Clinical Study Synopsis

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1 Clinical Study Synopsis This Clinical Study Synopsis is provided for patients and healthcare professionals to increase the transparency of Bayer's clinical research. This document is not intended to replace the advice of a healthcare professional and should not be considered as a recommendation. Patients should always seek medical advice before making any decisions on their treatment. Healthcare Professionals should always refer to the specific labelling information approved for the patient's country or region. Data in this document or on the related website should not be considered as prescribing advice. The study listed may include approved and non-approved formulations or treatment regimens. Data may differ from published or presented data and are a reflection of the limited information provided here. The results from a single trial need to be considered in the context of the totality of the available clinical research results for a drug. The results from a single study may not reflect the overall results for a drug. The following information is the property of Bayer AG. Reproduction of all or part of this report is strictly prohibited without prior written permission from Bayer AG. Commercial use of the information is only possible with the written permission of the proprietor and is subject to a license fee. Please note that the General Conditions of Use and the Privacy Statement of bayer.com apply to the contents of this file.

2 11-JAN-2018 Study no Page: 2 of 23 Date of study report: 19 JUL 2017 Study title: Sponsor s study number: NCT number: A prospective, single-arm, multicenter, uncontrolled, open-label Phase II trial of refametinib (BAY ) in combination with sorafenib as first line treatment in patients with RAS mutant Hepatocellular Carcinoma (HCC) NCT EudraCT number: Sponsor: Clinical phase: Study objectives: Bayer Phase II Primary objective To evaluate the efficacy of refametinib in combination with sorafenib in patients with KRAS or NRAS mutant unresectable or metastatic HCC. Secondary objective To evaluate the safety of refametinib in combination with sorafenib in patients with KRAS or NRAS mutant unresectable or metastatic HCC. Additional objectives The analysis of biomarkers and pharmacokinetics (PK). Test drug: Refametinib (BAY ) Name of active ingredient(s): Dose: Route of administration: Duration of treatment: Refametinib 50 mg twice daily (bid) Oral Patients were treated until disease progression as defined by modified Response Evaluation Criteria in Solid Tumors (mrecist) or clinical progression (e.g. Eastern Cooperative Oncology Group performance status [ECOG PS] of 3), or until another criterion was met for withdrawal from study treatment. Treatment could be continued past radiological progression assessed by central image review, provided the

3 11-JAN-2018 Study no Page: 3 of 23 patient derived clinical benefit as judged by the treating physician. The treatment period was divided into 3-week cycles. Reference drug: Background treatment: Dose: Route of administration: Duration of treatment: Indication: Diagnosis and main criteria for inclusion: Study design: Methodology: Not applicable Sorafenib (Nexavar, BAY ) Standard dose 400 mg (2x200 mg tablets) bid. In Cycle 1 reduced dose (600 mg daily; 200 mg in the morning mg in the evening), escalated to standard dose in Cycle 2, if no hand-foot skin reaction (HFSR), fatigue, or gastrointestinal (GI) toxicities of grade 2 or higher. Oral Patients were treated until disease progression as defined by mrecist or clinical progression (e.g. ECOG PS of 3), or until another criterion was met for withdrawal from study treatment. Treatment could be continued past radiological progression assessed by central image review, provided the patient derived clinical benefit as judged by the treating physician. The treatment period was divided into 3-week cycles. KRAS or NRAS mutant unresectable or metastatic HCC Male or female patients ( 18 years of age) with unresectable or metastatic HCC harboring RAS mutation. Patients were to be Child- Pugh A, were to have a life expectancy of at least 12 weeks, and an ECOG PS of 0 or 1. Patients could have received prior local therapy but no systemic therapy for HCC. Prospective, single-arm, multicenter, uncontrolled, open-label study This was a prospective, single-arm, multicenter, uncontrolled, openlabel phase II trial of refametinib (BAY ) in combination with sorafenib (Nexavar, BAY ) as first line treatment in patients with KRAS or NRAS mutant HCC. After confirmation of basic eligibility criteria at the visit for testing of RAS mutation (screening phase 1), a plasma sample for genotyping of free tumor DNA was collected to identify patients carrying a RAS mutation (KRAS or NRAS). Patients carrying RAS mutation were then evaluated for study treatment eligibility during screening phase 2. All patients who met the entry criteria received refametinib (50 mg bid) in combination with sorafenib (600 mg daily in Cycle 1 and 400 mg bid

4 11-JAN-2018 Study no Page: 4 of 23 from Cycle 2 onwards). For the purposes of data recording, the treatment period was divided into 3-week cycles. The start of the treatment period was defined by the first administration of study treatment. Treatment was continued until the occurrence of progressive disease (PD) as defined by the mrecist criteria (assessed by central image review) or clinical progression (e.g. ECOG performance status of 3), or until another criterion was met for withdrawal from study. An end of treatment (EOT) visit was performed within 7 days after discontinuation of study treatment and a safety follow-up visit (end of study visit) took place 30 (+ 5) days after the last administration of study drug. All patients who discontinued treatment were followed for overall survival. The primary efficacy variable was the central radiological assessment of objective tumor response rate (ORR) (confirmed complete response [CR] plus partial response [PR]) according to mrecist. ORR was defined as the proportion of patients with the best tumor response (confirmed PR or CR) that was achieved during the study. Radiologic tumor assessments (real-time central image review and investigator s assessment) were done at Screening and then every 6 weeks during the treatment. A further radiologic tumor assessment was done within 14 days after last study medications intake (not needed if the previous tumor evaluation was performed within 4 weeks). Secondary efficacy variables were ORR (investigator s assessment and centrally assessed ORR according to RECIST v.1.1), overall survival (OS), disease control rate (DCR), time to radiographic progression (TTRP), and duration of response (DOR). For OS, patients were followed up until death. Other variables included time to objective response, change in tumor size, best overall response, progression free survival (PFS), biomarkers and PK parameters. Safety evaluations included adverse events (AEs), physical examination, vital signs, electrocardiogram (ECG), cardiac function, laboratory analyses, ophthalmic examinations, and neurologic examinations. Furthermore, Child-Pugh, ECOG PS, and Barcelona Clinic Liver Cancer (BCLC) stage were assessed. At the safety follow-up visit, 30 (+ 5) days after the last dose of study treatment, AE and concomitant medication data were collected. Following completion of the safety follow-up visit, patients were contacted every 3 months (±14 days) to determine survival status, and if applicable, disease progression status and information on at least the first new anti-cancer regimen.

5 11-JAN-2018 Study no Page: 5 of 23 Study center(s): 80 investigational sites enrolled patients in 21 countries: Austria (1), Belgium (4), China (3), Czech Republic (2), France (8), Germany (8), Great Britain (2), Hong Kong (2), Hungary (4), Israel (4), Italy (4), Japan (11), New Zealand (1), Singapore (1), South Korea (7), Spain (6), Switzerland (1), Taiwan (3), Thailand (3), Turkey (4), USA (1). Publication(s) based on the study (references): None at the time of report creation Study period: Study Start Date: 27-SEP-2013 Cut-off Date of the Final Analysis: Last Patient Last Visit: 29-JUL FEB-2017 Early termination: Not applicable Number of subjects: Stage 1 Planned: About 350 patients to be tested for RAS mutations to identify 15 RAS mutant patients to be treated. Analyzed: 820 patients enrolled for RAS mutation testing and 16 patients were treated More details are given in the section on study subjects below. Stage 2 Planned: About 2,300 patients to be tested for RAS mutations to identify approximately 80 RAS mutant patients to be treated. Analyzed: Stage 2 was not performed. Criteria of evaluation: Efficacy: Primary efficacy variable: The central radiological assessment of ORR (confirmed CR plus PR) according to mrecist. ORR was defined as the proportion of patients with the best tumor response (confirmed PR or CR) that was achieved during the study. Secondary efficacy variables: ORR (investigator s assessment and centrally assessed ORR according

6 11-JAN-2018 Study no Page: 6 of 23 to RECIST v.1.1), OS, DCR, TTRP and DOR. Other secondary efficacy variables: Time to objective response, change in tumor size, best overall response, PFS. Safety: Safety evaluations included AEs, physical examination, vital signs, ECG, cardiac function, laboratory analyses, ophthalmic examinations, and neurologic examinations. Furthermore, Child-Pugh, ECOG PS, and BCLC stage were assessed. Other: Biomarkers and PK parameters. Patient Reported Outcome (PRO) / Health Related Quality of Life (HRQoL) at Stage 2. Statistical methods: Substantial protocol changes: As of 29 JUL 2015, the cut-off date of final analysis, there was no statistical testing at the end of Stage 1; all analyses were descriptive only as Stage 1 was exploratory. Data on 3 patients ongoing on study treatment after 29 JUL 2015 were presented as listings. No summary statistics were performed. The original protocol (version 1.0) dated 03 MAY 2015 was globally amended once. Protocol amendment 2, forming protocol version 2.0 dated 22 OCT 2013, introduced the following change: Wording regarding use of refametinib tablets was clarified. Based on final pharmacokinetic results from a clinical relative bioavailability study where tablets exhibited comparable bioavailability to capsules, refametinib tablets could be used in clinical trials as an alternative for capsules. Exclusion criteria were amended; - Patients with a QTc greater than 480 ms at the time of screening were excluded from the study due to the potential for QT prolongation with sorafenib. - Exclusion criterion regarding systemic anticancer therapy was clarified, as patients with prior systemic anticancer therapy were not eligible for this study. A dose modification scheme for hepatotoxic events was included, since hepatotoxicity is an identified risk for the refametinib-sorafenib combination. Additional safety ECGs were added in order to characterize the cardiovascular safety at anticipated maximum plasma

7 11-JAN-2018 Study no Page: 7 of 23 concentrations of the study treatment. Subject disposition and baseline Disposition The results of the final analysis represent data accumulated up to the cut-off date of 29 JUL Three patients were still under treatment at the time of the cut-off date and the data of these three patients are presented in the form of narratives for each patient. Only patients with unresectable or metastatic HCC who carried a KRAS or NRAS mutation were eligible for study treatment. A total of 820 patients were included in screening phase 1 for KRAS or NRAS mutation tests via BEAMing (Beads, emulsions, amplification, and magnetic) technology (signed informed consent [IC] for RAS mutation testing). Five of them (0.6%) were not tested due to failure of inclusion and/or exclusion criteria, thus the RAS mutation test was performed for 815 patients (99.4%). The RAS mutation test was positive in 27 patients (3.3%) while 788 patients (96.1%) were RAS mutation negative. The mutation rate was slightly lower in the Asia population (2.9%) compared with the Rest of the World (RoW) population (3.5%). Of the 27 RAS mutant patients, 3 patients did not sign the main IC. Altogether 24 patients (2.9%) signed the main IC, i.e. were enrolled in the screening phase 2. 8 patients out of the 24 patients did not complete or pass the screening phase 2: 7 patients were screening failures and 1 patient died of AE associated with clinical disease progression (jaundice and ascites). A total of 16 patients were assigned to treatment: 6 patients in the Asia population and 10 patients in the RoW population. All 16 patients who were assigned to treatment also started study treatment. At the time of the data cut-off for this final analysis, 13 patients (81.3%) had completed treatment. The most common primary reason for treatment termination was progressive disease (radiological progression) for 6 patients (37.5%). A total of 12 patients (75.0%) started the safety follow-up and 11 of them (68.8%) completed it. One patient (6.3%) who prematurely discontinued the safety follow-up was from the Asia population. The primary reason for discontinuation was death. A total of 11 patients (68.8%) entered the survival follow-up period. 3 patients (18.8%) discontinued the survival follow-up due to death (2 patients in the RoW region and 1 patient in the Asia region). For 2 of the 3 patients who were still under treatment at the time of the cut-off date, the primary reason for discontinuation of study treatment was radiological disease progression. The third patient discontinued due to AE associated with clinical disease progression, and died of liver decompensation (Medical Dictionary for Regulatory Activities Prederred Term [MedDRA PT]: hepatic failure). The death was considered unrelated to the study drugs. One of the three patients was on treatment up to Cycle 29. The other two were on treatment up to Cycle 13 and Cycle 12. The duration of study treatment from the first administration of study treatment to the last exposure to study treatment was 621, 267 and 233 days, respectively.

8 11-JAN-2018 Study no Page: 8 of 23 Analysis sets The primary analysis set for the analysis of efficacy variables was the full analysis set (FAS), which was defined as all patients assigned to study treatment. FAS consisted of all 16 patients. Per protocol analysis set (PPS) was used for supportive analyses of the efficacy variables. PPS comprised all FAS patients who received treatment and who did not have any major protocol deviations which could affect the primary efficacy variable. As there was 1 patient with a major protocol deviation (patient was assigned to treatment despite not having liver function status of Child-Pugh class A at screening), PPS consisted of 15 patients. Safety variables were analyzed using the safety analysis set (SAF). The SAF comprised all FAS patients with at least one intake of test drug. SAF consisted of all 16 patients. Demographics and baseline characteristics Out of the 820 patients enrolled in RAS mutation testing phase, 815 patients were tested for RAS mutations and 5 patients were not tested due to failure of inclusion and exclusion criteria. Of those tested for RAS mutations 335 were from Asia 1 and 480 from the RoW region. All patients from Asia were Asians. The population from the RoW region enrolled for RAS mutation testing consisted of 319 (38.9%) white patients, 9 (1.1%) black or African American, 11 (1.3%) Asian, 6 (0.7%) native Hawaiian or other Pacific Islander patients. The race was not available for 135 patients (16.5%) and there was 1 patient (0.1%) with multiple races reported. The majority of the patients (692, 84.4%) enrolled in the RAS mutation testing were male, 286 (34.9%) in Asia, and 406 (49.5%) in the RoW region. The mean age of patients enrolled in RAS mutation testing phase was 63.2 ± 11.2 years, with slightly more than half of the patients (470, 57.3%) being younger than 65 years. Overall there were no big differences in the demographics between the RAS mutant and Wild Type patients (N = 27 and 788, respectively, Missing N = 5). Nine (56.3%) out of the 16 treated patients were white, 6 (37.5%) were Asian and 1 patient (6.3%) was black or African American. In the Asia population there were only male patients treated, whereas in the RoW population both sexes were represented: 6 were male and 4 were female. The mean age at the time of enrollment was 67.2 ± 8.3 years (median 67.0 years) with the same amount of patients being more than 65 years old or less than 65 years old (8 patients, 50.0% each). At baseline, the mean weight was ± kg, mean height was ± 8.3 cm and mean body mass index was ± 4.74 kg/m 2. As required per protocol, all 16 patients had unresectable or metastatic HCC confirmed either histologically or clinically for cirrhotic patients, and were classified to have a liver function status of Child-Pugh class A on Day 1 of Cycle 1. Histologically verified HCC diagnosis was available for 8 patients (50.0%). 1 patient had a liver function status of Child-Pugh class B at screening and was thus not included in the PPS. As the status changed to class A on Cycle 1 Day 1 this patient was included in the FAS. ECOG performance status was 0 (fully active) for 10 patients (62.5%) and 1 (restricted active) for 6 patients (37.5%). The baseline BCLC stage was A (early stage) for 2 patients (12.5%), B (intermediate stage) for 2 patients (12.5%) and C (advanced stage) for 12 patients (75.0%). Macrovascular invasion was observed in 7 patients (43.8 %). 1 There were a total of 350 Asians enrolled in the study as the RoW population contained 11 patients of Asian race. In the CSR, the term Asia population is used for patients in the FAS (=SAF) who were from the region of Asia.

9 11-JAN-2018 Study no Page: 9 of 23 In 4 patients (25.0%), symptoms of HCC were present at initial diagnosis. The most frequent etiology of the underlying liver disease was hepatitis B in 5 patients (31.3%), followed by hepatitis C in 4 patients (25.0%) and alcohol use in 3 patients (18.8%). Some patients had mixed etiologies: alcohol use / hepatitis C and alcohol use / genetic / metabolic, 1 patient (6.3%) each. Nonalcoholic steatohepatitis (NASH) was reported as an etiology for 1 patient and for 1 patient the etiology was unknown. Liver cirrhosis was reported in 11 patients (68.8%), of which 3 (18.8%) were confirmed histologically, 5 (31.3%) clinically and 3 (18.8%) both histologically and clinically. According to mrecist, at baseline all (100.0%) patients had at least one lesion in the liver. One target lesion was presented in 4 patients (25.0%), two target lesions in 10 patients (62.5%), 3 target lesions in 1 patient (6.3%) and 4 target lesions in 1 patient (6.3%). In 6 patients (37.5%) extrahepatic spread was present. The most common extra-hepatic site was lung in 4 patients (25.0%), followed by lymph node in 3 patients (18.8%) and other sites in 1 patient (6.3%). Half of the patients presented only 1 non-target lesion (50.0%). Three or four non-target lesions were presented by 1 patient each. In 37.5% of the patients no non-target lesions were observed. In the Asia population, the median time from the initial diagnosis to study treatment start was weeks, time since first progression was weeks and time from most recent progression to study treatment start was 6.79 weeks. In the RoW population, the respective median times were: weeks, weeks and 9.07 weeks, respectively. Efficacy Primary efficacy variable The primary efficacy variable was the central radiological assessment (central image review) of ORR (confirmed CR plus PR) according to mrecist. By the cut-off date none of the patients in the FAS achieved confirmed CR or PR, and therefore the ORR was 0%. Of note, by cut-off date (29 JUL 2015), there were 3 patients with best response of unconfirmed PR, 1 patient in the Asia population and 2 patients in the RoW population. Out of the 3 patients with the best response of unconfirmed PR, 2 patients were still on treatment at the time of the cut-off and 1 patient had already discontinued the treatment due to progressive disease (radiological progression). The Asian patient with the unconfirmed PR was still on treatment at the time of the data cut-off, and the treatment response for this patient was assessed as confirmed PR after the cut-off date. The other patient with unconfirmed PR who was on treatment at the time of the cut-off date was assessed with PD by central review at the following tumor evaluation, and also by the investigator after the cut-off date, thus the PR was not confirmed. Secondary efficacy variables Based on independent (central) radiological assessment according to RECIST v.1.1, none of the patients in the FAS had confirmed CR or PR, and therefore the ORR was 0%. Based on investigator assessments according to both mrecist and RECIST v.1.1, there was 1 patient in the FAS who had confirmed PR in the RoW population, and therefore the ORR was 6.3% according to investigator.

10 11-JAN-2018 Study no Page: 10 of 23 The results for best overall response, DCR, OS, TTRP, DOR, time to objective response, change in tumor size and PFS based on central and investigator assessments according to mrecist or RECIST v.1.1 are described below for the FAS. Based on central assessment according to mrecist, 3 patients (18.8%) were classified with a best overall response of unconfirmed PR (1 in the Asia and 2 in the RoW population), 4 patients with a best response of SD (1 in the Asia and 3 in the RoW population), and 5 patients with a best response of PD (3 in the Asia and 2 in the RoW population). The best overall response was not evaluable for 1 patient in the Asia population and missing for 3 patients in the RoW population. Based on investigator assessment according to mrecist, 1 patient (6.3%) was classified with a best overall response of confirmed PR, 1 patient (6.3%) with unconfirmed PR, 5 patients (33.3%) were classified with a best response of SD, and 6 patients (40.0%) with PD. Response evaluation was missing for 3 patients (18.8%). Based on central assessment according to RECIST v.1.1, 1 patient (6.3%) was classified with a best overall response of unconfirmed PR, 6 patients (37.5%) were classified with a best response of SD, and 5 patients (31.3%) with PD. For 1 patient (6.3%) the response was not evaluable and for 3 patients (18.8%) the response evaluation was missing. Based on investigator assessment according to RECIST v.1.1, 1 patient (6.3%) was classified with PR and 1 patient (6.3%) with unconfirmed PR as a best overall response. 5 patients (31.3%) were classified with a best response of SD and 6 patients (37.5%) with PD. Data was missing for 3 patients (18.8%). The DCR (defined as the proportion of patients with confirmed CR, confirmed PR or SD for at least 6 weeks) was 43.8% (95% confidence interval [CI] [19.75;70.12]) based on either independent assessment or investigator assessment according to mrecist; And according to RECIST v.1.1, the DCR was also 43.8% (95% CI [19.75;70.12]) based on either independent assessment or investigator assessment. Analysis of OS resulted in the median survival time of 427 days with 95% CI [99; upper bound could not be estimated due to censored data] (range between 36 and 427 days, excluding censored values). Overall, by the cut-off date a total of 5 patients (31.3%) died and the OS rate was (95% CI [0.695;1.000]) at month 2, (95% CI [0.557;1.000]) at month 4, (95% CI [0.078;0.962]) at month 8 and (95% CI [0.000;0.683]) at month 16. For the 3 patients who were still under treatment at the time of the cut-off date, the OS was 652 days (censored data), 294 days (censored data) and 236 days. Analysis of TTRP resulted in median time to radiological progression of 84 days (range between 39 and 167 days, excluding censored values) based on central assessment according to mrecist. The 95% CI was [42; upper bound could not be estimated due to censored data]. A total of 7 patients (43.8%) had radiological progression. The rate of non-progression was (95% CI [0.760;1.000]) at month 1, (95% CI [0.285;0.858]) at month 2, (95% CI [0.105;0.753]) at month 4 and (95% CI [0.000;0.553]) at month 6. Based on central assessment according to RECIST v.1.1, a total of 8 patients (50.0%) with radiological progression were observed. The median time to radiographic progression was 69 days (range between 39 and 132 days, without censored data). The rate of non-progression was

11 11-JAN-2018 Study no Page: 11 of (95% CI [0.760;1.000]) at month 1, (95% CI [0.285;0.858]) at month 2, (95% CI [0.183;0.770]) at month 4 and (95% CI [0.000;1.000]) at month 6. Based on investigator assessment according to mrecist and RECIST v.1.1, the median time to progression was 69 days. There were no patients with confirmed CR or PR according to central assessment, however there was 1 patient with confirmed PR according to investigator s assessment in the RoW population. For this patient DOR was 83 days (censored) based on mrecist and RECIST v.1.1. Time to objective response was not applicable because no centrally assessed objective tumor responses were observed until the cut-off. Best percent change in target lesions from baseline by independent assessments (reader 1 and reader 2) and investigator assessments according to mrecist are displayed in Figure 1-1, Figure 1-2 and Figure 1-3. Of the 16 patients in the FAS: a best change could be determined for 13 patients by reader 1, for 12 patients by reader 2 and for 10 patients by the investigator. Based on assessment by reader 1, increase in tumor size was observed in 7 patients, while tumor shrinkage in target lesions was observed in 6 patients. Based on assessment by reader 2, increase and decrease in tumor size was observed in 6 patients each. Based on investigator s assessment 6 patients had increase in tumor size and 4 patients had observed tumor shrinkage.

12 11-JAN-2018 Study no Page: 12 of 23 Figure 1-1 Best percent change in target lesions from baseline by mrecist independent assessment Reader 1 (FAS) mrecist = Modified Response Evaluation Criteria in Solid Tumors; FAS = Full analysis set

13 11-JAN-2018 Study no Page: 13 of 23 Figure 1-2 Best percent change in target lesions from baseline by mrecist independent assessment Reader 2 (FAS) mrecist = Modified Response Evaluation Criteria in Solid Tumors; FAS = Full analysis set

14 11-JAN-2018 Study no Page: 14 of 23 Figure 1-3 Best percent change in target lesions from baseline by mrecist investigator assessment (FAS) mrecist = Modified Response Evaluation Criteria in Solid Tumors; FAS = Full analysis set

15 11-JAN-2018 Study no Page: 15 of 23 Based on independent assessment with respect to mrecist, the median PFS time was 46 days. A total of 10 patients (62.5%) were observed with disease progression or had died. The PFS rate was at month 1 (95% CI: 0.794,1.000), at month 2 (95% CI: 0.223,0.757), at month 4 (95% CI: 0.000,0.539) and at month 6 (95% CI: 0.000,0.359). Based on investigator assessment according to mrecist and RECIST v.1.1, median PRF time was 55 days. And independent assessment according to RECIST v1.1 resulted in median PRF time of 46 days. Overall, the combination treatment appears to have anti-tumor efficacy albeit not sufficient to warrant further development in this highly selected patient population. Safety evaluation Extent of exposure All 16 patients assigned to treatment started the intake of refametinib and sorafenib. The median overall duration of refametinib treatment (including interruptions) was 8.21 weeks in the total population; 7.71 weeks in the Asia population and 8.21 weeks in the RoW population. The median actual duration (excluding interruptions) was 7.14 weeks for refametinib treatment in the total population; 6.50 weeks in the Asia population and 7.57 weeks in the RoW population. The mean actual refametinib dose (excluding interruptions) per day was ± mg in the total population, ± mg in the Asia population, and ± mg in the RoW population. The median actual refametinib dose (excluding interruptions) per day was mg (ranging between 53.2 and mg) in the total population, mg (ranging between 53.2 and mg) in the Asia population, and mg (ranging between 66.0 and mg) in the RoW population. All patients received actual daily refametinib dose between 51 and 100 mg. In average, the patients took ± 23.86% of the planned refametinib dose (including interruptions, ± 26.25% in Asia and ± 23.68% in RoW populations). Overall, the mean total refametinib dose given to patients was ± mg, in the Asia population the total dose ( ± mg) was lower compared to the total dose of the RoW population ( ± mg). The median overall duration of sorafenib (including interruptions) was 6.43 weeks in the total population; 6.07 weeks in the Asia population and 6.43 weeks in the RoW population. The median actual duration (excluding interruptions) was 5.36 weeks for sorafenib in the total population; 5.00 weeks in the Asia population and 5.36 weeks in the RoW population. The mean actual sorafenib dose (excluding interruptions) per day was ± mg in the total population, ± mg in the Asia population, and ± mg in the RoW population. The median actual sorafenib dose (excluding interruptions) per day was mg (ranging between and mg) in the total population, mg (ranging between and mg) in the Asia population, and mg (ranging between and mg) in the RoW population.

16 11-JAN-2018 Study no Page: 16 of 23 The majority of the patients (75.0%) received actual daily sorafenib dose between mg. In average, the patients took ± % of the planned sorafenib dose (including interruptions); ± % in Asia and ± % in RoW populations. The mean total sorafenib dose given to patients was ± mg, which was similar in the Asia population ( ± mg) and in the RoW population ( ± mg). Per protocol the sorafenib dose was to be escalated to 800 mg/day from Cycle 2 onwards if no HFSR, fatigue, or GI toxicities of grade 2 or higher occurred. A total of 3 patients (18.8%) received the full dose of 800 mg sorafenib/day. Of these 1 patient started the treatment already with the escalated dose of sorafenib (400 mg mg) from Cycle 1 Day 1. For the rest of the patients the sorafenib dose could not be escalated to 800 mg due to different AEs. The median duration on full sorafenib dose level (800 mg/day) was 10 days (range 9-39 days) and comprised ± 40.66% of the total sorafenib treatment duration in these patients. Treatment-emergent adverse events At least one treatment-emergent adverse event (TEAE) was reported in all 16 patients (100%) during this study. The most common TEAEs occurring in >20% of the study population were: hypertension (81.3%), fatigue (75.0%), diarrhea (62.5 %), aspartate aminotransferase (AST) increased (50.0%), creatine phosphokinase (CPK) increased (50.0%), rash acneiform (50.0%), rash maculo-papular (37.5%), mucositis oral (31.3%), vomiting (31.3%), anorexia (25.0%), hypoalbuminemia (25.0%) and platelet count decreased (25.0%). Of these, the following TEAEs were more common ( 25% difference) in the RoW population compared to the Asia population: rash maculo-papular (50.0% vs. 16.7%), and anorexia (40.0% vs. 0%). The following TEAEs were more common ( 25% difference) in the Asia population compared to the RoW population: hypertension (100.0% vs. 70.0%), AST increase (66.7% vs. 40.0%), CPK increase (66.7% vs. 40.0%), rash acneiform (83.3% vs. 30.0%), mucositis oral (66.7% vs. 10.0%), and platelet count decreased (50.0% vs. 10.0%). In the total population, TEAEs occurred most commonly in Common Terminology Criteria for Adverse Events (CTCAE) categories of investigations (100.0%), general disorders and administration site conditions (87.5%), skin and subcutaneous tissue disorders (81.3%), vascular disorders (81.3%) and gastrointestinal disorders (75.0%). Grade 3 TEAEs (worst grade per patient) were reported in 11 patients (68.8%). The most commonly reported worst grade 3 TEAEs were hypertension (62.5%), AST increased (31.3%) and CPK increased (31.3%). Grade 4 TEAEs (worst grade per patient) were observed in 3 patients (18.8%): AST increased, CPK increased, and platelet count decreased. Grade 5 TEAEs were reported in 2 patients (12.5%): 1 patient had general disorders and administration site conditions - other, specify (reduced general condition) and 1 patient had dyspnea and pneumonitis. Drug-related adverse events Both refametinib- and sorafenib-related TEAEs were reported for all patients (100.0%). In the total population, 3 patients (18.8%) had refametinib-related TEAEs of worst CTCAE grade 2,

17 11-JAN-2018 Study no Page: 17 of 23 9 patients (56.3%) had grade 3 TEAEs, 3 patients (18.8%) had grade 4 TEAEs (AST increased, CPK increased and platelet count decreased), and 1 patient (6.3%) had a grade 5 TEAE (general disorders and administration site conditions other, specify [reduced general condition]) related to refametinib according to the investigator. The most common refametinib-related TEAEs occurring in >20% of the study population were: fatigue (56.3%), rash acneiform (50.0%), CPK increased (37.5%), diarrhea (37.5%), hypertension (37.5%), AST increased (31.3%), rash maculo-papular (31.3%), anorexia (25.0%), and mucositis oral (25.0%). Of these, the following refametinib-related TEAEs were more common in the RoW population compared to the Asia population: anorexia (40.0% vs. 0%), rash maculo-papular (40.0% vs. 16.7%), hypertension (40.0% vs. 33.3%), and AST increased (33.3% vs. 30.0%). The following refametinib-related TEAEs were more common in the Asia population compared to the RoW population: rash acneiform (83.3% vs. 30.0%), mucositis oral (50.0% vs. 10.0%), CPK increased (66.7% vs. 20.0%), diarrhea (50.0% vs. 30.0%), and fatigue (66.7% vs. 50.0%). 12 patients (75.0%) had sorafenib-related TEAEs of worst CTCAE grade 3, 3 patients (18.8%) had grade 4 TEAEs (AST increase, CPK increase, and platelet count decrease) and 1 patient (6.3%) had a grade 5 TEAE (general disorders and administration site conditions other, specify [reduced general condition]) related to sorafenib according to the investigator. The most common sorafenib-related TEAEs occurring in >20% of the study population were: hypertension (75.0%), diarrhea (62.5%), fatigue (62.5%), AST increased (31.3%), rash maculo-papular (31.3%), anorexia (25.0%), mucosits oral (25.0%), rash acneiform (25.0%), and vomiting (25.0%). Of these, the following sorafenib-related TEAEs were more common in the RoW population compared to the Asia population: anorexia (40.0% vs. 0%), diarrhea (70.0% vs. 50.0%), fatigue (70.0% vs. 50.0%), rash maculo-papular (40.0% vs. 16.7%), and vomiting (30.0% vs. 16.7%). The following refametinib-related TEAEs were more common in the Asia population compared to the RoW population: hypertension (100.0% vs. 60.0%), rash acneiform (66.7% vs. 0%), mucositis oral (50.0% vs. 10.0%), and AST increased (33.3% vs. 30.0%). Evaluation of cardiac, ophthalmic, neurologic and psychiatric AEs There was 1 patient with a cardiac AE of CTCAE grade 1 (atrioventricular block first degree). This patient belonged to the RoW population. This AE was considered not related to refametinib and sorafenib and it was not serious. The event was not resolved by the cut-off date for this report. A total of 5 patients (31.3%) experienced treatment-emergent eye disorders; 1 in the Asia population and 4 in the RoW population. One patient experienced two events (grade 2 retinal detachment, and grade 1 eye disorders other, specify [visual acuity reduced]), and one patient experienced 3 events (grade 1 glaucoma, grade 1 worsening of glaucoma and grade 2 worsening of glaucoma). Seven of these ophthalmic events (2 x blurred vision, 2 x worsening of glaucoma, eye disorders other, specify [visual acuity reduced], retinal detachment, and retinopathy) were assessed as related to refametinib, of which three events (blurred vision, and 2x worsening of glaucoma) were considered related also to sorafenib. All these ophthalmic events had the outcome recovered/resolved. Two events (grade 2 retinal detachment, and grade 2 worsening of glaucoma) were regarded as serious. The grade 2 retinal detachment led to interruption of refametinib medication and the grade 2 worsening of glaucoma led to withdrawal of sorafenib.

18 11-JAN-2018 Study no Page: 18 of 23 A total of 8 patients (50.0%) presented TEAEs belonging to the CTCAE category nervous system disorders, 2 in the Asia population and 6 in the RoW population. Neurologic events were assessed as related to refametinib for a total of 4 patients (grade 1 and grade 2 dizziness, grade 1 headache and grade 3 syncope [SAE]). A total of 6 sorafenib-related neurologic events were observed (grade 1 and grade 2 dizziness, grade 1 concentration impairment, grade 1 headache, grade 3 vasovagal reaction [SAE] and grade 3 syncope [SAE]). A total of 4 patients (25.0%) presented TEAEs belonging to the CTCAE category psychiatric disorders, 1 in the Asia population and 3 in the RoW population. Psychiatric events were assessed as related to both refametinib and sorafenib for 2 patients (anxiety of grade 2 and confusion of grade 1). None of the psychiatric events were regarded as serious. There were no patients with treatment-emergent ophthalmic, cardiac, neurologic or psychiatric disorders of worst grade 4 or 5. Deaths Overall, a total of 5 patients died (31.3%), of which 2 patients (12.5%) up to 30 days after the last dose of study medication and 3 patients (18.8%) later than 30 days after the last dose of study medication. No patients died during the study medication. Of the 5 deaths, 2 were reported in the Asia population and 3 in the RoW population. 2 patients died during the safety follow-up period: 1 patient from Asia (progressive disease - pneumonitis and dyspnea, not related to refametinib or sorafenib) and 1 patient from RoW population (AE associated with clinical disease progression - general disorders and administration site conditions-other specify [reduced general condition], related to both refametinib and sorafenib according to investigator s assessment). 3 patients died during the long-term follow-up period: 1 patient from Asia (progressive disease) and 2 from RoW population (progressive disease, and other - acute respiratory failure on bronchio-pneumopathy with Pseudomonas aeruginosa and Escherichia coli). Death was not related to refametinib and sorafenib in any of these patients. Moreover, one patient died before completion of the screening phase 2 (cause of death: AE associated with clinical disease progression - jaundice and ascites), and one patient died during screening phase 1 (cause of death: progressive disease). However, these were not captured in the database as reporting of AEs during the screening phases was not required per protocol. Serious adverse events SAEs were experienced by 13 patients (81.3%), 6 patients (100.0%) in the Asia population and 7 patients (70.0%) in the RoW population. The worst grade for SAEs was most commonly grade 3 with an overall incidence of 50.0%. 1 patient (6.3%) had a SAE with worst grade 4. Grade 5 treatment-emergent SAEs were reported in 2 patients (12.5%). The most common SAE occurring in 6 patients (37.5%) was CPK increased. Per protocol, CPK increase of grade 3 was considered as an AE of special interest and was to be reported as an SAE. The rest of the SAEs were reported in 1 patient (6.3%) each.

19 11-JAN-2018 Study no Page: 19 of patients (75.0%) had SAEs that were assessed as related to refametinib by the investigator and 10 patients (62.5%) had SAEs that were assessed as related to sorafenib. Out of the 12 patients with refametinib-related SAEs, 5 patients were from the Asia population and 7 from the RoW population. CPK increased was the most commonly reported refametinibrelated SAE with 5 patients, out of which 1 patient experienced a grade 4 SAE. All other refametinib-related SAEs were reported in 1 patient each. Most of the patients with refametinibrelated SAEs (43.8%) had worst grade 3 SAE. There were 3 patients who experienced worst grade 2 refametinib-related SAEs, 1 patient with worst grade 4 SAE (CPK increased) and 1 patient with a grade 5 SAE (general disorders and administration site conditions - other, specify [reduced general condition]). Out of the 10 patients with sorafenib-related SAEs, 5 patients were from the Asia population and 5 from the RoW population. Most of the patients with sorafenib-related SAEs (43.8%) had worst grade 3 SAE. There was 1 patient who experienced a worst grade 2 sorafenib-related SAE, 1 patient with worst grade 4 SAE (CPK increased) and 1 patient with a grade 5 SAE (general disorders and administration site conditions - other, specify [reduced general condition]). Follow-up safety data were collected between 29 JUL 2015 (cut-off of the final analysis) and 08 FEB 2017 (last patient s last visit). During this period, 6 new SAEs (MedDRA PTs) were reported: blood creatine phosphokinase increased (Grade 3) in 2 patients, and retinal vein occlusion (Grade 2), hepatic failure (Grade 3 and 5, both in the same patient), and diarrhea (Grade 4) in 1 patient each. Other significant AEs TEAEs leading to discontinuation of study drug or combination drug: A total of 5 patients (31.3%) in the SAF population experienced a total of 7 TEAEs causing discontinuation of refametinib or sorafenib. Of note for 2 of the patients the primary reason for discontinuation was progressive disease radiological progression, and for 2 of them the primary reason for discontinuation was AE not associated with clinical disease progression. One of the patients had discontinued the sorafenib treatment, but was still on active refametinib treatment at the time of the data cut-off. Four of these patients with TEAEs leading to study discontinuation were from the RoW population, and one from the Asia population. A TEAE with a worst grade of 2 was experienced by 1 patient (6.3%) (glaucoma). One patient (6.3%) experienced a grade 4 TEAE (AST increased), and this same patient had also two grade 3 TEAEs (alanine aminotransferase [ALT] increased and hepatic failure). There were two additional patients with grade 3 TEAEs (hypertension and fatigue) leading to discontinuation of the treatment. 5 of the 7 TEAEs leading to treatment discontinuation were assessed as refametinib-related and 6 of them as sorafenib-related. TEAEs leading to dose interruptions: TEAEs led to dose interruption in a total of 14 patients (87.5%) for both refametinib and sorafenib. In the Asia population TEAEs led to dose interruption in 5 patients (83.3%) for refametinib and in 6 patients (100.0%) for sorafenib. In the RoW population TEAEs led to dose interruption in 9 patients (90.0%) for refametinib and in 8 patients (80.0%) for sorafenib.

20 11-JAN-2018 Study no Page: 20 of 23 The most common TEAE leading to dose interruption for refametinib was AST increased in 5 patients (31.3%), and the most common TEAE leading to dose interruption for sorafenib was hypertension in 8 patients (50.0%). TEAEs that led to dose interruption were most commonly of worst grade 3 with 12 patients (75.0%) for refametinib and with 14 patients (100.0%) for sorafenib. There was 1 patient with a TEAE of worst grade 2 and 1 patient with a TEAE of worst grade 4 leading to dose interruption for refametinib. Investigator considered the TEAEs resulting in dose interruption for refametinib as refametinibrelated in a total of 13 patients (81.3%). These TEAEs were most commonly of worst grade 3 (62.5%). CPK increased was the most common refametinib-related worst grade 3 TEAE that led to dose interruption, and it was experienced by 3 patients (18.8%). One patient (6.3%) was reported with a worst grade 4 refametinib-related TEAE leading to refametinib interruption (AST increased). Investigator considered the TEAEs resulting in dose interruption for sorafenib as sorafenibrelated in a total of 14 patients (87.5%). These TEAEs were all of worst grade 3. Hypertension was the most common worst grade 3 sorafenib-related TEAE that led to dose interruption experienced by 7 patients (43.8%). TEAEs leading to dose reductions: Refametinib dose was reduced due to TEAEs in a total of 6 patients (37.5%) and sorafenib dose in 9 patients (56.3%), in the total population. In the Asia population TEAEs led to dose reductions in 2 patients (33.3%) for refametinib and in 3 patients (50.0%) for sorafenib. In the RoW population TEAEs led to dose reduction in 4 patients (40.0%) for refametinib and in 6 patients (60.0%) for sorafenib. The most common TEAEs leading to dose reduction for refametinib were AST increased and hypertension in 2 patients each (12.5%), and the most common TEAE leading to dose reduction for sorafenib was hypertension in 6 patients (37.5%). TEAEs that led to dose reduction were most commonly of worst grade 3 with 4 patients (25.0%) for both refametinib and sorafenib. There were no TEAEs with worst grade 4 leading to dose reduction. Investigator considered the TEAEs resulting in dose reduction for refametinib as refametinibrelated in a total of 5 patients (31.3%). These TEAEs were most commonly of worst grade 3 (18.8%). No TEAEs with worst grade 4 or 5 were observed. There were 2 patients (12.5%) reported with refametinib-related hypertension leading to dose reduction for refametinib. All other TEAEs were experienced by 1 patient each. Investigator considered the TEAEs resulting in dose reduction for sorafenib as sorafenib-related in a total of 9 patients (56.3%). These TEAEs were most commonly of worst grade 3 (25.0%). Hypertension was the most common sorafenib-related TEAE that led to dose reduction in 6 patients (37.5%).

21 11-JAN-2018 Study no Page: 21 of 23 Adverse events of special interest In previous trials with MEK inhibitors, CPK increase was one of the most commonly reported AE. Therefore, to gather more data on safety, CPK increase grade 3 was considered as an AE of special interest, and was to be reported as SAE per protocol. Overall, there were 6 patients who experienced CPK increase of grade 3 or higher, 1 patient had 2 events. There was one event of worst grade 4. All other events of special interest were of grade 3 in severity, reported as serious. 6 out of the 7 events were considered related to refametinib by the investigator s assessment and 4 of them were considered related to sorafenib. Laboratory abnormalities The most common pre-treatment laboratory abnormalities were Gamma-glutamyl transpeptidase (GGT) increased in 13 patients (81.3%), alkaline phosphate increased in 12 patients (75.0%), and AST increased and hyperglycemia both in 9 patients (56.3%). Two worst grade 4 pre-treatment laboratory abnormalities were found (hyperuricemia and hypocalcemia). The most common laboratory abnormality observed after the start of treatment was AST increased that was reported in all 16 patients (100.0%). The other common laboratory abnormalities after the start of treatment (occurred in 80% of the patients) were alkaline phosphatase increased, GGT increased and hypoalbuminemia in 15 patients (93.8%) each, and ALT increased in 13 patients (81.3%). Worst grade 4 laboratory abnormalities after the start of treatment (all reported in 1 patient each) were AST increased, CPK increased, platelet count decreased, hypophosphatemia, hypocalcemia and hyperuricemia, of which hypocalemia and hyperuricemia were reported already at baseline. Worst grade 3 laboratory abnormalities after the start of treatment that were reported in more than 1 patient were AST increased, GGT increased, CPK increased, ALT increased, hyperglycemia, lipase increased, serum amylase increased and hyponatremia. For CPK increase two grade 1 abnormal laboratory values were observed before the start of the treatment. During the treatment CPK increase was observed in 11/16 patients (68.8%). Of these, 1 patient had grade 4 CPK increase and 5 patients had grade 3 increase, which were reported as SAEs as described above. Before the start of the treatment, the liver function parameter laboratory abnormalities were as follows: AST increase was reported in 9 patients (56.3%), ALT increase in 4 patients (25.0%) and blood bilirubin increase in 5 patients (31.3%). These were mostly of grade 1 in severity. There was one grade 3 pre-treatment laboratory abnormality related to increase in AST. No grade 4 AST, ALT or bilirubin abnormalities were observed before the treatment. After the start of the treatment, AST increase was reported in all 16 patients (100.0%), ALT increase in 13 patients (81.3%) and blood bilirubin increase in 6 patients (37.5%). There was a grade 4 AST increase observed in 1 patient and AST increase was reported as grade 3 in 6 patients (37.5%). Grade 3 ALT increase was reported in 3 patients (18.8%) and grade 3 blood bilirubin increase in 1 patient (6.3%). No grade 4 ALT or bilirubin abnormalities were reported during the treatment.

22 11-JAN-2018 Study no Page: 22 of 23 Other safety evaluations Regarding electrocardiogram findings abnormal interpretations (however, not clinically significant) were reported in all cycles. At Cycle 5 Day 1, 1 patient had a clinically significant ECG test result: 1 st degree AV block. The ECG listing from the patient with abnormal interpretation contained: AV block 1 st degree was reported as an AE, grade 1, not drug related, and no action was taken with both drugs. According to investigator, there were no clinically significant cardiac function abnormalities observed in the study and at all visits all tested patients were New York Heart Association (NYHA) Class I. Evaluation of ECOG and Child-Pugh scores during the study are consistent with deterioration in patient s health status mainly due to progression of the underlying disease. Other evaluations PK analysis Plasma concentrations of sorafenib and refametinib and its metabolites (BAY [metabolite M-17] and BAY [metabolite M-11]) were generally consistent with historical clinical data. No additional analysis of PK data will be performed. Biomarker analysis Biomarkers associated with drug response or non-response will be determined retrospectively and reported in a separate report. PRO / HRQoL (Stage 2 only) As the study did not continue to Stage 2 there were no analyses. Overall conclusions In this trial using refametinib in combination with sorafenib in a selected RAS mutant HCC population the following can be concluded: Prospective testing for RAS mutation using circulating cell free tumor DNA was feasible resulting in a mutation rate of 3.3% in the overall HCC population tested. At the time of the data cut-off, no patient achieved a confirmed CR or PR (as assessed by central review) using mrecist. Therefore the target of Stage 1 of the trial (at least 5 out of 15 patients with a confirmed CR or PR) was not reached and the study did not continue to Stage 2. However, of note, out of 16 treated patients there was 1 patient assessed with confirmed PR after the cut-off date. In addition, 2 patients had unconfirmed PR suggesting some anti-tumor activity of this combination regimen. Frequent grade 3 toxicities mandated dose modifications that may have led to insufficient drug exposure of both compounds.