Perioperative PD-1 Inhibition Expands Treatment Opportunities for Select Patients With CSCC

As the role of immunotherapies extends to earlier treatment lines in the nonmelanoma skin cancer treatment armamentarium, increased attention to patient characteristics and disease factors is crucial to ensure all patients receive tolerable therapies at the optimal time during the course of their disease, according to Vishal Patel, MD, FAAD, FACMS.

In a phase 2 trial (NCT04154943), the PD-1 inhibitor cemiplimab-rwlc (Libtayo) administered in the neoadjuvant setting followed by curative-intent surgery produced a 12-month event-free survival rate of 89.0% (95% CI, 79.0%-94.0%) among 79 patients with stage II to IV cutaneous squamous cell carcinoma (CSCC).¹

Moreover, in the realm of basal cell carcinoma, cemiplimab received full FDA approval for patients with metastatic disease with prior exposure to a hedgehog inhibitor (HHI) or for whom an HHI is not appropriate.²

“We’re seeing a revolution when it comes to immunotherapy in cutaneous malignancies,” Patel said in an interview with OncLive^®.

In the interview, Patel highlighted the evolving role of PD-1 inhibitors in CSCC management, how treatment advances with immunotherapy have given way to using these agents in perioperative settings, and key factors to consider when determining whether to use PD-1 inhibitors in patients with nonmelanoma skin cancers.

Patel is an associate professor of dermatology at the George Washington (GW) School of Medicine and the director of the Cutaneous Oncology Program at the GW Cancer Center in Washington, DC.

OncLive: How might perioperative treatment approaches affect CSCC management?

Patel: We’re seeing a game-changer situation where the treatment paradigm for at least advanced cutaneous malignancies, both melanoma and nonmelanoma skin cancers, is changing. The term perioperative is key because our traditional paradigm is to treat tumors surgically and then consider adjuvant therapy, whether radiation or other types of systemic therapy, [such as] chemotherapy or immunotherapy.

Over the past few years, we have [garnered] exciting evidence both in the melanoma and CSCC realms where early treatment with immunotherapy can lead to superior outcomes for tumors that are surgically resected and lead to improved recurrence-free survival and metastasis-free survival in those patients. For example, in CSCC, a landmark study that was published approximately 18 months ago showed that perioperative cemiplimab therapy, [consisting of] treatment before surgery and then potentially after surgery as well, depending on the response, [elicited] impressive response rates, and those patients, now being followed out, have continued to be disease free after their surgery. That’s beginning to change how we think about approaching these advanced tumors.

What is the role of neoadjuvant PD-1 inhibitors in CSCC?

If we take a page out of the melanoma playbook, we’ve seen that anti–PD-1 therapy was initially used in the advanced, unresectable, metastatic cases, with more evidence and trials that investigated the utility of moving that therapy in early-stage diseases, whether surgically resectable lymph node–[positive] disease or potentially in primary tumors with no distant metastases or lymph node metastases. We know from those melanoma data that patients with certain risk factors do better when provided anti–PD-1 therapy earlier in their [treatment] course. We’re applying that evidence and information to nonmelanoma skin cancer, specifically [in clinical trials] in CSCC.

One major trial that has been published [assessed] patients treated with neoadjuvant cemiplimab therapy. Other ongoing trials with anti–PD-1 [inhibitors as monotherapies] or multiple combination immunotherapies show the same type of robust complete responses. Although surgery is still part of that treatment management, [neoadjuvant therapy is] changing how we think about how much treatment those patients may need to have long-lasting cure after that initial systemic immunotherapy and subsequent surgery. That is changing our [treatment] approach for those advanced tumors. We’re seeing that across the spectrum of melanoma and nonmelanoma skin cancers, and already clinical trials have started to investigate that in basal cell carcinoma as well.

What CSCC patient characteristics portend potential benefit from neoadjuvant PD-1 inhibition?

We’re focused on the subset of tumors that are on the higher-end advanced spectrum. Notably, the way the clinical trials [were] initially designed and in the ones that have been published, [such as the trial that investigated] neoadjuvant cemiplimab in advanced stage II to IV resectable CSCC, patients [had to] have multiple high-risk features. The National Comprehensive Cancer Network sometimes denotes [these tumors] as either very high–risk tumors or borderline resectable tumors. [These are] different than the unresectable cohort where surgery or palliative radiation is no longer an option, or we are limited in our treatment options. These are the patients who maybe have not been initially treated but have large and aggressive tumors where surgery is going to be difficult to do alone, and we have a high suspicion that after surgery they will require other types of therapy, whether radiation or systemic therapy.

Providing the therapy upfront prior to surgery when the tumor burden is high and the immune system can see much of that tumor antigen exposure to stimulate a robust immune response has supported the hypothesis that that time point allows the immune system to get primed, and then surgery can remove the tissue that has responded, and the immune system can continue to provide a clearance of the tumor after that time. Advanced tumors with multiple high-risk features that are borderline resectable [are eligible for neoadjuvant therapy]. We’re not in the realm where we’re thinking about the smaller tumors that are easy to manage with surgical resection alone.

What potential challenges exist for considering neoadjuvant therapy for patients with CSCC?

It should not be taken lightly that neoadjuvant therapy should [not] apply to every type of patient you see. Risk stratifying which of those tumors are advanced or borderline resectable enough is the first filter pass we think about. [I consider neoadjuvant therapy in] stage III and IV tumors where we may be able to do surgery, but it could be challenging.

However, along those realms, not every patient can be a candidate. In patients who are older and frail, where surgery alone may be too challenging and [in whom] we’re not considering surgical resection, the treatment is just systemic therapy, not neoadjuvant. In the same realm, there are other comorbidities where patients may be immunosuppressed or are organ transplant recipients. Those patients do not qualify, at least in this current setting for systemic immunotherapy. We have to consider those potential contraindications. In patients with other comorbidities, psychosocial issues, [barriers to their ability] to come in for infusion treatments, or tumors that are not advanced enough, neoadjuvant therapy may not make sense.

Lastly, the adverse effect [AE] profile [plays a role, including] whether patients can tolerate the potential AEs that come with immunotherapy, even if they are short course at the onset. With immunotherapy, [patients can experience] idiosyncratic AEs after 1 dose, potentially after multiple doses, or much later during the therapy. We need to consider those patients holistically to [determine] who makes the most sense [for neoadjuvant therapy].

What is the role of adjuvant therapy in CSCC?

For CSCC, the gold standard treatment for many years has been surgery followed by adjuvant radiation therapy when either tumor margins are not completely clear, certain high-risk features warrant that, or there’s concern for potential systemic spread down the line. That’s what we currently use in the adjuvant setting. We’re excited about several ongoing adjuvant immunotherapy trials investigating whether the addition of immunotherapy would benefit patients who have had surgery and radiation. There’s a high suspicion from investigators and experts that this [treatment approach] would make sense from what we know from melanoma literature and data, [where patients experience] a benefit from adjuvant immunotherapy. We’re hopeful those trials will be completed soon and we can get more information and evidence that there is a clear role for the use of adjuvant immunotherapy [in CSCC].

Beyond that, [the post-surgery CSCC setting] is a wild west where a lot of different treatments are potentially used, not necessarily in the adjuvant setting, but if patients recur after they’ve had surgery and radiation and may not qualify for systemic immunotherapy. We’ve used anti-EGFR medications or more classic chemotherapies, as well as radiation, in a palliative setting. However, as a whole that adjuvant world is an unmarked territory where we need to have a lot more clarity as to what makes sense.

In the neoadjuvant trials, after patients were treated in the neoadjuvant setting and had surgical resection, the adjuvant therapy was not clearly defined and was up to investigator discretion. This has not provided us the true clarity we need as to what makes the most sense in the adjuvant setting for a lot of these patients. Time will tell, and we’re excited about the next 12 to 18 months when we hopefully will have more information in that realm.

In which patients would you consider avoiding adjuvant treatment?

The patients [who we think] would not qualify for adjuvant immunotherapy [have characteristics that] are similar to what we think about with neoadjuvant immunotherapy. This relates to the AEs [associated with] immunotherapy and whether there’s a contraindication. The terms neoadjuvant, meaning before surgery, adjuvant, meaning after surgery, when combined, become perioperative, meaning around surgery. These are all different names to determine what timing of systemic therapy makes sense and how that can be additive with surgery, radiation, or potentially both. [Deciding which patients adjuvant therapy] would make sense for as well as [considerations for] contraindications are the same [as in the neoadjuvant setting and] relate to tolerability, comorbidities, and potential contraindications relating to the immune system or organ transplant patients. We [have to] think about that holistically.

For which patients would you consider using adjuvant cemiplimab?

We don’t have specific clinical trial data to support using any immunotherapy in the adjuvant setting outside of a clinical trial. There are ongoing clinical trials with cemiplimab, as well as with pembrolizumab [Keytruda] and other systemic immunotherapies. Without those data, making a non–clinical trial decision for adjuvant immunotherapy is murky, and we hope to have some of that clarity in the coming months. However, from a standpoint of selecting immunotherapy in a perioperative setting or in the unresectable patient cohort, data in the neoadjuvant setting for cemiplimab have been published, and [findings from] ongoing trials with other anti–PD-1 therapies, [including] pembrolizumab, nivolumab [Opdivo], and ipilimumab [Yervoy], have been partially presented or are completing for publication.

[These findings are] not surprising, as we know from the melanoma literature that this is a class type of effect. These types of therapies tend to work similarly to each other. However, as a whole, cemiplimab has been a leader in this field [because of studies with this agent] focusing on CSCC and basal cell carcinoma. Due to that, we have some of the most robust data and published literature that relate to that therapy. Often, we reach for that medication, depending on the unique clinical scenario.

In which patients with basal cell carcinoma might you use PD-1 inhibitors, and in which patients might you switch from HHIs to PD-1 inhibitors?

We’re lucky that in basal cell carcinoma, most tumors are easy to manage. Only a small subset of these tumors are truly advanced and need systemic therapy. For approximately a decade, we’ve had HHI therapies, and patients can respond to those [agents] well. However, their tolerability sometimes limits our ability to use [those therapies] long term and get a complete response.

[One AE mitigation strategy is using] alternate dosing. There are differences between the 2 classes of approved medications, and the AE profiles are different. Switching from vismodegib [Erivedge] to sonidegib [Odomzo] can help, and there are approved alternative dosing regimens with sonidegib.

We’re lucky now that there is an FDA approval for anti–PD-1 therapy with cemiplimab for patients who are intolerant or not candidates for systemic HHI therapy. Often, patients may not be able to be started on an HHI therapy. There may be psychosocial issues, tolerability [issues], or other comorbidities. Patients who are older or frailer [often] cannot tolerate the potential AEs [associated with HHIs, including] dysgeusia, or lack of taste, which could lead to weight loss. [Furthermore], mobility issues, muscle spasms, and pain are unacceptable toxicities. In some of those patients, we may determine that they need to move straight to anti–PD-1 therapy if that makes more sense. [Oncologists have opportunities to use their] expertise and clinical judgment to make those determinations and [decide which treatment strategies] make sense, focusing on the patient in a personalized approach.

What ongoing research is evaluating perioperative therapies for patients with basal cell carcinoma and CSCC?

As we’ve seen with CSCC and learned from melanoma data using anti–PD-1 therapy in different time courses, moving it earlier, and using it in a perioperative setting, several trials are evaluating anti–PD-1 therapy, as well as combination anti–PD-1 and CTLA-4 [inhibitors] or anti–PD-1 and LAG-3 inhibition, in patients with basal cell carcinoma. Other smaller studies are evaluating combination approaches of anti–PD-1 therapy and other experimental therapies, whether they’re interlesionally injected, or provided systemically, in basal cell carcinoma. That is also the case in squamous cell carcinoma.

In the nonmelanoma skin cancer world, [immunotherapies are] moving earlier in the patient’s [treatment], and probably what’s most exciting is considering how we can limit systemic toxicity and potentially inject immunotherapy into these tumors. That has been discussed, and ongoing trials are being planned for that as well. The next decade will elucidate some interesting and exciting information for [oncologists] who manage this epidemic of skin cancers, both low risk and high risk.

References

1. Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab and surgery for stage II–IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study. Lancet Oncol. 2023;24(11):1196-1205. doi:10.1016/S1470-2045(23)00459-X
2. Cemiplimab-rwlc (Libtayo). Prescribing information. Regeneron. Updated April 2023. Accessed April 23, 2024. https://www.regeneron.com/downloads/libtayo_fpi.pdf