Cemiplimab Therapy Shows Efficacy in Trial of Advanced CSCC

Michael K. Wong, MD

During a Targeted Oncology Case-Based Roundtable event, Michael K. Wong, MD, PhD, professor, Department of Melanoma, Medical Oncology, The University of Texas MD Anderson Cancer Center in Houston, TX, discussed the case of a 69.year-old patient with cutaneous squamous cell carcinoma.

Targeted Oncology^TM: What treatment options would be available to such a patient?

WONG: According to the National Comprehensive Cancer Network guidelines, the presence of local disease is a minimum for surgery, and systemic therapy is not recommended 1 There’s an acknowledgment in the field that if you can resect these tumors, you should try to do so. But cosmetic and functional issues should be taken into consideration, and a multidisciplinary approach is preferred. There are phase 2 data to support combining RT [radiation therapy] with cisplatin.^2,3 In situations in which the first 2 options are not available, cemiplimab [Libtayo] and pembrolizumab [Keytruda] checkpoint inhibitors are used.¹

The patient declined to pursue this approach given the extent of the surgery and high risk of local recurrence and development of metastases. He declined radiotherapy as well. Cemiplimab 350 mg every 3 weeks was initiated.

What is the evidence supporting the use of cemiplimab for these cases?

The cemiplimab data come from a phase 2 study [NCT02760498]. Patients were divided into 3 groups; groups 1 and 2 were given cemiplimab 3 mg/kg every 2 weeks, whereas group 3, composed of patients with advanced metastatic nodal or distant disease, was given 350 mg every 3 weeks as a set dosage, which is now the standard dosage.^2,3

In the first study [cemiplimab 3 mg/kg every 2 weeks] with groups 1 and 2, they separated those with metastatic [group 1] and locally advanced disease [group 2]. A key inclusion criterion for these studies was an ECOG performance status of 0 or 1. I want to emphasize this because these therapies rely on the immune system. Therefore, having a patient in the best possible shape is important, and comorbidities should be addressed before initiating therapy.

The aggregate data of the 3 groups showed that just under half of the patients had locally advanced disease [40.4%] and two-thirds [66.3%] had cemiplimab as a first-line therapy.3 The mean duration of exposure to cemiplimab was 51.1 weeks, which is a long drug exposure time compared with chemotherapy.

The overall response rate was significant at 42%, 46%, and 50% for groups 3, 2, and 1, respectively. In other words, about half the patients had a response. The durable disease control rate, meaning proven stable disease, a partial response, or a complete response [CR] over a period of time, was 61%, which is also very significant. An important aspect to point out is that there was a 9% to 12% chance of a CR even in groups 1 and 3, composed of patients with distant metastatic disease. [For these patients, a CR rate of 9% to 12% is unprecedented.] Additionally, patients treated with cemiplimab for advanced CSCC showed remarkable responses.⁴

All 3 groups, metastatic, locally advanced, and resectable, had similar responses. The 24-month overall survival rate was 73.3%. A median overall survival is not available because the study hasn’t reached the 50% mark. The data show that the survival curves are reaching a plateau, which is what we hope to see with immunotherapy.

Should PD-L1 staining or TMB [tumor mutational burden] be used as biomarkers for using cemiplimab?

Objective responses were observed in patients regardless of baseline PD-L1 TPS [tumor proportion score].⁵ Therefore, PD-L1 staining is not necessary for these patients, nor is it predictive because more than a third of the patients with very low PD-L1 staining responded to therapy.⁵ Some nonrespondents had a very high TMB. Therefore, the TMB cannot be used as a biomarker.

What do you think about the safety profile of cemiplimab?

Cemiplimab is an anti–PD-L1 drug in the same vein as pembrolizumab and nivolumab [Opdivo], and the safety profiles are consistent with those.⁵ Serious associated AEs [adverse effects] occurred in 23 patients (29%), and 9% were considered treatment related, of which the most common was pneumonitis (4%),⁵ which is typical of PD-L1 drugs. There were 2 cases of grade 5 toxicity; one was a case of infectious pneumonia, and the second was a case of aspiration pneumonia, which led to death,5 re-enforcing the point that it is important to monitor for pneumonitis with all PD-L1 drugs.

What is your recommended protocol for a patient who develops grade 3 pneumonitis after treatment?

The usual presentation for grade 3 pneumonitis is a patient who walks into an emergency department with shortness of breath 3 weeks after receiving a dose of cemiplimab. A CT scan is ordered to check for a fluffy infiltrate. However, this is indistinguishable from a COVID-19 case. Therefore, a COVID-19 test should be ordered, followed by ruling out other infections. I divide these patients into those who are ambulatory and those who are sick enough to be admitted. For the latter group, we don’t start steroids right away. We do an infectious work-up and a sputum culture, if possible. In the first 12 hours, we do everything we can to understand whether we have a pneumonitis case. We have a close look at the CT scan for any hint of an infectious cause.

We often start antibiotics on spec. If the patient does not get better after 24 hours, or if they get worse, we start thinking about pneumonitis. The gold standard diagnostic procedure is a bronchoscopy, but we use it only for recalcitrant cases that we cannot figure out. For pneumonitis cases, we first consult with a pulmonologist. Usually, the initial steroid dose for hospitalized patients is anywhere from 1.0 to 1.5 mg/kg of methylprednisolone [intravenously], usually divided into 12.

What is the evidence supporting the use of pembrolizumab for a patient such as this?

Pembrolizumab from the KEYNOTE-629 study [NCT03284424] also got approval.6 It had an overall response rate of 34%, and the medium duration of response is not available yet.

This study had a recurrent metastatic cohort and a locally advanced cohort. However, their entry criteria included patients with an ECOG performance score of 0 to 2. Therefore, these patients were a little worse off than the ones in the [the phase 2] study. But apart from that, the groups were similar. The overall response and the CR rates were not so stellar.⁷ However, we should not compare across studies. These trials had different patient populations as well. In general, huge differences in either of these PD-L1 drugs have not been reported.

The pembrolizumab AE profile was not different from what has been reported for other cancers and follows what is known about PD-L1 drugs. Despite a lower response rate, most patients had either stability or reduction in tumor volume. Another important aspect is that most patients who do get a response do so fairly early.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Squamous cell skin cancer, version 1.2021. Accessed May 18, 2021. 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, Migden MR, Lim AM, et al. Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixeddosing, long-term outcome of weight-based dosing. J Immunother Cancer. 2020;8(1):e000775. doi:10.1136/jitc-2020-000775}

_{4. 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}

_{5. 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}

_{6. Grob JJ, Gonzalez R, Basset-Seguin N, et al. KEYNOTE-629: phase 2 study of pembrolizumab for recurrent/metastatic or locally advanced unresectable cutaneous squamous cell carcinoma (cSCC). J Clin Oncol. 2019;37(suppl 15):TPS9598. doi:10.1200/JCO.2019.37.15_suppl.TPS9598}

_{7. Grob JJ, Gonzalez Mendoza R, Basset-Seguin N, et al. 3622 - pembrolizumab for recurrent/metastatic cutaneous squamous cell carcinoma (cSCC): efficacy and safety results from the phase 2 KEYNOTE-629 study. Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394}