When Does the PD-1 Inhibitor Come Before the Hedgehog Inhibitor for Neoadjuvant Basal Cell Carcinoma?

Vishal A. Patel, MD

When examining neoadjuvant strategies in non-melanoma skin cancers such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC), dermatologists and surgeons had differing opinions on circumstances where they would reach for the PD-1 inhibitor cemiplimab-rwlc (Libtayo). In an OncLive workshop on “Emerging Treatment Strategies for Skin Cancer,” Vishal A. Patel, MD, moderated a program with 11 faculty on when they would reach for the agent in the neoadjuvant setting.

Patel is the director of Cutaneous Oncology at GW Cancer Center, director of Dermatologic Surgery within the Department of Dermatology, and an associate professor of dermatology & medicine/oncology at George Washington University School of Medicine & Health Sciences in Washington DC.

PD-1 Inhibition With Cemiplimab vs Hedgehog Inhibition With Vismodegib in BCC

Before weighing the pros and cons of cemiplimab with other options such as the hedgehog inhibitor vismodegib (Erivedge) clinicians should first take a step back to determine whether systemic therapy is warranted at all. “The first decision is [asking if] the is patient no longer a candidate for curative resection [or] curative radiation. That’s when I start thinking about systemic options,”Sarah Arron, MD, PhD, Mohs Surgeon at the Peninsula Dermatology Medical Group in Burlingame, California, said.

“I have never put a patient on neoadjuvant vismodegib with the intent of it being neoadjuvant, but I have put patients on vismodegib which became neoadjuvant when they converted [to resectable disease] and went to surgery,” Arron added. “This patient population is challenging because of other psychosocial access to care issues that contribute to locally advanced BCC and so they are frequently very resistant to surgery. When I start [a patient on] vismodegib, I’m often thinking this may wind up bringing the patient to surgery, but in a formal sense, I’ve never declared it as such because of the labeled indications.”

The NCCN guidelines note that there is no preferred regimen in the neoadjuvant setting for locally advanced BCC although the hedgehog inhibitor vismodegib is a recommended regimen and the PD-1 inhibitor cemiplimab is useful in certain circumstances. Similar recommendations are seen in the adjuvant setting with sonidegib (Odomzo), which is also listed as a recommended regimen for nodal as well as locally advanced disease in addition to vismodegib.¹

The activity of neoadjuvant vismodegib was evaluated in the phase 2 VISMONEO trial (NCT02667574) conducted in France. The results showed that 80% (95% CI, 67%-90%) of patients with locally advanced BCC who received oral vismodegib 150 mg once daily (n = 55) for 4 to 10 months prior to planned surgery had a downstaging procedure. Additionally, the overall response rate was 71% (95% CI, 59%-88%) among patients (n = 55), and at 3 years 36% (95% CI, 22%-51%) of patients had disease recurrence. In terms of safety 98.2% (n = 54) of patients had at least 1 treatment-related adverse effect ([AE] grade 1/2, n = 42; grade ≥3, 11). Patients experienced 6.4 (± 3.6) AEs on average, the most common of which were dysgeusia, muscle spasms, alopecia, fatigue, and weight loss.²

“We all know that vismodegib and sonidegib are hard medications to tolerate long term—I have yet to have a patient who’s been on [a hedgehog inhibitor] for years and felt like they tolerated it well,” Anne Lynn S. Chang, MD, founding director of the Advanced Basal Cell Carcinoma Clinic, director of Dermatologic Clinical Trials, and a professor of dermatology at Stanford Medicine in California, said. “Patients almost invariably go off it within 6 months to a year for one reason or the other. I also think [if] we engage patients, show them that we can help them shrink the tumor down a little bit, and then reevaluate things, we can then rediscuss surgery and re-employ surgery.”

Patel noted he gets asked by head and neck surgeons about using a neoadjuvant hedgehog inhibitor and another doctor agreed they are asked as well, but John M. Strasswimmer, MD, PhD, FAAD, FACMS, a board-certified dermatologist and fellowship-trained Mohs surgeon at Dermatology Associates of the Palm Beaches in Florida, expressed concerns with using neoadjuvant hedgehog inhibitors.

“It’s rare for me to have a patient with 1 locally advanced BCC, usually they have multiple tumors,” Strasswimmer said. “Part of my concern has been that the hedgehog pathway inhibitors are relatively slow-acting medications. To get somebody [clear of tumors requires] months of therapy and if you need drug holidays in between it’s a long time. Meanwhile, they have other lesions that might not be BCCs, and some of my colleagues have said, ‘Let’s clean the tumors up with a hedgehog inhibitor, and then whatever’s left we’ll biopsy.’ Early on, 2 of those patients in whom we wanted to do that, fortunately, we biopsied very aggressively and found 2 synchronous invasive amelanotic melanomas. Therefore, I’ve been very concerned about putting a patient on a systemic therapy that’s going to address 1 of the 3 tumors that we worry about—basal cell, squamous cell, and melanoma. That’s been a limiting factor for me to use a hedgehog inhibitor [as] neoadjuvant therapy in these patients.”

Insurance and Staying on Label Affects PD-1 Inhibitor vs Hedgehog Inhibitor Decision in BCC

The participants also discussed staying on label as an important factor when deciding between neoadjuvant vismodegib and cemiplimab as cemiplimab is indicated for the treatment of patients with locally advanced or metastatic BCC who have been previously treated with a hedgehog inhibitor or for whom a hedgehog inhibitor is not an appropriate option.³ Michael R. Migden, MD, a professor at The University of Texas MD Anderson Cancer Center in Houston, highlighted that indications vary in the United States vs the European Union on when to use a hedgehog inhibitor.

However, Patel added, “We know from the melanoma literature that starting with immunotherapy, even if you switch to targeted therapy, is superior than starting [with other agents].” Migden countered, “I hear that but how do you do it and stay on label? How do you sign the [prescription] and then insurance looks at the label?”

When Patel asked the group who had gone straight to cemiplimab for a patient with advanced BCC without trying a hedgehog inhibitor first for any reason, 5 of the 11 faculty noted they had done so. Chang noted that many oncologists she works with are turning to PD-1 inhibition with cemiplimab first because they believe it works faster in shrinking tumors.

“I have a different perspective. I believe I have the published record for the fastest cure histologically and clinically with a hedgehog inhibitor, which is 2 weeks. We published those [data] in JMIR Dermatology and now I have the longest [record for] continuous treatment—which is more than 11 years nonstop with a patient on a hedgehog inhibitor—so patients can do it, but I’ve changed [my thoughts] about this a little. Recently, I started a patient not on a hedgehog inhibitor, but [instead went] straight to cemiplimab because the patient had a large tumor on the trunk [that was] BCC. Also one of the commonly reported metastatic locations [of BCC] is the lung and the patient had a questionable lung finding. In discussion with the oncologist, the concern was if this could be a second primary lung tumor for which cemiplimab has an indication or a metastatic basal cell [tumor on] the lung. That’s why we skipped the hedgehog inhibitor in that patient,” Strasswimmer said.

However, Strasswimmer noted that if opting for hedgehog inhibitors it is important to be mindful of the less common AEs associated this treatment class such as electrolyte imbalances, especially in older patients, as he had a patient hospitalized with a sodium of 199 [mEq/L].

From a community perspective,Rebecca I. Hartman, MD, MPH, FAAD, chief of Dermatology at the VA Boston Healthcare System and director of Melanoma Epidemiology at Brigham and Women’s Hospital as well as an assistant professor at Harvard Medical School in Massachusetts, noted, “Some things are harder, and some things are easier at the VA. One nice thing is instead of trying to battle with insurance, you’re playing with the same team. I know our pharmacist, we know what to write, and we can message them and have a discussion. [If the] first-line treatment is not the right treatment for our patient, then we’re able to get the appropriate treatment. There are some quirks in the VA sometimes about pricing—not specifically for this indication but for other indications—about what the preferred biologic is, [and] the VA does a cost analysis for immunotherapy for cancer treatment.”

Diving Into Multidisciplinary Care for Patients With CSCC

Dermatologists Highlight Key Instances Where Multidisciplinary Care Is Imperative

Findings from a phase 2 non-randomized trial (NCT04154943) revealed that 51% (95% CI, 39%-62%) of patients with stage II to IV CSCC (n = 79) who received neoadjuvant cemiplimab achieved a pathological complete response (pCR). Additionally, 13% (95% CI, 6%-22%) of patients experienced a major pathological response.4One-year follow-up from the trial demonstrated that the estimated 12-month event-free survival (EFS) rate was 89.0% (95% CI, 79.1%-94.3%); the median EFS was not reached (not estimable [NE]-NE).⁵ Regarding safety, 18% of patients had grade 3 or higher AEs during the study period and 1 death due to congestive heart failure exacerbation occurred, which may have resulted from treatment with cemiplimab.⁴

When considering neoadjuvant cemiplimab for patients with CSCC, which is cited as useful in certain circumstances by the NCCN, faculty noted that a multidisciplinary approach is critical. Dermatologists among the faculty cited they wanted close collaboration with oncologists to feel comfortable prescribing immunotherapy and many noted they are not allowed to prescribe it, making the collaboration key.

“What insurance company is going to cover it because I said that I would like to prescribe it?” Hartman asked. “University of California San Francisco wouldn’t let me write an order for cemiplimab when I was on faculty there and part of the cancer center, so what outpatient infusion center is going to take my order in the community?”

Another dermatologist noted he gets an oncologist to cosign with him to get the order for cemiplimab accepted. In addition to prescribing the PD-1 inhibitor, multidisciplinary care is key between surgeons and oncologists for various reasons but may take a longer period. Arron noted that her patients might wait longer for the medical oncology consultation to get started on treatment with a wait time of approximately 2 weeks at her practice.

“In my area, in private practice, I have patients who are on multiple insurance plans and come from a broad geographical area, so I work with a lot of different oncologists,” Strasswimmer said. “But I’ve worked hard [towards a] solution which is to [work with] at least one oncologist who understands that CSCC is a bad disease that needs to be addressed quickly. He greenlights [the patients] into his practice very soon.”

Trials are also currently recruiting in the adjuvant setting and include the phase 3, randomized, double-blind, placebo-controlled C-POST (NCT03969004) and KEYNOTE-630 (NCT03833167) studies evaluating immunotherapy in patients with high-risk CSCC following surgery and radiation therapy. C-POST examines adjuvant cemiplimab vs placebo, whereas KEYNOTE-630 examines adjuvant pembrolizumab (Keytruda) vs placebo with primary end points of disease-free survival and recurrence-free survival, respectively.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Basal cell skin cancer, version 3.2024. Accessed April 9, 2024.
2. Bertrand N, Guerreschi P, Basset-Seguin N, et al. Vismodegib in neoadjuvant treatment of locally advanced basal cell carcinoma: first results of a multicenter, open-label, phase 2 trial (VISMONEO study): neoadjuvant vismodegib in locally advanced basal cell carcinoma. EClinicalMedicine. 2021;35:100844. doi:10.1016/j.eclinm.2021.100844
3. Libtayo. Prescribing information. Regeneron Pharmaceuticals, Inc; 2024. Accessed April 9, 2024. https://www.regeneron.com/downloads/libtayo_fpi.pdf
4. Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab for stage II to IV cutaneous squamous-cell carcinoma. N Engl J Med. 2022;387(17):1557-1568. doi:10.1056/NEJMoa2209813
5. Gross ND, Miller DM, Khushalani NI, et al. Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study. Lancet Oncol. 2023;24(11):1196-1205. doi:10.1016/S1470-2045(23)00459-X