Experts Contemplate Realistic Treatment Goals Using Hedgehog Inhibitors in Basal Cell Carcinoma

Shailender Bhatia, MD

Hedgehog inhibitors are becoming more widely used for the treatment of Basal cell carcinoma. Two experts, Shailender Bhatia, MD, associate professor, Department of Medicine, Division of Medical Oncology, University of Washington School of Medicine associate member, Clinical Research Division of Fred Hutchinson Cancer Research Center along with Paul T. Nghiem, MD, PhD, director, Skin Oncology Clinical Program, Seattle Cancer Care Alliance, professor, Dermatology/Medicine George F. Odland Endowed Chair in Dermatology University of Washington School of Medicine, head of Dermatology, UW Medicine, affiliate Investigator, Clinical Research Division, Fred Hutchinson Cancer Research Center discussed the reality of hedgehog inhibitor use in practice during a virtual Targeted Oncology Case-Based Roundtable event.

Paul T. Nghiem, MD, PhD

Together, the experts review data from clinical trial research to determine which goals are realistic with hedgehog inhibitors.

Targeted Oncology^TM: Have you ever used a Hedgehog pathway inhibitor, and would you consider it for this patient?

NGHIEM: A lot of [patients] will respond to a Hedgehog pathway inhibitor, and they’re usually relatively transient responses, but the adverse effects [AEs] are quite problematic; loss of taste, hair loss, a lot of problems that are not well tolerated.¹

BHATIA: [Hedgehog pathway inhibitors] are drugs with a role for dose reduction. The only thing we can do is essentially dose interrupt, and my general experience is that the AEs tend to be more cumulative. As patients are staying on [the inhibitors] more and more, the [AEs] build up, and then I give them a break. However, I think the AEs come on a bit sooner the next time [they go on the inhibitor]. Eventually, most patients get tired of taking it, and in addition to the AEs that were mentioned [by Nghiem], debilitating leg cramps is another one that people have mentioned to me, which can be very painful.

How long would you treat the patient, and what arethe realistic goals for the treatment?

[Using vismodegib (Erivedge)] needs to be carefully discussed with the patient in advance because the concept that this is going to be a long-term, AE-free therapy is [not realistic]. However, it can shrink the tumor and allow for surgery, perhaps on a more limited basis. It could also be a bridge to something else; you could temporarily see how it’s tolerated until you have to move on to something else. But, yes, you’d need to be realistic in talking to patients.

BHATIA: The most common thing that happens is that when you use these drugs, the wound starts filling in, and the area starts looking more and more normal. The challenge that I run into is when surgeons say, “You’re making progress, so keep going.” But then, the patient’s having these AEs all this time, and ultimately it becomes a tolerance issue.

So, the question comes up: How much [of the tumor] do you remove? Should you now remove the smaller extent because there’s probably some cancer left there? Or should you do the same surgery that you would do [initially], but obviously, with less tumor in there? I’m not sure that’s been answered yet, but that’s one of the things that is always debated when we have these cases.

If this treatment achieves tumor shrinkage, how can a physician follow up?

NGHIEM: I think if there’s marked shrinkage, most people will then do a more modest surgery, based on what is evident at the time. There’s not a great situation, [because with] basal cells, about 1 in 50,000 metastasize or act aggressively. It’s a tiny number, but when they do, they’re pretty nasty.

After Mohs surgery is completed, are there still viable tumor cells that may have healed on the Hedgehog inhibitor?

NGHIEM: The problem is the [patches of normal skin that do not have BCC, called skip islands]. Normally, Mohs is a nice approach because BCCs grow like a ball. They don’t jump [to other areas]. They aren’t growing discontinuously. They grow like a ball, or at least the sclerosing ones grow with roots that are continuous. So, if you [treat the patient] with Mohs, a good surgeon hits a truly negative margin for BCC, and the patient is in great shape. That’s different from Merkel cell carcinoma. Merkel does not grow like a ball; it jumps. So, negative margins are much less confident.

But the issue is, once you’ve treated with neoadjuvant vismodegib or something [similar], you worry that there are islands left behind. I don’t know if that theory has been fully proved or disproved, but that’s always the worry, and I don’t think that there are thousands of patients in a study where they ask that question. It’s too rare.

With this case, has the patient met a satisfactory end point? Are there other approaches you recommend?

BHATIA: By the clinical response, we have [met an end point]. Have we obviated the need for the original extent of the surgery or original extent of radiation field? I don’t think that question has been answered.

Another [management] approach could be to watch this patient closely, and if there is something that shows up, then do the surgery. That way, you can, hopefully, not have to do the surgery on everybody. However, that’s one of the challenges of using any neoadjuvant therapy, to be honest.

For patients who have progressed on Hedgehog pathway inhibitor therapy, what treatment would you use?

BHATIA: Historically, there have been platinum-based chemotherapies, anthracycline-based chemotherapies, and, more recently, immune checkpoint inhibition. There are a lot of data coming out on the rationale for using immune checkpoint inhibitors in BCC.

BCC has one of the highest mutational burdens in most cancers and certainly has one of the highest in skin cancers. It also turns out PD-L1 expression is very prevalent. In 80% to 100% of specimens in multiple studies, PD-L1 expression was [relevant] to outcomes of the study.²

What other options are available for patients with progressive BCC on or after Hedgehog pathway inhibitor therapy?

BHATIA: Over the last few years, there has been an emerging number of case reports.…There were preliminary trial results that were written, not in much detail, but as a letter. [The proof-of-concept study looking at pembrolizumab for patients with advanced BCC only looked at 9 patients on pembrolizumab monotherapy]. This was in patients who did not have prior Hedgehog inhibition, so, up-front pembrolizumab [Keytruda]. And then, a second cohort got pembrolizumab plus hedgehog inhibition. Response rates were [relatively] high in the pembrolizumab monotherapy arm at 44% [range, 14%-79%] compared with the combination arm at 29% [range, 4%-71%].³

[Although there is a] very small number of patients [in the trial], the proof of concept here is that these drugs can work in the frontline setting [for patients with] BCC. There is also possible room for combining these treatments with Hedgehog inhibition, although there was no significant evidence of remarkable synergy among the 2 drugs. Moreover, similar to other skin cancers, when these drugs work and when the immunotherapy works, it can work for long periods. The median duration of response [DOR] in patients treated with pembrolizumab plus vismodegib was 52.8 weeks [range, 28.0-77.6] compared with patients on pembrolizumab alone at 67.6 weeks [range, 31.4-82.0].

What new data are out for those who have progressed on Hedgehog pathway inhibitors?

BHATIA: Recently at the 2020 European Society for Medical Oncology meeting, data were presented on [the use of cemiplimab (Libtayo)] in patients with locally advanced BCC. After Hedgehog inhibition, cemiplimab led to a response rate of 31% [95% CI, 21.3%-42.0%].4 These are refractory patients, so this is a remarkable number. [Cemiplimab was approved in this setting in February 2021.]

[Although median DOR was not reached in this study,] many of these patients have had ongoing responses for almost 2 years in this trial. [Furthermore, the estimated progression-free survival was 19.3 months (95% CI, 8.6–not evaluable), and estimated overall survival was not reached.]

There are also some other efforts going on. In one trial [NCT03521830], patients received either Hedgehog inhibition [then] nivolumab [Opdivo] or combination therapy with anti–PD-1 therapy plus Hedgehog inhibition.5 When they progressed, they got nivolumab plus ipilimumab [Yervoy] as an attempt to salvage treatment with combination immunotherapy, after PD-1 monotherapy didn’t worked. I think it’s an example of more and more efforts going at trying immunotherapy in these patients [with a challenging disease].

_References:

_{1. Harris L. Basal cell carcinoma: a pharmacist’s guide. US Pharmacist. August 19, 2019. Accessed November 30, 2020. https://bit.ly/2G4vNz3}

_{2. Lipson EJ, Lilo MT, Ogurtsova A, et al. Basal cell carcinoma: PD-L1/PD-1 checkpoint expression and tumor regression after PD-1 blockade. J Immunother Cancer. 2017;5:23. doi:10.1186/s40425-017-0228-3}

_{3. Chang ALS, Tran DC, Cannon JGD, et al. Pembrolizumab for advanced basal cell carcinoma: an investigator-initiated, proof-of-concept study. J Am Acad Dermatol. 2019;80(2):564-566. doi:10.1016/j.jaad.2018.08.017}

_{4. Stein JE, Soni A, Danilova L, et al. Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. Ann Oncol. 2019;30(4):589-596. doi:10.1093/annonc/mdz019}

_{5. Stein JE, Brothers P, Applebaum K, et al. A phase 2 study of nivolumab (NIVO) alone or plus ipilimumab (IPI) for patients with locally advanced unresectable (laBCC) or metastatic basal cell carcinoma (mBCC). J Clin Oncol. 2019;37(suppl 15):TPS9595-TPS9595. doi:10.1200/JCO.2019.37.15_suppl.TPS9595}