Pavlick Explores Role of Immunotherapy in Cutaneous Squamous Cell Carcinoma

Anna C. Pavlick, DO, MS, MBA

During a Targeted Oncology Case Based Peer Perspective event, Anna C. Pavlick, DO, MS, MBA, assistant professor of Medicine (Interim), Weill Cornell Medical College, Cornell University, Weill Cornell Medicine in New York, NY, discussed the case of a 69-year-old patient with cutaneous squamous cell carcinoma.

Targeted Oncology™: What are some of the tests you would recommend to treat this patient?

PAVLICK: You could consider an MRI to rule out perineural invasion, especially with the numbness. Because most of these [lesions] are usually locally invasive, I don’t think it is necessary to scan for distant disease without any palpable adenopathy. However, I would certainly want to get an MRI to look at perineural [invasion].

How do you define locally advanced squamous cell cancer?

For me, when I first started looking at and being referred patients with advanced squamous cell, I had a melanoma mind-set. So to me, locally advanced melanoma means that I have a deep melanoma that also has positive lymph nodes. [Those] criteria [do] not hold true when it comes to squamous cell carcinoma. If you have lymph node involvement in squamous cell carcinoma, it’s considered metastatic disease. That was something I had to get my head wrapped around, because I always wanted to make them stage III, when in fact, they’re stage IV. I would probably define it as a lesion [that] cannot be resected safely by the surgeons with adequate margins.

Most surgeons are going to say that they can resect pretty much anything. But the question is, do you have multifocal disease? Are you going to be able to get clean margins? It is the clean margins that are important. Many of these patients will have multifocal disease, as well.

I know I’m fortunate that I have a cutaneous oncology team, which incorporates a medical oncologist, a surgical oncologist, head and neck, pathology, radiation oncology, and dermatology. Sometimes, patients like this will come to oncology, and [other times] patients like this will go to the surgeons. I’m fortunate enough to have my surgeons call me and say that we need to talk about the case. They sometimes ask, “Can you downsize this for me before I take the patient to the [operating room]?”

I have the luxury of having radiation oncologists in the same building who can discuss radiating this lesion, maybe because the patient doesn’t want systemic therapy.

What kind of follow-up data do we have for cemiplimab?

The phase 2 EMPOWER trial [NCT02760498] essentially evaluated cemiplimab in patients over a 3-year follow-up.1 The first cemiplimab trial [NCT02383212] evaluated patients who were all comers, locally advanced, as well as metastatic.2 Then there was an additional expansion cohort that looked at patients with just distant disease or just localized disease, as opposed to just clumping them together.

In the Rischin study, these patients had a 15-month follow-up.1 Looking at the data, 193 patients were enrolled. Group 1 was a mixture of 59 patients with locally advanced and metastatic disease. Then group 2 was 75 patients [with] locally advanced disease. And group 3 was 56 patients, and that was metastatic patients. The average age was 72, which I don’t think anybody is surprised about, with a higher percentage of those patients being men. About 70% of patients had the primary presentation site of the head and neck. About 40% of patients had locally advanced disease, whereas 60% had metastatic disease.

Whether patients had locally advanced or metastatic disease, the study demonstrated that the responses were essentially equal across all comers, demonstrating roughly a 50% response rate.

What did the clinical activity in this trial demonstrate?

Looking at clinical activity at 1-year follow-up and 2-year follow-up, patients have prompt responses. Usually, the time it takes for patients to respond to immunotherapy is about 2 cycles. The data in this study suggest that over time, you can develop more durable responses. You might have a partial response, which can then lead into a complete response.

Keep in mind, however, that response rates are only 50%. If you don’t see a patient responding by the second or the third cycle, and their tumor is growing, just cut your losses, move on, and accept the fact that this is a nonresponder.

Also, there is a plateau associated with progression-free survival and overall survival. In patients who do have responses, about 40% of those responders will have long-term durable responses. If you look at overall survival, 73% of patients are alive, which is exciting compared with the chemotherapy data. If you look at the chemotherapy data of 5FU [fluorouracil]/platinum or 5FU/platinum with cetuximab, you have about an 8-month average response. But there is no durability to that. These were exciting data.

Do any trials evaluate tumor mutational burden or PD-L1 status?

Both factors were evaluated in a phase 2 single-arm study [NCT02760498].3 Sixty-two percent of patients who enrolled in this trial had PD-L1 status checked before receiving treatment. PD-L1 expression was either less than 1%, which is negative, or 1% or higher, which is positive. Thirty of 31 patients were positive, which means that most patients with squamous cell carcinoma usually overexpress PD-L1.

When reviewing responses, if the patient is a PD-L1 overexpresser, there is a much higher chance of responding, meaning 55%. However, just because you have less than 1% PD-L1 expression doesn’t mean you won’t respond. So ordering a PD-L1 test to exclude somebody from therapy is not appropriate. I think it just helps you stratify in your mind whether these patients are, in fact, going to respond. But these patients should be offered the option of immunotherapy, because 35% is certainly not 0% or 5%. There’s a reasonable chance of response.

How does the toxicity profile for cemiplimab look?

The top 3 most common any-grade treatment-emergent adverse effects (TEAEs) reported are fatigue, diarrhea, and nausea.1 I can honestly tell you that I have not seen anybody develop diarrhea as a consequence. I don’t see a whole lot of diarrhea with any of the PD-1 single agents. It’s very rare. Clearly, fatigue being the most important, not so much nausea, but rash and itching are what makes most of my patients crazy. I think pneumonitis is exceedingly low unless you have someone who is a smoker.

What other clinical trials are available to treat similar patients?

In patients with high-risk lesions, you can consider a phase 3 trial that is comparing survival outcomes for patients with high-risk cutaneous squamous cell carcinoma who are treated with adjuvant cemiplimab, compared with patients who are treated with a placebo, after surgery and radiotherapy [NCT03969004]. The patients in the trial will undergo surgery followed by radiation therapy, because the lesions are deep or there is perineural invasion. After radiation, these patients get randomized to either observation or receive adjuvant cemiplimab.

We also have the survivorship trial that’s open. It’s looking at quality of life, because so many of these patients with squamous cell carcinoma present with perineural invasion and pain. We are looking to see whether pain can be essentially a biomarker for response for these patients, because many times patients will have an improvement in their pain prior to even noticing a difference in their cutaneous lesion.

_References:

_{1. Rischin D, Khushalani NI, Schmults CD, et al. Phase II study of cemiplimab in patients (pts) with advanced cutaneous squamous cell carcinoma (CSCC): longer follow-up. J Clin Oncol. 2020;38(suppl 15):10018. doi:10.1200/JCO.2020.38.15_suppl.10018}

_{2. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341-351. doi:10.1056/NEJMoa1805131}

_{3. Migden MR, Khushalani NI, Chang ALS, et al. Cemiplimab in locally advanced cutaneous squamous cell carcinoma: results from an open-label, phase 2, single-arm trial. Lancet Oncol. 2020;21(2):294-305. doi:10.1016/S1470-2045(19)30728-4}