Immunotherapy Approval Offers New Hope in CSCC

Anna C. Pavlick, BSM, MS, DO, MBA

Treatment for cutaneous squamous cell carcinoma (CSCC) took a great leap forward in September 2018 with the PD-1 inhibitor cemiplimab (Libtayo) becoming the first agent specifically approved by the FDA for advanced CSCC, Anna C. Pavlick, BSM, MS, DO, MBA, said in a session at the 36th Annual CFS^®.

Cemiplimab was specifically approved for the treatment of patients with metastatic CSCC or patients with locally advanced CSCC who are not candidates for curative surgery or curative radiation.

The FDA based its approval on a combined analysis of data from the phase II EMPOWER-CSCC-1 (Study 1540) trial and 2 advanced CSCC expansion cohorts from a phase I trial (Study 1423). The 108-patient combined analysis included 75 patients with metastatic CSCC and 33 patients with locally advanced CSCC.

Across the entire population, the overall response rate (ORR) at a median follow-up of 8.9 months was 47% (95% CI, 38-47). The complete response (CR) rate was 4% and the partial response (PR) rate was 44%. The duration of response (DOR) ranged from 1 month to over 15 months. Sixty-one percent of patients had a duration of response ≥6 months.

Among 75 patients with metastatic CSCC, the ORR was 47% (95% CI, 35-59). The CR rate was 5% and the PR rate was 41%. The DOR ranged from 3 months to over 15 months. Sixty percent of patients had a DOR ≥6 months.

In the 33 patients with locally advanced disease, the ORR was 49% (95% CI, 31-67), comprising all PRs. The DOR ranged from 1 month to over 13 months. Sixty-three percent of patients had a DOR ≥6 months.

Explaining the original rationale for exploring PD-1 inhibition in CSCC, Pavlick noted that these tumors do have durable responses to most conventional therapies and they have a very high mutational burden.

“Mutational burden in squamous cell is actually much higher than even [in] melanoma, which is commonly thought to be one of the highest mutational burden tumors that we know of, which is why it responds very well to immunotherapy,” said Pavlick, professor, Department of Medicine and Ronald O. Perelman Department of Dermatology, assistant director for Clinical Research Education, and co-director Melanoma Program, NYU Medical Oncology Associates in New York, New York.

Results from EMPOWER-CSCC-1, presented at the 2018 American Society of Clinical Oncology Annual Meeting and published in the New England Journal of Medicine, showed that cemiplimab induced an ORR of 47.5% in patients with metastatic CSCC.^1,2 At a median follow-up of 7.9 months, 28 of 59 patients had a response, including 4 (6.8%) CRs and 24 (40.7%) PRs. Among the responders, 57% had responses >6 months, and 82% had an ongoing response and continued to receive the PD-1 inhibitor. Responses were observed irrespective of prior systemic therapy.

The median time to response was 1.9 months (range 1.7-6.0 months). The median DOR had not been reached at the data cutoff. Beyond the 47.4% (95% CI, 34-61) ORR, the stable disease rate was 15% (n = 9) and the progressive disease rate was 19% (n = 11). Twelve percent (n = 7) of patients could not be evaluated and 7% (n = 4) had nontarget lesions only. The durable disease control rate (DCR) was 61.0% (95% CI, 47.4-73.5).

The trial also included 23 patients with locally advanced CSCC. In this group, the ORR was 43.5%, composed of all partial responses. Nine (39.1%) patients had stable disease, 2 had progressive disease, and 2 were not evaluable. The durable DCR was 69.6% (95% CI, 47.1-86.8). The median duration of response had not been reached.

For the cohort of 59 patients with metastatic disease, the median age was 71 (range, 38-93), with 43 (73%) patients aged ≥65 years. Ninety-two percent of patients were male, 39% had and ECOG performance score of 0 and 61% had a score of 1. Forty-four percent of patients were treatment naïve, 37% had 1 prior regimen for CSCC, and 19% had ≥2 prior regimens. Three-fourths (76%) of patients had distant metastasis and 24% had regional metastasis only.

In the locally advanced CSCC arm, the median age was 67 (95% CI, 47-96), and there were 17 males and 6 females. Thirteen patients had an ECOG performance status of 0 and the remaining 10 had a status of 1. Six patients had prior cancer-related systemic therapy, with 14 having prior radiotherapy.

Commenting on the safety profile of the PD-1 inhibitor, Pavlick said, “Cemiplimab has a tolerable side effect profile for elderly patients in whom this disease is most commonly diagnosed.”

She specifically highlighted safety data for the group of patients with metastatic CSCC. In this arm, grade ≥3 adverse events (AEs) occurred in 42% of patients, leading to treatment discontinuation in 3 patients, and were linked to 3 patient deaths. Grade ≥3 AEs included diarrhea (n = 1), fatigue (n = 1), constipation (n = 1), anemia (n = 1), and pneumonitis (n = 2). Serious AEs occurred in 29% of patients. There were also 8 patient deaths due to disease progression.

Going forward, Pavlick said, “Future research needs to build on the foundation of anti—PD-1 therapy to further improve outcomes and survival.”

She noted several treatments being explored in clinical trials that are currently enrolling, including pembrolizumab (Keytruda) for recurrent/metastatic or locally advanced CSCC, erlotinib (Tarceva) for recurrent/metastatic CSCC, talimogene laherparepvec (T-VEC; Imlygic) for locally advanced/metastatic CSCC, and adjuvant cemiplimab versus placebo following resection and radiation for high-risk CSCC.

References

1. Rischin CD, Migden MR, Chang A, et al. Primary analysis of phase 2 results for cemiplimab, a human monoclonal anti-PD-1, in patients with metastatic cutaneous squamous cell carcinoma (mCSCC). J Clin Oncol. 2018;36 (suppl; abstr 9519).
2. Migden MR, Rischin CD, Schmults A, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma [published online June 4, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1805131.