Although basal cell carcinoma (BCC) generally has a good prognosis, improving tolerance to targeted Hedgehog (HH) inhibitors and optimizing second-line treatment with immune checkpoint inhibitors are important for the small subset of patients who develop locally advanced or metastatic disease, according to panelists who participated in a virtual 

 Scientific Interchange and Workshop on October 9, 2020.

The session, which was moderated by Ragini Kudchadkar, MD, a medical oncologist at Winship Cancer Institute of Emory University, included oncologists and dermatologists who specialize in the management of cutaneous malignancies.

BCC is the most common malignancy encountered in humans, with over 4 million cases diagnosed per year in the United States.

 The incidence of BCC has been increasing in recent years, likely due to a combination of improved detection, increased sun exposure, and longer life expectancy.

A large retrospective analysis of 3.2 million commercially insured persons followed in the Kaiser Permanente Northern California database identified 221,624 cases of BCC diagnosed between 1998 and 2012 (N = 147,093 unique persons).

 When the number of cases was stratified by year (allowing a single person to contribute no more than 1 BCC case per year) and then standardized to the 2010 US census population according to age, sex, and race, the overall incidence increased by approximately 17% between 1998 and 2012 (from 513 cases per 100,000 person-years in 1998 to 600 cases per 100,000 person-years in 2012).

 When multivariable regression models were used to determine the effect of age, sex, and race/ethnicity on incidence of BCC cases identified in the year 2012, the rates were significantly higher in persons aged 65 to 79 and at least 80 years versus 40 to 64 years, in men versus women, as well as in Whites compared with Hispanics, Asians, Blacks, and those considered to be multiracial.

Most cases of BCC have a very favorable prognosis and a high cure rate.

 However, some subtypes of BCC exhibit a more aggressive course and can be resistant to standard treatment modalities.

 The percentage of BCC cases having an aggressive histology is widely variable, with reports ranging from 2.5% to 44%.

BCC that is metastatic at diagnosis is extremely rare.

 If metastatic, BCC can involve large areas of soft tissue, cartilage, and bone and lead to substantial disfigurement.

 Because of the rarity of metastasis in BCC, the tumor-node-metastasis staging system so commonly applied to other cancers is rarely, if ever, used with BCC.

 Estimates currently cited in the literature for the incidence of metastatic BCC (mBCC) rely on studies dating back to the 1970s and 1980s, and most authors cite an incidence for mBCC of less than 0.1%, with other authors citing a range from 0.0028% to 0.55%.

 Although most cases of nonmetastatic BCC are completely curable, mBCC has historically been associated with a very poor prognosis and few treatment options.

Exposure to UV radiation from the sun is considered to be the primary environmental risk factor for development of BCC, with intense, intermittent exposure and a history of frequent sunburns being associated with the highest risk compared with smaller amounts accumulated continuously over time.

Other risk factors for BCC include light hair (red or blond), light eyes (blue or green), and fair skin; exposure to ionizing radiation therapy (RT) for cancer treatment at a young age; long-term exposure to arsenic (via contaminated water, food, or medications); immunosuppression (HIV infection or immunosuppressive medication following solid organ transplantation); phototherapy using oral methoxsalen (used for skin conditions, such as psoriasis); and certain genetic syndromes, such as albinism, xeroderma pigmentosum, Rombo syndrome, Bazex syndrome, and Gorlin syndrome.

 Kudchadkar noted that, in her experience, the majority of cases are related to sun exposure, especially in patients with red hair or light skin.

BCC is characterized by abnormally proliferative keratinocytes derived from the basal cell layer of the epidermis.

 Pathohistologic subtypes of BCC include nodular, superficial, morpheaform (also known as sclerosing or desmoplastic), infiltrative, fibroepithelial, micronodular, and basosquamous (also known as metatypical or mixed BCC).

 Of note, multiple histopathological subtypes can colocalize within the same lesion.

 Nodular and superficial BCC are the most common, have less aggressive growth patterns, and have a lower risk of recurrence.

 The other subtypes are less common, have more aggressive growth patterns, and have a higher risk of recurrence.

 The reported prevalence of BCC having an aggressive histology ranges from 2.5% to 44% in large studies of referral centers.5 According to 

, a medical oncologist at Johns Hopkins University, the histologic subtype may play a factor in treatment decision-making, particularly for aggressive subtypes that may respond better to systemic therapy than topical treatment. However, Lipson cautioned against making “blanket statements” about each subtype and emphasized the importance of consulting with dermatology colleagues when developing a treatment strategy.

Given a patient’s constellation of clinical and pathological risk factors, the risk of recurrence forms the basis of treatment selection.

 The National Comprehensive Cancer Network (NCCN) guidelines classify any of the following as risk factors for high likelihood of recurrence: (1) a large lesion (≥ 20 mm in a low-risk area [eg, the trunk and extremities] or ≥ 10 mm in a medium-risk area [eg, the cheeks, forehead, scalp, neck, pretibia], (2) a lesion of any size in a high-risk area (eg, mask areas of the face [the central face, eyelids, eyebrows, periorbital area, nose, lips, chin, mandible, preauricular and postauricular skin, temples, and ears], genitalia, hands, or feet), (3) a lesion with poorly defined borders, (4) a lesion that has already recurred at least once, (5) immunosuppression, (6) a lesion that occurs at a site of prior RT, (7) aggressive pathohistology, and (8) perineural involvement.

 For patients with high-risk tumors (ie, having ≥ 1 of the aforementioned risk factors for recurrence), the NCCN guidelines recommend any of the following primary treatment options: (1) Mohs micrographic surgery (MMS), (2) excision with complete circumferential peripheral and deep margin assessment with permanent section analysis or intraoperative frozen section analysis, or (3) standard excision with wider surgical margins than what is used for low-risk disease and postoperative margin assessment with linear or delayed repair.

For high-risk patients who are nonsurgical candidates, RT should be utilized.

 If curative RT is not feasible in a high-risk, nonsurgical candidate, systemic therapy with an HH pathway inhibitor (vismodegib or sonidegib) can be attempted.

 Primary treatment recommendations for low-risk patients (ie, those without risk factors for recurrence) include (1) electrodessication and curettage (ED&C) and (2) standard excision with 4-mm clinical margins and postoperative margin assessment and second-intention healing, linear repair, or skin grafts. For low-risk, nonsurgical candidates, RT therapy is recommended.

, Mohs surgeon and cutaneous oncologist at The University of Texas MD Anderson Cancer Center, indicated that due to the increased availability of targeted immunotherapies, he does not typically consider RT a primary treatment modality for high-risk patients. However, Migden stated that he occasionally uses radiation in the adjuvant or palliative care setting for patients with large lesions and perineural involvement. 

, dermatologist, Mohs surgeon, and clinical investigator in private practice in Charleston, South Carolina, noted that superficial RT may be used relatively frequently in the community setting.

Anatomic location of BCC also plays a factor in rate of recurrence, with BCC lesions located on the head and neck (eg, face or ear, the “H zone,” or mask area) associated with more aggressive tumor behavior and a higher recurrence rate than those in other locations (eg, trunk and extremities).

 This observation may be related to several factors, including (1) the more aggressive morpheaform and nodular subtypes occurring more frequently on the face, where greater sun exposure usually occurs (the less aggressive superficial BCC occurs more frequently on the trunk),

(2) inadequacy of initial treatment on the cosmetically sensitive areas of the face, and (3) cancerous cells in lesions on the face having easier access to bone and cartilage.

The panelists agreed that a multidisciplinary team is critical for the management of patients with locally advanced BCC (laBCC) or mBCC, and although these account for a small proportion of BCC, Kudchadkar pointed out that even a small percentage of 4 million cases represents a “fair number of cases.” 

, a medical oncologist from the University of Colorado, said that his team has a multidisciplinary cutaneous oncology tumor board that includes head and neck surgeons, surgical oncologists, Mohs surgeons, and radiation oncologists. He said that he often receives referrals from the dermatologist, Mohs surgeon, or surgical oncologist after they have assessed the resectability of the patient’s disease.

, a dermatologist at Duke University, said that she and her dermatology colleagues give an HH inhibitor with curative or neoadjuvant intent based on tumor response to patients with laBCC having legions that are not easily surgically resectable. “Depending upon the response to the HH [inhibitor], whether it’s partial or complete, stable or progressive, we consider other treatment options, such as radiation; potentially, surgery; and then—now—immunotherapies,” she said. Kudchadkar said that the management approach is similar at her institution (Emory), although patients may be referred to a medical oncologist if they are started on an HH inhibitor.

Schlesinger noted that the multidisciplinary treatment approach model is often challenging to manage in private practice because there is no defined multidisciplinary team for BCC. However, he stated that he has multiple options for contacts as needed and said that he refers patients to surgical oncology at his institution or a local medical university if he feels that the patient would be better served by those colleagues.

“We’ve put together a group that we employ,” said Schlesinger. “I’ve got…these people on my speed dial on my cell phone when I want to get hold of somebody…but nobody has a defined time to get together, which I think is a big challenge.”

Surgical techniques for BCC include ED&C, cryosurgery, excision with postoperative assessment of margins, and MMS.

 When performed by highly skilled surgeons, these techniques have 5-year cure rates of approximately 95% or higher (91%-97% for ED&C, > 98% for excision with postoperative margin assessment, and 99% for cryosurgery).

 MMS has been associated with 5-year cure rates of 95% to 99% (5-year recurrence rate of 1.0% for primary BCC and 5.6% for recurrent BCC).

Migden emphasized that a surgeon’s skill and selection of appropriate techniques are critical. “Unless you have a very small superficial tumor, I think that ED&C is especially operator dependent,” he noted. “I see a lot of people that have lot of rapid ED&Cs in a very high-paced kind of clinic where it’s going through the motions, but it wouldn’t be the same as me doing one. I do cryo[surgery] and curettage instead of ED&C, but I’m extremely thorough in going up over the lip of the clinical lesion onto the normal skin and really being meticulous about it.”

, a Mohs surgeon in private practice in Phoenix, Arizona, cautioned about the potential discordance between the pathology on biopsy and specimens obtained from MMS, particularly in tumors with mixed histology. She estimated that up to one-third of histology on biopsy is discordant with the histology of the specimen. “Many people may be thinking they’re doing an ED&C on a superficial BCC, which actually is probably nodular or nodular infiltrative,” she said.

While surgery is the primary treatment of choice in many cases, particularly for low-risk BCC, determining tumor resectability is not always straightforward, said the panelists. Zeitouni shared that she typically obtains imaging to assess for involvement of bone and invasion into major nerves and arteries. Migden added that palpation and “using all your senses,” in addition to imaging and even ultrasonography, are important. “Imaging doesn’t have enough granularity to show all cases of bone involvement,” he said. “Sometimes you see micropitting or gross pitting when you get down to the bone, even when the imaging says ‘no bony involvement.’ ”

Some of the panelists noted that they also consider positron emission tomography (PET) imaging for cases with extensive disease in which metastasis is suspected, and 

D, a medical oncologist at Inova Schar Cancer Institute, said that he performs computed tomography (CT) or PET-CT in patients who have had nodal metastases or extensive BCC. Migden pointed out that the histology of many mBCCs has shifted to a basosquamous type, and Kudchadkar added that repeat biopsy and evaluation of the lesion should be considered after metastases.

“A lot of the biopsies of [metastases] end up being way more squamatized than the original skin lesions,” he said. “A lot of my head and neck surgeon colleagues believe that if it’s metastatic, almost always it’s become a squam[ous type] in terms of its behavior.”

For borderline resectable cases, the panelists said that the ability to achieve clear margins and adequate reconstruction are the primary considerations in the decision to pursue surgery. In the sample clinical case of an 88-year-old man with an infiltrative BCC with perineural invasion on the lateral aspect of the nose, Schlesinger posited that the depth of invasion and status of the involved nerves also need to be considered. Zeitouni added that the overall functional status of the patient (but not specifically age) should also factor into the patient’s surgical eligibility. However, Migden pointed out that this and other borderline resectable cases “can go either way” in terms of cosmetic and oncologic outcomes. “Even with imaging, sometimes it’s hard to know where you’re going to end up because of the lack of granularity from imaging compared to what you see on histology,” he said.

The sonic HH (SHH) signaling pathway is involved in proper maintenance, renewal, and regeneration of tissues. Mutations in this pathway have been identified as a key driver in the pathogenesis of BCC.

The protein patched homologue 1 gene (PTCH1) codes for the SHH receptor, and mutations have been observed in 30% to 90% of cases of sporadic BCC.

 Vismodegib (Erivedge) and sonidegib (Odomzo) are approved for laBCC, and vismodegib is also approved for mBCC.

Approval of vismodegib was based on results from the ERIVANCE trial, which showed response rates of 43% and 30% in patients with laBCC and mBCC, respectively, who were ineligible for surgery.

Adverse events (AEs) reported in at least 20% of patients included muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, decrease in appetite, and diarrhea.

Sonidegib was approved at the 200-mg dose based on results from the phase 2 BOLT trial, which showed similar objective response rates with the 800-mg and 200-mg doses (36% and 34%, respectively) and fewer AEs leading to dose interruptions or reductions or discontinuation of treatment with the 200-mg dose in patients with laBCC or mBCC who were not eligible for surgery.

 Similar to vismodegib, the most common AEs with sonidegib were muscle spasms, dysgeusia, alopecia, nausea, elevated serum creatine kinase levels, weight loss, and fatigue.

Serious AEs occurred in 14% of patients in the 200-mg group and 30% of patients in the 800-mg group.

 However, Lipson noted that antitumor responses can be maintained even after repeated interruptions for toxicity reasons, which may be “reassuring” for patients and providers. “Oftentimes, we rely on that as a…way to cheerlead patients through the toxicities,” he said.

Although many panelists commented that they have not noticed many differences between the 2 drugs in terms of efficacy and AE profiles, Migden cautioned that subtle differences in the design of the ERIVANCE and BOLT trials prevent accurate head-to-head comparison of the 2 drugs. Migden noted, however, that the longer half-life of sonidegib could allow for longer “drug holidays” for relief from AEs. He also pointed out that de novo or acquired resistance to one drug does not necessarily indicate resistance to the other one, suggesting that switching to the other HH inhibitor is worth trying if the patient is not responding to the first one. Jang added that gene mutations, such as those in the smoothened gene, could confer primary resistance to vismodegib but not sonidegib, and this information (if available) could inform the decision to start with sonidegib. Zeitouni added that patients taking CYP3A inhibitors or inducers should avoid sonidegib because of potential drug interactions.

Finding the optimal duration of treatment with HH inhibitors has been challenging because patients who appear to have a complete clinical response often experience tumor regrowth eventually, according to Migden. “[The tumors] don’t grow while you’re treating them,” he said. “They just lie and wait for the time when you take the HH inhibitor away, and then they start growing again.”

However, the panelists indicated that they generally do not continue treatment after the patient achieves a complete clinical response because of the AE profile. Kudchadkar said that in her experience, HH inhibitors become more difficult to tolerate over time and lead to reductions in quality of life. Similarly, 

, a medical oncologist at Northwestern University, said that she often stops treatment after a negative biopsy (while continuing to monitor the patient closely) because her patients generally find the drugs to have unpleasant effects.

The panelists discussed some of the remedies they use for management of AEs with HH inhibitors. Zeitouni said that giving L-carnitine 2 weeks prior to starting the HH inhibitor can help reduce the intensity of muscle spasms and improve drug tolerance. Migden and Lipson noted that hot sauce can often improve taste sensation. Drug holidays, medical marijuana, and shorter durations of therapy were also cited as potential strategies to improve management. Lipson and Kheterpal said that they monitor patients regularly with laboratory testing for electrolytes and creatine phosphokinase levels every 4 to 6 weeks during the first few months of treatment. Kheterpal noted that dosing on alternate days can often minimize the severity of AEs, particularly in the first 6 to 8 months.

Immune checkpoint inhibition has been proposed as a promising strategy for BCC because of its high rate of cancer-testis antigen expression

and high tumor mutational burden due to UV light-induced sun damage.

 In addition, multiple checkpoint inhibitors have demonstrated efficacy in Merkel cell carcinoma (MCC; reviewed in Samimi, 2019

)and cutaneous squamous cell carcinoma (CSCC; reviewed in Patel and Chang, 2019

Pembrolizumab (Keytruda), a programmed cell death protein-1 (PD-1) inhibitor, has demonstrated efficacy in multiple cancer types, including MCC18 and CSCC.

 A proof-of-principle, nonrandomized, open-label study showed a response rate of 38% (6 of 16 patients) with pembrolizumab given with or without vismodegib in patients with advanced BCC, with a median duration of response of 67.3 weeks and 1-year progression-free survival (PFS) and overall survival (OS) of 70% and 94%, respectively.

 No life-threatening AEs or deaths were reported; one of the 3 grade 3 AEs (hyponatremia) was attributed to pembrolizumab.

 However, the response rate in patients who received pembrolizumab and vismodegib was similar to that in patients who received pembrolizumab alone (29% vs 44%, respectively).

, a medical oncologist at Johns Hopkins Hospital, and Lipson indicated that they typically discontinue the HH inhibitor when they use pembrolizumab off-label for patients who have disease progression on vismodegib.

Cemiplimab (Libtayo) is a PD-1 inhibitor approved for patients with metastatic or locally advanced CSCC who are not candidates for curative surgery or RT.

The trials leading to approval in this setting (NCT02383212 and NCT02760498) showed objective response rates of 50% in the expansion cohorts of the phase 1 study, which included patients with locally advanced or metastatic CSCC, and 47% in the phase 2 study, which included patients with metastatic CSCC.

Based on these results—and that patients with laBCC have no approved therapeutic option after progression on HH inhibitor therapy—a pivotal phase 2 study (NCT03132636) investigated cemiplimab in patients with mBCC (group 1) or laBCC (group 2) who had disease progression on HH inhibitor therapy, were intolerant to prior HH inhibitor therapy, or had no better than stable disease after 9 months on HH inhibitor therapy.

 In the primary analysis of the laBCC cohort presented at the 

European Society for Medical Oncology’s Virtual Congress 2020

, the study population (N = 84) had the following characteristics: median age of 70 years, 66.7% male, 89.3% whose primary tumor site was the head and neck, and 71.4% who had progression of disease on HH inhibitor therapy.

Overall response rate, as assessed by independent central review, was 31%, including 5 complete responses (CRs) and 21 partial responses (PRs), with an estimated 85% of responses ongoing at 12 months.

 The estimated median PFS was 19.0 months, and the median OS was not reached.

Zeitouni noted that, although only 5 patients had a CR, the study findings were “clinically significant,” given the response rate and the estimated 12-month progression-free and OS probabilities of 56.5% and 92.3%, respectively.

A preliminary analysis of the cohort with mBCC was published in a news release on May 5, 2020, and showed an objective response rate of 21% (n = 28) and an estimated duration of response that exceeded 1 year in 83% of responders.

 Although the response rate was numerically lower in the metastatic cohort, the panelists cautioned against drawing conclusions about a lower response rate with metastatic disease, considering the low number of patients in the metastatic cohort relative to the locally advanced cohort. Migden added that the disease burden and prognosis of patients with metastatic disease can vary considerably, which may also affect response to cemiplimab.

“There’s such a big difference between the really difficult-to-budge metastasis, such as the bony lesions, and the ones that are ‘easier’ metastatic lesions,” he said. “With small numbers, it really depends on what the composition of that smaller cohort is in terms of queuing the data.”

Lewis added that although the data in BCC are encouraging, the time to response tends to be slower with BCC than with squamous cell carcinoma (SCC), in his experience. “With SCC, we actually see very dramatic early responses,” he said. “These [in BCC] were somewhat delayed, but certainly there is a significant proportion of patients who derive benefit from PD-1 in this disease setting.”

Migden speculated that histologic architectural differences and lower levels of tumor-infiltrating lymphocytes in BCC compared with CSCC may alter the local immune response environment, which may contribute to the slightly lower and more gradual rate of response in patients with BCC. Nevertheless, Kudchadkar said that these data make a strong case for cemiplimab as second-line therapy after HH inhibitor therapy in patients with laBCC or mBCC.

The most common treatment-emergent AEs identified in the cohort with laBCC were fatigue (25%), pruritus (14%), and asthenia (14%).

 Immune-related AEs occurred in 25% of patients, with hypothyroidism (10%) and colitis (6%) being the most common.

Kudchadkar said that although many of these AEs are considered typical of PD-1 inhibitors, the adrenal insufficiency observed in 2 patients, while uncommon, may introduce the question of whether giving cemiplimab is worth risking permanent adrenal insufficiency in patients with locally advanced disease.

Kheterpal stated that although the trial results were promising, the patient’s prior response (or lack of response) to HH inhibitors may make a difference in the decision to use cemiplimab. “If you have [an] initial response to [an HH inhibitor] and the lesion becomes surgically resectable or [can be] treated with radiation, that [strategy] may be a reasonable option and may avoid some of these adverse effects long term,” she said.

The panelists also pointed out that, similar to the trial with pembrolizumab,

 the study did not show an association between tumor PD-L1 expression and response to cemiplimab. “It’s a hot topic that PD-L1 expression by tumor may not be the most relevant assessment, that PD-L1 expression in immune cells may actually be far more important than in [the] tumor,” said Migden.

Although the panelists agreed that they do not generally test for PD-L1 expression, Chandra said that she obtains next-generation sequencing for a select group of her patients with advanced BCC. “The question is, do [their tumors] have any targetable genomic alterations that we can then target?” she said. “Despite [the tumors] having a large mutation[al] burden, we often don’t have something that’s quite targetable. But we generally discuss those cases at our molecular tumor board to see if there are any other treatment options for them.” Similarly, Sharfman said that he obtains next-generation sequencing to assess for tumor mutational burden, which may influence his decision to give pembrolizumab off-label in the second-line setting. Migden stated that longer follow-up data are needed to determine whether some patients may achieve a PR or CR several months after starting cemiplimab, reiterating that the architectural characteristics of BCC may make it slow to respond to immune-targeted therapy. “A lot of people in practice try a few months of anti–PD-1 [therapy] and then make a determination of whether it’s working or not,” he said. “I think in these nonmelanoma skin cancers, we may actually need a lot longer than that.”

Nivolumab with or without ipilimumab for laBCC or mBCC is being studied in an ongoing phase 2 open-label trial (NCT03521830). Nivolumab as a single agent is being given to patients who are PD-1 inhibitor na.ve and have unresectable disease previously treated with up to 2 prior systemic therapies (cohort A). Nivolumab in combination with ipilimumab is being given to patients with disease progression after being on PD-1 inhibitor therapy (cohort B).

 The primary outcome measure is objective response rate, and the secondary outcome measures include PFS, duration of response, and OS.

 Lipson, principal investigator of the study, added that although multiple other trials of combination therapy for BCC are ongoing across the country, identifying which patients are likely to respond to PD-1 inhibitor therapy and biomarkers that predict response are important for selecting which patients should receive PD-1 inhibitor therapy.

The panelists discussed the possibility of using PD-1 inhibitor therapy in the neoadjuvant setting. “I think the concept has great promise, given that we’ve seen successes in other skin cancers, including melanoma and MCC,” said Lipson. “It’s being investigated actively right now in CSCC, and so there’s no reason it couldn’t be used, even for a small percentage of the patients with BCC.” However, he added that determining efficacy is difficult because use in the neoadjuvant setting is rare for patients with BCC and the uptake on an off-label basis is low. Jang added that when considering therapy in the neoadjuvant setting, more data are needed on the time to response to PD-1 inhibitor therapy and HH inhibitors, respectively, and whether pathologic response and recurrence-free survival are correlated.

The panelists also discussed the possible effect of surgery on response to immune checkpoint inhibitor therapy. Migden noted that he has observed lower response rates in patients who have undergone multiple surgeries, which he proposed may be related to the increase in regulatory T cells and a decrease in the local immune response with surgery or the local effector cells brought in by the large amount of scar tissue that surrounds the tumor nest. He suggested that the tumors that recur after surgery may have more aggressive biologic characteristics and return “if you don’t get every cell.”

At the end of the discussion, the panelists concluded that although the data are promising on HH inhibitors and checkpoint inhibitor therapy, more treatment options, such as intralesional therapies, oncolytic viruses, and therapeutic combinations and sequences, will be important to accommodate the high heterogeneity among patients with laBCC or mBCC.

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Articles

Although basal cell carcinoma generally has a good prognosis, improving tolerance to targeted Hedgehog inhibitors and optimizing second-line treatment with immune checkpoint inhibitors are important for the small subset of patients who develop locally advanced or metastatic disease. 

Updates and Advances in Basal Cell Carcinoma | Supplements and Featured Publications

Updates and Advances in Basal Cell Carcinoma