Systemic Therapy Remains a Successful Strategy for Patients Refusing Surgery for CSCC

For patients with cutaneous squamous cell carcinoma who refuse surgery as a treatment for their disease, systemic therapies like cemiplimab (Libtayo),nivolumab (Opdivo), avelumab (Bavencio), and pembrolizumab (Keytruda) can still improve outcomes, explained Asim Amin, MD, PhD, a medical oncologist, Levine Cancer Institute. Atrium Health during a Targeted Oncology Case-Based Peer Perspectives event.

Targeted Oncology^TM: What are some noteworthy factors that affect the prognosis in this patient?

AMIN: One of the things is that [the lesion is] in the mask area of the face. It is on the face. It is behind his ear. You have all of those [high-risk] features. One of the features is the location; if it is on the trunk or extremities, it’s relatively lower risk compared with on the face. The location, the numbness, the diameter, thickness, the poorly differentiated pathological invasion beyond the subcutaneous fat, and granular involvement [give this a high-risk categorization].

The same [is said in the] NCCN [National Comprehensive Cancer Network] guidelines.1 The area and the size greater than 2 cm are both considered high-risk factors. If it is greater than 1 cm, even on the face, it is high risk. With the rapidly growing phenotype and neurologic symptoms, it’s poorly differentiated. The invasion is beyond the subcutaneous fat.

If this patient were referred to you, what would you recommend most as the first-line option?

Traditionally, for these localized lesions, radiation would be the standard of care.

The NCCN is always broadly amenable to surgery. Systemic therapy is not recommended for locally advanced disease in nonsurgical candidates. Again, that is not really defined, but there are potential options for radiation, clinical trials, chemotherapy, and for systemic treatment alone. Cemiplimab is preferred [for systemic therapy alone] or a clinical trial. For regional disease, if the lymph nodes are not involved or external distention is noted after surgery, radiation is recommended. For those who are inoperable or incompletely resected, there’s radiation with some level of evidence for sensitization in this setting.

For those folks who are not curative and are not surgical candidates, cemiplimab or a clinical trial is preferred. If the patient is ineligible for immune checkpoint inhibitors, there are other options.¹

What were the key aspects of the pivotal trial that led to the approval of cemiplimab in this setting?

The [EMPOWER-CSCC-1 trial (NCT02760498)] led to the approval of cemiplimab at the initial dose of 3 mg/kg. Initially, group 1 had metastatic nodal or distant disease [n=59]. Group 2 was the locally advanced CSCC group [n=78]. Subsequently, fixed dosing was used, 350 mg intravenously every 3 weeks [n=56].²

The data were updated at the American Society of Clinical Oncology 2020 Virtual Scientific Program [for all] 193 patients. The key inclusion criteria for groups 1 and 3 [was at least 1 lesion measurable by RECIST 1.1], but in group 2, at least 1 lesion had to be measurable by distal medical photography. Exclusion criteria for all groups included ongoing autoimmune diseases, prior exposure to PD-1 or PD-L1 inhibitors, and solid tumor transplants.³

Baseline demographics for the 193 patients [revealed that] 78, or 40.4%, had locally advanced CSCC. Two-thirds received cemiplimab as first-line therapy and one-third had received prior treatment. The median duration of response was close to a year and the median number of doses of cemiplimab was 18.

In group 1, the patients with metastatic CSCC, there was a 50.8% overall response rate [ORR]. Group 2 with locally advanced CSCC had a 44.9% ORR. Group 3 was the fixed-dose cemiplimab group, with a 42.9% ORR. The response rate [in all groups was] 46.1%. The complete response rate in the metastatic disease group was 20.3% versus 12.8% with the locally advanced disease. The durable disease control rate was 61.0% for the metastatic, 62.8% for the locally advanced, and 60.6% overall.

Do you ever use cemiplimab as a neoadjuvant therapy?

[Sometimes] we would use cemiplimab upfront as a neoadjuvant intervention. If you’re going to do a neoadjuvant intervention, you need to know how long you’re going to do that intervention for if you are going to decide this is working or not. The median time to response is close to 2 months for the locally advanced cases. If you’re going to use cemiplimab for a locally advanced case that may not be readily resectable or that may have significant hazards or contraindications to radiation, then keep this number in mind. In about 6 to 8 weeks, you should be seeing the median response.

It is important to note that if you’re going to use that approach, then these patients need to be followed closely with your surgical colleagues. It is important not to lose that window of opportunity for local control for these folks, either by the surgeons or the radiation oncologists. Keep that in a close loop if you’re going to use systemic treatment up front. This is about when you should start seeing a significant response in at least half of the patients.

What do the survival data indicate about cemiplimab use in patients with locally advanced or metastatic CSCC?

At 24 months, the progression-free survival rate was 44.2% and the overall survival rate was 73.3%. These responses, when they happen, can be doable. Initially, the [Kaplan-Meier] curve will come down like most immunotherapy options we’ve seen and then the curve flattens.

What are the safety concerns with cemiplimab?

Cemiplimab did not show any new signals in advanced CSCC. The [grade 3/4] treatment-emergent adverse events occurred in about 44% of the 78 patients. Surprisingly, there were 8% of patients with hypertension and 5% with pneumonia, but it was not clear if some of these were pneumonitis.

There were 2 grade 5 events. One was infectious pneumonia and the other was aspiration pneumonia that was deemed to be related to the study treatment as per the investigator.

Which agents are approved in this setting?

In 2018, cemiplimab was approved for patients who had metastatic or locally advanced CSCC and are not eligible for curative surgery [or] curative radiation or who refused the above interventions.⁴

Pembrolizumab was approved in June for recurrent metastatic CSCC that is not curative by surgery or radiation. This [approval] was based on the KEYNOTE-629 trial [NCT03284424]. The ORR was 34%.⁵

What other approaches are being explored for patients with unresectable CSCC?

A bunch of trials are recruiting at this point. Cemiplimab with or without RP1 is [looking at genetically modified] herpes simplex virus 1 that is locally injected [CERPASS; NCT04050436].

Other agents used in addition to cemiplimab include nivolumab, avelumab, avelumab with radiation, and pembrolizumab. All of these are being looked at.

How would you use tumor mutational burden (TMB) in these patients?

The [EMPOWER-CSCC-1] study looked at TMB. Responses were seen in folks with low and high tumor mutational burden.⁶

The FDA has approved pembrolizumab for TMB-high solid tumors in both adults and children. High burden was defined as greater than 10 mutations per megabase, and they also approved the FoundationOne CDx assay [to determine] this.7 Not that it really matters in this setting, but the tumor mutational burden by itself, like [microsatellite instability] with respect to the tumor type, has now been approved as a criterion.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Squamous cell skin cancer, version 2.2020. July 14, 2020. Accessed November 25, 2020. https://bit.ly/3f0m9dO}

_{2. 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}

_{3. 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}

_{4. FDA approves cemiplimab-rwlc for metastatic or locally advanced cutaneous squamous cell carcinoma. FDA. September 28, 2018. Accessed November 25, 2020. https://bit.ly/32BXQ0L}

_{5. FDA approves pembrolizumab for cutaneous squamous cell carcinoma. FDA. June 24, 2020. Accessed November 25, 2020. https://bit.ly/3f3O3pi}

_{6. 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}

_{7. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. FDA. June 16, 2020. Accessed November 25, 2020. https://bit.ly/33gtS2F}