Rabinowits Analyzes the Use of Anti–PD-1 Therapy in cSCC

Guilherme Rabinowits, MD,

During a Targeted Oncology Case-Based Peer Perspectives event, Guilherme Rabinowits, MD, medical oncologist/hematologist, Miami Cancer Institute, discussed the case of 69-year-old patients with cutaneous squamous cell carcinoma (cSCC).

Targeted Oncology^TM: What are some of the high-risk features of this patient?

RABINOWITS: [The lesion] is large—greater than 2 cm—and it is postauricular, which is part of the face mask high-risk [area]. There’s clinical numbness sensation, which is translated in elective nodal irradiation, as well, it was poorly differentiated, and there is invasion beyond subcutaneous fat.¹

He also had neurological symptoms, which translate into perineural invasion, likely large caliber or more than 1 nerve involved. Usually, it’s considered high risk when there are at least 3 if it’s a high-caliber [nerve], meaning greater than 0.1-mm thickness.

How would a patient with cSCC be treated?

[According to National Comprehensive Cancer Network guidelines,] if something is localized and small, there’s no indication for systemic therapy. For patients who are nonsurgical candidates and have locally advanced disease, radiation therapy with or without the addition of systemic therapy can be considered, even though there are no prospective data that show a benefit.¹ Most of the people added systemic therapy, as in a cytotoxic agent, as a way of optimizing radiation as an extrapolation from mucosal head and neck cancer, which is considered standard of care in locally advanced disease. Finally, systemic therapy can be considered alone in situations in which patients are not a surgical candidate or they refuse surgery, either because of morbidity or they don’t feel as though radiation therapy is in their best interest. Among all the drugs that are currently available for that, an anti–PD-1 [therapy] is indicated. Cemiplimab [Libtayo] and pembrolizumab [Keytruda] will be options for systemic therapy alone.¹

Chemotherapy and radiation are another extrapolation for mucosal head and neck cancer. The only phase 3 trial that randomized patients with high-risk features to radiation or chemoradiation [was NCT00193895]—in that particular case it was carboplatin— this was a study that was presented and published by the Trans Tasman Radiation Oncology Group and [whose results] did not show a benefit of the addition of carboplatin.² Whether [oncologists] chose the right drug, used cisplatin instead, or maybe used a combination of platinum, 5-FU [fluorouracil], and platinum-taxane, we don’t know whether this was benefited.

For recurrent metastatic disease, systemic therapy is typically used. The standard of care is now an anti–PD-1 [therapy].

[However,] clinical trials should be kept in mind. Even though [there may be a] standard of care, particularly if [the disease] is potentially not curable, [it’s best] to think outside the box and consider clinical trials as a way of optimizing the outcome for these patients.

Which data led to the approval of cemiplimab?

The phase 2 EMPOWER-CSCC-1 study [NCT02760498], which has a 3-year follow-up, had 3 groups. Groups 1 and 3 were patients who had metastatic disease, both nodal and distant. Group 2 had locally advanced disease. The only difference between group 1 and 3 is the scheduling and dosing of cemiplimab. Initially, when the trial started, investigators gave participants 3 mg/kg every 2 weeks intravenously for up to 2 years. When they opened cohort 3, it was to look at 350-mg dosing every 3 weeks. Investigators treated these patients for up to 1 to 2 years.³

I think the most important key inclusion criterion to look at is that tumors were not amenable for curative intent surgery or curative intent radiation therapy by investigator assessments.

Patients were a median age of 72, were mostly male, and had an ECOG [performance status] of 0 or 1. The primary site was head and neck in 67.9% [of patients], metastatic [disease] was [reported in] about 59.0%, and locally advanced was [reported] in 40.4%.

Most patients [66.3%] received cemiplimab as first-line therapy. A third of patients received second-line or beyond. The median duration of exposure to cemiplimab was about 51 weeks, and the median number was 18.

With all groups combined, about 46% of patients responded. About 16% of 31 patients had a complete response, and another 30% had a partial response. Stable disease was [reported in] about 24% [of patients], for a disease control rate of 72%. They were durable response rates, meaning 105 days or beyond. Responses were quick. The majority [received] an average of 2.0 months of therapy, to a median of only 2.1 months to see a response and activity.

At a median follow-up of 15.7 months, the median progression- free survival [PFS] was 18.4 months. Based on the Kaplan-Meier curves, the 24-month PFS rate was 44.2%. The median overall survival [OS] has not yet been reached. [However,] the Kaplan- Meier–estimated probability of OS at 24 months was 73.3%. [Those are] pretty exciting data that we didn’t see prior to the immunotherapy era with either platinum-based therapy or cetuximab [Erbitux], which was commonly used before all of this.

Can you describe the adverse events (AEs) associated with this trial?

The safety profile was consistent with that of other studies of any anti–PD-1 therapy with the same class of drugs. Grade 3 and 4 treatment-emergent AEs [TEAEs] occurred in 44% of the patients, the most common being hypertension, anemia, and cellulitis. Serious TEAEs happened in about 29% of the patients. Seven were considered treatment related, the most common being pneumonitis. Unfortunately, 2 patients died. One died of infectious pneumonia that investigators felt to be unrelated to the drug, and the other died of aspiration pneumonia 10 days after developing pneumonia, so investigators felt this death was related to the study drug.⁴

What led to the approval of pembrolizumab for cSCC?

In the KEYNOTE-629 study [NCT03284424], patients with locally advanced disease or recurrent metastatic disease with excellent ECOG performance status received pembrolizumab as standard dosing at 200 mg every 3 weeks until disease progression and/ or 35 infusions over time. The primary end point was overall response rate [ORR], with secondary end points of duration of response, disease control rate, PFS, OS, and safety.⁵

Among the 105 patients accrued, most were male, with a median age of 72 years. But it’s important to point out that 86.7% of the patients received this anti–PD-1 [therapy] in the second line or beyond. The ORR was 34.3% [95% CI, 25.3%-44.2%], with close to 4% of the patients getting a complete response and 30.5% getting a partial response. Those responses were durable [>12 months] in about 65% of patients. The median PFS was 6.9 months [95% CI, 3.1-8.5], and the 12-month PFS rate was 32.4 months.

The safety was not different from what is expected for this class of agents [66.7% of patients experienced a treatment-related AEs]. One patient died of a treatment-related cranial nerve neuropathy. Pruritus, asthenia, and fatigue were the most common treatment-related AEs.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Squamous cell skin cancer, version 2.2020. Accessed November 12, 2020. https://bit.ly/3f0m9dO}

_{2. Porceddu SV, Bressel M, Poulsen MG, et al. Postoperative concurrent chemoradiotherapy versus postoperative radiotherapy in high-risk cutaneous squamous cell carcinoma of the head and neck: the randomized phase III TROG 05.01 trial. J Clin Oncol. 2018;36(13):1275-1283. doi:10.1200/JCO.2017.77.0941}

_{3. Migden MR, Khushalani NI, Chang ALS, et al. Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti–PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (laCSCC). J Clin Oncol. 2019;37(suppl 15):6015. doi:10.1200/JCO.2019.37.15 suppl.6015}

_{4. 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}

_{5. Grob JJ, Gonzalez R, Basset-Seguin N, et al. Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629). J Clin Oncol. 2020;38(25):2916-2925. doi:10.1200/JCO.19.03054}