Longer Follow-Up Data Confirms Cemiplimab’s Utility in CSCC, Though Challenges Remain

The introduction of the PD-1 inhibitor cemiplimab (Libtayo) has transformed the treatment paradigm of patients with advanced cutaneous squamous cell carcinoma (CSCC), said Anna C. Pavlick, DO.

“The advent of immunotherapy, particularly cemiplimab, for this patient population has been a game changer,” said Pavlick. “For many of these patients, the responses are good and durable, and the toxicity is low. We consider the drug to be very tolerable for patients well into their 90s.”

Cemiplimab received regulatory approval in September 2018 for the treatment of patients with metastatic CSCC or locally advanced CSCC who are not eligible for curative surgery or curative radiation, according to results of the phase 2 EMPOWER-CSCC-1 study (NCT02760498).

During the 2020 ASCO Virtual Scientific Program, longer follow-up data from the studyrevealed continued response rates, and clinically meaningful survival and duration of response (DOR) with the agent.¹

At up to 3 years of follow-up and among 89 responders, cemiplimab induced an overall response rate of 46.1%, a complete response (CR) rate of 16.1%, and a median time to CR of 11.2 months. The median DOR had not yet been reached.

Additionally, post-hoc exploratory analyses demonstrated a clinically meaningful and rapid reduction in pain, as well as improvement in global health status and health-related quality of life (QOL) with cemiplimab in this patient population.²

Now, research is underway to identify biomarkers of response and potential combination therapies that could extend cemiplimab’s reach to the 50% of patients who will not derive benefit from the agent, said Pavlick.

In an interview with OncLive, Pavlick, of Weill Cornell Medicine, discussed the benefit of cemiplimab for patients with CSCC, the impact of these longer follow-up data, rare, but notable, toxicities that can arise with the agent, and ongoing research efforts aimed at increasing responses to immunotherapy in the CSCC space. 

OncLive: What does the current treatment landscape of CSCC look like? How has it evolved with the introduction of immunotherapy?

Pavlick: CSCC is a cancer that is managed primarily by dermatologists because most patients have small resectable lesions. After [resection], patients don’t have to worry about them.

However, if left unattended, [lesions] can become large and ulcerated. They are much more common in older patients because they can happen on sun-exposed areas that may not get noticed. They can also happen in areas of trauma such as an injury that won’t heal. For example, diabetics, who sometimes have these chronic ulcers, can sometimes develop CSCC from that trauma. Plus, [these individuals] are immunocompromised from their uncontrolled diabetes.

CSCC has become [a disease] that has [garnered] a lot of interest in oncology, although it was something that we never saw before. However, now that we have immunotherapy and we know that CSCC [harbors] many mutations with a high tumor mutational burden, we looked at using immunotherapy for those patients who had locally advanced disease. Since many of these CSCCs can occur as multiple lesions along a patient’s scalp or along the ears, they can be invasive. That is not to say that they can’t be resected, but many times surgery is a high-risk procedure for older patients. It can be a deforming surgery where the patient may lose their nose, or an ear.

We’ve looked at using immunotherapy as a way to control CSCC. It is effective in about 50% of patients, and [responses] appear durable. About 80% of [responders] go on to have long-term control of their disease.

Prior to that, if lesions were not resected, patients were offered either radiation of chemotherapy. Again, radiation is very effective for CSCC, but this [disease] occurs in an older population. Many times, going [to the clinic] every day, 5 days a week, for several weeks is exhausting and not feasible in an older patient population.

Chemotherapy was extrapolated from the head and neck squamous cell carcinoma (HNSCC) data. When we didn’t have immunotherapy, if it was something that couldn’t be surgically excised or the patient wasn’t a candidate for surgical excision or radiation, we would give patients chemotherapy with either a 5-fluorouracil (5FU)-based regimen or cisplatin/carboplatin.

When EGFR [inhibitors] became available and were being used in HNSCC, we also used those agents [in CSCC]. These tumors do respond [to EGFR inhibitors]; however, responses are not durable. Many times, these agents are very toxic with a lot of adverse effects that our [elderly] patient population [cannot handle]. Their quality of life (QOL) is good, but they are still in their 80s and 90s with multiple comorbidities. You just may not want to give them chemotherapy for fear that you are going to ruin the QOL they have.

How have the longer follow-up data with cemiplimab informed its use in CSCC?

The updated data looked at the group of patients that was treated with a flat dose of 350 mg of intravenous cemiplimab every 3 weeks. In the longer-term follow-up, we saw that the responses were in the 50% range. We also saw that there is very much a tail on the curve where patients will remain in remission for long periods of time.

The data also indicate that the responses in CSCC in about 80% of patients will occur very rapidly, which means within the first 6 weeks [of treatment]. After 2 cycles, most patients are already seeing a clinical response.

More importantly, many of these patients have pain because these tumors have a tendency to track a lot of nerves due to perineural invasion. At the 2020 ASCO Virtual Scientific Program, we also saw QOL data showing that within the first 2 cycles, patients had resolution of their pain very quickly. That was more of an indicator of response, even before we started to see the clinical response. These patients went from being on narcotics to being narcotic-free in a very short period of time after starting cemiplimab. These data were compelling.

The data also provided us with information indicating that some patients will take a longer period of time to show a response. If you don’t see a rapid response within 6 weeks, if the tumors are stable and not growing, stick with [cemiplimab] for a while.

We do have to remember though that 50% of patients are not going to respond. If tumors do start to grow, rather than decide, this is late progression, the best thing to do is to biopsy 1 of the new tumors to see if it is pseudoprogression. Yes, there is going to be tumor there, but it is going to be chock full of T cells and inflammatory cells rather than aggressive, necrotic tumor.

It’s not [so cut and dry] where if patients have progressive disease, they really have progressive disease. The determination between whether this is pseudoprogression—which is incredibly rare—[or truly progressive disease] is nuanced. You don’t want to throw away an effective therapy, [so] you [have to show] progressive disease with a biopsy [before you do].

You mentioned that the agent is well tolerated. What is the safety profile of cemiplimab, and what are some of the most common adverse effects (AEs)?

Like many of the PD-1 agents, the most common toxicities are what we call the “-itises” because they cause inflammatory AEs. These include dermatitis, hepatitis, thyroiditis, nephritis, and colitis. These are the toxicities that we see most frequently. Many times, they are not dose limiting and don’t require patients to come off therapy.

The most common AE is rash and itching. I tell patients that they can have a rash, they can itch, or they can have an itchy rash. That is one of the things that is most bothersome for patients because sometimes they just itch, but they don't have a rash. They don’t understand why they are itchy if they don't have a rash. That is an AE that patients need to be aware of and report because we can manage it.

Colitis or diarrhea is observed very infrequently. These drugs are metabolized through the liver and kidneys, so some patients can see some drug-induced hepatitis or nephritis. Especially for older patients it is important to keep a close eye on them to make sure their labs are checked before they receive an infusion.

Endocrinopathies are not very common; however, you can see patients who get hypothyroidism. Again, that is pretty easy to check for because you are going to be check thyroid function tests every time you see the patient to give them an infusion.

Patients do need to understand that if they develop these endocrinopathies, 99% of the time they are permanent. If a patient [develops hypothyroidism] and you have to give them levothyroxine (Synthroid) for thyroid replacement, they are going to have to take that drug for the remainder of their life.

In rare circumstances, any of the PD-1 drugs can cause adrenal insufficiency or insulin-requiring diabetes. Those too are going to be lifelong and require medical supplementation.

It is not as though there are no significant toxicities associated with cemiplimab, they are just exceedingly rare. However, patients do need to know about them because if they do occur, they are permanent.

What are some of the remaining challenges in the CSCC space?

Cemiplimab represents a huge advancement because the responses are durable. However, 50% of patients are not going to have a response.

We have to think about what to do next. The challenge ahead of us is to try to determine what we need to do in order to get that other 50% of patients to respond. Can we make these non-responders respond? Can we identify biomarkers or [characteristics] about their tumors? Is there something that we can identify that is going to tell us that a patient is going to be a responder or not? If we know what tumor characteristics or biomarkers lead us to a nonresponder, what do we need to do or what kind of drugs can we develop that will turn these “cold” tumors into “hot” tumors that will respond?

The other very challenging thing about treating patients with CSCC is that many of them are immunocompromised, so they either have chronic lymphocytic leukemia or underlying autoimmune diseases. Importantly, they can be transplant patients. Patients who receive kidney, liver, heart, or lung transplants are put on chronic immunosuppressive therapies so they do not reject their organs. As a consequence, these patients frequently develop multiple CSCCs that eventually become invasive. What do we do for them?

There are no good data showing that PD-1 inhibitors are safe in this patient population. We are doing those studies, and it seems as though sometimes you can get away with [using these agents] and sometimes you can’t. Depending on which organ is transplanted, if you have no choice but to give a PD-1 inhibitor, it is a whole lot easier of a discussion if the patient had a kidney transplant because if they reject the organ, you have dialysis as a backup. Somebody with a heart, lung, or liver transplant doesn’t have that backup. These studies are important to determine whether we can safely give these checkpoint inhibitors, particularly PD-1 inhibitors, to manage CSCC.

Are there any emerging approaches or agents on the horizon that appear particularly promising in CSCC?

We’re looking at how we can [improve these responses] by evaluating combination therapies. We are looking at adding EGFR inhibitors to PD-1 checkpoint inhibitors. Can we get the one-two punch by targeting a receptor and the immune system? Studies are underway.

Many times, because patients have locally advanced disease and do not have visceral disease, these lesions are visible and palpable. We’re now looking at combining PD-1 checkpoint inhibitors with injectable antivirals or viral vectors to try to generate an immune response locally at the site in conjunction with the immunotherapy. Some topical agents are also being looked at in conjunction with PD-1 blockade.

What is your take-home message to your colleagues?

If there is a clinical trial out there for your patient, that should be your go to. I understand these drugs are FDA approved and available, but we haven’t hit a 100% cure rate. We have to push that needle even further. If we don’t put patients on study, we are going to be stuck at 50%, which in my opinion is not good enough.

References:

1. 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

2. Migden MR, Rischin D, Sasane M, et al. Health-related quality of life (HRQL) in patients with advanced cutaneous squamous cell carcinoma (CSCC) treated with cemiplimab: post hoc exploratory analyses of a phase II clinical trial. J Clin Oncol. 2020;38(suppl 15):10033. doi:10.1200/JCO.2020.38.15_suppl.10033