Adjuvant Immunotherapy Represents Potential New Frontier in CSCC

Previously reported data regarding the use of neoadjuvant cemiplimab-rwlc (Libtayo) for patients with cutaneous cell carcinoma (CSCC) provide rationale that the use of the immunotherapy in the adjuvant setting could provide a benefit for this patient population, according to Axel Hauschild, MD.¹

“Immunotherapy in the adjuvant setting has a good future. In the presence of [positive] data for neoadjuvant therapy, there is no reason to believe that [therapies] in the adjuvant setting will not work,” Hauschild said.

In an interview with OncLive, Hauschild elucidated the evolving landscape of treatment approaches for CSCC and basal cell carcinoma (BCC), particularly focusing on perioperative treatment strategies; highlighted the unique aspects of treating CSCC compared with melanoma; and expanded on the use of anti–PD-1 agents such as cemiplimab in second-line treatment of locally advanced or metastatic BCC.

Hauschild is a professor of dermatology and the head of the Skin Cancer Trial Center at the University Hospital Schleswig-Holstein, Campus Kiel, Germany.

OncLive: Based on your experience treating these malignancies in Germany, how may perioperative treatment approaches impact the treatment landscape for CSCC?

Hauschild: Thus far, we don't have good data for perioperative treatment. We have the neoadjuvant cemiplimab data, which are outstanding. [In a phase 2 trial (NCT04154943), the pathologically confirmed complete response [pCR] rate [for patients with stage II to IV CSCC treated with neoadjuvant cemiplimab] was 50.6% [95% CI, 39.1%-62.1%], which is also really good. Many patients may not even need an adjuvant treatment in [following neoadjuvant cemiplimab] if they have a pCR.

I believe [this treatment strategy] is the future [for CSCC]. Perioperative treatment in melanoma is strong; I don't see any reason why it should not be as strong in CSCC and, eventually, other skin cancers.

What is the role of anti–PD-1 agents in the neoadjuvant setting?

We have data on anti–PD-1 in the neoadjuvant setting, and we don't have data on combination treatment. For any treatment that will be used now or in the future, the question [will be whether] combination treatment may be better than anti–PD-1 alone. There [are no data for anything other than] anti–PD-1 in the neoadjuvant setting. Therefore, I hope that we [can utilize combination approaches] in the future.

Based on the limited data thus far, what type of patients with CSCC could benefit from neoadjuvant PD-1 inhibition? Are there any challenges when considering neoadjuvant therapy for this patient population?

The neoadjuvant treatment of CSCC is special because in contrast to melanoma, patients [with CSCC] are much older. The average age [of patients treated in the phase 2] trial was 73 years. I have personally treated patients up to the age of 96. [Cemiplimab] is special in the sense that it is very well tolerated. In most of the patients, you don't see autoimmune [adverse effects] or fatigue. The toxicities are being tolerated by patients.

It is also special in that the patients are responding very quickly. Typically, you see the response after the first cycles of infusion, and after 3 or 4 cycles, the job is done.

What do you believe will be the role of adjuvant therapy in CSCC?

In our international guidelines, we don't have an adjuvant treatment defined right now because there are no data [to support its use]. If there were data in the past, they were negative; particularly, chemotherapy is not an option.

Therefore, we are looking forward to 2 clinical trials [in the adjuvant setting of CSCC]. One is evaluating cemiplimab [vs placebo] in the adjuvant setting for patients with high-risk CSCC [the phase 3 C-POST trial (NCT03969004)]. [Additionally, the phase 3 KEYNOTE-630 trial (NCT03833167)] is evaluating pembrolizumab [(Keytruda) vs placebo] for high-risk patients.

[In these trials], high risk is meant as patients who have high risk for relapse. Patients are undergoing surgery before being randomly assigned [to cemiplimab in C-POST or pembrolizumab in KEYNOTE-630] vs placebo. We are waiting eagerly results. By the end of [2024], these 2 clinical trials will be mature enough to [potentially] discuss new guidelines for the adjuvant treatment of CSCC.

What may be the role of adjuvant radiation in CSCC?

The role of radiation in the adjuvant treatment of CSCC is different across the world. In the United States and Australia, there is quite a high role for this. More or less, it is given after [surgery] in every high-risk scenario. In Germany, we are using [adjuvant radiation] less often.

If you have an effective adjuvant treatment, I believe it will replace radiation. However, I say this in the absence of data. The patients [enrolled in C-POST and KEYNOTE-630] need to be pretreated with radiation. Therefore, we cannot talk about these data [and how these adjuvant treatments could replace radiation]. However, in Germany, I believe [adjuvant therapy] will replace radiation in many cases.

Since CSCC is a tumor that is caused by an abuse of UV light, the more you have a clear carcinogen, such as UV light, the higher the chance is for these patients to have a benefit [from therapy]. This makes me very confident to believe that adjuvant immunotherapy is the way to go.

Are there patients with CSCC who may not be candidates for adjuvant treatment?

I would not consider adjuvant treatment for patients with serious underlying diseases, including patients with organ transplants, [including those with] renal, cardiac, lung, or liver transplants. These complicated patients are who are heavily immunosuppressed, and this is a problem because the benefit from [immunotherapy] is not the same for patients [who are immunocompromised] vs those who are immunocompetent; this is something you need to discuss.

Additionally, there are patients with underlying autoimmune diseases who have a serious risk for either a relapse or an exacerbation of the autoimmune disease. Therefore, I would be cautious in these kinds of patients.

Shifting to BCC, when would you potentially use anti–PD-1 agents or switch from hedgehog inhibitors to anti–PD-1 agents?

The labeled indication for cemiplimab is for the second-line treatment [of BCC], meaning that in locally advanced and metastatic BCC, patients must have had pretreatment with the hedgehog inhibitors vismodegib [Erivedge] or sonidegib [Odomzo]. Additionally, [anti–PD-1 therapy is indicated for use] only if patients were pretreated and did not have a response to a hedgehog inhibitor—meaning stable disease or progressive disease—or were intolerant to hedgehog inhibitors, which is very often the case.

[Although] these patients are candidates for cemiplimab in the second line. The overall response rate [reported in a phase 2 trial (NCT03132636) that supported its approval] was only 32% [in patients with locally advanced disease] and [24% in patients with metastatic disease]; therefore, it is not the approximate 50% [ORR] observed in first-line treatment in other cutaneous malignancies. However, these patients had been pretreated, and this is a typical situation, as pretreated patients don't have the same ORR as treatment-naive patients.

I am waiting for the first patient whom I can treat in the first line with cemiplimab in order to talk about the higher ORRs [associated] with [first-line treatment], but there is no clinical trial on the horizon, as far as I know.

Are there any ongoing studies with emerging data either in the neoadjuvant or perioperative setting of BCC that you would like to highlight?

There are clinical trials underway in BCC in the perioperative and neoadjuvant treatment space. However, BCC trials are not as easy as CSCC trials because BCC has a discontinuous growth pattern, which means that you cannot well define the tumor bed, which needs to be excised after the intralesional or systemic treatment.

I would trust that the systemic treatment for primary tumors is not as effective as we are believing, but I believe the intralesional treatment enhances the opportunity to see nice responses. The way to go for BCC in the future might be intralesional treatment with anti–PD-1 therapy, and then you need to compare [those results] with surgery. We will then see who is the winner at the end of the day. I would also believe that the data on intralesional treatment are good enough to justify more clinical trials.

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 Oncl. 2023. doi:10.1016/S1470-2045(23)00459-X
2. FDA approves cemiplimab-rwlc for locally advanced and metastatic basal cell carcinoma. News release. FDA. February 9, 2021. Accessed May 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-locally-advanced-and-metastatic-basal-cell-carcinoma