With immune checkpoint inhibitors in particular, patients are seeing greater results with fewer adverse effects.
In an interview with Pharmacy Times at the Oncology Pharmacists Connect conference, Heather Armbruster, PharmD, BCOP, outpatient clinical pharmacy manager at Ohio State University Comprehensive Cancer Center, discussed the growing armamentarium of treatment options for non-melanoma skin cancers. With immune checkpoint inhibitors in particular, patients are seeing greater results with fewer adverse effects.
Q: Research on immunotherapy for skin cancer has traditionally focused more on cutaneous carcinoma. Why has there been a more recent shift in attention to non-melanoma skin cancers?
Heather Armbruster, PharmD, BCOP: Yeah, so historically, there have not been great number of treatment options for our non-melanoma skin cancers; those options are very limited. And we know immune checkpoint inhibitors (ICIs) in melanoma are very efficacious. They're efficacious in other disease states as well. So, I think kind of given the similarity from the skin cancer perspective, it makes sense to kind of pivot and start looking at the use of ICIs for those non-melanoma indications as well.
Q: What were the traditional treatment approaches for non-melanoma skin cancers, and at what point did ICIs begin to be used more widely?
Heather Armbruster, PharmD, BCOP: So, the mainstay of treatment for the non-melanoma skin cancers is surgical resection, and basal cell and squamous cell are the 2 most common skin cancers that exist in the United States. And so, the majority of those can be surgically resected. It's when we get into those few cases that do have metastatic or unresectable disease where we're looking at systemic therapies. With basal cell carcinoma, hedgehog inhibitors are really our 1 drug class that we have to treat that type of cancer. With squamous cell carcinoma, it was really standard chemotherapy, but response rates were not very good and varied across patient populations. And so, it’s really kind of a niche for immunotherapy to move into. And so, the first FDA approval occurred, I think, about 3 years ago now, so it is still relatively new, in terms of being able to use those ICIs for basal cell and squamous cell carcinoma.
Q: Where are ICIs typically placed in the treatment sequence?
Heather Armbruster, PharmD, BCOP: So, for basal cell carcinoma, it's primarily in the second line. So, the indication is for patients who have previously received or are not candidates for a hedgehog inhibitor, so you're going to typically see it in patients if they either had an inadequate response to or progressed on those hedgehog inhibitors, or if they weren't able to tolerate the hedgehog inhibitors due to their toxicity. It's the primary point. You can also sometimes see it, though, in the first line setting, in that part of the indication where they're not candidates for a hedgehog inhibitor. So, maybe due to toxicity concerns or not being able to swallow oral medications—since those hedgehog inhibitors are oral—those may be situations where you would see ICIs, specifically cemiplimab, used in the first line setting.
Squamous cell carcinoma is a little bit different. So, our preferred regimens there are ICIs, and it's specifically cemiplimab and pembrolizumab. So, those 2 are both preferred regimens. And for squamous cell, you'll see them in the first line setting. There's also some data to now looking at using some ipilimumab for neoadjuvant treatment of squamous cell carcinoma. So again, it being used earlier in treatment and for some patients who can still undergo surgical resection.
Q: How do ICI approaches differ between the adjuvant and neoadjuvant setting?
Heather Armbruster, PharmD, BCOP: Yeah, so to be honest, from a treatment standpoint, there isn't a whole lot of difference. So, we use the same medications, the same doses, it's really just which patients are receiving it neoadjuvant–only versus adjuvantly. And that's kind of a multidisciplinary discussion amongst teams and providers. If it tends to be larger, more bulky disease, we may go with a neoadjuvant approach for easier surgical resection. But if we're able to, you know, excise more easily, it's not as bulky or as extensive of disease, then doing that surgical resection first and using the ICIs in the adjuvant setting.
Q: What are the key front-line ICIs that you see used in non-melanoma skin cancers, and is there key data supporting their use?
Heather Armbruster, PharmD, BCOP: Yeah, so, the 2 that have indications are cemiplimab and pembrolizumab. So, cemiplimab is approved for both basal cell and squamous cell carcinoma, pembrolizumab just for squamous cell carcinoma. So, we’ll see both of those. Data supporting their use comes from phase 2 trials where, really, we see high objective response rates and good durable responses. The other thing, unlike other cancers but similar to melanoma, is that response is not dependent on PD-L1 status. So, in the trials, there were higher objective response rates in patients with PD-L1 positive disease, but, really, we see those responses regardless of PD-L1 status. So PD-L1 positivity is not required for treatment with either cemiplimab or pembrolizumab for our non-melanoma skin cancers.
Q: How are ICIs used or potentially used in combination regimens for patients who do not have durable benefit with front-line treatments?
Heather Armbruster, PharmD, BCOP: Yeah, so this is actually an area of ongoing research right now. So currently, there are not any approvals for a combination ICI regimens for our non-melanoma skin cancers, but there are studies undergoing looking at combination immunotherapy regimens. So, there are some trials looking at nivolumab in combination with ipilimumab. There are other trials looking at our newer combination product of nivolumab and relatlimab together, so looking at some dual ICIs there for basal cell carcinoma. There are also some studies looking at anti-PD-1 inhibitors in combination with vismodegib, which is a hedgehog inhibitor, so targeting 2 different classes of medications.
Similar to that, there's a number of intra-tumoral studies that are going on as well. So, trials that use a medication that's injected intra-lesionly for targeting, you know, the cutaneous lesions. And they're doing that in combination with an anti-PD-1 inhibitor for a more systemic approach. So, a number of trials are ongoing now that are exciting, but not yet completed. So, [we’re] waiting for that data to come to fruition and see what the benefits are with those combination regimens.
Q: What are pharmacists’ roles in managing the associated immune-related adverse effects?
Heather Armbruster, PharmD, BCOP: Pharmacists play a big role in the medication management. So, when patients have these immune related adverse events, helping dose the high dose steroids and other immunosuppressive medications. When patients are on those large doses of steroids, there's also other supportive care meds that are warranted, so thinking about [gastrointestinal] prophylaxis to help protect against stomach ulcers, or potentially antibiotic prophylaxis to prevent against [pneumocystis jiroveci pneumonia]. So, making sure those medications are on board, you know, with giving patients 2 or 3 new medications to take, as well, that have varying schedules.
Patient education is a large piece. So, making sure patients understand how to take everything, what time of day, and if there's any special administration administration instructions with those medications. And then I would say, too, you know, once symptoms start to improve and we look at being able to taper patients off their immunosuppressive regimens, pharmacists are involved with that standpoint as well, coming up with a plan and, again, making sure the patient understands the correct way to take those medications.
Q: What are some future directions or areas of research in this space?
Heather Armbruster, PharmD, BCOP: Yeah, so a number of trials [are] going on with ICIs. We've touched on some of them, but others that are going on as well. So, there's more studies looking at use in the neoadjuvant and adjuvant setting for squamous cell carcinoma, so giving ICIs up front before surgery or afterwards, different combination studies like we talked about, and then also an ongoing study looking at administering ICIs to patients who previously had a kidney transplant. So, patients with solid organ transplants were excluded from all the ICI trials, because there's a concern that if you give immunotherapy to those patients, they could potentially lose their transplanted organ. And so, there's an ongoing study looking at administering ICIs, but doing it in combination with tacrolimus, to see if they're able to reap the benefit of the ICI but still have some immunosuppression on board to limit or eliminate that risk of graft rejection. So, another exciting area, but still waiting to see what the data is there.