Khushalani on Building Upon the Benefit Achieved With Cemiplimab in CSCC

Supplements And Featured Publications, New Developments in the Use of Immunotherapy for the Treatment of Advanced or Metastatic Cutaneous Squamous Cell Carcinoma, Volume 1, Issue 1

Nikhil Khushalani, MD, discusses cemiplimab-rwlc, which has become the preferred agent for the frontline treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma.

Cemiplimab-rwlc (Libtayo) has become the preferred agent for the frontline treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC), according to Nikhil Khushalani, MD, who added that additional research is still needed to build upon the benefit observed with the anti–PD-1 agent.

“Cemiplimab is a checkpoint inhibitor that targets PD-1 by interfering with the binding of PD-1 with its ligand PD-L1. As a result, the T cells are able to escape the immunosuppressive effect of a tumor,” Khushalani explained. “The T cells become reinvigorated, which gives them the strength they need to elicit an antitumor effect. Similar to other FDA approved anti–PD-1/PD-L1 therapies, it releases the brakes on the normal immune system.”

In September 2018, cemiplimab-rwlc (Libtayo) was approved by the FDA for the treatment of patients with metastatic or locally advanced CSCC who were ineligible for curative surgery or radiation based on clinically meaningful and durable objective response rates (ORR) from 2 early-phase trials.1

Updated data from the pivotal phase 2 EMPOWER-CSCC-1 trial (NCT02760498) showed that, at up to 3 years of follow-up, the agent demonstrated continued response rates and a clinically meaningful survival and duration of response (DOR). Specifically, the ORR was 46.1% with a complete response rate of 16.1%. The DOR had not yet been reached at the time of data cutoff.2

Now, investigators are focused on identifying additional targeted agents to combine with the anti–PD-1 therapy, examining the agent in the localized setting to improve outcomes for patients who have undergone complete surgical resection, and in the neoadjuvant setting for patients who present with palpable lymph nodes, macroscopic nodes, or locally advanced disease.

In an interview with OncLive, Khushalani, the vice chair of the Department of Cutaneous Oncology at Moffitt Cancer Center, discussed the significance of cemiplimab in the CSCC treatment paradigm, ongoing research efforts with the agent, and other PD-1 inhibitors that are showing activity.

OncLive: What does the current treatment landscape look like for CSCC?

Kushalani: Until recently, the treatment landscape in CSCC was primarily comprised of either systemic chemotherapy or EGFR targeted therapy; this is primarily for patients with locally advanced unresectable disease or distant metastatic disease. In other words, these patients not candidates for surgery and/or radiation. In selective cases with locally advanced disease, we would combine chemotherapy with radiation or an anti-EGFR with radiation, but that typically was the mainstay of treatment. Unfortunately, although responses were modest, they tended to be brief; the durability was lacking.

On September 28, 2018, cemiplimab received FDA approval in this space. Cemiplimab is a fully human monoclonal antibody targeted agent against the PD-1 receptor. The regulatory decision was based on findings from the phase 1/2 EMPOWER-CSCC-1 trial, where early and quick responses of about 50% were demonstrated [with the agent] in that setting. Importantly, the responses observed with cemiplimab have been quite durable.

As such, cemiplimab has now become the first-line agent that should be used for patients with advanced CSCC, who are not candidates for curative surgery or radiation. Recently, at the end of June 2020, pembrolizumab (Keytruda), another anti–PD-1 agent has also been approved. As such, we now have 2 drugs in this setting. For all patients who do not have any contraindications to immunotherapy, anti–PD-1–based immunotherapy should be the first-line treatment.

Could you shed light on the EMPOWER-CSCC-1 trial?

This trial was initially designed as a phase 1/2 study, so it had expansion cohorts. In the phase 1 portion, the expansion cohort consisted primarily of patients [with metastatic disease] who were treated with cemiplimab on a biweekly dosing schedule; they received 3 mg/kg of cemiplimab every 2 weeks.

In cohort 2, the patients primarily had locally advanced disease; they did not have distant metastases. There was a slight difference here, compared with the KEYNOTE-629 trial, for example, where patients with nodal metastases were typically defined as having distant metastatic disease. In cohort 3, patients were on a fixed-dose regimen of cemiplimab of 350 mg every 3 weeks, which is now the FDA-approved dose for its use in patients with CSCC. In this study, patients were treated depending on the site and extent of disease.

The safety profile was very similar to what has been seen with other anti–PD-1 agents. The most common toxicity tended to be fatigue, while the more severe toxicities, grade 3 and 4, typically included diarrhea, although this is was anticipated. No unusual safety signals were reported. The toxicities that were observed were typical for that of an immune checkpoint inhibitor therapy.

Where should future research efforts be focused?

Given that this anti–PD-1 therapy is now the standard of care for these patients, I believe that 3 avenues should be further investigated. For one, we need to build upon the current backbone of anti–PD-1 therapy for advanced disease. As mentioned earlier, the response rates [with cemiplimab] are between 47% and 50%. Recent data presented during the 2020 ASCO Virtual Scientific Program demonstrated that these responses can be durable. With continuation of therapy, some of the patients who previously had a partial response are actually getting converted into a complete response; this is very reassuring to see.

As such, the drug works, and it’s effective for a long period of time; ongoing data will hopefully continue to affirm this. The problem is, there is a percentage of patients who either show no response at all or only for a finite period of time; this is the cohort that we need to expand upon. We need to better understand the molecular underpinnings in this disease to investigate additional pathways by which patients are deemed to have primary or acquired resistance to anti–PD-1 therapy and we need to target this group for therapeutic advance.

To this end, ongoing studies are specifically looking at additional targeted agents to combine with anti–PD-1 therapy; however, the bar has already been set pretty high. We are now looking at studies where we want the response rates to be between 65% or higher. That's going to be a tough bar to scale. Understanding the molecular biology of the disease, followed by developing rationally-designed trials, is the first avenue toward achieving this.

The second avenue is, given that this [approach] works in the advanced setting, we clearly have to move this to the localized or regional setting to improve outcomes for those patients who have undergone complete surgical resection. An example would be a patient with a high-risk situation. Patients with high-risk CSCC, including those with nodal disease, who have also undergone surgery and potentially post-operative radiation, still have a fairly high-risk of recurrence. We need to ensure that these patients do not relapse. As such, consideration of cemiplimab in the adjuvant setting is necessary. An ongoing study is examining that question; patients are being randomized to cemiplimab or placebo after completion of definitive regional treatment. This trial is specifically for patients who are deemed to be high risk.

Finally, what about the patients who present with palpable lymph nodes, macroscopic nodes, or locally advanced disease, where although up-front surgery can be performed, it may potentially be morbid? In this case, there should be consideration of neoadjuvant anti–PD-1 immunotherapy to shrink the tumor down. Next, the biology of the disease should be studied because neoadjuvant therapy has the ideal ground for obtaining tumor biopsies prior to treatment, during treatment, and then at the time of surgery. This will help us to better understand the tumor.

To this end, an ongoing trial of cemiplimab in the neoadjuvant setting is being done, as well. Here, patients are receiving up to 4 doses of cemiplimab, followed by planned surgery. After surgery, it’s up to the investigator whether should receive radiation therapy or continue with cemiplimab alone.

Beyond cemiplimab, could you highlight some other agents generating excitement?

Pembrolizumab is another anti–PD-1 agent that has broad approval across a multitude of tumors; this agent is now also approved for the management of [patients with] advanced CSCC. Treating physicians now have 2 choices for front-line therapy.

This study, KEYNOTE-629, which was recently published in the Journal of Clinical Oncology, and ultimately led to the approval of the drug, was slightly different [than what we previously discussed]. This trial included more of a real-world population. In other words, greater than 80% of these patients had already been previously treated with multiple lines of therapy. Moreover, greater than 80% of them received 1 or more lines of systemic therapy. Thus, this was more of a refractory population.

This is a patient population that is typically older; the median age tends to be 70 years or older, depending on which geographic part of the world you are in. In some places, [the age] may be above 80 years. However, anti–PD-1 agents can be safely used, even in the geriatric population. Within the 105 patients on this trial, the response rate [with pembrolizumab] was 35%; this is clearly numerically less than what we have seen with cemiplimab. We must ask ourselves why this is so. No major difference exists with regard to the mechanism of action of these drugs.

When subdividing KEYNOTE-629 into frontline therapies for patients who have not received prior treatment, their response rate was actually 50% to 51%; this was very similar to what you would see with cemiplimab. In the refractory setting, the response rate was slightly lower. Personally, I believe pembrolizumab could also potentially be used, but when it comes to the duration, we have more mature data with cemiplimab, with longer follow-up. With time, I anticipate that the data on patients on KEYNOTE-629 will also mature with longer follow-up and soon we should be able to look at the durability of response there as well.


  1. FDA approves cemiplimab-rwlc for metastatic or locally advanced cutaneous squamous cell carcinoma. News release. FDA. September 28, 2018. Accessed August 10, 2020.
  2. Rischin D, Khushalani NI, Schmults CD, et al. Phase II study of cemiplimab in patients (pts) with advanced cutaneous squamous cell carcinoma (CSCC): longer follow-up. J Clin Oncol. 2020;38(suppl 15):10018. doi:10.1200/JCO.2020.38.15_suppl.10018