Neoadjuvant Cemiplimab Underscores Push to Bolster Treatment of CSCC

Neil D. Gross, MD, FACS

Emerging data for the use of neoadjuvant cemiplimab-rwlc (Libtayo) for the treatment of patients with cutaneous squamous cell carcinoma (CSCC) have shown the potential value of utilizing immunotherapy prior to surgery in this patient population, and approaches like this could help select patients maintain function after surgery, according to Neil D. Gross, MD, FACS .

Data from a phase 2 trial (NCT04154943) showed that the estimated 12-month event-free survival rate among enrolled patients (n = 79) was 89% (95% CI, 79%–94%). Notably, no patients who experienced a pathological complete response (n = 40) experienced disease recurrence. In the 70 patients who completed surgery, the estimated 12-month disease-free survival rate was 92% (95% CI, 82%-97%).

“We have new tools now with immunotherapy that can be beneficial for the right patients. It all comes down to picking the right patients, for this and also for us to develop the data, like has been done for melanoma,” Gross explained in an interview with OncLive® following a workshop on non-melanoma skin cancers, which he moderated.

In the interview, Gross expanded on the investigation of neoadjuvant cemiplimab in CSCC; discussed patient factors that can inform the use of this approach and why additional phase 3 data are needed to better guide its use; and detailed updates in the treatment of patients with basal cell carcinoma (BCC).

Gross, MD, FACS is a professor in the Department of Head and Neck Surgery, Division of Surgery, at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What safety and efficacy data for neoadjuvant cemiplimab have been in patients with CSCC?

Gross: One of the themes that came up was the emerging data around neoadjuvant approaches, both for melanoma and non-melanoma skin cancers, including CSCC.

We discussed some of the safety [data] around neoadjuvant approaches using cemiplimab [in patients with CSCC]. Fundamentally, the data show that the safety of this approach is well recognized. That was borne out of the clinical experience of the experts who [attended the workshop], with the caveat that data are still emerging. Unlike melanoma, [the CSCC space] lacks randomized, phase 3 data, which we hope to have in the near future to help us better guide [treatment] decisions.

How might these phase 3 data for neoadjuvant cemiplimab potentially affect the treatment paradigm for patients with CSCC?

There has already been a shift in the management of advanced CSCC based on the phase 2 trial data. Patients who are at risk of significant functional loss with an up-front surgical approach are increasingly considered for a neoadjuvant approach in the hopes of preserving function, [such as patients with] tumors that encroach on the eye, the ear, the mouth, or the nose. There are patients who progress on neoadjuvant [cemiplimab], and it's possible for patients to progress to an inoperable state. Therefore, there is certainly caution around considering [neoadjuvant cemiplimab] broadly in the absence of randomized data. However, the experience of the experts who were present [at the workshop] was all very positive in applying this [neoadjuvant] approach, specifically in the hopes of preserving [patient] function.

What factors do you consider when determining if neoadjuvant cemiplimab is an appropriate option for a patient with CSCC?

The patients who were included in the [phase 2] trial were immunocompetent. The best approach for patients who are immunosuppressed [is still unknown], and there is a lot of [ongoing] research in that area. We also discussed some of the emerging data specifically for patients who underwent kidney transplant with respect to immunotherapy.

In the phase 2 trial, the median age of the patients included was 73 years. It's an older population, and that was well recognized by the group [at the workshop. Clinical experience [has shown us] that patients [with CSCC] tend to be older and often have medical comorbidities. [There can also be logistical challenges, such as] getting back and forth to the clinic or the hospital for treatment. [This older patient population] is likely to benefit from this [neoadjuvant] approach. For patients who have advanced locoregional disease that would require surgery and radiation, [these treatments] can have quite a taxing role on their bodies and their function.

However, patients have to have resectable [disease to consider neoadjuvant cemiplimab]. In patients who are borderline resectable, [you have to consider the] risk of progression. If patients are borderline resectable and advance to an unresectable state, those are patients who may be less suited for [neoadjuvant treatment].

Therefore, older patients with locally advanced disease that would require multimodality treatment are the patients that we’re generally considering [for neoadjuvant cemiplimab] and are those whom we would be looking to enroll in a randomized, phase 3 trial.

There are so many unanswered questions that remain [regarding the neoadjuvant use of cemiplimab in CSCC]. Even with randomized trials, we'll have more and more questions that [emerge]. For example, what is the ideal number of neoadjuvant doses before surgery? In the pilot trial, we used 2 doses; in the phase 2 trial, we used up to 4 doses, and this will be replicated in the phase 3 trial, but [the ultimate answer] remains unknown.

There are many other unknown questions. Are there biomarkers that can help us predict response? Imaging, in general, has underestimated pathologic responses to treatment; therefore, imaging by itself is not sufficient. PD-L1 status and tumor mutational burdens are not predictive [of response either]. Then there are a lot of questions around how can we adapt our treatment based on the response to neoadjuvant treatment. For example, in which patients can we safely withhold adjuvant radiation? We have a good idea, but there's still more to learn. How can we adapt surgery for patients who respond [to neoadjuvant cemiplimab] to preserve function?

Finally, a big question from regulatory agencies is: what is the value of adjuvant treatment after neoadjuvant therapy? This is a vexing question. They're learning a lot [regarding the value of adjuvant treatment] in melanoma, and we have a lot to learn in advanced non-melanoma skin cancers. What's the sweet spot in terms of neoadjuvant vs adjuvant therapy? There are a couple of randomized phase 3 trials [evaluating] adjuvant treatment [in non-melanoma skin cancers] that I expect will read out in the next year or so, and [those data] may help better inform [adjuvant treatment decisions].

What key trials and discussions were highlighted throughout the workshop with regard to BCC?

Advanced BCC remains a real challenge, and that was highlighted from a lot of the discussion. These patients often have recurrent disease, and it can also often encroach on critical structures and be relatively recalcitrant to treatment. Currently, hedgehog inhibitors are indicated in the first line and have been applied in the neoadjuvant setting as well, and there was some discussion of our experience with this [during the workshop]. [The experience with neoadjuvant hedgehog inhibitors] was fairly muted compared with CSCC. [The experience] is just less robust. We recognize that and understand the role of a neoadjuvant approach with a hedgehog inhibitor remains something to be more fully elucidated.

There was discussion around the role of second-line cemiplimab for patients with unresectable [BCC] and some experience with good results [using this approach]; however, BCC is a disease that’s much less responsive vs other non-melanoma skin cancers, specifically Merkel cell carcinoma and CSCC. [Similar to patients with CSCC who are] immunosuppressed, BCC remains a challenging disease for patients with advanced, recurrent, borderline unresectable, or unresectable disease.

Could neoadjuvant immunotherapy play a role in the treatment of patients with BCC?

There are not a lot of data at this point to support the use of neoadjuvant immunotherapy for resectable BCC. The best data we have [for immunotherapy in BCC] is for patients whose disease has [progressed on] a hedgehog inhibitor in the unresectable or metastatic setting where there is an indication [for cemiplimab in the second line after a hedgehog inhibitor] and there can be efficacy. Off-label use in a neoadjuvant approach, I would consider with caution; the benefit is just unknown, unlike in CSCC, where we have a strong signal and we can see that patients can have a complete pathologic response to neoadjuvant approaches. With BCC, it would be rare to see [those types of responses], at least in my estimation at this point.

However, there is further research to be done. Maybe there are combination treatments [using immunotherapy] that will be more promising, and this is an area that is ripe for some disruption in the future.

What is the importance of continuing to investigate immunotherapy approaches in the management of non-melanoma skin cancers?

It's important to recognize that non-melanoma skin cancers in general—such as CSCC and BCC—are ubiquitous. They're so common that they've been overlooked for decades, yet they're still managed every day in the community by dermatologists and surgeons. Therefore, patients who have advanced or recurrent disease that is resistant to treatment are the ones we end up seeing.

I feel like we're almost a decade behind with CSCC [in terms of developing the level of data for immunotherapy from clinical trials that we have for melanoma]. There's a lot of push to enroll patients in trials to help us learn which patients will benefit from these approaches and shift the approach over time for the betterment of all our patients.

[Treating] advanced non-melanoma skin cancers remains a significant clinical challenge. A lot of this has to do with the disease, but [these malignancies are generally seen in] patients who are older and often have a lower tolerance for treatments. However, there are emerging approaches, including neoadjuvant strategies, that could bring a lot of promise to patients in the future. It's incumbent upon us to develop those data so we know with certainty which patients will benefit.

Reference

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