The introduction of checkpoint inhibitors and targeted therapy with kinase inhibitors revolutionized the treatment options for patients with advanced-stage melanoma. While there is already a lot of evidence for immunotherapy in the adjuvant setting, anti-PD-1 therapy also delivered convincing results in the neoadjuvant setting in a recent study. There are also interesting new findings on the mechanisms of immunotherapy resistance and the use of oncolytic viruses and therapeutic vaccinations.
In advanced-stage melanoma patients, immune checkpoint inhibitors can now achieve a lasting treatment response in almost half of those treated. This is a significant advance compared to previous standard chemotherapies, emphasized Prof. Dr. med. Clinic Director Dermatology Clinic University Hospital Zurich and Head of the Skin Tumor Center [1]. The principle of these innovative therapeutic agents is that the patient’s own immune cells are stimulated to fight the cancer cells themselves. It has been shown that by blocking inhibitory signaling pathways, their inhibitory effect on useful immune responses in the fight against tumors could be reversed. “Our immune system is able to control the evolution of cancer cells,” summarized the speaker [1].
What is the optimal treatment sequence for PD1 checkpoint blockers?
The question of the optimal therapy sequence is increasingly attracting the attention of experts. Whereas in the past systemic therapy options were only used after the possibilities of surgical treatment (primary tumor, lymph node metastases, distant metastases) and radiotherapy had been exhausted, nowadays systemic therapy is also used in the adjuvant and neoadjuvant setting. Long-term data from a 5-year follow-up show that prophylactic anti-PD-1-based therapy with pembrolizumab in the adjuvant setting (i.e. after resection of a high-risk melanoma or the sentinel lymph nodes) resulted in significantly longer recurrence-free survival than placebo, reported Prof. Dummer [1,2]. However, for patients with advanced malignant melanoma that can still be surgically removed, it is apparently also worthwhile to carry out supportive neoadjuvant immunotherapy with a PD1 (programmed-cell death protein 1) checkpoint blockerbefore surgery. “The neoadjuvant approach is very interesting,” said the speaker [1].
In a phase III study published in the New England Journal of Medicine in 2023, 313 patients with resectable stage IIIB or IVC melanoma were randomized to two treatment arms (Fig. 1) [3]. One group received 3 cycles of the anti-PD-1 antibody pembrolizumab in the neoadjuvant setting, followed by surgery and 15 cycles of pembrolizumab adjuvant (n=154). In the other group (n=159), surgery was performed first, followed by adjuvant treatment with pembrolizumab (18 cycles in total) for approximately 1 year or until recurrence or intolerable toxic side effects occurred. Pembrolizumab was administered intravenously at a dose of 200 mg every 3 weeks. After a median observation period of 14.7 months, significantly fewer new disease events had occurred in the neoadjuvant-adjuvant group than in the adjuvant group. Landmark analyses showed that after two years, no further events occurred in 71% of the neoadjuvant-adjuvant group, while this was the case in 49% of the adjuvant group.
Resistance mechanisms: new findings on TIM-3, LAG-3 and TIGIT
The fact that not all patients respond to immunotherapy indicates that resistance mechanisms develop and a specific tumor microenvironment develops [4]. “Primary resistance is the main problem in the immunotherapy of cancer patients,” explained Prof. Dummer. Research is therefore also focusing on the mechanisms by which melanoma evades the anti-tumor immune response. Immune checkpoint molecules that play an important role in this process are the T cell immunoglobulin and mucin domain 3 (TIM-3), the T cell immune receptor with Ig and ITIM domains (TIGIT) and LAG-3 (lymphocyte activation gene 3 protein) (Fig. 2) [5].
At this year’s annual meeting of the American Society of Clinical Oncology (ASCO), results of the RELATIVITY-047 study were presented showing that patients with non-operable malignant melanoma benefit from combination therapy with a PD1 inhibitor and a LAG3 inhibitor. 355 patients received a combination therapy of PD1 and LAG3 blocker and 359 only the PD1 blocker alone. After a follow-up period of around two years, recurrence-free survival proved to be significantly longer in the combination therapy group, and overall survival and response rates were also better than with the PD1 blocker alone. However, severe grade 3-4 side effects and treatment-related deaths occurred more frequently in the combination therapy group. [6,7].
Oncolytic viruses: long-term data on T-VEC
The active principle of oncolytic virus therapy is based on the fact that oncolysis, apoptosis, necrosis and autophagic cell death are induced and a general anti-tumor immune response is stimulated [8]. Talimogen-Laherparepvec (T-VEC) is a recombinant, modified herpes simplex virus type 1 (HSV-1) that is used as an oncolytic immunotherapy for malignant melanoma. The virus replicates selectively in tumor cells and supports the local destruction of tumor cells by promoting the recruitment of T cells and natural killer cells [9]. The OPTiM clinical trial showed that patients with non-resectable advanced-stage melanoma treated with T-VEC monotherapy had a significantly better durable response compared to granulocyte-macrophage colony-stimulating factor (GM-CSF) (Box) [10].
T-VEC monotherapy: Phase III OPTiM study 436 patients with non-resectable stage IIIB, IIIC or IV melanoma were included in the OPTiM study and randomized 2:1 to talimogene laherparepvec (intralesional every 2 weeks) or GM-CSF (s.c. in the first 14 days of each 28-day cycle). After a median follow-up period of 49 months, the median overall survival (OS) in the T-VEC arm was 23.3 months (95% confidence interval [KI]; 19.5-29.6) and in the GM-CSF arm 18.9 months (95% CI; 16.0-23.7) (unstratified HR; 0.79; 95% CI; 0.62-1.00; p=0.0494) [10]. T-VEC showed the best efficacy in patients with IIIB-IVM1a melanoma, which is consistent with previous analyses. The 5-year data from the study are now also available, showing that T-VEC also proved to be superior over this follow-up period [9]. |
mRNA vaccine in addition to immune PD1 checkpoint blockade
Prophylactic vaccinations are used to prevent infections, while therapeutic vaccinations are intended to activate the body’s defenses against specific antigens. The latter is the principle behind vaccinations to combat tumor cells (Fig. 3) [11]. Therapeutic vaccinations with mRNA vaccination in combination with checkpoint inhibitors are currently the subject of intensive research. T cells recognize tumor-specific antigens, which are specifically produced only in cancer cells due to somatic mutations, as foreign and therefore represent an ideal target for cancer vaccines [11,12]. Also presented at the ASCO congress were the results of a study showing that a combination of a personalized mRNA vaccination with immunotherapy can significantly reduce the risk of relapse after surgery [13,14]. This is the mRNA-4157-P201/Keynote-942 Phase 2 study in adult patients with stage IIIB/C/D or IV melanoma who were at high risk of recurrence after complete tumor removal due to certain tumor characteristics. In addition to adjuvant immunotherapy with a PD1 blocker, some of the patients received an mRNA vaccine, which was administered every three weeks up to a total of nine doses. After two years, significantly more relapses had occurred in the group treated with the PD1 blocker alone than in the PD1/mRNA vaccine group. Furthermore, distant metastases were significantly less frequent in the PD1/mRNA vaccine group.
Congress: SGAI Annual Meeting
Literature:
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- Patel SP, et al.: Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med 2023; 388(9): 813–823.
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- Tawbi HA, et al.: Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year results from RELATIVITY-047. Präsentation auf ASCO 2023, abstract 9502.
- «Doppeltherapie bei fortgeschrittenem malignem Melanom langfristig vorteilhaft», Deutsche Krebsgesellschaft, 12.06.2023.
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- Dummer R, et al.: Final 5-Year Follow-Up Results Evaluating Neoadjuvant Talimogene Laherparepvec Plus Surgery in Advanced Melanoma: A Randomized Clinical Trial. JAMA Oncol 2023; Aug 10: e232789.
- Andtbacka RHI, et al.: Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III–IV melanoma.
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DERMATOLOGIE PRAXIS 2023; 33(5): 35–37