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Novel Treatment Strategies Under Study in Advanced Melanoma


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Several novel strategies for the treatment of patients with stage III or IV melanoma showed promise in studies presented at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium.1,2

Vaccine for High-Risk Patients After Resection

A tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine was protective against recurrence in high-risk patients with stage IV melanoma, in a phase IIb trial presented by R. Connor Chick, MD, of Brooke Army Medical Center, Fort Sam Houston, Texas.1


“The vaccine was most effective in patients with stage IV resected melanoma and, furthermore, appeared to have a synergistic effect when used with checkpoint inhibitors.”
— R. Connor Chick, MD

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Patients with stage IV resected melanoma who received the vaccine had a 24-month disease-free survival of 43%, compared with 0% of patients who received a control injection. “The vaccine was most effective in patients with stage IV resected melanoma and, furthermore, appeared to have a synergistic effect when used with checkpoint inhibitors,” said Dr. Chick.

The TLPLDC vaccine uses yeast cell wall particles to load tumor lysate into autologous dendritic cells. Tumor lysate is derived from the resected tumor, broken down into its component antigens via freeze-thaw cycling, and then loaded into the yeast cell wall particles. These particles are exposed to the patient’s own dendritic cells isolated from their blood. Dendritic cells are the major antigen-presenting cells, especially in skin and soft tissue. “The idea is this vaccine uses the whole antigenic array of the patient’s tumor,” Dr. Chick explained to The ASCO Post.

Study Details

This phase IIb trial of the TLPLDC vaccine vs placebo enrolled 144 patients with resected stage III or IV melanoma. The study determined the 24-month disease-free survival in the per-treatment analysis and evaluated efficacy by stage, immunotherapy, and concomitant use of checkpoint inhibition. These patients were considered disease-free after surgery and were randomly assigned 2:1 to the vaccine vs unloaded yeast cell wall particles and autologous dendritic cells at 0, 1, 2, 6, 12, and 18 months.

The protocol was amended to allow concurrent checkpoint inhibitors once they became approved for adjuvant melanoma treatment (which were received by more patients with stage IV disease than with stage III disease). The prespecified per-treatment analysis included just the 98 patients who completed the primary vaccine/placebo series at 6 months.

Benefit in Stage IV Disease—Not Stage III Disease

Patients with stage IV disease appeared to derive a strong benefit from the vaccine, as 73% of this group were disease-free at 24 months, compared with no patients in the control arm (P = .002). In the intent-to-treat analysis, a strong trend was observed, with a 43% disease-free survival rate vs 0% (P = .098). However, no differences were observed between treatment arms in the stage III cohort in either analysis, Dr. Chick reported.

The strongest benefit was observed in patients who received a checkpoint inhibitor along with the vaccine; among patients not receiving a checkpoint inhibitor, no differences were observed between the arms, Dr. Chick said. The use of checkpoint inhibitors did not increase the occurrence of immune-related adverse events, he added.

KEY POINTS

  • A tumor lysate, particle-loaded, dendritic cell vaccine was protective against recurrence in patients with high-risk stage IV melanoma in a phase IIb trial.
  • Among patients with stage IV disease, 73% of patients receiving this vaccine were disease-free for 24 months compared with no patients in the control arm (P = .002).
  • In patients with metastatic BRAF-mutated melanoma, BRAF inhibition paired with inhibition of programmed cell death protein 1 and the novel antibody spartalizumab yielded a 78% response rate (42% complete response rate).

Dr. Chick believes the greater use of the checkpoint inhibitor in patients with stage IV disease may help to explain the greater benefit seen in this subgroup vs stage III. “It’s a confounding factor. After the protocol was amended (when checkpoint inhibitors were approved in the adjuvant setting), only the final one-third of our patients were able to receive this therapy at the discretion of the treating physician and that included 50% of patients with stage IV disease vs 26% of patients with stage III disease (P = .003).”

Dr. Chick continued: “Based on these findings and those from some other trials we and others have done, we think there may be a synergistic effect to taking off the brake with the checkpoint inhibitor and pressing on the gas with the vaccine.” This theory will be evaluated in a phase III study in which patients with resected stage IV melanoma receive the vaccine with and without a checkpoint inhibitor.

Anti–PD-1 Agent in BRAF-Mutated Melanoma

High response rates were achieved in metastatic BRAF-mutated melanoma when BRAF inhibition was paired with inhibition of programmed cell death protein 1 (PD-1), in a study led by Georgina V. Long, MD, PhD, Co-Medical Director of Melanoma Institute Australia (MIA) and Chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, The University of Sydney.

The approach of the COMBI-I trial is based on the fact that BRAF inhibition increases T-cell infiltration, melanoma antigen expression, and the expression of PD-1/programmed cell death ligand 1. This may lead to synergistic activity with anti–PD-1 therapy, she explained in her poster.

Georgina V. Long, MD, PhD

Georgina V. Long, MD, PhD

COMBI-I is investigating first-line treatment of patients with unresectable or metastatic BRAF V600–mutant melanoma using dabrafenib at 150 mg twice daily and trametinib at 2 mg daily, plus the experimental anti–PD-1 antibody spartalizumab at 400 mg every 4 weeks. Spartalizumab has shown antitumor activity in melanoma and non–small cell lung cancer.

At the Symposium, Dr. Long and colleagues reported on the pooled efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort) of the study, involving 35 previously untreated patients.2 A total of 20 patients (56%) had stage IV M1c disease, and 15 (42%) had elevated baseline lactate dehydrogenase (LDH) levels.

Objective Response Rate of 78%

After a median follow-up of 19.9 months, treatment was ongoing in 13 of 36 patients. The confirmed objective response rate by investigator assessment was 78%, with 42% being complete responses. Among the 15 complete responders, 20% had elevated LDH levels at baseline, and 40% had stage IV M1c disease. The disease control rate with this triplet was 94%, Dr. Long reported.

The median duration of response was 20.7 months. The median progression-free survival was 23.7 months overall and 10.7 months in patients with elevated baseline LDH levels. At data cutoff, 22% of patients had died, and the median overall survival was not reached. The 12-month duration of response rate was 80.3%; at 12 months, 66.7% of patients were progression-free and 86.1% were alive.

All patients had at least one treatment-related adverse event, which was ≥ grade 3 in 72%. Almost half the patients stopped one drug due to an adverse event, and 17% discontinued treatment with all three agents. These toxicities included increased levels of gamma-glutamyl transferase, elevated liver enzyme levels, dermatitis, hyperkalemia, paresthesia, immune-mediated hepatitis, and interstitial lung disease. Pyrexia was the most common toxicity, occurring in 89% of patients.

“No new safety signals were observed, and adverse events were consistent with the individual toxicity profile of each study drug,” Dr. Long noted.

Part 3 of the study will be a global, double-blind, randomized, placebo-controlled trial, which is ongoing (NCT02967692). 

DISCLOSURE: Dr. Chick’s study was funded by Elios Therapeutics, and Dr. Chick reported no conflicts of interest. Dr. Long’s study was funded by Novartis, and Dr. Long has served as an advisor or consultant to Aduro, Amgen, Bristol-Myers Squibb, Mass-Array, Merck, MSD, Novartis, OncoSec Medical, Pierre Fabre, Roche, and Sandoz.

REFERENCES

1. Chick RC, Faries MB, Hale DF, et al: Multi-institutional, prospective, randomized, double-blind, placebo-controlled phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine to prevent recurrence in high-risk melanoma patients: A subgroup analysis. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 63. Presented February 7, 2020.

2. Long GV, Lebbe C, Atkinson V, et al: The anti–PD-1 antibody spartalizumab in combination with dabrafenib and trametinib in previously untreated patients with advanced BRAF V600–mutant melanoma: Updated efficacy and safety from parts 1 and 2 of COMBI-I. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 57. Presented February 7, 2020.

 


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