Inside the Clinic: Basal Cell Carcinoma Treatment Advances - Episode 5
Dr Jennifer Atlas leads a conversation on systemic therapy options in basal cell carcinoma with a review of clinical trial data.
Jennifer Atlas, MD: Let’s talk about systemic therapy options for locally advanced high-risk disease. I want to start first by talking about the mechanism of action of our 2 different drug classes that we can use. First-line therapy for patients who have locally advanced un-resectable disease or are not amenable to radiation would include using hedgehog inhibitors. We have 2 approved agents on the market, and they work in a similar manner. The hedgehog signaling pathway is crucial in causing basal cell proliferation and can lead to tumor growth.
Mutations can happen in one of 2 locations in this signaling pathway at patched one homolog or at SMO location, which is smoothened muscle. These are the 2 locations that we are trying to use hedgehog inhibitors for patients, which most of them are going to have mutations in those locations that lead to the pathogenesis of a basal cell carcinoma. The 2 trials that led to the approvals of these agents first with this vismodegib was the ERIVANCE trial. And secondly, the BOLT trial for sonidegib. These are our 2 commercially available hedgehog inhibitors.
The objective response rates for our 2 hedgehog inhibitors specifically with vismodegib as per data from the ERIVANCE trial is 43%. And for locally advanced patients for sonidegib is 44%. Both of these are acceptable options to administer for patients with locally advanced basal cell carcinomas. Patients will receive these medications orally and they are at flat based dosing of the medications. Looking at our other potential drug class that can be used is a PD1 inhibitor called penpulimab. This is a mechanism of action that many of us in the oncology world are well familiar with now using an anti-PD1 antibody, which is a monoclonal antibody to help recuperate the anti-tumor response of exhausted T-cells with finding two PD-L1 and PD-L2 for certain PD1 inhibitors on the tumor cell. In the study that led to the approval of cemiplimab we had patients including in cohorts that had a locally advanced cohort and a metastatic cohort. This was the 1620 study, which is a phase 2 open-label non-randomized study. On that study 84 patients had locally advanced disease. To meet eligibility criteria to go on to receive cemiplimab patients had to either have had progressive disease while on a hedgehog inhibitor were not an appropriate patient for hedgehog inhibition or patients had stable disease as their best response after nine months of therapy. Another qualifying factor was a patient who had received hedgehog inhibition but had to discontinue due to intolerance to therapy. Which initial treatment would we select for this patient, Dr Babakoohi?
Shahab Babakoohi, MD: For advanced basal cell the decision is made that patient is not a candidate for surgery or radiation at the first stage, usually we proceed with inhibitor therapy trial. In some patients, if the patient responds well then in dermatology close monitoring that we do for our advanced BCC [basal cell carcinoma] patients here we monitor clinically and after couple of months on average, the time that we expect some response it can change based on our clinical exam clinical evaluation. We do surveillance biopsies from several spots of the tumor if the patient is responding which is obviously great, then the next step will be the decision or for example, if the tumor is small enough to go for surgery or depending on patients’ preference or demographic, they may want to continue patient individual therapy. In that case also we need to consider the tolerance, sometimes patients have side effects and they're tolerating because of the response, and they achieve good response. They prefer to have your input for having some intermittent therapy lowering the dose or some strategies or drug to see if they stay in remission for that. However, if our clinical evaluation shows that the patient is not responding in that case we need to go back in multidisciplinary approach and see whether patient is a candidate or surgery or radiation treatment that was not chosen at the first step because of all considerations that we discussed or if not then we need to consider second line of systemic therapy by medical oncology, which will be immunotherapy.
Jennifer Atlas, MD: I agree. This patient would be an ideal patient to start with a neoadjuvant systemic approach as his frontline treatment. And that would be with a hedgehog inhibitor in this situation. And once again, with close surveillance and repeat evaluation with multiple team members, including dermatology based on response intolerance to drug, for some of those scenarios, we discussed developing intolerance or stable disease after 9 months of therapy. That may be the patient that if they are not a candidate for local regional management with either surgery or radiation with curative intent, that we would be looking at second-line systemic therapy in the form of cemiplimab, which does have based on that phase 2 study objective response rates of 29% with the vast majority of patients who fell into the response group, having partial responses, 23% were partial responses versus 6% with complete responses. It does require multiple checkpoints with the multidisciplinary team as a patient's case or care advances.
Transcript edited for clarity.