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

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.

In an interview with OncLive® regarding her presentation at the 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.

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

Mitchell: 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.

Reference

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.