Early Data Underscore the Potential of Neoadjuvant Immunotherapy in Advanced Resectable CSCC

Preliminary data from a phase 2 study (NCT04154943) indicated that neoadjuvant cemiplimab (Libtayo) was highly active in patients with resectable cutaneous squamous cell carcinoma (CSCC). If long-term outcomes prove to be favorable, this approach may improve quality of life (QOL) for this population and positively disrupt the treatment paradigm, according to Neil D. Gross, MD, FACS.

Data presented at the 2022 ESMO Congress showed that the pathologic complete response (pCR) rate achieved in evaluable patients treated with cemiplimab (n = 79) was 50.6% (95% CI, 39.1%-62.1%); the major pathologic response rate was 12.7% (95% CI, 6.2%-22.0%). The combined pathologic response rate in these patients was 63.3% (95% CI, 51.7%-73.9%). Moreover, the agent induced an objective response rate (ORR) by RECIST v1.1 criteria of 68.4% (95% CI, 56.9%-78.4%).

“Right now, the standard of care [SOC] for advanced CSCC is surgery and adjuvant radiation, and the impact of these treatments can be devastating to patients,” said Gross, who is the lead study author and director of clinical research in the Department of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center, in Houston, Texas. “If patients can be successfully treated with a few doses of neoadjuvant immunotherapy, with relatively low toxicity, [they could] potentially avoid radiation or in the future, [they might] avoid surgery altogether, that's a win for our patients.”

In an interview with OncLive^®, Gross discussed the current deficits in the treatment of patients with CSCC in the curative setting, avenues for continued research generated by the primary analysis of the phase 2 trial examining neoadjuvant cemiplimab in this population, and how immunotherapy has emerged as a viable option for this disease.

OncLive^®: What was the rationale for investigating the use of cemiplimab as a neoadjuvant treatment for patients with CSCC in the phase 2 study presented at the 2022 ESMO Congress?

Gross: CSCC is extremely ubiquitous. [The disease] is so common in the United States that it’s not even included in our national registries. Most patients are successfully treated with surgery alone, so local therapy; [however,] a certain percentage will advance and require more extensive surgery, and often, adjuvant radiation.

The cumulative effects of [all of this] can be devastating to patients and can have a real impact on their QOL. Some patients can lose significant function, because most of these cancers affect the head and neck region, which is sun exposed. The proximity of pathology to structures [that are] critical to speech, vision, and hearing, make it a high-risk area. The impetus for the trial was to improve not only the oncologic outcomes, but the functional outcomes for these patients.

Please expand on the patient population included on the study.

We focused on patients with stage II to IV, resectable, CSCC. The patients [with stage II disease] had to have tumors that were greater than 3 centimeters in size, and [located] in an aesthetically sensitive area. The vast majority of the patients included in the trial had advanced stage disease. [The] SOC for [these patients] would be surgery and radiation. These patients [have] the most to gain [from] a neoadjuvant approach if the surgery can be tailored, as it was [here], and if adjuvant therapy can be more judiciously applied.

Is there anything you would like to note regarding the trial design?

This study does not track the long-term outcomes; those data are not mature yet, so we don’t know long-term survival. We don’t know which patients received radiation or not, because [the choice of adjuvant therapy] was at investigator discretion. However, it will be very telling once we have those data. [We will be able to better] understand the impact this approach had on QOL.

What were the key findings presented at the meeting?

The neoadjuvant approach [with cemiplimab resulted in] a dramatic pathologic complete response [pCR] rate in [patients with resectable CSCC]. Over half of patients had no residual viable tumor within the specimens and another 10 patients had a major pathologic response, so [approximately] two-thirds of patients [experienced] a deep pathologic response to treatment.

These [data were produced in a] multicenter trial, [which was done] across Europe, the United States, and Australia. [Moreover,] an independent central pathology review had confirmed these responses. [The results] could hearken to a paradigm shift in how we manage this disease in the future, given the deep pathologic responses.

We’re very excited about the preliminary outcome of this study, meaning its primary clinical endpoint of pCR. The responses were similar to what we saw with the pilot data, but still very, very dramatic. The data presented during the meeting were [also] accepted for [concurrent] publication in the New England Journal of Medicine.

What will be even more exciting to see is the long-term outcomes of these patients. We know from the pilot data that at 3 years [follow-up], patients who had a complete or near-complete response to neoadjuvant treatment did well with or without adjuvant therapy. [Accordingly], the long-term prognosis is excellent, but it needs to be confirmed in this multicenter trial.

The one caveat [of these data] is that the radiographic responses underestimated pathologic responses. [As such, these findings] underscore that patients still need tissue confirmation to know that they’re responding to treatment.

What else might be learned from the long-term outcome data? What remaining questions do you hope to see addressed in the future?

First and foremost, we need to follow these patients to confirm the oncologic results [we have seen thus far] and to track QOL. We did check circulating tumor DNA as part of the study, so it will be very interesting to see whether that correlates with outcome. We did check baseline tumor mutational burden and PD-L1 status and that was not informative in selecting patients for the neoadjuvant approach.

Many questions were generated from this research, [such as, what is] the optimal number of treatments before surgery? What the role of adjuvant radiation in this case and are there patients who can avoid radiation [or surgery] altogether? We don’t know the answer to these [questions, and] it will take a lot of work to sort that out. However, I think the future is very bright for our patients in improving not only outcomes, but QOL.

What should your colleagues take away from this research?

These data are very exciting, and we are delighted that they would be published in the New England Journal of Medicine, but [it is still early. Right now, we only have information on] pathologic response rates. We know from [what we have seen in] melanoma and [from] the PILOT [trial done] in CSCC, that pathologic responses to immunotherapy can be durable. I expect that will prove to be the case [in our research, as well]—but we need to know that [for certain] before [we] implement [this approach] into practice.

[It is also important to] really define the appropriate use of surgery in patients who respond and the appropriate use of adjuvant radiation or even adjuvant immunotherapy. [Addressing these] unanswered questions in future studies will be [key].

Reference

Gross N, Miller DM, Khushanlani N, et al. Neoadjuvant cemiplimab in patients (pts) with stage II–IV (M0) cutaneous squamous cell carcinoma (CSCC): primary analysis of a phase II study. Ann Oncol. 2022;33(suppl 7):S904-S905. doi:10.1016/j.annonc.2022.07.915