Neoadjuvant and Adjuvant Immunotherapy in Skin Cancer: Key Updates

Dr Vishal Patel discusses how emerging evidence suggests neoadjuvant immunotherapy may improve outcomes and personalize treatment planning for patients with high-risk melanoma and cutaneous squamous cell carcinoma, prompting a shift toward earlier multidisciplinary intervention.

Transcript

Hi, my name is Vishal Patel. I'm an associate professor of dermatology and of medicine oncology at the Georgia Washington University School of Medicine and Health Sciences. And I also serve as the director of cutaneous oncology at the GW Cancer Center and the Director of Dermatologic Surgery at the GW Department of Dermatology.

What's the biggest shift in how we are thinking about neoadjuvant versus adjuvant immunotherapy in skin cancer today?

Dr Patel: Well, the biggest shift is that we are no longer thinking about systemic therapy as something that only happens after surgery. Historically, surgery came first and we would add adjuvant therapy afterwards for those patients that were deemed to be highest risk for recurrence. Now, especially in melanoma and in high-risk squamous cell carcinoma, we're recognizing that giving immunotherapy before surgery may actually generate a stronger and more durable immune response. And this neoadjuvant approach allows the immune system to see the intact tumor and mount a broader antitumor response. So, trials like SWOG-S1801 and NADINA in the melanoma world have really changed the conversation by showing improved event-free survival with neoadjuvant strategies. So, the paradigm is shifting from that surgery first to a much more integrated multidisciplinary approach where timing of surgery and systemic therapy are now really critically important.

Which patients or tumor types should prompt clinicians to consider treatment intensification before surgery?

Dr Patel: Well, the patients we worry about the most are those with biologically aggressive disease or those that are at high risk for recurrence, recurrence after surgery and adjuvant therapy. And so, in melanoma, this includes those patients that have clinically detectable stage 3 or nodal disease like bulky nodal disease, satellitosis, in-transit metastases, rapidly progressing tumors, but we're also beginning to increasingly discuss this in high-risk stage 2 melanoma as well. For squamous cell carcinoma, high risk tumors, those with extensive perineural invasion, recurrent tumors, nodal involvement, tumors in anatomically challenging locations may prompt that multidisciplinary discussion and approach. And so, the key point is risk stratification, identifying which patients have the highest risk of recurrent or potentially occult metastatic disease. When that risk is high, clinicians should be considering whether upfront systemic therapy could improve the long-term outcome and really help optimize surgery.

How do you decide between a neoadjuvant and an adjuvant approach in melanoma or high-risk SCC?

Dr Patel: Well, we're just beginning to figure out the risk and benefits of these two different approaches. It really comes down to balancing tumor biology, surgical feasibility, patient factors. If a patient has resectable disease but is at high risk for systemic relapse, neoadjuvant therapy has become very attractive, not only because we can improve the systemic control, but also potentially tailor surgery based on the response, downstage the surgery, or even eliminate most of the surgical approach and have a much smaller surgical intervention. On the other hand, if the tumor is small, it's straightforward to resect, maybe the patient has contraindications to immunotherapy and a surgery first approach to fully risk stratify, and then followed by adjuvant therapy when necessary may still be the best path for those patients. So, another thought or another approach is thinking about just the multidisciplinary coordination. And so, these decisions work best when we have the multidisciplinary team at hand.

Sometimes that may not be available and sometimes there are external factors that may push towards one or the other approach. But these decisions really work best when the dermatologists, the Mohs surgeon, the surgical oncologists, medical oncologists, radiation oncologists, we're all communicating very early in the patient journey to make that decision upfront.

What are the key benefits of treating patients in the neoadjuvant setting?

Dr Patel: Well, one of the biggest benefits is the improved immune activation. Intact tumor, larger tumor, more antigen exposure, that essentially acts as a source of antigen. It helps prime the immune system upfront more effectively than if the tumor has been already removed. Another major advantage is that we can directly measure the pathologic response. We can see how much of the tumor shrinks and give us real-time biologic information about how the tumor is behaving, and it may help guide the extent of surgery or whether additional therapy adjuvant therapy is necessary. And in some patients, neoadjuvant treatments can downstage disease. It can reduce surgical morbidity. It can potentially improve long-term recurrences outcomes. And most importantly, it gives us an early sense of whether the patient is responding to therapy and may need more aggressive, more alternative strategies, or just longer-term treatment after the surgery.

What risks or challenges should clinicians be aware of when introducing immunotherapy before surgery?

Dr Patel: Well, obviously the biggest concern is balancing the oncologic timing of either surgery or immunotherapy, where that fits in with the potential risk of treatment-related toxicity. The immune-related adverse event really is the rate-limiting step. It can occasionally delay surgery. It can complicate the perioperative management. Generally, in experienced multidisciplinary settings, we really can manage that, but that can throw a wrench into the plans. Another challenge can be that not every patient responds. So, a subset of tumors may progress even on therapy. And so careful selection, close monitoring, not losing the surgical window if a patient is not going to respond is something that you should be thinking about. And then there's just the logistical challenges. The patient requires coordination between multiple specialists. The timelines can be nuanced as in comparison to the traditional biopsy and then surgery workflow that we are all typically used to.

So, while the benefits are exciting, there still are important factors to consider. The successful implementation really depends on strong multidisciplinary communication, careful patient selection from the get-go.

How should Mohs surgeons and dermatologists coordinate care with medical oncology in these cases?

Dr Patel: Well, Mohs surgeons and dermatologists are often the first physicians to identify these high-risk tumors to either triage them, be the gatekeeper. So, the role is becoming increasingly important in triaging the patients appropriately. Thinking even if you're not going to take these approaches with these patients, thinking about them, referring them appropriately is key. And that key driver is early communication. If a patient has features that are suggestive of a high-risk melanoma or cutaneous squamous cell carcinoma, involve the medical oncologist early, not necessarily after surgery, but before surgery. It can open the door towards neoadjuvant options that may have otherwise been missed. Maybe the surgeon may not have considered that, and this decision is already made and that window has passed. So, I think the dermatologists play a major role in that triaging, but also in the longitudinal surveillance, the toxicity recognition, patient education. In certain scenarios, patients may not have been high risk at the initial triaging time point; later, they're denoted to be high risk after surgery and may need to consider adjuvant therapy in those cases.

So, the dermatologist doesn't just have an isolated role anymore. They're really part of the multidisciplinary team. These are multidisciplinary cancer patients, and so collaboration is really key to optimizing outcomes.

Looking ahead, do you see neoadjuvant approaches becoming the standard of care in certain skin cancers?

Dr Patel: Absolutely. I think we've already moved in that direction and we're going to continue to move in that direction in melanoma, particularly in stage 3 melanoma. The data from the trials like SWOG-S1801 and NADINA are extremely compelling. It's really reshaping the standard practice. Certainly, we have begun to adopt utilizing neoadjuvant immunotherapy within our stage 3 and higher melanoma presentations with upfront immunotherapy, whether with dual or single systemic therapy before surgery is our approach. We have also incorporated that and are utilizing that for our borderline resectable high-risk squamous cell carcinomas, given those impressive results. And I think that's only going to move earlier and earlier. We're especially excited about how neoadjuvant therapy will allow us to individualize treatment, specifically that we can measure the pathologic response either by doing the surgery or using other markers, and that's a major step towards personalized care and then limiting how much adjuvant therapy, whether radiation or adjuvant systemic therapy we need to utilize.

And this is, as I said, it's going to move early. We're already seeing that move to earlier stage melanoma, high-risk melanoma, earlier stage squamous cell carcinoma. In melanoma and high-risk melanoma, we're seeing new adjuvant trials within stage 2 disease. So, these are not macroscopic lymph node diseases as we saw with SWOG and NADINA, but earlier high-risk tumors. We're even potentially seeing intralesional approaches both with melanoma of injecting immunotherapies into earlier but high-risk stage tumors. There's an ongoing phase 3 trial with intralesional cemiplimab in lower risk squamous cell carcinoma. So, all of these types of approaches earlier on in the disease process is just confirming what we know that skin cancer is an immunologically driven disease and immunologically responsive disease. And so, I really do believe that neoadjuvant or perioperative approaches are going to increasingly become the standard of care if they have not already within these high-risk patients, and that over the next several years and decades, immunotherapy is going to be the cornerstone for skin cancer treatment as a whole.