Among patients with locally advanced cutaneous squamous cell carcinoma (CSCC) who were enrolled in the pivotal EMPOWER-CSCC-1 phase II study, cemiplimab exhibited substantial antitumor activity and induced durable responses similar to those experienced in patients with metastatic CSCC who were enrolled in the same study.
Michael R. Migden, MD
Among patients with locally advanced cutaneous squamous cell carcinoma (CSCC) who were enrolled in the pivotal EMPOWER-CSCC-1 phase II study, cemiplimab (Libtayo) exhibited substantial antitumor activity and induced durable responses similar to those experienced in patients with metastatic CSCC who were enrolled in the same study.
The Kaplan-Meier estimated progression-free probability at 12 months was 58.1% (95% CI, 43.7%-70%), and the estimated probability of survival at 12 months was 93.2% (95% CI, 84.4%-97.1%).
The 43.6% ORR in this group is similar to that observed in patients with metastatic CSCC, who had a response rate of 47%. The results in the latter cohort were published last year in the New England Journal of Medicine.2
Results of the study led to FDA approval of cemiplimab for patients with metastatic CSCC, or those with locally advanced disease who are not candidates for curative surgery or radiation. The recommended dosage is at 350 mg intravenously every 3 weeks until disease progression or unacceptable toxicity.3
“Prior to the FDA approval of cemiplimab, there was no approved therapy for the treatment of advanced CSCC, whether locally advanced or metastatic,” said Migden, professor in the Departments of Dermatology and Head and Neck Surgery at the University of Texas MD Anderson Cancer Center. “The therapies that were used were standard chemotherapy agents or epidermal growth factor-targeted agents that were associated with lower response, but more importantly, a shorter duration of response and lots of tolerability issues.”
Patients with locally advanced disease were eligible for inclusion in the cohort if they were not candidates for surgery or radiation therapy, according to the trial investigator. Surgery was considered inappropriate in patients who had disease recurrence in the same location after 2 or more surgical procedures and curative resection was deemed unlikely, for those whom the treating clinician anticipated that surgery would result in substantial complications or deformity, or where there was significant local invasion that precluded complete resection.
Radiotherapy was considered inappropriate in patients whose further treatment would result in an excessive cumulative dose of radiation, in those with tumors that were unlikely to respond to radiotherapy, or if the risk—benefit of radiotherapy was judged to be unfavorable.
Eligible patients had to have an ECOG performance status of 0 or 1, adequate organ function, and the presence of at least 1 measurable lesion.
The primary CSCC site was of the head/neck in 79.5% of patients, an extremity in 17.9%, and the trunk in 2.6%. Twelve (15.4%) patients had prior cancer-related systemic therapy and 43 (55.1%) had prior radiotherapy.
At data cutoff (October 10, 2018), 6.4% of patients completed the planned treatment, 30.8% remained on treatment, and 62.8% discontinued treatment due to disease progression (21.8%), adverse events (AEs), investigator’s decision, a complete response (CR) to treatment, or patient’s decision.
At a median follow-up of 9.3 months, 10 (12.8%) patients had a CR, 24 (30.8%) had a partial response (PR), and 28 (35.9%) had stable disease (SD) as their best response. The durable disease control rate was 62.8% and the median observed time to response was 1.9 months.
These results were similar to those reported in the metastatic CSCC group, with 7% of patients achieving a CR, 41% with a PR, and 15 with SD as their best response. The durable disease control rate was 61% and the median observed time to response was 1.9 months.
In the patients with locally advanced disease, 12 patients have had responses lasting ≥12 months and the longest duration of response at data cutoff was 24.2 months and ongoing.
ORR was also assessed in a subgroup analysis where patients were stratified by the reasons for why they were not considered to be candidates for curative surgery, and these data may support earlier use of cemiplimab in this patient population, said poster discussant Katharine A. Price, MD, of the Head and Neck Cancer Center at the Mayo Clinic in Rochester, Minnesota. Standard treatment approaches in locally advanced CSCC often exhaust local therapies first, she noted.
Among 20 patients with unresectable CSCC lesions with significant local invasion, the ORR was 50%. Among 30 patients with lesions in anatomically challenging locations for which surgery may result in severe deformity or dysfunction, the ORR was 56.7%. Among 25 patients with CSCC lesions in the same location after 2 or more surgical procedures and where curative resection is deemed unlikely, the ORR was only 24%.
“In my mind, this raises questions about the tumor microenvironment in the setting of a site treated with prior surgery,” said Price. “Surgery has been shown to generate an immunosuppressive environment with an increase in T-regulatory cells and proinflammatory cytokines, and a decrease in CD8-positive cells, all of which could explain an attenuated response to cemiplimab.”
Understanding the tumor microenvironment is critical for the development of novel and effective immunotherapy combinations, she added.
In a biomarker analysis, there was only slight enrichment for response for patients with high tumor mutational burden (TMB) levels, and PD-L1 staining was a weak biomarker for response. Median TMB values were 74.2 mutations/Mb in the 21 responders and 28.7 mutations/Mb in the 29 nonresponders. Among the 29 patients who achieved durable disease control and the 21 who did not, median TMB values were 64.9 mutations/Mb and 31.5 mutations/Mb, respectively. “These are exploratory data and not to be used to determine who should be on treatment,” said Migden.
The ORR was 54.8% in patients with PD-L1 expression ≥1% and 35.3% in those with PD-L1 expression <1%. “This would suggest that we should not be limiting these drugs to PD-L1—positive tumors only,” Price said.
The disease control rates were 77.4% and 82.4% and the durable disease control rates were 67.7% and 58.8% in patients with PD-L1 expression ≥1% and <1%, respectively.
The most common treatment-emergent (TE)AEs were fatigue (42.3%), diarrhea (26.9%), and pruritus (26.9%), which were grade ≥3 in 1.3%, 0%, and 0%, respectively. Twelve grade ≥3 immune-related AEs occurred in 8 (10.3%) patients. Two patients with TEAEs died, 1 due to infectious pneumonia and 1 due to unknown cause.
Out of 78 patients with locally advanced CSCC, the objective response rate (ORR) as assessed by independent central review per RECIST 1.1 was 43.6%,1 reported Michael R. Migden, MD, at the 2019 ASCO Annual Meeting. The median duration of response, the median progression-free survival, and the median overall survival had not yet been reached at the time of data cutoff.