This pipeline report presents insights into drugs currently in phase 2, phase 3 or recently approved for the treatment of melanoma.
In 2018, an estimated 96,480 patients in the United States were diagnosed with melanoma, and about 7,230 patients died from the disease.1,2 Drug development within melanoma has focused on cutaneous melanoma therapeutics and later stages of disease when surgery is not an option.
Melanoma has historically been a disease that is difficult to treat with pharmacotherapy and drug development made limited progress. In recent
years, developments in molecular biology, have led to an increased understanding of the molecular heterogeneity of melanoma that has resulted in introducing new insights into the role of oncogenes, immune checkpoints, and signaling pathways which has accelerated the discovery rate of therapeutic targets and their associated novel drugs. Breakthrough drug approvals in recent years, checkpoint inhibitors and MEK/BRAF combination therapies have prolonged survival and changed the treatment landscape.
Even with the impact of these breakthrough therapies, unmet needs still remain for safer and more effective therapies. The greatest promise in addressing these needs may come in the form of combining novel therapeutics with currently marketed therapies to provide effective treatment and improve patient survival.
Know these innovative melanoma therapeutics on the horizon.
APX005M BY APEXIGEN
APX005M is a humanized monoclonal antibody and a potent CD40 agonist designed to reverse the systemic immune suppression. CD40 is a co-stimulatory receptor that is essential for activating both innate and adaptive immune systems. APX005M is administered by intratumoral injection and has the potential to be used as a single agent and in combination with other immune-oncology agents, targeted therapies and vaccines.3 A phase 1/2 dose escalation and cohort expansion, safety and tolerability study of intratumoral APX005M in combination with systemic pembrolizumab in 41 patients with metastatic melanoma is scheduled to be completed in June of 2020.4
DAROMUN BY PHILOGEN
Daromun is a combination of Darleukin, a human vascular targeting monoclonal antibody (L19) fused to interleukin-2 (IL-2), and Fibromun, the L19 antibody linked to tumor necrosis factor (TNF). Daromun is being developed as a neoadjuvant intralesional treatment for stage IIIB and C melanoma.
Philogen received an Orphan Drug designation from the FDA in 2017. Daromun would be the first neoadjuvant therapy aimed at blocking or delaying progression to stage IV melanoma. In a phase 2 study of intralesional treatment with Daromun in stage III/IVA melanoma patients (EudraCT No. 2012-001991-13) efficacy was demonstrated in terms of complete and partial response of the injected metastases, as well as a systemic immune response in non-injected lesions that resulted in shrinking the lesions or in some cases disappearing. In addition, a decelerated progression to stage IV melanoma of treated patients with respect to historical controls was recorded.
A randomized, controlled phase 3 registration trial of intralesional application of Daromun as a neoadjuvant, followed by surgery and compared to surgery alone is presently ongoing in Europe and USA with a projected enrollment of 248 patients with fully resectable stage IIIB/C melanoma. The primary endpoint is recurrence-free survival, with overall survival as key secondary endpoint.5,6
The data for this article were compiled from the Pharmaceutical Research and Manufacturers of America 2018 Medicines in Development for Cancer Report; NIH www.clinicaltrials.gov; corporate websites, and Pubmed.
1. NCCN Clinical Practice Guidelines: Cutaneous Melanoma; Version 2.2019, March 2019.
2. American Cancer Society. Cancer Facts & Figures 2019. Atlanta: American Cancer Society;2019
4. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT02706353. APX005M in Combination With Systemic Pembrolizumab in Patients With Metastatic Melanoma. Available: https://clinicaltrials.gov/ct2/show/NCT02706353. Updated May 9, 2019.
6. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT03567889. Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C Melanoma Patients (Neo-DREAM). Available: https://clinicaltrials.gov/ct2/show/NCT03567889. Updated March 21, 2019.
8. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT02437136. Ph1b/2 Dose-Escalation Study of Entinostat With Pembrolizumab in NSCLC With Expansion Cohorts in NSCLC, Melanoma, and Colorectal Cancer. Available: https://clinicaltrials.gov/ct2/show/NCT02437136. Updated November 28, 2018.
9. Sullivan R, et al. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in pati3nts with melanoma previously treated with anti-PD-1 therapy. 2019 American Association for Cancer Research Annual Meeting, Atlanta, GA.
12. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT03153085. A Study of Combination With TBI-1401(HF10) and Ipilimumab in Japanese Patients With Unresectable or Metastatic Melanoma. Available: https://clinicaltrials.gov/ct2/show/NCT03153085. Updated January 24, 2019.
14. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT01335009. Efficacy Study of Pharmacokinetic(PK)/Pharmacodynamic(PD) Relationship of Monotherapy MORAb-004 in Metastatic Melanoma. Available: https://clinicaltrials.gov/ct2/show/NCT01335009. Updated April 22, 2019.
15. D’Angelo SP, et al. A phase 2 study of ontuxizumab, a monoclonal antibody targeting endosialin, in metastatic Melanoma. Investigational New Drugs 2018.36(1):103-113.
17. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT02644967. A Study to Assess the Safety and Efficacy of Intratumoral IMO-2125 in Combination With Ipilimumab or Pembrolizumab in Patients With Metastatic Melanoma (ILLUMINATE-204). Available: https://clinicaltrials.gov/ct2/show/NCT02644967. Updated April 25, 2019.
18. Diab A, et al. The safety and efficacy of intratumoral injection of the TLR9 agonist tilsotolimod (IMO-2125) in combination with ipilimumab in patients with PD-1 inhibitor refractory metastatic melanoma: An analysis of efficacy in injected and uninjected lesions. Presented at ESMO Congress, October 2018.
19. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT03445533. A Study of IMO-2125 in Combination With Ipilimumab Versus Ipilimumab Alone in Subjects With Anti-PD-1 Refractory Melanoma (ILLUMINATE-301) (ILLUMINATE-301). Available: https://clinicaltrials.gov/ct2/show/NCT03445533. Updated May 10, 2019.
21. Myers j. Interim analysis of a prospective , randomized, double-blind, placebo-controlled, Phase 2b trial o TLPLDC vaccine to prevent recurrence in resected Stage III or IV melanoma patients. 2018 ASCO Annual Meeting , Poster #352 Melanoma/Skin Cancers Poster Session, June 4, 2018.
23. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT03190824. Evaluate Efficacy, Immunological Response of Intratumoral/Intralesional Oncolytic Virus (OBP-301) in Metastatic Melanoma. Available: https://clinicaltrials.gov/ct2/show/NCT03190824. Updated April 16, 2019.
25. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT03132675. Tavo and Pembrolizumab in Patients With Stage III/IV Melanoma Progressing on Pembrolizumab or Nivolumab Treatment (PISCES). Available: https://clinicaltrials.gov/ct2/show/NCT03132675. Updated April 5, 2019.
26. Arraybiopharma.com; braftovimektovi.com
27. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). NCT01909453. Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS). Available: https://clinicaltrials.gov/ct2/show/NCT01909453. Updated April 26, 2019.