Hedgehog pathway inhibitor real-world treatment patterns in patients with basal cell carcinoma: a claims-based analysis

Basal cell carcinoma (BCC) is the most common type of non-melanoma skin cancer, accounting for approximately 70–80% of cases [1]. In the USA, more than 2 million patients are diagnosed with BCC annually [2,3]. Most cases of BCC are treated by surgery alone, but approximately 1% of patients develop advanced BCC (locally advanced or metastatic) and require additional systemic therapy such as radiation or chemotherapy [2,4–10]. Activation of the Hedgehog signaling pathway resulting from genetic mutations has been identified as a key contributor to BCC formation [11].

Hedgehog pathway inhibitors (HHIs), such as vismodegib (approved in 2012 in the USA [12]) and sonidegib (approved in 2015 in the USA [13]), were the first treatments approved for use in patients with advanced BCC. More recently, cemiplimab, a PD-1-blocking antibody, was approved for use in patients with locally advanced or metastatic BCC previously treated with HHIs or for whom an HHI is not appropriate (approved in 2021 in the USA as cemiplimab-rwlc [14]). Until the approval of cemiplimab, treatment recommendations beyond HHIs were limited to noncurative surgery or radiation, along with clinical trial participation.

While HHIs are efficacious in the treatment of advanced BCC, they are associated with significant toxicities. The primary analysis of the pivotal trial of vismodegib once-daily treatment, ERIVANCE BCC, reported objective responses for 43% of patients with locally advanced BCC and 30% of patients with metastatic BCC [15]. The primary analysis of the pivotal study of sonidegib once-daily treatment, BOLT, reported objective responses for 39% of patients with locally advanced BCC and 17% of patients with metastatic BCC [16]. Close monitoring for toxicities during HHI therapy is recommended [17,18], and both reactive interruption (discontinuing HHI treatment for 8 weeks when adverse reactions occur [19]) and preventive interruption (prospectively alternating between HHI treatment for 8 or 12 weeks, with scheduled 8-week interruptions [20]) have been investigated as treatment strategies to improve HHI tolerability. The use of modified or reduced dosages may also improve tolerability and allow continuation of HHI therapy when adverse reactions occur [21–23].

There is currently no consensus recommendation on the optimal duration of use of HHI, and few studies have investigated patterns of HHI use among real-world patients with BCC [24]. The objective of this study was to describe HHI treatment discontinuation and reinitiation patterns among patients with BCC in the real-world setting.

Patients & methods

Data source, study design & study population

This retrospective cohort study used healthcare insurance claims and enrollment data from IBM MarketScan^® Commercial and Medicare Supplemental databases, which include approximately 30 million enrollees annually across the USA. MarketScan data are deidentified; thus ethics committee approval was not required. The study population included new users of HHIs (identified using National Drug Codes for vismodegib or sonidegib) between 1 January 2013 and 30 June 2019 (data cutoff date). The index date was the patient’s first HHI dispensation (i.e., the date of initiation) in this period (Figure 1). Patients were required to: have at least 6 months of continuous enrollment pre-index (baseline period); be aged 18 years or older on the index date; have at least one diagnosis claim for BCC (International Classification of Diseases [ICD]-9: 173.x; ICD-10: C44.x) in the baseline period; and have no HHIs dispensed during the baseline period. Patients were followed up from the index date until whichever of the following occurred first: observance of the outcome of interest, the end of enrollment or the end of the study period.

Patterns of HHI discontinuation & reinitiation

Instances of HHI treatment discontinuation and reinitiation following the index HHI dispensation were identified. The date of HHI treatment discontinuation was the date of expiration of the last prescription day’s supply, with a 60-day grace period (i.e., permissible gap) allowed between the last day’s supply and the subsequent dispensation. A 60-day grace period was selected because HHIs are generally dispensed in a 30-day supply and treatment interruptions for up to 8 weeks were allowed to manage toxic effects in clinical trials of vismodegib [15,16,25,26]. When a dispensation occurred before exhaustion of the previous dispensation day’s supply, it was assumed that the patient did not stockpile the drugs and started the new prescription on the date of dispensation. Reinitiation was defined as any HHI dispensation after the first treatment discontinuation. Among patients who reinitiated HHI treatment, we also identified the first subsequent discontinuation, defined in the same manner as the first discontinuation.

Type of HHI use

The patient’s first episode of HHI use was categorized as follows: primary therapy (no surgery or radiation within 60 days pre- or post-index); likely adjuvant therapy (surgery or radiation 60 days pre-index); likely neoadjuvant therapy (surgery or radiation 60 days post-index); or likely adjuvant and neoadjuvant therapy (surgery or radiation both 60 days pre-index and 60 days post-index). For these analyses, surgery and radiation for BCC were identified using ICD-9/ICD-10 procedure, Current Procedural Terminology or Healthcare Common Procedure Coding System codes.

Other variables

Demographic characteristics including age, sex, region and payor were determined at index date. Locations of BCC were determined using ICD-10 Clinical Modification codes during the baseline period. Baseline Charlson comorbidity index (Quan version [27,28]) was calculated without considering malignancy, which was present in all patients.

Statistical analysis

Patient characteristics on the HHI index date were summarized using descriptive statistics and frequency tabulation. Kaplan–Meier survival analysis was used to estimate median time (95% CIs) in days to treatment discontinuation, the risk of discontinuation at 3, 6, 12 and 24 months for the first and second episodes of HHI use, and the probability of reinitiating treatment at 6 and 12 months. Patterns of HHI discontinuation and reinitiation were stratified by type of HHI use. A sensitivity analysis was performed using grace periods of 14, 30, 90 and 120 days, rather than 60 days. Data were analyzed using Panalgo (Panalgo, MA, USA), a rapid analytics platform.

Results

Patients

A total of 526 patients with BCC who initiated an HHI between 1 January 2013 and 30 June 2019 were included in the analysis. Characteristics of the study population are summarized in Table 1. Median age at index was 64 years (25th–75th percentile: 56–81) and 65.4% of patients were men. Most patients (75.9%) had BCC in the head and neck areas. The proportion of patients covered by commercial insurance was 53.4%. Most patients (99.2%) initiated vismodegib.

Type of HHI use

A total of 366 patients (69.6%) initiated HHI as primary therapy, 117 (22.2%) as likely adjuvant therapy, 20 (3.8%) as likely neoadjuvant therapy and 23 (4.4%) as likely adjuvant and neoadjuvant therapy. Between 78.3 and 95.0% of patients who were categorized as receiving likely adjuvant HHI, likely neoadjuvant HHI or likely adjuvant and neoadjuvant HHI underwent surgery within 60 days of the index date (Figure 2). Among those characterized as neoadjuvant and adjuvant users, the predominant treatment type was tumor resection (78.3–91.5% of patients); nodal surgery and radiation were less common (Figure 2).

Patterns of HHI discontinuation & reinitiation

The median duration of follow-up was 437 days (25th–75th percentile: 161–844). For the first episode of HHI use, the median treatment duration was 144 days (95% CI: 131–162) and the cumulative probability of HHI discontinuation was 60.1% (95% CI: 55.0–64.6) by 6 months and 88.0% (95% CI: 83.6–91.2) by 12 months (Figure 3A). Among the 360 patients who discontinued the first episode of HHI, the probability of HHI reinitiation was 10.8% (95% CI: 7.4–14.1) by 6 months and 19.7% (95% CI: 15.0–24.2) by 12 months; median time to reinitiation was not reached (Figure 3B). Among the 75 patients who reinitiated HHI therapy, the median treatment duration for the second episode of HHI therapy was 118 days (95% CI: 89–172) and the probability of discontinuation was 68.6% (95% CI: 54.4–78.3) by 6 months and 84.7% (95% CI: 69.6–92.3) by 12 months (Figure 3C).

Analysis of HHI treatment patterns stratified by type of therapy suggested that time to first discontinuation was longer for patients initiating an HHI as primary therapy (median: 148 days; 95% CI: 134–172) than for patients initiating an HHI as likely adjuvant therapy (median: 128 days; 95% CI: 118–171), as likely neoadjuvant therapy (median: 107 days; 95% CI: 86–not estimable) or as likely adjuvant and neoadjuvant therapy (median: 90 days; 95% CI: 40–not estimable; Figure 4A). Analyses of time to reinitiation (Figure 4B) and time to second discontinuation of HHI use (Figure 4C) stratified by type of therapy were limited by the sample sizes, but the probability of HHI reinitiation at 12 months after the first discontinuation was low, with rates of 19.4% (95% CI: 13.7–24.8) if the first use of HHI was as primary therapy and 22.0% (95% CI: 11.7–31.1) if the first HHI use was as likely adjuvant therapy.

Sensitivity analysis

Time to first HHI treatment discontinuation using different grace periods is shown in Figure 5. The median duration of the first HHI use ranged from 94 days (95% CI: 90–109), using a 14-day grace period, to 172 days (95% CI: 155–190) using a 120-day grace period. Across the different grace periods, the probability of reinitiation by 12 months after the first discontinuation was ≤40.9% (range: 13.6–40.9%) and probability of discontinuation by 6 months after reinitiation was >55% (range: 55.8–88.4%) for the second episode of HHI use (Table 2). Apart from the 120-day grace period, the median treatment duration for the second HHI use was approximately 20–30 days shorter than the first episode of HHI use for each grace period.

Discussion

In this study of real-world treatment patterns among patients with BCC initiating an HHI, the median treatment duration of HHI (<5 months) was shorter than in pivotal clinical trials (10–12 months) [29,30]. The probability of reinitiating an HHI after the first discontinuation was also low overall (11% by 6 months and 20% by 12 months), suggesting that many treatment discontinuations in routine clinical practice are much longer than the 8 weeks studied in the MIKIE trial [20].

In our study, 84.7% of patients had discontinued the HHI by 12 months, which is higher than the discontinuation rates in the ERIVANCE BCC and BOLT studies, or in STEVIE, a prospective, open-label safety study of vismodegib as primary therapy in patients for whom surgery or radiation was inappropriate. In the ERIVANCE BCC study of vismodegib 150 mg once daily, 73% of patients discontinued treatment by 12 months, including >50% due to disease progression, patient decision or physician decision, and >20% due to adverse events such as muscle spasms, dysgeusia, weight loss, alopecia or asthenia [25]. In the BOLT study of sonidegib treatment once daily, 78% of patients discontinued sonidegib treatment by 12 months, due to adverse events (25% for 200 mg and 34% for 800 mg), progressive disease (29% for 200 mg and 10% for 800 mg) or patient decision (9% for 200 mg and 19% for 800 mg) [26]. Median treatment duration of vismodegib in STEVIE was 8.6 months, shorter than in the controlled trials but still longer than in our study (<5 months), although we allowed almost the same time period for treatment interruptions (8 weeks in STEVIE vs 60 days in the current study) [19]. By the time of the primary analysis data cutoff date of STEVIE (with a median follow-up of 17.9 months for efficacy analysis), 88% of patients (1068/1215) had discontinued vismodegib; reasons for discontinuation among these 1068 patients included adverse events (32.7%), disease progression (17.7%), patient request or physician decision (17.7%), death or loss to follow-up (5.4%) and other reasons (26.5%). While some patients may have discontinued HHI treatment upon achieving a response, discontinuation due to response was not reported as a category for discontinuation in the clinical trials or STEVIE.

While approximately 70% of patients initiated HHIs as their primary treatment in this analysis, the likely use of an HHI as an adjuvant or neoadjuvant to surgery or radiation may have contributed to a shorter median duration of HHI use overall. The duration of treatment in the adjuvant (median: 128 days) or neoadjuvant setting (median: 107 days) was approximately 3–4 weeks shorter than in the primary therapy setting. It may be that a limited course of HHI therapy was planned in these patients. HHIs have not been approved for neoadjuvant or adjuvant use, and there does not seem to be a consensus recommendation on the appropriate duration of neoadjuvant or adjuvant use of HHIs in the treatment of BCC. Most clinical trials investigating neoadjuvant use of vismodegib have reported planned or observed treatment for 3 or 4 months [31–34].

We observed few reinitiations among patients after they discontinued HHIs. After the first HHI discontinuation for >60 days, the probability of reinitiating HHI use was low overall (~20% by 12 months), suggesting that many treatment discontinuations in routine clinical practice are much longer than the recommended 8 weeks or that some discontinuations may be permanent. In sensitivity analyses, reinitiation rates remained low, even with a grace period of 120 days. Some patients may have discontinued after achieving a response, but we could not confirm that from the information available in the database.

To our knowledge, only two previous studies have evaluated HHI treatment patterns in real-world clinical practice in the USA (Table 3). One of those studies also analyzed MarketScan claims for HHI use, but included index claims only through 2015 [24]. Consistent with our results, that study reported high rates of treatment discontinuation in the first 12 months (22% of patients remained on treatment at 12 months), a short time to discontinuation (median: 4.5 months; 95% CI: 3.9–5.5; 60-day grace period), and approximately 80% of patients were not observed to reinitiate treatment over a median follow-up of 12.0 months. A prospective, multicenter, observational registry study of patients with locally advanced BCC treated at 75 academic and community practices in the USA that included 115 patients who were treated with vismodegib also reported results consistent with those from this study [35]. The authors found that almost all patients (94%) had an interruption or change (e.g., receiving other treatment) in vismodegib treatment, most often due to adverse events, and that the median time to vismodegib discontinuation was 6.3 months. A nationwide study in Argentina of 63 patients with BCC treated with vismodegib reported a median treatment duration of 6.3 months [36], and a single-center study in Greece of 18 patients reported a median treatment duration of 6.6 months [37]; the exact methods for determining treatment discontinuation were not reported in either study.

This large study of patients with BCC treated with HHIs in the real-world setting has limitations, consistent with analyses of claims data. Information regarding disease severity (e.g., stage of BCC) at treatment initiation and reasons for discontinuing or restarting HHI treatment, such as relapse or toxicity, are not available in medical claims. Though prescribed doses were available in claims data, the actual doses and details of exactly how patients took their HHIs, the duration of the treatment holidays, as well as whether and how treatment holidays were built into the treatment regimen (i.e., in anticipation of or in response to emergent toxicities), were not available. In addition, we could not distinguish between permanent and temporary discontinuation of HHI treatment. However, our sensitivity analyses using varying grace periods consistently revealed short treatment duration on HHIs and low rates of reinitiation. It is possible that some patients discontinued HHI therapy when it was felt they had achieved their maximum benefit, which was a common reason for vismodegib discontinuation in a recent registry study [35], but this could not be determined from the claims data used for our study. Neoadjuvant or adjuvant therapy could not be confirmed and was inferred from timing of the index HHI dispensation relative to claims for surgery or radiation. Sample sizes limited the interpretability of time to reinitiation and time to second episode of HHI use when stratified by type of therapy.

Conclusion

Persistent use of HHI therapy for BCC may be difficult to achieve in real-world settings. High rates of HHI discontinuation, short times to discontinuation and low rates of reinitiation among patients with BCC may affect the effectiveness of these medications in real-world clinical practice. Future research should evaluate the introduction of new therapies to address this unmet need.