studies in the adjuvant treatment setting are also on the horizon.
Overall, both TIGIT and personalized neoantigen mRNA vaccines have the potential to become valuable partners for PD-1 inhibitors in the adjuvant and neoadjuvant treatment of melanoma.
