CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: May 09, 2023
Expiration: May 08, 2024
Cutaneous Squamous Cell Carcinoma
Zeynep Eroglu, MD:
Now, we will move on to cSCCs. cSCC is also a very common form of skin cancer, similar to BCC.14 Most cSCCs are small, localized tumors on the skin that are typically treated with surgical excision alone. Many of these patients are typically treated primarily by dermatologists. However, there is a small subset of patients who have lacSCC or, rarely, mcSCC, meaning they are no longer eligible for curative surgery or radiation.
Similar to BCC, risk factors for skin cSCC are sun damage or exposure to UV radiation and immunosuppression. Like BCC, cSCC tumors tend to have a high mutational burden with UV signatures. Patients receiving immunosuppressive drugs for solid organ transplants, unfortunately, are at a higher risk of developing cSCC, particularly aggressive ones. Also, patients with other immunosuppressive malignancies, such as chronic lymphocytic leukemia, have higher rates of cSCC than other patients.
Currently, there are 2 anti–PD-1 antibodies, cemiplimab and pembrolizumab, that are approved by the FDA for the treatment of advanced cSCCs.10,15
EMPOWER-CSCC-1: Cemiplimab in Advanced cSCC
Zeynep Eroglu, MD:
The study that led to the approval of cemiplimab in 2018 was the EMPOWER-cSCC-1 study.16 It was a phase II trial that enrolled patients with lacSCC or mcSCC. mcSCC was defined as having lymph node spread or distant metastases. In this trial, cemiplimab was either dosed based on weight (3 mg/kg) or given at a fixed dose of 350 mg.
There were 3 cohorts in this trial. The first 2 cohorts included patients with lacSCC or mcSCCcSCC who received the weight-based dosing, whereas the third cohort included patients with mcSCC who received the fixed dosing of cemiplimab. To be eligible for the study, patients had to be ineligible for any curative approaches such as surgery or radiation.
The primary endpoint of the study was ORR.
EMPOWER-CSCC-1: Response
Zeynep Eroglu, MD:
There were 193 patients with either lacSCC or mcSCC enrolled in this trial. The median follow-up averaged approximately 15 months. The ORRs were quite high, ranging from approximately 45% to 50% in lacSCC and mcSCC. This rate is higher than what we see with aBCC.9 The median DoR was more than 40 months.16
So, anti–PD-1 drugs can be quite effective in our patients with advanced cSCCs.
EMPOWER-CSCC 1: PFS and OS
Zeynep Eroglu, MD:
Here is a breakdown of the PFS and OS. As can be seen, the median PFS ranged between approximately 18 months and 22 months (nearly 2 years) across all cohorts. The median OS was between 4 and nearly 5 years for the cohorts with mcSCC. In addition, the median OS in the lacSCC cohort has not yet been reached.
Without question, cemiplimab is our first treatment option for patients with advanced cSCC for whom curative approaches such as surgery or radiation are no longer options.
EMPOWER-CSCC 1: PFS and OS
EMPOWER-CSCC-1: Safety Summary
Zeynep Eroglu, MD:
Safety signals in the study were as expected with anti–PD-1 antibodies. Approximately 30% of patients had serious grade ≥3 AEs. Only approximately 10% of patients who had an AE discontinued the study. Overall, the most common AEs included fatigue, diarrhea, nausea, and pruritus.
KEYNOTE-629: Phase II Trial of Pembrolizumab in Recurrent/Metastatic cSCC or lacSCC
Zeynep Eroglu, MD:
Pembrolizumab is another anti–PD-1 antibody that is approved by the FDA for advanced cSCC.15 It was approved in 2020 based on the results of the KEYNOTE-629 trial.17 This was a single-arm phase II study, where again, to be eligible, patients had to have locally recurrent or mcSCC, and surgery or radiation was no longer an option. In total, this study enrolled 159 patients separated into 2 cohorts of lacSCC and recurrent mcSCC, and patients were given a fixed dose of pembrolizumab 200 mg every 3 weeks up to 2 years. Most of these patients had prior surgery or radiation and many received prior lines of systemic therapy, such as chemotherapy or epidermal growth factor receptor (EGFR) therapy.
The primary endpoint was ORR.
KEYNOTE-629: Overall Response
Zeynep Eroglu, MD:
In this trial, the ORR was 50% in the locally advanced cohort, which is similar to that seen with cemiplimab. Approximately 17% had a CR with median DoR not yet reached in those 54 patients.
In the recurrent metastatic cohort, the ORR was 35%. However, when the data were broken down further in terms of patients who received pembrolizumab as their first-line systemic therapy, the ORR was 50%, whereas, for the patients who were receiving pembrolizumab as a second-line or later-line systemic therapy, the response rate was 33%.
Overall, we consider the anti–PD-1 antibodies cemiplimab and pembrolizumab as having similar rates of efficacy and benefit for our patients with advanced cSCC.
KEYNOTE-629: Survival in LA Cohort and Recurrent/Metastatic Cohort
Zeynep Eroglu, MD:
The 1-year PFS rate was 54% in the locally advanced cohort, whereas the median PFS was not yet reached. The 1-year OS was 74%, whereas the median OS was also not reached.
Not surprisingly, these rates were a little lower in the recurrent/metastatic cohort with a 1-year OS of 36% and a median PFS of 5.7 months. The 1-year OS was 61%, and the median OS was 24 months.
KEYNOTE-629: Survival
KEYNOTE-629: Safety Summary
Zeynep Eroglu, MD:
Here again, the safety profile of pembrolizumab in the KEYNOTE-629 trial was as expected with 14% of patients having to discontinue treatment because of AEs. Common treatment-related AEs (TRAEs) were pruritus (18%), fatigue (15%), and asthenia (13%). There were 2 (1%) deaths in the study because of immunotherapy-related AEs, colitis, and cranial nerve disorder.
Anti–PD-1 Therapy in cSCC: Summary
Zeynep Eroglu, MD:
In summary, the use of cemiplimab or pembrolizumab in advanced cSCC is appropriate for most of our patients with cSCC who are not candidates for surgery or radiation. Responses in general are seen within the first 2 months, although we have seen patients with delayed benefits as well. The duration of treatment in both of these studies was not any longer than 2 years. So, at this point, we do not know the optimal duration of treatment, but typically in patients who have had good responses to anti–PD-1 therapy, often we will stop treatment at approximately 2 years. If they have had a CR to treatment, we may even consider stopping their immunotherapy earlier, at 1 year, and then following them closely with surveillance scans and physical examinations afterward.
Modest Activity With Anti-EGFR Agents in Prospective Phase II Studies in Advanced cSCC
Zeynep Eroglu, MD:
Now, let us consider the treatment options for patients with PD-1 refractory cSCC. As previously mentioned, anti–PD-1 therapy gives ORRs of approximately 50% in patients with cSCC. The other 50% of patients may benefit from anti-EGFR agents.
There have been a few trials on the off-label use of these agents for cSCC. For example, cetuximab is approved by the FDA for head and neck squamous cell carcinoma, but it has been investigated in a small, single-arm phase II study for patients with unresectable cSCC.18 Response rates were close to only about 30%. The median DoR was also limited at approximately 7 months. Other EGFR inhibitors have shown similar outcomes to cetuximab.
For patients with advanced cSCC that is refractory to anti–PD-1 therapy, single-agent carboplatin or cisplatin, platinum-based doublet chemotherapy, or chemotherapy like cisplatin with or without fluorouracil may be an option. However, we typically do not see high rates of response with chemotherapy. In addition, chemotherapeutic agents are associated with numerous AEs.
In the PD-1 refractory setting, we encourage clinical trial enrollment and, if necessary, referral to academic centers that have clinical trials for these patients.
First-line Use of Immunotherapy Drugs in Immune-Related Preexisting Conditions
Zeynep Eroglu, MD:
First-line use of immunotherapy drugs can be more challenging for patients with autoimmune disease who are receiving immunosuppressive therapy or those with chronic immunosuppression. For patients with preexisting autoimmune diseases (inflammatory bowel diseases, rheumatoid arthritis, lupus, etc), in most cases, we would still favor the use of first-line anti–PD-1 therapy. However, there is a risk of a flare-up of the underlying autoimmune disease. To manage this risk, it is important to collaborate closely with the patient's physician who is managing the autoimmune disease. Before starting immunotherapy, we try to minimize the immunosuppression that the patient may be receiving by lowering the dose of prednisone to 10 mg/day. For patients with chronic immunosuppressive diseases, such as chronic lymphocytic leukemia or HIV, we will still use anti–PD-1 therapy first, although the response rates may be lower than in other patients.
The major exceptions to the use of first-line anti–PD-1 therapy are patients with solid organ transplants such as kidney, liver, and other organs. Retrospective data have demonstrated a high risk of allograft rejection, with some studies showing a potential rejection risk of up to 50% of the transplanted organ in patients where anti–PD-1 immunotherapy drugs had to be used.19 For these patients, we typically use anti-EGFR agents or chemotherapy drugs first or other clinical trials when available. But in refractory cases, we will still need to use anti–PD-1 drugs.
Nivo + Tacro + Pred ± Ipi for Kidney Transplant Recipients With Advanced Cutaneous Cancers
Zeynep Eroglu, MD:
One prospective clinical trial specifically looked at the use of immunotherapy drugs in kidney transplant patients with advanced skin cancers.20
The patients enrolled on this small phase I trial were kidney transplant recipients with various skin cancers, including 8 evaluable patients with melanoma, MCC, or cSCC. The immunosuppressive regimen for the transplant was defined for enrollment at a maximum dose of 5 mg prednisone in combination with tacrolimus, an immunosuppressive drug. The serum goal for tacrolimus was between 2 and 5 ng/mL, which is lower than the usual target. Patients were then started on nivolumab, which was continued as long as they were benefiting or had stable disease. Patients with progression could be switched to combination immunotherapy with ipilimumab 1 mg/kg and nivolumab 3 mg/kg.
The primary endpoint in this study was a response or stable disease without allograft loss after 16 weeks of receiving nivolumab treatment.
Complete Tumor Regression With Nivo + Ipi
Zeynep Eroglu, MD:
Of the 8 evaluable patients enrolled on this multicenter study, 5 had cSCC, 2 had MCC, and 1 had melanoma. Unfortunately, all 8 patients had progressive disease with nivolumab. Two patients also had a loss of their kidney transplants. Six of the patients were switched to the combination of nivolumab and ipilimumab as part of the study. Of the 6 patients who were switched, 2 had a CR to nivolumab plus ipilimumab, despite having progression on nivolumab alone. These are very early data, but for any treatment-refractory organ transplant recipients, whether it is cSCC, MCC, or another malignancy, immunotherapy should be considered.
A multidisciplinary approach would be very important in this setting. The recommendation is typically to refer these patients to academic or high-volume centers, given the complexity of their care. Close coordination with the transplant physician is needed. For patients with kidney transplants, it is important to be aware that they may need dialysis if the transplant is rejected. And of course, for those with liver, heart, and lung transplants, there is certainly the risk of death if immunotherapy leads to irreversible loss of their transplanted organs.
IGNYTE: First-in-Human Trial of RP1 + Nivolumab in NMSC
Zeynep Eroglu, MD:
There are several investigational treatments currently being explored in cSCC. Ongoing trials, some of which are early-phase studies, are looking at anti–PD-1 drugs, combined with radiation therapy, immunomodulators such as IAP 17, targeted therapies such as combining with EGFR or MEK inhibitors, and oncolytic viruses. One advantage of cSCC and BCC is that lesions are often on the skin and allow for easy accessibility for intralesional approaches.
There have been several studies exploring oncolytic viruses in cSCC, BCC, and MCC. One such virus is RP1, an intratumoral oncolytic herpes simplex type 1 virus that is constructed to destroy the tumor cells and elicit an antitumor immune response.
IGNYTE is a multicohort phase I/II study investigating the safety and efficacy of RP1 plus nivolumab in patients with solid tumors.21 This trial included a cohort of patients with NMSCs (n = 60) who received intratumoral RP1 plus nivolumab injections into their accessible skin lesions.
Primary endpoints were ORR, safety, and tolerability.
IGNYTE: Efficacy of RP1 + Nivolumab in NMSC
Zeynep Eroglu, MD:
When looking at the 17 patients with cSCC, the ORR with RP1 plus nivolumab was 65%. Of the 4 patients with BCC, 1 had a response (25%), and 3 of 4 (75%) patients with MCC had a response with RP1 plus nivolumab.
Although the study enrolled a small number of patients, oncolytic viruses are likely worth further exploration in clinical research in NMSCs.
Phase II Trial Evaluating Neoadjuvant Cemiplimab for Stage II-IV Cutaneous Squamous Cell Carcinoma
Zeynep Eroglu, MD:
The use of anti–PD-1 therapy in earlier-stage cSCCs has been explored in neoadjuvant and adjuvant settings. But of note, anti–PD-1 drugs are not yet approved in the neoadjuvant and adjuvant settings.
This small phase II study explored neoadjuvant cemiplimab for patients with resectable stage II-IV cSCC.22,23 Eligibility was based on the presence of resectable disease with no history of radiotherapy. Patients (N = 79) received up to 4 cycles of immunotherapy with cemiplimab, after which they underwent surgery. They could then receive cemiplimab in the adjuvant setting, receive radiation, or undergo observation based on the investigator’s discretion. The primary endpoint here was the rate of pathologic complete response (pCR).
Neoadjuvant Cemiplimab in Stage II-IV cSCC
Zeynep Eroglu, MD:
The data demonstrate a pCR rate that is quite high at 50%, and another 13% of patients had a major pathologic response.23
Neoadjuvant Cemiplimab in Stage II-IV cSCC: Safety
Zeynep Eroglu, MD:
Looking at the safety of neoadjuvant cemiplimab, most (87%) patients experienced a TEAE, and approximately 17% had grade 3 AEs. Common TEAEs included fatigue, diarrhea, nausea, maculopapular rash, and constipation.
Neoadjuvant Cemiplimab in Stage II-IV cSCC: Clinical Implications
Zeynep Eroglu, MD:
The study needs longer follow-up in terms of looking at relapse-free survival and OS, but it appears that neoadjuvant cemiplimab appears to be quite effective. This is an exciting development because many of our patients with advanced cSCC have tumors in locations that can be quite morbid for surgery, typically in their faces or in locations that require very large surgery. Hence, a neoadjuvant approach may help to decrease the morbidity of the surgery for some of our patients.
In general, we encourage trial enrollment if considering a neoadjuvant approach in cSCC and would emphasize the importance of a multidisciplinary approach with the medical oncologists, surgeons, radiation oncologists, and dermatologists, ideally in tumor boards to determine if a patient with cSCC may be a good candidate for a neoadjuvant approach.
Select Ongoing Trials in cSCC
Zeynep Eroglu, MD:
One of the largest ongoing current studies with RP1 is the CERPASS trial, which is evaluating intratumoral RP1 with cemiplimab vs cemiplimab alone in patients with advanced cSCC who have not had prior immunotherapy.24 There are similar efforts in other NMSCs as well. We will see more data in the upcoming years with the use of intratumoral therapies, including oncolytic viruses in advanced NMSCs.
C-POST is another study that is looking at patients who have had high-risk cSCC that has been surgically resected with or without radiation and randomizes them to either receive adjuvant cemiplimab or placebo.25 However, this trial is still enrolling, and we do not yet have any data on the adjuvant use of immunotherapy in advanced cSCCs.
cSCC Key Takeaways
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