Cemiplimab Is Effective as Anti–PD-1 Therapy in Cutaneous Squamous Cell Carcincoma

During a virtual Targeted Oncology Case-Based Roundtable event, Ezra Cohen, MD, professor of Medicine, associate director, Translational Science Chief, Division of Hematology-Oncology, codirector, San Diego Center for Precision Immunotherapy, Moores Cancer Center at US San Diego Health, lead a discussion on the efficacy of cemiplimab-rwlc (Libtayo) for the treatment of cutaneous squamous cell carcinoma.

Targeted Oncology^TM: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for treating a patient like this?

COHEN: The NCCN would say systemic therapy is not recommended [for a patient with cSCC] who has regional disease but is, in theory, resectable and local disease amenable to surgery.¹ However, given that this is a fairly extensive surgery, I think one could consider systemic therapy alone with either an anti–PD-1 antibody or a clinical trial. I don’t think there is necessarily a wrong answer between the 2 top choices. Certainly, it hinges on the resectability in that conversation with the surgeon.

What study led to the approval of cemiplimab, which was used for this patient?

The [phase 2] EMPOWER-CSCC 1 [NCT02760498] trial that was done in 3 [adult patients] groups [led to the approval for this patient population]. Group 1 was patients with metastatic [disease] including nodal metastases or distant metastases. Group 2 was patients with locally advanced disease. And then Group 3 was patients with metastatic disease, but they were treated with a fixed dose of cemiplimab rather than a weight-based regimen like in groups 1 and 2. Objective response was the primary end point in all 3 groups.²

Patients had to have RECIST measurable disease, and in group 2 the lesion had to be nonamenable to curative surgery or curative radiation therapy. These are patients who had locally advanced disease but did not have curative options for one reason or another.

One thing to note about the exclusion—patients could not have a history of autoimmune disease, and they also could not have solid organ transplant. That’s important to note because skin cancers [such as] cSCC do occur more frequently in patients with solid organ transplants, but those patients would not have been included in the studies.

[There were] 193 patients [enrolled in the study], and the majority were male [83.4%], which is pretty typical of this disease.³ The head and neck were the primary site in [approximately] two-thirds of patients, [which is], again, very typical of what we see in patients with cSCC. About 40% had locally advanced disease, and [in approximately] two-thirds of these patients, cemiplimab was used as the first-line therapy. [That two-thirds of patients] had not had a prior cytotoxic chemotherapy or EGFR inhibitor.

Please describe the outcomes of the study.

What we see is that the overall response rates [ORRs] were similar across study groups. So groups 1, 2, and 3 had very similar response rates, hovering [approximately] mid-40% to 50% [with the total group of patients having an ORR of 46.1%].³

The [durable] disease control rate was also quite high, about 60% in total. Then the median observed time to response was at first assessment, so [approximately] 2 months. On average, responses happened relatively quickly. I’ll also note the median duration of response. At the time of this report, this was not reached, so at least for most patients, these responses appear to be durable.

[When looking at pictures from the patient involved in the case], you can see fairly extensive involvement in the first patient on the scalp, and you can see a near complete response after 6 weeks of cemiplimab.⁴ Then a patient with a postauricular lesion, similar to the patient in our case, after 8 weeks of cemiplimab [showed] a very good response with nearly complete healing of that ulcer with what looks like a fistula or the start of a fistula. These were pictures included in the [published journal article].

The median PFS [progression-free survival] was [18.4 months], and the median overall survival [OS] was not reached. However, 24-month OS was 73.3%.³ That OS figure is certainly affected by cemiplimab, but one of the main issues with these patients, as we know from treating them, is the disease progression and the adverse effects, such as locoregional disease. That PFS of 18 months, I think, is still clinically meaningful.

How does the PD-L1 status of a patient affect the efficacy of cemiplimab in this patient population?

In a post hoc subgroup analysis based on PD-L1 status, many patients expressed PD-L1 at some level. However, what’s interesting is that...it did seem to influence response rates, even in the PD-L1 less than 1% group, [which consisted of 17 patients]. So we can talk about the importance of stromal staining, but there still is a fair number of patients that respond, [with an ORR of 35%].⁵ Objective responses were observed in patients regardless of baseline PD-L1, and certainly in both PD-L1–negative and PD-L1–positive groups, patient responses were seen.

These cancers are often associated with a high tumor mutational burden [TMB]. The median mutations per megabase in these patients is [in the range of] 50. These are tumors with high TMB. You can also see that the responders had a slightly higher TMB, at least numerically, both in terms of response and durable disease control. There is a broad range, and certainly even in the patients on the other side of the median, on the lower side of the TMB, those patients still had durable responses. TMB doesn’t serve us incredibly well as a biomarker because of the range that we see in TMB.

What were the safety data?

In terms of safety, it was consistent with other anti–PD-1 antibodies. We saw immune-related adverse events as expected. Serious treatment-emergent adverse events [TEAE] occurred in 29% of patients, and 9% were considered treatment related. The most common TEAE was pneumonitis [4%], so pretty typical of an anti–PD-1 antibody. There were 2 grade 5 events, both were pneumonia—1 considered infection and 1 considered aspiration.

Are there other anti–PD-1 antibodies that are FDA approved?

We now have 2 anti–PD-1 antibodies that are FDA approved. The first was cemiplimab for patients with metastatic or locally advanced cSCC that are not eligible for curative surgery or curative radiation based on the clinical trials that we just talked about.

The second, in 2020, pembrolizumab [Keytruda] was approved for recurrent or metastatic disease not curable by surgery or radiation. That was based on the KEYNOTE-629 trial [NCT03284424] that showed an ORR of 34%.⁶

[The recurrent metastatic cohort in the phase 2 KEYNOTE-629 trial] was akin to group 1 and group 3 in the cemiplimab study of fixed-dose pembrolizumab. The primary end point was the ORR, and at 1 year about two-thirds of the patients were still in response. The median PFS was 6.9 months, demonstrating the efficacy and activity of an anti–PD-1 antibody. [Safety was consistent with other anti–PD-1 therapies.]

Are there any ongoing trials for this patient population?

[There are ongoing] neoadjuvant studies, and some of them are looking at patients who are immunocompromised and some of them are now combining immunotherapies. There’s an adjuvant study involving cemiplimab versus placebo that is currently recruiting. That’s a registrational trial.

There is also a pembrolizumab adjuvant trial, a registrational study, but [other] agents [being looked at] include avelumab [Bavencio] and nivolumab [Opdivo]. So there is an exploration of multiple anti–PD-1 antibodies in this disease.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Squamous cell skin cancer, version 2.2020. Accessed March 15, 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. Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629). J Clin Oncol. 2020;38(25):2916-2925. doi:10.1200/JCO.19.03054}