Ahmad Tarhini, MD, PhD, is a tenured senior member of the Departments of Cutaneous Oncology and Immunology, the director of Cutaneous Clinical and Translational Research, and the leader of the Neoadjuvant and Adjuvant Translational Science Program at the Moffitt Cancer Center and Research Institute; as well as a professor of oncologic sciences at the University of South Florida Morsani College of Medicine

Dr Tarhini on the Rationale for Studying Vidutolimod Plus Pembrolizumab in Melanoma

“There continues to be an important need for improving the efficacy [of standard therapies], as well as reducing systemic toxicity that may be associated with immune checkpoint blockade combination therapies. This was the main trigger for us to do this study."

Ahmad Tarhini, MD, PhD, a tenured senior member of the Departments of Cutaneous Oncology and Immunology, the director of Cutaneous Clinical and Translational Research, and the leader of the Neoadjuvant and Adjuvant Translational Science Program at the Moffitt Cancer Center and Research Institute; as well as a professor of oncologic sciences at the University of South Florida Morsani College of Medicine, discussed the rationale for the phase 2 ECOG-ACRIN EA6194 trial (NCT04708418) investigating neoadjuvant pembrolizumab (Keytruda) plus vidutolimod (formerly CMP-001) in patients with macroscopic, resectable stage III melanoma.

This randomized clinical trial enrolled patients with locoregionally advanced melanoma, including those with clinically detectable bulky disease who were at elevated risk of recurrence and mortality following definitive surgery, Tarhini began. Although significant therapeutic advances have been achieved for this population in recent years, there remains a clear need to enhance the efficacy of standard treatment approaches and simultaneously reduce systemic toxicities commonly associated with combination immune checkpoint blockade, he stated. These considerations provided the rationale for the initiation of this study, he added.

The investigation was further motivated by the novel mechanism of action of the experimental agent vidutolimod, a TLR9 agonist, according to Tarhini. TLR9 is an endosomal receptor expressed on B cells and plasmacytoid dendritic cells, he explained. Its activation induces the production of type I interferons, which in turn stimulate both innate and adaptive antitumor immune responses, he noted. This mechanism suggests the potential to augment antitumor activity and mitigate the toxicity profile observed with conventional checkpoint inhibitor combinations, he continued.

Prior studies examining the combination of vidutolimod with PD-1 blockade in the metastatic, PD-1–refractory setting have demonstrated the encouraging clinical activity of these types of combinations, Tarhini said. These findings prompted the evaluation of vidutolimod plus pembrolizumab in the neoadjuvant setting, where the therapeutic potential may be optimized, he reported. The hypothesis is that such a combination could improve efficacy outcomes with minimal systemic immune-related adverse effects, he concluded.

Videos

Ahmad Tarhini, MD, PhD, discussed the rationale for evaluating preoperative pembrolizumab plus vidutolimod in macroscopic, resectable stage III melanoma. 

Dr Tarhini on Neoadjuvant Pembrolizumab  Plus Vidutolimod in Resectable Melanoma

“The study met its primary end point of improved pathologic complete response [with pembrolizumab plus vidutolimod vs pembrolizumab monotherapy], which was 71% on the combination arm.”

Ahmad A. Tarhini, MD, PhD, a tenured senior member in the Departments of Cutenaous Oncology and Immunology; the director of Cutaneous Clinical and Translational Research; leader of the Neoadjuvant and Adjuvant Translational Science Program at Moffitt Cancer Center; and a professor of oncologic sciences at the University of South Florida Morsani College of Medicine, discussed data from the phase 2 ECOG-ACRIN EA6194 trial (NCT04708418) presented during the 

ECOG-ACRIN EA6194 evaluated pembrolizumab (Keytruda) with or without vidutolimod for the treatment of patients with high-risk resectable melanoma. The primary end point of the trial was pathologic complete response (pCR) rate.

Among all enrolled patients, those who received the combination (n = 28) achieved a pCR rate of 71% (95% CI, 51%-87%), meeting the primary end point, Tarhini said. Comparatively, patients who received pembrolizumab monotherapy (n = 29) achieved a pCR rate of 48% (95% CI, 29%-67%).

The overall response rate (ORR) in the combination arm was 43%, including a complete response (CR) rate of 7%. These respective rates were 50% and 4% in the monotherapy group.

The major pathologic response (MPR) rate among patients who were treated with the combination was 79%, Tarhini added. The MPR rate in the monotherapy arm was 58%. At a median follow-up of 19 months (range, 2-36), the 1-year event-free survival rates were 89% (95% CI, 78%-100%) and 75% (95% CI, 59%-91%), respectively, he added. In addition to comparing favorably to the monotherapy arm, the efficacy data compared well with historical controls, he noted.

In terms of safety, no grade 5 adverse effects (AEs) were reported. Grade 3 or 4 AEs were reported at rates of 25% in the monotherapy arm and 29% in the combination arm. Any-grade treatment-related AEs (TRAEs) in the monotherapy arm included fatigue (39%), maculopapular rash (32%), and nausea (29%). In the combination arm, common any-grade TRAEs consisted of fatigue (68%), maculopapular rash (43%), and increased aspartate aminotransferase and/or alanine aminotransferase levels (39%).

Ahmad A. Tarhini, MD, PhD, discusses findings from the ECOG-ACRIN EA6194 trial of pembrolizumab plus vidutolimod in resectable melanoma.

Dr Tarhini on Neoadjuvant Pembrolizumab Plus Vidutolimod in Resectable Melanoma 

Dr Tarhini on the Combination of High-Dose Bolus IL-2 and CTLA-4 Inhibition in Advanced Melanoma

Ahmad Tarhini, MD, PhD, director, Cutaneous Clinical and Translational Research, leader, Neoadjuvant and Adjuvant Translational Science Program, senior member, Moffitt Cancer Center, Research Institute Departments of Cutaneous Oncology and Immunology; professor, Oncologic Sciences, the University of South Florida Morsani College of Medicine; chair, Scientific Committee, Oncology Research Information Exchange Network (ORIEN); chair, ORIEN ImmunoOncology Research Subcommittee, discusses the rationale for investigating high-dose bolus interleukin-2 (IL-2) plus concurrent low-dose ipilimumab (Yervoy), followed sequentially by nivolumab (Opdivo), in patients with advanced melanoma.

At the 2024 ASCO Annual Meeting, investigators presented data on this combination in patients who had previously progressed on anti–PD1-based immunotherapy and BRAF-MEK inhibition. Tarhini states that the hypothesis for the study was that the pro-inflammatory cytokine IL-2 may work synergistically with CTLA-4 blockade to enhance the immunogenicity of the tumor microenvironment (TME). This hypothesis was grounded in preclinical animal model data that have demonstrated the necessity of high concentrations of IL-2 to achieve the antitumor activity associated with CTLA-4 blockade, he explains.

Further supporting this hypothesis, other animal model studies have shown that the combination of IL-2 and PD-L1 blockade may reinvigorate exhausted T cells, leading to an increased expansion of CD8-positive T cells and improved T-cell function, Tarhini continues. The combination may upregulate immune responses, he notes. Additionally, prior research has highlighted the ability of the anti–CTLA-4 agent ipilimumab to induce a significant infiltration of CD8-positive T cells into the TME, supporting the potential benefits of combining these treatments, according to Tarhini.

Building on these findings, investigators designed a phase 2 clinical trial to explore the effects of combining IL-2 with an anti–CTLA-4 agent, Tarhini reports. In this study, IL-2 and ipilimumab were administered concurrently, followed sequentially by anti–PD-1 therapy. This design leveraged the potential synergistic effects of these agents to enhance the overall antitumor immune response, offering a promising approach to improving therapeutic outcomes in patients with cancer, he states. Through this study, investigators provided further insight into the complex interactions within the TME and identified an effective treatment strategy for patients with advanced melanoma, Tarhini concludes.

Ahmad Tarhini, MD, PhD, discusses the hypothesis for investigating high-dose bolus IL-2 plus an anti–CTLA-4 agent in patients with advanced melanoma.

Dr Tarhini on Hogh-Dose Bolus IL-2 With Ipilimumab Followed by Nivolumab in Melanoma

Ahmad Tarhini, MD, PhD, director, Cutaneous Clinical and Translational Research, leader, Neoadjuvant and Adjuvant Translational Science Program, senior member, Moffitt Cancer Center, Research Institute Departments of Cutaneous Oncology and Immunology; professor, Oncologic Sciences, University of South Florida Morsani College of Medicine; chair, Scientific Committee, Oncology Research Information Exchange Network (ORIEN); chair, ORIEN ImmunoOncology Research Subcommittee, discusses the use of high-dose bolus interleukin-2 (IL-2) with concurrent low-dose ipilimumab (Yervoy), followed sequentially by nivolumab (Opdivo), in patients with advanced melanoma.

These patients had experienced disease progression despite receiving immunotherapy, specifically anti-PD-1-based treatments either alone or in combination, as well as BRAF and MEK inhibitors if their tumors had 

 mutations, Tarhini begins. The treatment protocol involved up to 3 courses of combination therapy, each lasting 12 weeks and divided into 4 cycles, with each cycle spanning 3 weeks.

The regimen began with a low dose of ipilimumab administered concurrently with high-dose IL-2 during the first week of the first 2 cycles, he explains. Starting in the first week of the third cycle, nivolumab, an anti–PD-1 therapy, was introduced. Disease assessments were conducted at the 12-week mark, and patients who demonstrated stable disease or a positive response were eligible for further treatment courses, Tarhini states.

This regimen was relatively well tolerated and yielded promising clinical activity, though the data are still preliminary, he continues. Among the 13 patients who reached the first response assessment, 2 achieved complete responses. These responses have proven durable, with 1 patient remaining in remission for over 37.7 months and the other for more than 14.1 months, Tarhini reports. This finding is particularly significant in a field where alternative treatment options are scarce, according to Tarhini. The study is ongoing, and as a next step, Tarhini states that investigators are conducting biomarker analyses and mechanistic studies to understand why some patients benefit from this regimen but others do not. This research will help refine eligibility criteria to better enroll patientswho are most likely to respond to this treatment, Tarhini concludes.

Ahmad Tarhini, MD, PhD, discusses the use of high-dose bolus IL-2 with ipilimumab followed by nivolumab in advanced melanoma following prior progression.

Dr Tarhini on the Utility of a Prognostic Model in Advanced Melanoma Following ICI Treatment

Ahmad Tarhini, MD, PhD, director, Cutaneous Clinical and Translational Research, leader, Neoadjuvant and Adjuvant Translational Science Program, senior member, Moffitt Cancer Center, Research Institute Departments of Cutaneous Oncology and Immunology; professor, Oncologic Sciences, the University of South Florida Morsani College of Medicine; chair, Scientific Committee, Oncology Research Information Exchange Network (ORIEN); chair, ORIEN ImmunoOncology Research Subcommittee, discusses insights from research presented at the 

This research investigated a prognostic model based on selected cell state and cellular community scores in patients with advanced melanoma treated with immune checkpoint inhibitors (Ecotype-ICI score) as a predictor of ICI immunotherapeutic benefits. In this study, investigators used a machine learning framework to analyze molecular data from patients treated with immune checkpoint inhibitors, Tarhini begins. The goal was to examine the immune cell states and ecosystems within the tumor microenvironment (TME) to refine patient selection for immunotherapy and understand the molecular mechanisms of immune resistance, which may inform future immuno-oncology drug development, Tarhini says. This computational tool profiles gene expression signatures unique to specific cell types and immune cell states. It helps develop an immune cell state atlas, facilitating the resolution of complex immune architecture within the TME created by these immune cells and states.

Tarhini reports that investigators began this research by assessing clinical and transcriptomic data from patients treated with immune checkpoint inhibitors who were enrolled in the Total Cancer Care protocol within a network of specific cancer centers. Initially, investigators developed a predictive survival model for this patient population, he says. They then validated this model in 2 independent external cohorts, he reports. The first cohort was enrolled in the phase 3 E1609 study (NCT01274338) that treated high-risk patients with adjuvant ipilimumab (Yervoy; n = 456), with the control arm receiving interferon alpha, a non-immune checkpoint inhibitor (n = 248). The second cohort consisted of a harmonized group of patients from public datasets treated with PD-1 inhibitor monotherapy (n = 121), CTLA-4 inhibitors (n = 40), and a combination of PD-1 and CTLA-4 inhibitors (n = 66), he concludes.

Ahmad Tarhini, MD, PhD, discusses a prognostic model evaluating patients with advanced melanoma treated with immune checkpoint inhibitors.

Ahmad Tarhini, MD, PhD, director, Melanoma and Skin Cancer Program, Center for Immuno-Oncology Research, Cleveland Clinic, discusses recent practice-changing clinical trials in melanoma.

Over the past year or so, there have been 3 positive studies testing adjuvant therapy in melanoma, 2 of which were presented at the 2017 ESMO Congress. CheckMate-238 tested the PD-1 inhibitor nivolumab (Opdivo) as adjuvant immunotherapy versus the standard ipilimumab (Yervoy) in patients with high-risk disease. Data showed that nivolumab significantly reduced risk of relapse for that patient population. An FDA approval for nivolumab in this setting soon followed these results.

The next study tested the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with 

-mutated melanoma. Tarhini says there were unprecedented data from this study in terms of reducing risk of relapse. Most recently, data were presented from the KEYNOTE-054 study, which tested adjuvant pembrolizumab (Keytruda) in patients with high-risk surgically resected melanoma.

Ahmad Tarhini, MD, PhD, director, Melanoma and Skin Cancer Program, Center for Immuno-Oncology Research, Cleveland Clinic, discusses some recent practice-changing clinical trials in melanoma.

Dr. Tarhini on Recent Practice-Changing Clinical Trials in Melanoma

Ahmad Tarhini, MD, PhD, director, Melanoma and Skin Cancer Program, Center for Immuno-Oncology Research, Cleveland Clinic, discusses adjuvant therapy for patients with melanoma.

Adjuvant therapy for melanoma is used in patients who are considered high risk for relapse or death, says Tarhini. For these patients, there is an indication to administer systemic treatment, which historically has been with interferon alpha. In 2015, ipilimumab (Yervoy) was approved for the adjuvant treatment of patients with melanoma. In April 2018, the FDA approved the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for the adjuvant treatment of patients with 

 V600E— or V600K–positive stage III melanoma following complete resection.

The problem with the currently available adjuvant treatment options have been the toxicity profiles, says Tarhini. Specifically, the cumbersomeness of interferon can negatively affect quality of life. Due to the toxicities, the survival advantage of interferon has been taken into question. In a recent analysis, Tarhini says that only a minority of patients will go onto receive adjuvant therapy after lymph node surgery—either with interferon or ipilimumab.  