(UPDATE) Cemiplimab in Cutaneous Squamous Cell Carcinoma

Commentary by Karl D. Lewis, MD, Non-melanoma Skin Cancer Site Editor for JNCCN 360

Associate Professor, Division of Medical Oncology, University of Colorado Denver School of Medicine

Approval of Cemiplimab-rwlc for Squamous Cell and Basal Cell Carcinomas

The approval of cemiplimab-rwlc to treat advanced cutaneous squamous cell carcinoma was a major breakthrough. Prior to cemiplimab’s approval, there was no systemic therapy specifically indicated for patients with this devastating disease. Clinicians would generally use cytotoxic chemotherapy, but this was associated with limited efficacy and often significant side effects. Using a PD-1 antibody/immunotherapy approach has proven to result in meaningful response rates and a durable benefit in a significant number of patients. Longer follow-up of this cohort of patients confirms the durability of these responses.

The approval of cemiplimab is also a major development in the treatment of patients with locally advanced or metastatic basal cell carcinoma. Although targeted therapy with Hedgehog inhibitors has been associated with significant response rates in this disease, these drugs are difficult for most patients to tolerate long term due to their side effects. In addition, patients can have primary or secondary resistance to these agents. Cemiplimab has demonstrated a meaningful response rate in the locally advanced basal cell carcinoma cohort, and these responses seem to be durable, consistent with immune responses seen in other cutaneous malignancies, such as melanoma and squamous cell carcinoma. Although the results for the metastatic cohort are based on an interim analysis, with the response rate of 21% and all responders maintaining the response for at least 6 months, there is reason to be optimistic that these results will hold up with longer follow-up.

Disclosure: Dr. Lewis has received honoraria from Incyte and Array BioPharma; received research funding from Roche, Merck, Incyte, Array BioPharma, Nektar, Iovance Biotherapeutics, and Bristol Myers Squibb; and served as a consultant or advisor to Array BioPharma, Merck, Roche, and Regeneron Pharmaceuticals.

The study of cemiplimab-rwlc (cemiplimab) in advanced cutaneous squamous cell carcinoma (CSCC) has continued to progress since its approval in late 2018 (See Original Cemiplimab Spotlight). Longer follow-up data from the pivotal phase II study of cemiplimab—in patients with advanced CSCC not amenable to curative surgery or radiation—have demonstrated deepening clinical responses with cemiplimab over time, providing new insight into longer treatment of advanced CSCC.^1-3 Additionally, early studies suggest that upfront treatment with cemiplimab in patients with locally advanced disease may eliminate the need for invasive, disfiguring surgery.^4,5

Longer Follow-up of Pivotal Phase II Trial

In the 2-year follow-up of the pivotal phase II study of cemiplimab, the authors reported that in patients with metastatic CSCC who were treated with a fixed dose (350 mg) of cemiplimab every 3 weeks, the PD-1 inhibitor “produced substantial antitumor activity with durable response and an acceptable safety profile.” Moreover, analysis of the patient cohort that received a weight-based dosage of cemiplimab at 3 mg/kg every 2 weeks “demonstrated ongoing durability of responses.”¹ In the open-label, single-arm, phase II trial (which used the weight-based dose of 3 mg/kg every 2 weeks), almost half (44%) of patients demonstrated an objective response to cemiplimab treatment, with 10 patients (13%) achieving a pathologic complete response over time and 24 (31%) achieving a partial response.² The median duration of follow up was 9.3 months. A subsequent report with longer follow up suggests that 20% have now achieved a complete response, a substantial increase compared with the primary analysis.³

According to the more recent publication [not yet peer reviewed], in responding patients, the estimated proportion of patients with an ongoing response at 24 months was 76%. The estimated overall survival at 24 months was 73.3%, and the median overall survival has not been reached.³

Investigating Upfront Use

Several recent studies have explored the use of cemiplimab prior to surgical intervention,^4,5 a contrasting approach to the approved use of cemiplimab in patients who are not eligible for curative surgery or radiation—often due to disease recurrence despite previous surgical procedures.⁶ By giving cemiplimab prior to surgical resection and/or radiation, researchers aim to diminish the need for more extensive subsequent treatment.⁵ [Editor’s Note: The NCCN Guidelines for Squamous Cell Skin Cancer do not include the use of cemiplimab in the neoadjuvant setting.⁷]

In a phase II study, neoadjuvant cemiplimab induced an overall response rate of 30% in patients with CSCC of the head and neck for whom surgery and radiation therapy were planned.⁵ Overall, more than half of patients (55%) did not require planned radiotherapy after surgery based on the pathologic responses. The study included 20 patients with stage III (n = 8) or IV (n = 12) CSCC (M0) of the head and neck who were treated with two doses of cemiplimab at 350 mg intravenously every 3 weeks prior to surgery. A pathologic complete response was observed in 11 patients (55%), and a major pathologic response was seen in an additional 3 patients (15%). After a median follow-up of 3.8 months, no recurrences were observed. Grade 1 or 2 adverse events were reported in 35% of patients, most commonly rash and pruritus (30%).

Another small study reported similar results with the neoadjuvant use of cemiplimab. The single-institution retrospective trial found that upfront treatment with cemiplimab in patients with locally advanced CSCC may eliminate the need for disfiguring or complex surgery or radiation therapy in the majority of patients.⁴ Of the 36 patients with locally advanced CSCC requiring more than simple excision and/or complex repair or regional disease with nodal involvement, 22 patients (61%) treated with at least two doses of upfront cemiplimab were able to avoid local intervention with surgery and/or radiation therapy. Local intervention was still required for 3 patients (8%), and 11 (31%) are continuing to receive cemiplimab, with the decision to proceed with local intervention still pending.

Upfront treatment with cemiplimab in patients with locally advanced CSCC may eliminate the need for disfiguring or complex surgery or radiation therapy in the majority of patients.

A larger multicenter phase II study is underway to confirm these results in the neoadjuvant setting (ClinicalTrials.gov identifier NCT04154943). Additionally, the phase II NEOCESQ trial is slated to investigate neoadjuvant plus adjuvant therapy with cemiplimab in patients with high-risk, surgically resectable, stage III CSCC (NCT04632433).

Cemiplimab Therapy: Cost Versus Outcomes

The authors of an economic analysis concluded that cemiplimab is cost-effective for the treatment of advanced CSCC and that cemiplimab may be expected to provide “value for money compared with the standard of care.”⁸

 Presenting data from the base case, the authors explained: “Cemiplimab versus the standard of care resulted in an incremental cost-effectiveness ratio of $99,024 per quality adjusted-life year, where incremental costs and quality adjusted-life years were $372,425 and 3.76, respectively. At a willingness-to-pay threshold of USD $150,000 per quality adjusted-life year, the sensitivity analysis suggests a 91% probability that cemiplimab is cost-effective when compared with the standard of care.”⁸

REFERENCES

1. Rischin D, Migden MR, Lim AM, et al. Phase 2 study of cemiplimab in patients with metastatic cutaneous squamous cell carcinoma: primary analysis of fixed-dosing, long-term outcome of weight-based dosing. J Immunother Cancer 2020;8:e000775.
2. 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;21:294–305.
3. Rischin D, Khushalani NI, Schmults CD, et al. Phase II study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma: Longer follow-up. J Clin Oncol 2020;38:10018.
4. Atlas JL, Kanos M, Symanowski JT, et al. Cemiplimab as first intervention for patients with locally advanced cutaneous squamous cell carcinoma. J Clin Oncol 2020;38:10065.
5. Gross N, Ferrarotto R, Nagarajan P, et al. Phase II study of neoadjuvant cemiplimab prior to surgery in patients with stage III/IV (M0) cutaneous squamous cell carcinoma of the head and neck. ESMO 2019 Congress. Abstract 7194.
6. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379:341–351.
7. Schmults CD, Blitzbau R, Aasi, SZ, et al. NCCN Clinical Practice Guidelines in Oncology: Squamous Cell Skin Cancer. Version 2.2020. Accessed January 25, 2021. To view the most recent version, visit org.
8. Paul E, Kuznik A, Keeping S, et al. Assessing the value of cemiplimab for adults with advanced cutaneous squamous cell carcinoma: A cost-effectiveness analysis. J Clin Oncol 2020;38:e19397.