AJMC®: Among patients with more advanced cases of basal cell carcinoma (BCC), how do you identify those at high-risk for disease progression or intolerability when it comes to the use of Hedgehog inhibitors?
Hamid: There are multiple ways of identifying patients with basal cell carcinoma with high recurrence risk. They are clearly delineated in multiple different publications and categories, but I would say, per the National Comprehensive Cancer Network, those at high risk have locations that are on the cheeks, forehead, scalp, neck, or periorbital area. Otherwise, if the lesions are on the trunk and extremities, they’re greater than 2 cm. We often talk about the mask area of the face and the central eyelids and eyebrows in the periorbital area where the borders are poorly defined. Here, recurrent BCC is high risk.
Then, of course, we talk about the population of patients with significant risk [for] any type of nonmelanomatous skin cancer. These are patients with prior immunosuppression, whether they’re on immunosuppressive agents for a connective tissue or autoimmune disease, if they have CLL [chronic lymphocytic leukemia], or if they have some other form of immunosuppression.
Sites of prior radiation or prior surgery and recurrence are also high risk. There are subtypes that are low risk: nodular and superficial. There are also subtypes that are high risk, which are those with an aggressive growth pattern.
AJMC®: What factors affect treatment sequencing for patients with locally advanced and metastatic BCC?
Hamid: The treatment algorithm is important here for patients with high-risk disease. You need to [determine] if surgery is possible, and then you need to look at greater margins. If it’s not surgery, then it’s radiation. Then, for someone for whom surgery is not feasible, [or] those who refuse surgery, or [in] whom there’s evidence of locally advanced or metastatic disease, it’s important to bring in an interdisciplinary tumor board like we do here at The Angeles Clinic to take care of patients with BCC.
Clearly, [choosing] which therapy would be appropriate is important, as is how to discuss this with the patient. The modalities that have been utilized to treat patients are mostly surgery radiation excision, and curettage and excision. With recurrent BCC, the risk of recurrence is greater. The standard for a patient with primary BCC should be surgery with Mohs therapy, and if that is not possible, then the decision is surgical excision vs radiation.
AJMC®: What factors do you consider when a patient with BCC moves beyond their initial treatment? What influences your therapeutic decision-making in that second-line setting?
Hamid: The first thing to know in primary BCC is that there are huge discussions about what you would utilize as an appropriate therapy; that requires an understanding of the role of the therapy initially as well as the functionality and cosmesis of the area. You clearly have areas that are high risk, but these are also significant for loss of function, in an area like the eyelid. If you have a cosmetic outcome that is deformative, or if you have fibrosis from radiation, there is morbidity. The goal at this time is the ability to support the patient in the best way possible.
In recurrent disease, you need to have an extensive discussion about whether returning to surgical or radiation modalities is appropriate because the tumor history has told you that you will be back where you are again. [That’s when] we start discussing the application of Hedgehog inhibitors or other therapeutic agents to prevent recurrence, or they are used in a neoadjuvant fashion. That’s a setting that’s currently in flux, but it is important. Before we had Hedgehog inhibitors in the setting of multiple recurrences, the only options were disfiguring surgeries. One of the greatest aspects of being involved in the development of Hedgehog inhibitors is the ability to avoid the severe morbidity from surgery.
AJMC®: What is your experience with tolerability concerns with Hedgehog inhibitors? What types of adjunctive care and monitoring do you use for patients who experience adverse events?
Hamid: There is another side of Hedgehog pathway inhibitors: the adverse events that are significant. These include alopecia; muscle spasms, which are cramps that are unrelated to anything that you can manipulate with electrolytes; and weight loss from increased glucose uptake but also from dysgeusia and ageusia. Dysgeusia is a change in taste, and ageusia is a loss of taste. It’s not that you’re nauseous or vomiting; it’s that the taste is different. Patients talk about a metallic taste in their mouths such that they don’t have the desire to eat, or they don’t get that same type of benefit and satisfaction from eating. There are also some cardiac concerns. For these patients, managing adverse events leads to discussions about minoxidil for the hair loss, nutrition consultation, or hydration and stretching for the muscle spasms. These are clearly important for patients, as the majority of them are older, when recovering from a significant morbidity is harder.
AJMC®: What is immunotherapy’s role in patients with recurrent BCC? What factors would you consider when selecting a Hedgehog inhibitor vs immunotherapy?
Hamid: The current approval for immunotherapy is in consideration for treatment after failure and progression on a Hedgehog inhibitor, but it also entails this idea of intolerance to a Hedgehog inhibitor. I think that’s where we spend the majority of our time talking about the appropriate first-line therapy. Obviously, with these approvals, we will look at first-line immunotherapy and the benefits vs Hedgehog inhibitors. Those data are coming forward.
In immunotherapy, which is my sphere of research, we’ve known that BCCs have high mutational burdens—meaning they have a high level of neoantigens, which are proteins that stimulate the immune system. Just as we’ve known that in melanoma, we’ve known that in Merkel cell carcinoma, and we’ve known that in cutaneous cell carcinoma. It made scientific sense to look at immunotherapies and the PD-1 inhibitors, more importantly, in these patients. We have seen the ability to have a significant response rate and the ability to have durable and deep responses with significant progression-free survival and duration of response.
We have now brought something else to our armamentarium. I was involved in some of the phase 1 and phase 2 work with Hedgehog inhibitors and have been intimately involved with checkpoint inhibitors. I can tell you that they both have different toxicity profiles that you need to look at when you discuss this with patients. You have the ability and time to evaluate both, and you also have the time to utilize immunotherapy. When we talk about immunotherapy, we talk about the need for a runway of time for the immune system to get activated. Most BCCs have slow growth kinetics; therefore, you have the ability to utilize them.
AJMC®: How do you envision the future of care in BCC? Will any ongoing clinical trials in this sphere have an impact on the overall treatment landscape?
Hamid: The future of care for BCC will include our evaluation of combinations of these therapies. There are trials of pembrolizumab and vismodegib for advanced BCCs that have been published, presented, and updated. There will likely be randomized trials for the first-line setting. Then of course, as we have learned about the utilization of combination immunotherapies, I would recommend for anyone involved to look at phase 1 trials studying combinations of immune therapies because they’re everywhere. This is where I would ask patients to go. The focal utilization of radiotherapy to stimulate an immune response is a paradigm that has garnered significant import in other solid tumors and will do so for patients with a BCC, as these can metastasize to lymph nodes and bone.
There’s never been a more promising time [to treat BCC]. As I look back on my experience with patients with locally advanced and metastatic BCC and understand what they had to go through, all we had were radiation and surgical procedures. Now 2 pillars have been added to the care paradigm: targeted therapy with Hedgehog inhibitors and immunotherapy with PD-1 inhibitors, which not only have the ability to control disease, but they are also manageable.
AJMC®: What patient- or treatment-related factors most influence your strategy for the overall management of patients with advanced BCC? Do you have any advice for clinicians to best optimize their approach to treatment for these patients?
Hamid: I would say that this is like any other situation: Trying to classify a single patient among the group is difficult. The toxicity spectrum needs to be evaluated in addition to the efficacy that we can get from these drugs. It’s a paradigm that’s in flux. The best way to improve outcomes for patients is to utilize a multidisciplinary team approach to care, which includes supportive care, palliative care, and nursing. Also, the pathologist is very important, as is the surgical oncologist, the radiation oncologist, and the medical oncologist—and of course, the most important person is the patient.
As far as we have come, [we have] become more intricate in our care of patients, given our options and the benefits that we’ve seen. Years ago, when a basal cell carcinoma was recurrent, we were without options. We now have significant therapies that are giving us a road map on how to take care of each patient. Clearly, we’ve been reintroduced to the role of surgery and radiation as adjuncts to Hedgehog inhibitors and immunotherapies.