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PER® International Symposium on Melanoma and Other Cutaneous Malignancies

Sapna Patel, MD, discusses the potential for adjuvant immunotherapy in patients with high-risk cutaneous squamous cell carcinoma. 

Dr Patel on the Potential for Adjuvant Immunotherapy in CSCC

“When we resect these squamous cell cancers of the skin, often there’s a question [of whether] we should follow the [same] paradigm we follow with melanoma of the skin. Should we be giving [patients] immunotherapy after surgery?”

Sapna Patel, MD, professor, Division of Medical Oncology; leader, Cutaneous Oncology Program; William Robinson Endowed Chair in Cancer Research, University of Colorado Cancer Center, discusses the potential for immunotherapy as adjuvant therapy in patients with high-risk cutaneous squamous cell carcinoma (CSCC).

A common question within the CSCC space is whether patients could be treated with adjuvant immunotherapy, Patel begins. It remains unclear whether the adjuvant treatment paradigm for patients with melanoma should be followed in the CSCC realm, especially for patients at high risk of recurrence who could potentially benefit from adjuvant immunotherapy, she says.

Studies exploring adjuvant immunotherapy strategies in CSCC included the phase 3 KEYNOTE-630 trial (NCT03833167) evaluating pembrolizumab (Keytruda) vs placebo as adjuvant treatment for patients with high-risk, locally advanced CSCC, Patel notes. However, in August 2024, the study’s data monitoring committee recommended the trial be 

 after the treatment of pembrolizumab vs placebo did not demonstrate a statistically significant improvement in recurrence-free survival, the trial’s primary end point. Therefore, adjuvant pembrolizumab may not be beneficial in this patient population, Patel emphasizes.

Furthermore, the phase 3 C-POST trial (NCT03969004) is evaluating adjuvant cemiplimab-rwlc (Libtayo) vs placebo in patients with high-risk CSCC. The study 

 of disease-free survival (DFS), with data showing that at a median follow-up of 24 months (range, 2-64), cemiplimab reduced the risk of recurrence or death by 68% vs placebo (HR, 0.32; 95% CI, 0.20-0.51; 

 < .0001). In patients in the cemiplimab (n = 205) and placebo (n = 204) arms, any-grade adverse effects (AEs) occurred in 91% vs 89% of patients, respectively. Of note, grade 3 or greater AEs were reported in 24% vs 14% of patients, respectively; AEs leading to treatment discontinuation were recorded in 10% and 1.5% of patients in the respective arms.

As of now, this is the most data available, although Patel anticipates more real data will be released in 2025, which could help identify the magnitude of benefit cemiplimab will provide for patients with high-risk CSCC, she concludes.

Adjuvant PD-1 blockade is approved for patients with stage IIB/IIIA melanoma following curative-intent surgery; however, observation should be considered as a reasonable and tolerable alternative, given the lack of long-term survival data supporting adjuvant PD-1 inhibition in melanoma, according to Tara C. Mitchell, MD. She added that ongoing trials are also aiming to determine whether treatment with immunotherapy in the neoadjuvant setting could reduce recurrence risk and improve long-term outcomes for select patients.

21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies

, Mitchell highlighted the prognostic significance of sentinel lymph node status in determining recurrence risk for stage IIB/IIIA melanoma, discussed the ongoing investigation of and potential role for neoadjuvant PD-1 blockade, and emphasized the importance of shared decision-making when weighing adjuvant PD-1 inhibition against observation due to the lack of long-term survival data and potential toxicities.

“The idea of giving systemic therapy with PD-1 blockade before the curative-intent surgery—the wide excision and the sentinel lymph node biopsy—is something that’s being tested,” said Mitchell in the interview. “It may be interesting to see randomized data in terms of outcomes. If we see [outcomes] similar to what we’ve seen in clinical stage III disease with neoadjuvant therapy and [observe] a significant reduction in recurrence, then it may be reasonable to start therapy prior to surgery for patients who are [already] considering systemic therapy [in the adjuvant setting] for stage IIB/IIIA disease.”

Mitchell is section chief of Melanoma and Sarcoma in the Department of Hematology-Oncology and an assistant professor of medicine at Perelman School of Medicine, the University of Pennsylvania, in Philadelphia.

: Which clinical and pathological factors should be considered when determining the risk of recurrence in stage IIB/IIIA melanoma?

: For [the management of] stage IIB/IIIA melanoma, we go by the 8th edition of the American Joint Committee on Cancer [AJCC 8] staging [guidelines] to look at the patient’s individualized risk of recurrence. That takes into consideration the Breslow thickness in mm from the outermost epidermal surface down. The thickness is prognostic of recurrence, as well as the lymph node status.

Lymph node surgical staging is important in these patients to know their accurate stage; that gives us a better understanding of their risk of recurrence, which [accordingly] informs decision-making regarding adjuvant therapy use and follow up for these patients. Sentinel lymph node staging is essential. We have long-term follow-up data [showing that,] although the procedure of sentinel lymph node biopsy itself doesn’t confer any survival advantage, it’s a key prognostic factor in determining the patient’s risk of recurrence.

Is there a role for neoadjuvant immunotherapy in stage IIB/IIIA melanoma? What evidence would support its use?

In stage IIB/IIIA melanoma, I would consider neoadjuvant therapy to be an investigational approach. There are clinical trials evaluating neoadjuvant therapy, meaning systemic therapy given prior to surgery, which in clinical stage IIB/IIIA disease means a wide excision and a sentinel lymph node biopsy. These patients are eligible already for FDA-approved regimens of PD-1 blockade as adjuvant therapy.

The question is: If [patients already have] stage IIB/IIC [disease] after their biopsy, should they be receiving a dose of PD-1 [inhibition] prior to their wide excision and sentinel lymph node biopsy? That would be a use for neoadjuvant therapy in these patients. [However], it’s not currently approved. It’s something that we have been testing at the University of Pennsylvania, and other clinical trials are ongoing and planned. As of now, the standard of care for those patients is wide excision and sentinel lymph node biopsy, [followed by a] discussion about adjuvant therapy after the curative [surgical] attempt has been done. Whether it is considered a reasonable risk for patients to receive systemic therapy along with curative-intent surgery if they are a candidate for systemic therapy and to consider giving [this therapy] upfront is an interesting research question.

What factors would lead you to select observation instead of adjuvant PD-1 inhibition for patients in this disease setting?

This is a discussion to have with every patient who has stage IIB and any stage III melanoma; shared decision-making with the patient and their doctor [is vital]. [There needs to be] consideration of the patient’s individual risk of recurrence, the potential benefit with adjuvant PD-1 blockade, and lowering the risk of recurrence. Then [we have to assess] the risk of toxicity for PD-1 blockade including the risk of severe, permanent, or life-threatening toxicity, [as well as] toxicity that [decreases] wellbeing or quality of life.

[We need to discuss observation] and offer [this approach] to all patients with stage IIB resected disease and above. I would consider observation to be an equally reasonable option for any of these patients, given that there are no long-term survival data to support the use of adjuvant therapy in melanoma. [The FDA-approved adjuvant agents for melanoma] are approved because [they generated] statistically significant improvements in recurrence-free survival.

These drugs work in select patients and lower the risk of recurrence, but in the absence of survival data and with the efficacy of these drugs in the setting of advanced disease, it’s always an option to pursue observation in a patient who is hesitant to accept some of these severe risks of toxicity. Then we can monitor these patients with a thorough history and physical exam, including cross-sectional imaging every several months. [This will allow us to] reserve immunotherapy for the time of recurrence. Most of these patients will not recur, so they may live well and cancer-free long term without adjuvant therapy and may be spared long-term toxicities by choosing the path of observation.

Is there a consensus on the optimal duration of adjuvant therapy for these patients?

All the studies that led to the approvals of adjuvant immunotherapy and PD-1 blockade tested 1 year of therapy compared with placebo. In general, when I discuss [treatment options] with patients, I present the option for adjuvant therapy [to be administered] for up to 1 year, but I note that I’m quick to stop sooner [due to] any unacceptable or serious toxicity. We don’t want to cross the line of doing more harm than benefit.

What is the optimal surveillance strategy for detecting recurrence in stage IIB/IIIA melanoma?

In patients with IIIA melanoma, we need to closely monitor the nodal bed for regional recurrence, because that risk is high. We alternate imaging with ultrasounds of the nodal bed and cross-sectional imaging to look for more distant metastatic disease recurrence in these patients. In patients with clinical stage IIB/IIC disease after surgical resection and [those with] AJCC 8 stage IIB/IIC disease, I also monitor with cross-sectional imaging every 6 months to detect both regional and distant metastatic disease.

If disease recurrence occurs following adjuvant therapy, how should subsequent systemic treatment decisions be made?

If patients have had recurrence after receiving single-agent PD-1 [inhibition] as adjuvant therapy, and if it’s a regional recurrence, we should still consider surgical resection with a curative intent. If they have distant metastatic disease recurrence, these patients need to go on to receive dual [immune] checkpoint blockade as their first line of therapy with a PD-1/CTLA-4 inhibitor [regimen]. In my mind, that’s the standard and the most active first-line therapy for which we have the longest follow-up data showing a high response rate in patients even after progression on PD-1 blockade alone.

Mitchell T. Controversies in melanoma treatment: how to manage stage 2B/3A patients peri- and postoperatively. Presented at: 21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies; February 8, 2025, Cranbury, New Jersey.

Tara C. Mitchell, MD, discusses considerations and lingering questions regarding pre- and post-operative management strategies in stage IIB/IIIC melanoma.

Observation Is a Reasonable Alternative to Adjuvant PD-1 Blockade in Stage IIB/IIIC Melanoma

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“The fact that [activity is observed in non-injected lesions] can happen suggests that [RP1 has] the ability to educate the immune system in such a way that it can help [lead] to [the] attack of tumors that [were not] injected and [are not] nearby, and that’s pretty interesting.”

Ryan Sullivan, MD, director, Center for Melanoma, Massachusetts General Hospital, discusses 

findings from the phase 2 IGNYTE trial (NCT03767348)

 evaluating RP1 in combination with nivolumab (Opdivo) in patients with advanced melanoma who progressed on prior anti–PD-1 therapy.

RP1 is an oncolytic herpes simplex virus engineered to selectively infect and lyse tumor cells, releasing tumor-associated antigens and stimulating an immune response. This approach aims to activate immune cells capable of recognizing both injected and non-injected tumors. When combined with nivolumab, RP1 could enhance systemic immune activation, potentially overcoming resistance to immune checkpoint inhibition.

Sullivan notes that the trial enrolled patients with anti–PD-1–refractory melanoma, including a subset with primary resistance, defined as those who derived no initial benefit from checkpoint inhibition. Results demonstrated an objective response rate (ORR) of 33.6% by modified RECIST 1.1 criteria and 32.9% by standard RECIST 1.1 criteria per independent central review.

Sullivan highlights that responses were observed in both injected and distant, non-injected lesions, suggesting that RP1 induces immune activation beyond local tumor lysis. Although some responses may result from regional immune stimulation, similar to 

talimogene laherparepvec (T-VEC), an FDA-approved oncolytic virus

,the IGNYTE data suggest that RP1 has the potential for broader systemic tumor control.

Given the observed clinical activity in this heavily pretreated, checkpoint inhibitor–resistant population, Sullivan concludes that further randomized trials are warranted to confirm RP1’s efficacy and define its role in the second-line setting for melanoma. If validated, RP1 in combination with nivolumab could represent a promising therapeutic option for patients with limited treatment alternatives following progression on a PD-1 inhibitor.

Ryan Sullivan, MD, discusses RP1 plus nivolumab in patients with advanced melanoma who progressed on prior anti–PD-1 therapy.

Dr Sullivan on RP1 Plus Nivolumab in Anti–PD-1–Refractory Melanoma

Dr Petrella on Selecting Frontline Therapy in Metastatic Melanoma

“The DREAMseq and SECOMBIT trials have told us that using the combination of nivolumab and ipilimumab [results in better outcomes compared] with giving targeted therapy, first. Based on all that data, this is pretty much [how] our first-line therapies for patients with metastatic melanoma have [come into being].”

Teresa Petrella, MD, MHSc, FRCPC, medical oncologist, affiliate scientist, Evaluative Clinical Sciences, Odette Cancer Research Program, Sunnybrook Research Institute; and associate professor, Department of Medicine, University of Toronto, discusses key considerations in selecting frontline therapy for patients with metastatic melanoma based on long-term survival data and therapeutic sequencing findings. 

Over the past decade, multiple studies have evaluated the efficacy of combination immunotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy) compared with single-agent checkpoint inhibitors. 

Updated 10-year results from the phase 3 CheckMate 067 trial

 (NCT01844505) continue to demonstrate a survival benefit with combination therapy, with overall survival (OS) rates of 43% for nivolumab plus ipilimumab, 37% for nivolumab monotherapy, and 19% for ipilimumab monotherapy. Petrella notes that these findings indicate that the benefit of combination therapy remains durable beyond the 3-year mark.

Beyond treatment with CTLA-4 and PD-1 blockade, Petrella explains that 

of nivolumab plus relatlimab-rmbw (Opdualag), a LAG-3 inhibitor, demonstrated a progression-free survival (PFS) advantage vs nivolumab alone in this patient population (HR, 0.79; 95% CI, 0.66-0.95). Investigators observed a trend in favor of the combination for OS (HR, 0.80; 95% CI, 0.66-0.99), with 3-year OS rates of 55% (95% CI, 49.2%-59.6%) and 48% (95% CI, 42.7%-53.1%), respectively.

Petrella adds that therapeutic sequencing trials, including the phase 2 SECOMBIT (NCT02631447) and phase 3 DREAMseq (NCT02224781) trials have also provided additional insights into the optimal order of systemic therapy in metastatic melanoma.

Findings from these studies suggest that initiating treatment with combination immunotherapy, rather than targeted therapy, leads to superior long-term outcomes, she explains. In patients with 

mutated disease, early use of immune checkpoint blockade has been associated with prolonged survival compared with targeted therapy.

Given the evolving treatment landscape of this disease, Petrella explains that combination immunotherapy remains the preferred first-line approach for eligible patients, providing the potential for durable responses and long-term survival benefits.

Teresa Petrella, MD, MHSc, FRCPC, discusses considerations in selecting frontline therapy for patients with metastatic melanoma.

Omid Hamid, MD, provides insight on the potential role of cancer vaccines in melanoma.

Dr Hamid on the Potential for Cancer Vaccines in Melanoma

“[There’s] an off-the-shelf [vaccine] that’s in the phase 2 [setting] showing the highest complete response rates we’ve seen with metastatic melanoma, [along with] high overall response rates and durability. If we step back, can we utilize those vaccines now in a neoadjuvant approach? They’re looking at [that approach].”

Omid Hamid, MD, professor, medicine, Cedars-Sinai; director, Clinical Research and Immunotherapy, director, Cutaneous Oncology and Melanoma, The Angeles Clinic and Research Institute, provides insight on the potential role of cancer vaccines in the treatment of patients with melanoma.

Currently, multiple developmental paths continue to move vaccines forward s in the oncology space, Hamid begins. Within melanoma specifically, Hamid highlights the investigative vaccine IO102-IO103, which is designed to target IDO- and PD-L1–positive cells. Previous data from a phase 1/2 trial (NCT03047928) showed that the addition of IO102-IO103 to nivolumab (Opdivo) led to complete response in patients with metastatic melanoma, Hamid says. Now, the off-the shelf vaccine is being evaluated in combination with pembrolizumab (Keytruda) vs pembrolizumab alone in the phase 3 IOB-013/KN-D18 trial (NCT05155254) for the first-line treatment of patients with metastatic melanoma.

Hamid also explains that IO102-IO103 is constructed using a platform with other targets, which could allow for additional vaccines directed against different markers.

Notably, vaccines had previously displayed limited benefit in the metastatic setting, highlighting the potential for IO102-IO103. Given that this vaccine has displayed activity in the metastatic setting, additional research will aim to evaluate its activity in the perioperative setting, Hamid says.

On the other end of the spectrum, personalized vaccines derived from tumor tissue from an individual patient could also play a role in this space, Hamid continues. He compares this approach to the way tumor-infiltrating lymphocyte (TIL) therapy works. He concludes that it works similarly because the T-cells are targeting more than only the tumor antigen—there are multifunctional T-cells that target multiple antigens.

Dr Orloff on Treatment Strategies for Rapidly Progressing Uveal Melanoma

“We don’t have the tools in our toolbox the way that [we do for] cutaneous melanoma…we have treatments that certainly can work in more than half of patients. That said, there are clinical trials looking at drugs that elicit higher response rates. If and when they are approved, they will be a nice tool.”

Marlana M. Orloff, MD, associate professor, Jefferson University; physician, Department of Medical Oncology, Sidney Kimmel Cancer Center, discusses optimal treatment strategies for patients with aggressive uveal melanoma.

For patients with rapidly progressing tumors, the ideal approach is to initiate treatment with the highest likelihood of leading to tumor shrinkage or disease control, Orloff begins. Therapies with a high overall response rate (ORR) or rapid onset of action are therefore generally preferred in this setting, she says. However, unlike cutaneous melanoma, where highly effective therapies exist that benefit a significant proportion of patients, the therapeutic arsenal for this population is more limited, Orloff states.

Ongoing clinical trials are evaluating novel agents with the potential for higher ORRs, Orloff continues, adding that if these treatments receive regulatory approval, they could become valuable options for patients with aggressive disease. Additionally, liver-directed therapies have demonstrated high disease control rates in select patient populations and may be considered for those with rapidly progressing tumors, particularly in cases of liver metastases, she notes.

Conversely, some treatments that provide an overall survival (OS) benefit may not be the most effective first-line options for patients with rapidly progressing disease, Orloff states. These therapies may require more time to produce a clinical response, making them less suitable for individuals in need of urgent tumor control, she explains. Tailoring treatment selection based on tumor kinetics and individual patient factors remains crucial to optimizing outcomes, Orloff concludes.

Marlana M. Orloff, MD, discusses optimal therapeutic approaches for patients with uveal melanoma that is rapidly progressing.

Dr Faries on Emerging CAR T-Cell and TCR Cell Therapies in Melanoma

“[CAR T-cell and TCR cell therapies] are hopefully the next generation of TIL [therapies]. Those are cells that are engineered outside of the body to become melanoma specific. There aren’t any therapies that have crossed the line to prove efficacy, but there are encouraging candidates.”

Mark Faries, MD, surgical oncologist, Cedars‑Sinai, The Angeles Clinic and Research Institute; associate director, Surgical Oncology Experimental Therapeutics, Cedars Sinai Department of Surgery; and head, surgical oncology, Cedars-Sinai Medical Center, discusses how CAR T-cell therapies and transgenic T-cell receptor (TCR) cell therapies compare with current tumor-infiltrating lymphocyte (TIL) approaches in melanoma.

CAR T-cell and TCR therapies represent potential advancements over other adoptive cell therapies in melanoma, Faries begins. TIL therapy relies on naturally occurring lymphocytes that have infiltrated the tumor, recognizing melanoma cells through the body’s innate immune response, he explains. These cells are harvested, expanded ex vivo, and reinfused to enhance their antitumor activity, he says.

In contrast, CAR T-cell and transgenic TCR therapies involve genetic engineering to create tumor-specific immune cells, Faries states. Unlike TIL therapy, which requires tumor-infiltrating cells, these approaches utilize peripheral blood lymphocytes that are modified in the laboratory to specifically recognize melanoma-associated antigens, he details. CAR T-cell therapy employs chimeric antigen receptors to enable T cells to target surface antigens, whereas transgenic TCR therapy engineers T cells to recognize intracellular tumor antigens presented by major histocompatibility complex molecules, Faries explains.

Although these engineered cell therapies are still under investigation in melanoma, they offer potential advantages over TIL therapy, including broader applicability, more precise targeting, and the ability to circumvent immune evasion mechanisms, Faries says. No CAR T-cell or transgenic TCR therapies have yet demonstrated definitive efficacy in melanoma, but ongoing trials are evaluating several candidates that could enhance treatment options in the future, Faries concludes.

Mark Faries, MD, discusses how CAR T-cell and TCR cell therapies compare with TIL approaches in melanoma.

 PER® International Symposium on Melanoma and Other Cutaneous Malignancies

Paolo A. Ascierto, MD, director, Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, National Tumor Institute Fondazione G. Pascale, discusses treatment sequencing considerations for patients with advanced 

-mutant melanoma, based on findings from the phase 2 SECOMBIT (NCT02631447) and phase 3 DREAMseq (NCT02224781) trials.

Ascierto notes that each of these trials demonstrated improved overall survival when initiating treatment with immune checkpoint inhibitor–based therapy rather than targeted therapy in the first-line setting for this patient population, suggesting that resistance to targeted agents may compromise subsequent immunotherapy efficacy. Additionally, SECOMBIT evaluated a sequential "sandwich" approach, incorporating a short course of targeted therapy before transitioning to immunotherapy, which may benefit select patients with high tumor burden or elevated lactate dehydrogenase levels, Ascierto explains. These findings contribute to ongoing discussions on optimizing first-line treatment strategies in 

Paolo A. Ascierto, MD, discusses findings from the SECOMBIT and DREAMseq trials and their implications for first-line treatment selection for patients with BRAF-mutant melanoma.

Dr Ascierto on First-Line Treatment Selection in Advanced BRAF+ Melanoma

Caroline Robert, MD, PhD, head, Dermatology Unit, Gustave Roussy, discusses the role of adjuvant anti–PD-1 therapy in the treatment of patients with resected stage IIB/C melanoma, highlighting findings from the phase 3 KEYNOTE-716 (NCT03553836) and CheckMate 76K (NCT04099251) trials that have informed treatment decisions in this setting.

These trials evaluated the efficacy of adjuvant pembrolizumab (Keytruda) vs placebo and nivolumab (Opdivo) placebo, respectively, in this patient population, and data demonstrated a statistically significant improvement in recurrence-free survival with the immunotherapies. Despite the absence of lymph node metastases, Robert notes that stage IIB/C melanoma carries a recurrence risk comparable with certain stage III cases, warranting investigation into adjuvant immunotherapy. Although Robert notes that the absolute benefit is lower than in more advanced disease, these findings support the integration of PD-1 inhibitors into clinical practice with treatment decisions guided by individualized risk-benefit assessments.

Caroline Robert, MD, PhD, discusses the role of adjuvant anti–PD-1 therapy in resected stage IIB/IIC melanoma based on findings from the KEYNOTE-716 and CheckMate 76K trials.

PER® International Symposium on Melanoma and Other Cutaneous Malignancies | Conference