Migden Reviews Updated Data for PD-1 Agents in Case Review of cSCC

September 20, 2019

Michael R. Migden, MD, spoke with a group of physicians during a <em>Targeted Oncology </em>live case-based peer perspectives discussion about responses in patients with cutaneous squamous cell carcinoma to immunotherapy treatment.

Michael R. Migden, MD

Michael R. Migden, MD, spoke with a group of physicians during aTargeted Oncologylive case-based peer perspectives discussion about responses in patients with cutaneous squamous cell carcinoma (cSCC) to immunotherapy treatment. Migden, an associate professor in the Departments of Dermatology and Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, reviewed the treatment options and potential responses based on a case scenario of a patient with cSCC.

CASE

An otherwise healthy, single, 69-year-old, fair-skinned man presented to his primary care physician with what he described as a wound behind his ear that was not healing; he reported first noticing it at least 4 months earlier and complained of recent onset of numbness in the area. He was a retired construction worker. He had an ECOG performance status of 1.

The visible ulcerated lesion was 4.5 cm in diameter and >5 mm deep. There were no palpable nodes. A biopsy confirmed a poorly differentiated, infiltrative, postauricular cSCC lesion with 7-mm invasion into subcutaneous fat.

TARGETED ONCOLOGY:What additional testing would you order to aid treatment planning for this patient?

Migden:I would order a CT of the area, including the neck. We would want to make sure both the carotid [artery] and neck are clear.

TARGETED ONCOLOGY:What are some of the high-risk features of this patient with cSCC?

Migden:Size is a factor. In this patient, we need to be aware of the >2-cm [diameter] along with the 7-mm depth with invasion into the subcutaneous fat. The numbness is also concerning, as are the poorly differentiated [borders].

TARGETED ONCOLOGY:How do you define locally advanced cSCC?

Migden:I am one of the proponents who say we do not want to make it too narrow because it could exclude patients. Locally advanced cSCC is a nuanced, multifaceted presentation. It can occur in a wide range of presentations. There are many patient-specific diagnosis and treatment considerations, one of which is surgical aversion or surgical fatigue. For example, I had a patient who told me, “I’d rather die than have another major surgery.” He had undergone many big surgeries and did not want to go through another one.

So I’m not one of these people who are in favor of saying, “Well, if the surgery can technically be done, then all I can offer you is surgery.” I’m not one who can make that judgment.

I’m more in favor of saying that locally advanced disease is defined as a patient who is not a good candidate for surgery for a variety of reasons, has failed prior surgeries, is not a good candidate for radiation, failed prior radiation, or is unable to take more because of the total dose. That is the kind of defini&shy;tion that is more broad and that allows for these patient-specific considerations.

You should always have a multidisciplinary discussion with a tumor board if possible. If not, maybe call a colleague, or call a head and neck surgeon if you are a medical oncologist. If you are a dermatology oncologist, call a medical oncologist. Even if it is not a formal board, just call to have the discussion: “This is what I have. What do you think?”

From there, go to the patient and say, “These are the recom&shy;mendations from my colleague and me.” If the patient gives a lot of pushback and decides not to follow your advice, you have to think about looking at options besides the aggressive ones.

People want to put “locally advanced” in a box. I am not a proponent of that because I do not want to harm any patients by telling them that they don’t meet the criteria. If I had to sum up what locally advanced is, I’d say it involves multiple surger&shy;ies failing or patients who are not good surgical candidates for a variety of reasons: either the tumor cannot be removed in its entirety because of its large size, or the tumor could be removed, but the removal will result in significant disfigurement or dysfunction.

TARGETED ONCOLOGY:How do you define metastatic disease?

Migden:Most folks know this: It is either local regional [lymph] node metastases, or it is distant metastases, which often end up in the lungs or bone.

It is interesting because I was looking at the enrollment criteria for CARSKIN [NCT02883556] and KEYNOTE-629 [NCT03284424], but [patients on these trials] had a lot of distant metastases. My understanding is that about 20% of the cases involve distant metastases compared with local regional disease. If you look at the morbidity and mortality, the locally advanced and the local regional disease have substantial morbidity and mortality. It is the lion’s share of the problem.

TARGETED ONCOLOGY:What about the cosmetic effects of the surgery?

Migden:I was the principal investigator on the phase II registration trial for cemiplimab [Libtayo], and I helped develop some of the criteria. One of the criteria for locally advanced disease would be [that it was] technically possible for surgery but could result in severe dysfunc&shy;tion or deformity. I was specific that this needed to be included. This would include loss of most or all of a facial appendage, and an auric&shy;ulectomy was one of the things that could qualify.1

TARGETED ONCOLOGY:What type of responses to cemiplimab can be expected? Is there a way to determine who is going to have a good response to cemiplimab?

Migden:We have seen response rates in the 45% to 50% range.1

That is a hot topic these days because there is a lot of discus&shy;sion about biomarkers, and it is an active area of investigation. The things that people talk about are PD-L1 expression and tumor mutational burden [TMB]. Unfortunately, there are many types of PD-L1 analysis. There is analysis in the tumor itself and analysis within the immune cells that have infiltrated the tumor, and you could get potentially different results. There are also different anti&shy;bodies, like 22C3 from the autostainer Dako [North America, Inc] and others.2These use IHC [immunohistochemistry], where they process the tumor. The pathologist is visually [inspecting] what percentage of the total tumor has this label that lights up.

PD-L1 does not always track with response. In some cancers, [PD-L1] may track, but in cSCC, it does not appear to be a great correlation. Actually, there is not much correlation, whereas TMB looks promising based on early exploratory analysis. TILs [tumor-infiltrating lymphocytes] are another option undergoing research, as are neoantigens. These are things that are, hopefully, coming.

TARGETED ONCOLOGY:What do the guidelines say about cemiplimab?

Migden:The guidelines do not include it as a systemic therapy option yet, [but it is cited as a consideration for patients with advanced or metastatic disease who are not candidates for curative radiation or surgery].3But I expect that to change because it is approved by the FDA.

TARGETED ONCOLOGY:What do you tell patients about the potential benefits and risks of using cemiplimab?

Migden:Certainly, you talk about the infusion reaction. Although that is a potential risk, it is not the most common thing. Immune-related adverse events [irAEs] such as pneumonitis are important. I tell all my new patients who are taking this that the slightest new cough or diarrhea needs to be taken seriously and requires a work-up.

TARGETED ONCOLOGY:How would you do a work-up on these patients? How would you stage them, what kind of laboratory work would you order, and how often?

Migden:There is no real requirement, but something to keep in mind is that any organ can be attacked. So any “-itis” is possible. Although it is not in the study, I get metabolites, CBC [complete blood count], LFTs [liver function tests], thyroid function, blood urea nitrogen, and creat&shy;inine. I would order a couple of these close together, then spread them out every 2 to 3 months.

TARGETED ONCOLOGY:If the patient does not achieve a response, what would your next steps be?

Migden:You could consider chemotherapy, radiation, or things like epidermal growth factor receptor—targeted agents. Of the responders that came from the phase II study in the locally advanced cohort, 20% of 34 responders had an unconventional later response. It took between 6 and 10 months to go from stable disease to a response.4

TARGETED ONCOLOGY:Does this change your recommendation for how long to administer cemiplimab to patients in this setting?

Migden:If the patient is tolerating [the drug] and does not have progres&shy;sion, you might consider continuing with therapy. I am not saying you have to, but if 20% of patients have this type of [delayed] response, you may want to wait a bit.

TARGETED ONCOLOGY:Is it possible for one anti—PD-1 agent to work better than another, and how does cemiplimab compare?

Migden:People are familiar with other anti—PD-1 agents, so this is another similar agent. There are no head-to-head comparisons to give us scientific background. I have had people come to me and say they think cemiplimab is working better. I can tell you 1 differ&shy;ence [between cemiplimab and others]: It is a fully human monoclonal antibody, not a humanized one that still has mouse fragment left in it.

It is possible for one anti—PD-1 to work better than another. But do we know that is the case? Not at all. And the CARSKIN study and studies of pembrolizumab [Keytruda] in this disease are limited.

TARGETED ONCOLOGY:Please discuss the use of cemiplimab in advanced cSCC.

Migden:We have newer data that were published in theNew England Journal of Medicine. This study used the expansion cohort from the phase I study and only the metastatic cohort group from the phase II study. In a review of the baseline characteristics of the 2 groups, patients in the metastatic group showed a larger percentage of head and neck lesions, rates of prior systemic therapy were around 50%, and the majority of patients received previous radiotherapy. There was a higher percentage of distant and regional spread in the metastatic group.1

Let us talk about the objective response and durable disease control numbers. In the expansion cohort, the objective response rate [ORR] was 50% and was 47% in the metastatic group. That’s no progression for 105 days with a durable disease control of 65% and 61%, respectively. The median time to response was short, around 2 months. Durable disease control was defined as 105 days without progression.

TARGETED ONCOLOGY:How does previous radiotherapy affect the response?

Migden:That is a good question. I do not think we have an answer. I see radiation recall in some people who have had prior radiation. Their radiation field can light up like a beacon just because you are giving the PD-1. Maybe there are neoantigens from the radi&shy;ation effect. I have seen that in at least 2 patients.

Some articles that discuss radiation recall [suggest it is like] radiation dermatitis. I see skin being torn up; it is all eroded.

But when it heals, there is a better outcome. The people who have the sensitivities, whether they are pseudoprogression or the irAEs, typically seem to be more responsive to the treatment.

We have a patient who has been off the active drug for a long time. He was eventually considered to have a CR [complete response], but he had lots of exposed bone. He had immune-related dermatitis, so he had blisters. He had this radiation recall. We reduced his dose until he completed his therapy. He has been off treatment a long time, and we are still trying to get this skin to calm down; I mean, it just keeps going. The response is still active even though he has been off drug for a long time.

TARGETED ONCOLOGY:What about AEs in the phase II study?

Migden:This disease usually affects an older population. Things like constitutional symptoms, diarrhea, and nausea are not immune related, except perhaps rash. Most are constitutional-type AEs.

Many patients are in their 70s or 80s and will suddenly show up because they claim that [the lesion or wound has] never both&shy;ered them for 30 years, but now it is a catastrophe. This disease definitely affects an older population with a male dominance.

People have said that this drug is better in the older popula&shy;tion compared with other immuno-oncology therapies. There are not many AEs.

TARGETED ONCOLOGY:Please expand on the phase II study.

Migden:There were 2 cohorts—all metastatic or locally advanced disease. The original cohorts received a weight-adjusted dose of 3 mg/kg every 2 weeks. I am bringing this up because we want to raise awareness of what constitutes locally advanced disease. It has taken some time for people to latch on to what this actually is. The surgeons and radiation oncologists say, “I have a hammer, and everything I see looks like a nail.” If you are a surgeon and you can see the disease on the skin, a lot of them will continue to try to operate, especially aggressive head and neck surgeons. Radiation oncologists might say, “If I can see the disease, I can radiate it.”

[Changing] the mind-set to consider other things than what the surgeon or radiation oncologist can do and what actually works takes some time. It took some time to fill [the locally advanced] cohort, even though there are more of these patients out there.

This is important. In this trial, patients with progression were allowed to remain on active treatment if deemed in their best interest. This is the largest prospective systemic therapy trial in advanced cSCC.

The ORR at the 12-month update went up from 47% primary data to 49.2% [in the metastatic-disease cohort]. The durable disease control rate was 63%, which included a number of complete responders. The median duration of response was not reached, and the median overall survival was also not reached, primarily because patients continue to do well with few events. The longest duration of response at data cutoff was 21.6 months and ongoing. Also, median progression-free survival was 18.4 months.4

Again, in the locally advanced patients, a substantial number have a late response. I do not think there is a guideline for when to stop; I have heard oncologists stopping pembrolizumab after 5 cycles because there was no response. I think 9 months is a reasonable amount of time to give for this agent to work. If I were one of these patients who do not have a good alternative and I was doing OK, I would not want someone to pull my treatment. The longest delayed response in the study was almost 10 months.

Locally advanced disease is a clinical assessment, although some locally advanced tumors can be followed by both clinical assessment as well as imaging. That was captured in this trial. There were people whose locally advanced disease did not show up at their baseline screening. The investigator said it is not worth doing the imaging anymore, and then these patients were followed just by clinical assessment. If the tumor could be seen on imaging and then assessed, then they had a composite response.

References

  1. 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.
  2. PD-L1 IHC 22C3 pharmDx — P150013/S009. FDA website. www.fda.gov/medical-devices/recently-approved-devices/pd-l1-ihc-22c3-pharmdx-p150013s009. Updated June 19, 2018. Accessed July 3, 2019.
  3. NCCN Clinical Practice Guidelines in Oncology. Squamous Cell Skin Cancer, version 2.2019. National Comprehensive Cancer Network website. nccn.org/professionals/ physician_gls/pdf/squamous.pdf. Published October 23, 2018. Accessed July 3, 2019.
  4. Updated Libtayo (cemiplimab-rwlc) results reinforce durable and substantial response rates in advanced cutaneous squamous cell carcinoma [news release]. Cambridge, MA, and Tarrytown, NY: Sanofi and Regeneron Pharmaceuticals Inc; May 15, 2019. www.news. sanofi.us/2019-05-16-Updated-Libtayo-R-cemiplimab-rwlc-Results-Reinforce-Durable-and-Substantial-Response-Rates-in-Advanced-Cutaneous-Squamous-Cell-Carcinoma. Accessed July 3, 2019.