MO28682 RONNIE - SYNOPSIS OF CLINICAL STUDY REPORT STUDY DESIGN

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1 ROCHE-NO.: TITLE OF STUDY: SHORT TITEL: DRUG: INDICATION: CLINICALTRIALS.GOV IDENTIFIER: STUDY PHASE: SPONSOR: SPONSOR S MEDICAL OFFICER: SPONSOR S SIGNATORY: NAME OF PRINCIPAL INVESTIGATOR: REPORT PREPARED BY: RECORDS RETENTION: STUDY DATES: REPORT DATE PERSONNEL RESPONSIBLE FOR CLINICAL AND STATISTICAL ANALYSIS: GCP-COMPLIANCE: MO28682 A multi-center, multi-national, retrospective medical record review to describe treatment patterns and outcomes for patients with locally advanced or metastatic basal cell carcinoma RONNIE n.a. Advanced Basal Cell Carcinoma n.a. n.a. retrospective observational study F. Hoffmann-La Roche Basel, Switzerland Sandra Horning, MD Florin Sirzen, MD PhD N/A Miller Medical Communication c/o Lee Miller F. Hoffmann-La Roche Central Records Initiation of first site: 20-Sep-2012 Completion (database lock): 20-Sep Dec-2014 Damian Page, Ph.D. International Scientific Director Cedric Revil Senior Statistician This study was conducted in accordance with GCP guidelines STUDYDESIGN Title of Study: RONNIE A Multi-Center, Multi-National, Retrospective Medical Record Review to Describe Treatment Patterns and Outcomes for Patients with Locally Advanced or Metastatic Basal Cell Carcinoma Phase of Development: N/A Retrospective observational study Study Period: 1 January 2005 to 31 December 2011 (Patient enrolment from 1 January 2005 to 31 December 2010; Patient follow-up ended 31 December 2011) Investigators / Centres and Countries: A total of 38 sites participated in the study in France (24 sites), Germany (4 sites), Italy (7 sites) and the United Kingdom (3 sites). 1 von 6

2 Publication (Reference): Final results of RONNIE, a retrospective chart review to describe treatment patterns and outcomes in advanced basal cell carcinoma before availability of hedgehog pathway inhibitors. Oral presentation at the 10 th European Association of Dermato Oncology. May Objectives: To describe the following domains in a historical cohort of patients with advanced basal cell carcinoma (BCC): Patient characteristics, including demographic and clinical variables Treatment patterns, including the types, frequencies/dates, impact of surgery on organ function (e.g. loss of an organ, organ failure, amputation of the limb) and outcomes (namely complete response, partial response, stable disease, disease progression and survival) associated with any various therapy used for the treatment of advanced BCC (abcc). Number of Subjects: Approximately 100 patients were planned. A total of 134 patients were enrolled, of which 121 patients were considered eligible. Diagnosis and Main Criteria: To be considered eligible for the study, consenting adult patients at participating centers must have had a new diagnosis of abcc, defined as: (1) locally advanced BCC (labcc) (inoperable as determined by the site investigator or surgery contraindicated) with receipt of radiation therapy (unless radiation was contraindicated), or (2) metastatic BCC (mbcc), from 1 January 2005 through 31 December Patients could not have received treatment with a Hedgehog pathway inhibitor, and were also excluded if they had been participating in an interventional trial during the study time period or within 90 days prior to individual patients study enrolment dates. Trial and Reference Drug: Not applicable Dose / Route / Regimen /Duration: Not applicable Criteria for Evaluation: Data related to disease history, assessment and treatment, including outcomes, for patients with abcc were collected through medical record review. Data elements of interest included the following: Patient demographics o Age o Sex o Race/ethnic origin (where permitted by local regulations) o Country BCC disease history o Date of initial BCC diagnosis o Date of diagnosis of abcc o o Family history of disease Skin cancer risk factors (e.g. light skin colour, exposure to ultraviolet radiation, tanning bed use) Other significant medical history o Comorbidities (e.g., cardiovascular disease, hypertension, diabetes, immunosuppression / transplant recipient) 2 von 6

3 o Non-BCC surgeries and procedures (types, dates) BCC assessment o Type of BCC (locally advanced, metastatic) o Site of primary lesion (e.g. head, neck, trunk) o Number and size of lesions o Histopathology (e.g., mixed, micronodular, infiltrative, basosquamous, morpheaform) o BCC nevus syndrome status o Eastern Cooperative Oncology Group (ECOG) performance status o Biopsies (dates, types, results) BCC treatments o Type - Surgery (Mohs, laser, excisional, curettage and electrodessication, cryosurgery) - Radiation - Photodynamic therapy - Chemotherapy - Supportive/palliative care - Other, including systemic and topical therapies (e.g., imiquimod, 5- fluorouracil) o Doses / frequency / dates of treatments o Outcomes of BCC treatments - complete response - partial response - stable disease - progression of disease - overall survival (OS) - progression-free survival (PFS) - BCC biopsy results o Impact of surgery on organ function (e.g. loss of an organ, organ failure, amputation of the limb) Statistical Methods: As the study was descriptive in nature, there were no predefined hypotheses. Patient demographics and clinical variables (e.g., treatment types) were characterized using descriptive statistics, including measures of central tendency (means, medians) and spread (variance, range) for continuous variables (e.g., age); and frequency distributions for categorical variables (e.g., sex). The proportion of patients meeting the outcomes of interest (e.g., objective response to treatment) were calculated, along with corresponding 95% confidence intervals. Kaplan-Meier (KM) curves were used to illustrate OS and PFS rates. Methodology: Details of the study can be found in the protocol (see Appendix 8.1.1) Safety Conclusions: This is a retrospective medical record review. Safety data was not collected. RESULTS: A total of 134 patients were enrolled in the study between 1 January 2005 and 31 December Of these, one patient had no data collected, meaning that 133 patients were included (Included Population). Subsequent analysis of the eligibility criteria identified 12 patients that were not 3 von 6

4 considered eligible, resulting in 121 eligible study patients (Effectiveness Population). Only four of the enrolled patients had mbcc. Due to this small relative sample size and potentially significant differences in treatment patterns and disease outcomes between mbcc and labcc, the labcc patient population is the focus of this report. The most prevalent treatment was radiation, and over 30% received surgery as first treatment after labcc diagnosis. Approximately half of the labcc patients went on to receive a second treatment. Very few patients received chemotherapy, and if radiation was used, it was typically not repeated as another subsequent treatment. The study outcomes of interest for this study were based on the clinician s assessment. Most patients had a single target lesion, and over the course of their disease during the follow-up period, the majority of target lesions either remained the same or decreased in size as compared to the baseline measurement. The median OS was 78.8 months (n=11 patients, 95% CI ), and median PFS for the first line of treatment administered during the study was 32.1 months (n=53 patients, 95% CI ). DISCUSSION AND CONCLUSIONS: As this study was not intended to contribute to the evaluation of the effectiveness of any product, or provide definitive information on clinical pharmacology, an abbreviated clinical study report was considered to be appropriate. This study describes the disease burden, treatment patterns, and clinical outcomes in a historical cohort of patients with abcc. The RONNIE study patient population consisted mostly of patients with labcc. As anticipated, the prevalence of mbcc was quite rare (3.3%). In an ongoing global safety study (STEVIE, MO25616) only 22 (7.3%) of the first 300 patients enrolled had metastatic disease [Grob JJ, et al. J Clin Oncol 2013;31: suppl (abstr 9036)]. While this percentage is higher than the proportion seen in RONNIE, this difference might be explained by the increased awareness of mbcc that has occurred in the oncology community since the RONNIE study was initiated. Although the eligibility criteria required that patients be deemed inoperable or have surgery as a contraindication, 35% of patients had surgery (including Mohs, excisional and cryosurgery) as the first treatment after labcc diagnosis. Although this number appears high in light of the surgical exclusion criterion, it is not unexpected that surgery is widely used given the lack of viable alternative treatment options for patients with labcc. At baseline, 39.3% of the 117 labcc patients were considered inoperable and 48.7% had surgery as a contraindication. Despite that only the remaining 12% of patients were considered as operable or having no contraindications for surgery, one in three patients actually received surgery as first labcc treatment. Of the 27 patients who received excisional surgery as their first treatment after labcc diagnosis, the complete visual response rate was only 51.9%. This is a modest result given the curative intent of the procedure, which confirms that most of these study patients were not well suited for surgery. Despite, or perhaps because of, this lack of optimal outcome, many patients went on to receive multiple surgeries over the course of their disease. For the purposes of study entry, patients were required to have received prior radiotherapy, unless contraindicated. Radiation was considered to be inappropriate in only 3.4% of labcc patients at time of entry, and only 8.5% of patients had experienced disease progression after prior radiotherapy. This low incidence might explain why 43.4% of labcc patients received radiation as their first treatment after labcc diagnosis. Only a small number of patients received supportive or palliative care as their first labcc treatment, and only 1 complete visual response was seen in this treatment group. Patients received multiple subsequent treatments, with either the same or different treatment modalities being administered. No apparent trend or predictable pattern was detected in the study in terms of which treatments are used and in which order, and which treatments are given alone or 4 von 6

5 in combination. Multiple treatments given in relatively short intervals were most common, and patients rarely experienced a durable response after receiving just one treatment. This large variety of treatments suggests that there has been no established standard treatment for this patient population in the time period. Assessment of response is usually difficult in a retrospective study. Target lesions were assessed at a frequency according to the standard of care at each study site. In addition, the length of follow-up was dependent on when the patient was diagnosed with abcc during the 6-year data collection period. Given the entire number of enrolled labcc patients, the number of patients represented at each follow-up visit is quite low, especially from Month 36 onwards. The time-to-event outcomes and the KM curves give no indication that missing data was random or not random, and the unexpectedly low number of observations of some endpoints makes it difficult to implement imputing rules. In addition, the group of patients reported at one study assessment visit might have been different from the group of patients reported at the next study assessment visit, which makes interpretation of these data fairly difficult. Given the multiple number of treatments given to most study patients, any treatment-specific analysis of overall survival or PFS is impossible to attribute to any one treatment. Due to the descriptive nature of this study, there are some limitations to the robustness of the analyses. However, as so little is known about the general survival of the labcc population, these overall analyses of OS and PFS contribute additional information regarding this disease. Some of the subgroup analysis populations were small, such as mbcc (n=4), Mohs (n=7) and palliative/supportive care (n=8), and therefore findings in these sub-populations should be interpreted with some degree of caution. It is not known how representative the study patients are of the abcc patients in general. To minimize selection bias, the eligibility criteria were selected to be as broad as possible. Furthermore, where possible, patients were recruited from a diverse pool of clinical settings, including dermatology and oncology clinics, community and non-community-based facilities, and urban and rural sites. In this, the first large multi-country retrospective analysis of treatment for abcc patients before availability of Hedgehog pathway inhibitors, there appeared to be no standard established treatment options for patients with abcc between 2005 and Patients enrolled were clinically diverse and received a broad spectrum of treatments; radiotherapy and surgery were the most widely used, although surgery was considered inappropriate or contraindicated for the majority of patients. The data from RONNIE indicate that study patients with abcc suffered from a disease that was poorly-defined and for which there were few viable treatment options. The heterogeneous treatment landscape may change as the use of Hedgehog pathway inhibitors becomes standard. Further disease classification is also required to improve treatment decision and management of labcc. Date of the Report: 2 December von 6

6 Glossary of Preferred Terms 5-FU abcc BCC BCCNS CI CRF CV ECOG ecrf IEC IRB KM labcc mbcc OS PD PFS PR SAP SD SD UK 5-flurorouracil Advanced basal cell carcinoma Basal cell carcinoma Basal cell carcinoma nevus syndrome Confidence interval Case report form Curriculum vitae Eastern Cooperative Oncology Electronic case report form International ethics committee Institutional review board Kaplan-Meier Group Locally advanced basal cell carcinoma Metastatic basal cell carcinoma Overall survival Progressive disease Progression-free survival Partial response Statistical analysis plan Stable disease Standard deviation United Kingdom 6 von 6