Innovations in Systemic Therapy for Advanced Nonmelanoma Skin Cancers

Explore the evolving treatment landscape for advanced basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC). In this expert discussion, Dr Elliott Campbell covers hedgehog inhibitors, PD-1 immunotherapies, treatment resistance, patient selection, safety considerations, and emerging approaches including neoadjuvant therapy, combination regimens, and biomarker-driven precision medicine.

Transcript

How have treatment options evolved for advanced CBCC and CSCC in recent years, and what are the most significant breakthroughs?

Dr Campbell: In the past decade, treatment for advanced cutaneous basal cell carcinoma and cutaneous squamous cell carcinoma have shifted dramatically with the advent of targeted and immune-based therapies. For advanced basal cell carcinoma, the mainstay of therapy is the hedgehog pathway inhibitors such as Vismodegib or Erivedge that was approved in 2012 and several other pharmacotherapies with similar mechanisms of actions to follow. These target aberrant patch and smooth and signaling and are indicated for locally advanced and metastatic basal cell carcinoma that is not amenable to surgery or radiation, which is key. The response rate is going to vary by study. The objective response rate's going to somewhere be around 60% for local advanced disease with a median duration of response around 26 months.

Now for advanced squamous cell carcinoma, the most transformative breakthrough was the approval of cemiplimab, a PD-1 inhibitor in 2018. In the pivotal and power cutaneous squamous cell carcinoma trial, cemiplimab achieved an objective response rate of 46% and a 13% complete response with sustained efficacy. And of course there's pembrolizumab, which has shown some prominence, particularly in the KEYNOTE-629 trial.

In advanced cases, what factors influence the decision to use systemic therapies, such as hedgehog pathway inhibitors or immune checkpoint inhibitors?

Dr Campbell: First question that we have to ask is, does this patient need systemic treatment? And I would say this is the minority of cases. Is this truly unresectable and/or metastatic? And this question is, of course, evolving now with the recent neoadjuvant and adjuvant studies, which are opening new indications. We need to be thinking about prior treatments that the patient has received and of course about the histology and the molecular profile of the tumor. One classic example would be a smooth and patched pathway mutation in basal cell carcinoma. Of course, we're going to pick a hedgehog inhibitor.

Patient comorbidities and immune status is critical. This is obviously a huge discussion here, but one example of that would be organ transplant with the associated risk of rejection if given immunotherapy.

In a nutshell, of course, the hedgehog inhibitors are going to be favored for locally advanced basal cell carcinoma and the PD-1 inhibitors are first line for metastatic or unresectable squamous cell carcinoma and are also used off-label for select basal cell carcinoma cases that have previously failed a hedgehog inhibitor.

What challenges do dermatologists face when managing patients with locally advanced or metastatic CBCC and CSCC, particularly regarding treatment resistance?

Dr Campbell: Primary or acquired resistance to hedgehog inhibitors occurs in between 20 and 30% of patients and this is often due to secondary smooth in mutations or pathway bypass mechanisms. Immunotherapy resistance remains poorly understood but is likely influenced by low tumor mutational burden, a poor antigen presentation and T-cell exhaustion. We also need to manage toxicity, especially in elderly and polypharmacy patients, which can significantly complicate care. These medications have unique side effect profiles with very common adverse effects that limit their long-term use. And lastly, we have to coordinate across specialties such as oncology, surgical oncology, radiation oncology, ENT and palliative care, which is all crucial. I think of the dermatologists as the quarterback in many of these patients' care.

Can you discuss the latest clinical trial data on immunotherapies for advanced CSCC and how they compare to traditional approaches like surgery or radiation?

Dr Campbell: Exciting preliminary news for cutaneous squamous cell carcinoma is the use of adjuvant treatment with cemiplimab, which elicits a statistically significant and clinically meaningful improvement in the primary endpoint of disease-free survival among patients with high-risk cutaneous squamous cell carcinoma after surgery. Again, the key is this is after surgery, this is adjuvant treatment. According to the findings from the phase 3C post-trial, this showed an impressive 68% reduction in the risk of disease recurrence or death in patients with high-risk squamous cell carcinoma after surgery versus placebo with a median duration follow-up of around 24 months. Recent trials for cutaneous basal cell carcinoma focus on patients who have previously failed or cannot tolerate a hedgehog inhibitor. Cemiplimab, a PD-1 inhibitor, has been a focus both alone and in combination with other therapies. Trials also explore other immunotherapy agents like pembrolizumab and nivolumab and investigate their efficacy in various settings, including the neoadjuvant and adjuvant treatment space.

What are the key safety considerations and adverse events associated with systemic treatments for advanced CBCC and CSCC, and how do you manage them?

Dr Campbell: Hedgeog inhibitors have common adverse events and these include muscle spasms, which occur in about 70% of patients, alopecia and dyscusia in around 50% of patients. Dose interruptions or reductions are often effective in managing this toxicity, but discontinuation due to side effects occurs in around 15% of cases and in my experience can be even higher than this. Checkpoint inhibitors such as cemiplimab and pembrolizumab have immune-related adverse events with prevalence that vary by study, but these of course include dermatitis, hypothyroidism, pneumonitis, and colitis. And this is oftentimes managed with steroids immunosuppressants with treatment interruption in severe cases. Grade 3-plus adverse events occur in about 5 to 10% of patients.

Are there any patient-specific factors, such as genetic markers or comorbidities, that influence treatment selection for advanced nonmelanoma skin cancers?

Dr Campbell: So for genetic factors, of course, PASH-1 and smooth in mutations support the use of hedgehog inhibitors in BCC. High tumor mutational burden and PD-L1 expression may predict better response to PD-1 blockade and cutaneous squamous cell carcinoma, though PD-L1 is not required for treatment eligibility. There are patient-specific factors such as autoimmune disease or organ transplant status that may preclude immunotherapy, although this is a litle bit more controversial for renal transplantation and poor performance status or frailty may favor hedgehog inhibitors or palliative options. Comprehensive geriatric and functional assessments help tailor treatment decisions, especially given the median age of onset or around the 70s for these cancers.

Looking ahead, what emerging therapies or novel treatment combinations show the most promise in improving outcomes for patients with advanced CBCC or CSCC?

Dr Campbell: I'm excited about combination approaches. Trials are exploring hedgehog inhibitors added to PD-1 inhibitors to overcome resistance or enhance immunogenicity. Neoadjuvant PD-1 blockade and cutaneous squamous cell carcinoma is under investigation with early trials suggesting it may reduce tumor burden preoperatively and improve outcomes.

Oncolytic viruses and tumor-infiltrating lymphocyte therapies are also being studied in refractory cases, and also exciting is the biomarker-driven therapy, which will hopefully play a larger role with next-generation sequencing guiding patient selection and resistance monitoring