Real-World Treatment Patterns and Outcomes Among Patients with Basal Cell Carcinoma Following First-Line Hedgehog Inhibitor Discontinuation

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Basal cell carcinoma (BCC) is the most common cancer in the USA, with an estimated 2 million patients diagnosed annually and an increasing incidence of disease [1, 2]. For most patients diagnosed with BCC, local treatment, including surgical excision, radiotherapy, or superficial therapies, is curative [3]. The prognosis worsens, however, if medical attention is delayed or if BCC recurs after local treatment, in which case patients may present with locally advanced or metastatic BCC [4]. It is estimated that locally advanced BCC occurs in 0.8% of cases, while metastatic BCC occurs in 0.0028% to 0.55% of cases [4, 5].

The approved first-line (1L) treatment for patients with locally advanced or metastatic BCC consists of hedgehog pathway inhibitors (HHIs) [3]. Prior to US Food and Drug Administration (FDA) approval of cemiplimab-rwlc in February 2021, patients who required subsequent treatment or did not tolerate HHIs [3] were limited to noncurative surgery or radiation, along with clinical trial participation [3, 6]. While other studies have evaluated use and outcomes among patients initiating HHIs in the real-world setting [5, 7, 8], to our knowledge, no studies have examined treatment patterns or outcomes following 1L HHI treatment discontinuation for BCC. The aim of this study was to assess the characteristics, treatment patterns, and outcomes of patients in the community oncology setting with BCC who discontinued 1L HHIs.

The results of this study describe the patient characteristics, treatment patterns, and clinical outcomes of patients with BCC who discontinued 1L HHI treatment in the community oncology setting. In a small cohort of patients with BCC discontinuing 1L HHIs, we found that approximately half discontinued because of documented disease progression or toxicity. We observed that few of these patients initiated another line of treatment and that most patients were either lost to follow-up or had died without initiating subsequent systemic treatments.

Few studies have described characteristics and outcomes of real-world patients with locally advanced or metastatic BCC [5, 7, 8]. Goldenberg et al. (2016) performed a retrospective cohort study using insurance claims data from October 2011 to September 2012 to estimate the incidence and prevalence of BCC in the USA [5]. In this study, the mean age of patients with incident locally advanced BCC (n = 261) was 72.2 years [standard deviation (SD) 13.7] and 53.3% were male, and the mean age of patients with incident metastatic BCC (n = 7) was 71.3 years (SD 14.9) and 85.7% were male. The mean ages of patients with incident locally advanced and metastatic BCC from the Goldberg study were similar to the median age of 2L initiators in our study (69 years), but considerably younger than the median age of 80 years observed among the 2L non-initiator cohort. The fact that patients who were not subsequently treated were older than the 2L initiators may be due to patient or physician decisions regarding benefit and risk assessments of further BCC treatment due to factors such as advanced age, frailty, and willingness or ability to travel for treatment.

Cozzani et al. (2020) examined real-world use of vismodegib among patients with locally advanced or metastatic BCC who were ineligible for curative surgery or radiotherapy in Argentina [7]. All patients initiated vismodegib, and 90% of patients had locally advanced disease, similar to our study in which all patients were treated with vismodegib and 78.5% of 2L initiators and 2L non-initiators with available data (n = 11/14) had locally advanced disease at initial BCC diagnosis. In the Cozzani study, the cohort had a median age of 73 years and 66.2% were male; in comparison, we observed a median age of 80 years and 80% male in our 2L non-initiator cohort, and a median age of 69 years and 0% male in our 2L initiator cohort.

In our study, all patients received 1L vismodegib monotherapy, even though nearly half initiated HHI treatment after the FDA approval of sonidegib in July 2015 [15]. Similar use of vismodegib was reported in an analysis of MarketScan Commercial and Medicare Supplemental claims data from 2013 to 2018. Among the 469 patients with BCC initiating an HHI, 99.2% received vismodegib. It is hypothesized that the higher use of vismodegib observed in these real-world studies may be due to the earlier approval of vismodegib and better recognition among patients and providers compared with sonidegib.

The median duration of 1L HHI treatment among patients discontinuing HHIs was 7 months among the 2L non-initiator cohort and 9 months among the 2L initiator cohort, shorter than the 10–12-month average treatment duration reported from the pivotal trials [16, 17]. Duration of treatment in this study, however, was similar to the estimated median duration of 8.6 months reported in the STEVIE trial of vismodegib among patients (n = 1215) with locally advanced or metastatic BCC [18]. A retrospective cohort study of patients with locally advanced BCC (n = 48) or metastatic BCC (n = 11) initiating vismodegib in the Netherlands also found that the median treatment duration was 6.4 months (range 1.4–38.5 months) among those with locally advanced BCC and 7.5 months (range 1.6–18.5 months) among those with metastatic BCC [8]. Although we estimated average treatment duration only among patients discontinuing HHI treatment because of toxicity and progression rather than complete response, our findings add to the accumulating evidence that persistence on HHI treatment in the real world is likely considerably shorter than in the trials.

In our study, we also found that the most common reason for HHI 1L treatment discontinuation was toxicity. Clinical trials have reported tolerability issues with HHIs, and both reactive interruption (discontinuing HHI treatment for 8 weeks when adverse reactions occur [16, 17, 19]) and preventive interruption (prospectively alternating between HHI treatment for 8 or 12 weeks, with scheduled 8-week interruptions having been investigated as treatment strategies to improve HHI tolerability) [19‐22]. 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% (n = 1068/1215) of patients had discontinued vismodegib. Reasons for discontinuation 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%) [18, 23]. In this study, we relied on physician-documented reason for discontinuation. Among 2L non-initiators, 14 of 15 had toxicity documented as the reason for discontinuation compared with none among the 4 2L non-initiators. While reliance on physician-documented reason for discontinuation may favor capture of toxicity as a reason, particularly for patients who did not tolerate treatment, our findings suggest tolerability is the most frequently documented reason for discontinuation, particularly among those who do not go on to initiate other treatments for locally advanced or metastatic BCC.

Until recently (2020), the National Comprehensive Cancer Network (NCCN) guidelines recommended surgery, radiation therapy, or a clinical trial after discontinuation of an HHI [3, 6]. In our study, we observed that most patients who discontinued HHIs because of toxicity or progression rather than complete response did not initiate a subsequent treatment. At the end of a median of approximately 10 months of follow-up, most 2L non-initiators either died (33%) or were lost to follow-up (40.0%), when they may have died, entered hospice, or stopped seeking care. It is possible that some patients may have also initiated treatment elsewhere (e.g., through a transfer to an academic medical center), although this is unlikely since transfers are usually documented in patients’ medical records and we specifically searched for transfers during chart abstraction. We observed that only 4 patients initiated a subsequent 2L treatment, and that all of them initiated different treatments. At the end of approximately 6 months of follow-up, 75% of patients who initiated a treatment had died (25%) or were lost to follow-up (50%). Our findings underscore that there was an important unmet need for effective therapeutic options with acceptable risk–benefit profiles for patients with BCC who discontinue initial 1L HHI because of disease progression or toxicity and not complete response. Current NCCN guidelines (version 2.2021) now recommend cemiplimab-rwlc for patients who were previously treated with an HHI or for whom an HHI is not appropriate [3]. Future studies should examine how treatment patterns and outcomes have changed following the introduction of novel immunotherapies [24].

The study utilized clinical data from the EHR system of The US Oncology Network, a large system of community oncology practices. The use of real-world data is advantageous because it reflects community oncology practice trends as opposed to tightly controlled clinical trials. Moreover, results for this study were drawn from both structured and unstructured EHR data. By verifying patients’ eligibility and key study variables through a manual review of records, the study dataset was enhanced beyond structured records.

Despite the advantages of this real-world data source, the results of this study should be contextualized by a number of limitations. Most prominently, while it provides insights into the rarity of subsequent treatment for BCC, we identified few patients meeting the study eligibility criteria. While this study applied several steps to verify that the appropriate patients were selected for inclusion, other information of interest may be incomplete, inaccurate, or inconsistently documented in the EHR. For example, some patients who died or transferred to hospice care may have been misclassified as being lost to follow-up because of incomplete capture of these events in the EHR or the LADMF. Owing to lack of information on care provided in academic medical centers, it is possible that 2L non-initiators lost to follow-up may have been treated in an academic medical center, although we would anticipate this to be rare. Use of HHIs, including whether they were used as adjuvant to surgery/radiation, could have been misclassified. Reasons for discontinuation were unlikely to have been recorded for all patients, resulting in a smaller and more select group of patients experiencing HHI treatment failure; and, owing to known tolerability issues with HHIs, physicians may have been more likely to record toxicity as a reason for discontinuation. To ensure that the study population was ineligible for curative surgery or radiation, the index date for the 2L non-initiator cohort was defined to be 90 days following 1L treatment discontinuation and comparisons between the cohorts were further precluded. Lastly, it was not possible to contextualize treatment decisions, including reasons 2L non-initiators were not treated with systemic treatments.

The results of this study encompass a small number of patients, but still serve to illustrate the lack of standardized care options for patients with BCC who are ineligible for curative therapies following 1L HHI treatment failure in the US community oncology setting. In addition to the high proportion of patients who did not advance to subsequent treatment following 1L HHI discontinuation, unfavorable outcomes were also observed irrespective of whether patients received 2L treatment. This suggests an unmet need for effective treatment options with acceptable risk–benefit profiles after 1L HHI discontinuation. Further studies are necessary to evaluate the impact of newer treatment options recommended by NCCN guidelines for patients who were previously treated with an HHI or for whom an HHI is not appropriate.