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Vemurafenib in BRAFV600 mutated metastatic melanoma: a subanalysis of the Italian population of a global safety study Michele Del Vecchio*,1, Paolo Antonio Ascierto2, Mario Mandalà3, Vanna Chiarion Sileni4, Michele Maio5, Lorenza Di Guardo1, Ester Simeone2 & Paola Queirolo6
ABSTRACT Aim: We describe the ad interim analysis of the Italian cohort of the global safety study on vemurafenib in patients with metastatic melanoma. Patients & methods: A total of 385 patients received vemurafenib 960 mg twice daily. Results: In total, 330 patients (86%) reported adverse events; 16 serious adverse events were observed (three related to vemurafenib). The response rate was 30.4%. Median progression-free survival (PFS) and overall survival (OS) were 5.9 months and 16.3 months, respectively. In patients with brain metastasis (BM; n = 83), median PFS was 4.3 months and OS was 7.6 months. In patients without BM, PFS was 6.5 months and OS was not reached. Median PFS was 12.6 months in patients with M1a stage of disease, 9.6 months in those with M1b stage and 5.4 months in subjects with M1c stage. Conclusion: Vemurafenib appears safe and active in clinical practice, and seems particularly active in patients without BM and low tumor burden. Metastatic melanoma (MM) is associated with poor prognosis, with a 5-year survival rate of about 60% in patients with regional metastasis and 15% in patients with distant metastasis [1,2] . Of note, chemotherapy has only limited efficacy for the treatment of this disease [3–6] . In clinical trials, biological agents such as vemurafenib – an inhibitor of the BRAF kinase – and the anti-CTLA-4 antibody ipilimumab have been shown to prolong survival in patients with MM and are now established treatment options in clinical practice [7–9] . It is, however, widely acknowledged that clinical trial patients are not entirely comparable with those treated in daily clinical practice. For example, patients enrolled in clinical trials usually have a good performance status; more specifically, in the MM setting, patients with brain metastases are often considered not eligible, while about one out of three stage IV MM present CNS involvement [10,11] . Large, well-conducted observational studies can provide further details on data emerging from clinical trials and also help gather evidence on the safety and effectiveness of different treatment strategies in daily practice [12,13] . Expanded access and safety clinical practice studies are also important in documenting rare adverse events (AEs), such as secondary melanomas or other malignancies [14,15] . The safety and the effectiveness of vemurafenib in clinical practice has been already assessed in a very recent large global study, conducted in 44 countries [16] . Overall, at the third ad interim analysis of this study, at a median follow-up of 11.5 months, the safety and efficacy of this molecule was consistent with those reported previously. In addition, the global safety study suggested that vemurafenib may be safe and effective in patients who have poor prognosis and are typically excluded from clinical trials [16] .
KEYWORDS
• metastatic melanoma • safety • vemurafenib
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Unit of Melanoma, Cancer Immunotherapy & Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy 3 Papa Giovanni XXIII Hospital, Bergamo, Italy 4 Veneto Institute of Oncology (IOV) – IRCCS, Padua, Italy 5 Istituto Toscano Tumori, University Hospital, Siena, Italy 6 Istituto Nazionale Tumori, San Martino Hospital, Genoa, Italy *Author for correspondence: [email protected] 1 2
10.2217/FON.15.55 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(9), 1355–1362
part of
ISSN 1479-6694
1355
Research Article Del Vecchio, Ascierto, Mandalà et al. We describe the ad interim analysis of the Italian cohort of the global safety study on vemurafenib, in order to provide a picture of the results collected in a limited number of reference centers with experience in the treatment of MM; of note, the Italian cohort accounted for more than 10% of the entire study population. Patients & methods In this paper, we consider only the results achieved in the Italian cohort of the global safety study on vemurafenib (study code NCT01307397) [17] . This is the third ad interim safety analysis, with a data cutoff on 31 January 2013. The final analysis will be performed after all enrolled patients have died, withdrawn consent, have been lost to follow-up or have been followed up for secondary malignancy for 24 months after the enrollment of the last patient. The methods of this study have been described in detail elsewhere [16] . Only a synopsis of the methods is reported here. ●●Study design & patients
This was an open-label, multicenter study aimed at assessing the safety, tolerability and effectiveness of vemurafenib in untreated or previously treated patients with unresectable stage IIIC or stage IV melanoma carrying a BRAFV600 mutation. The study comprised a screening period (days -28 to -1), treatment phase, follow-up visit 28 days after the last vemurafenib dose and a safety phase lasting until 24 months after the last patient was enrolled. The study protocol was approved by the institutional review boards or independent ethics committee at each study center, and the study was performed in accordance with Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent. ●●Procedures
Patients received oral vemurafenib 960 mg twice a day until progression of disease, unacceptable toxicity, withdrawal of consent or death. Dose interruption and reduction to 720 mg twice a day and then 480 mg twice a day was allowed for intolerable grade 2 or 3 toxicity. ●●Outcomes
The primary end point was safety, with clinical assessments for safety being performed every 28 days during treatment. The main efficacy variable
1356
Future Oncol. (2015) 11(9)
was the proportion of patients with an investigator-assessed confirmed objective response according to the RECIST criteria (version 1.1). Other efficacy variables included progression-free survival (PFS; defined as the time between the first dose of vemurafenib and the date of progression or death for any cause) and overall survival (OS; time from the first vemurafenib dose to the date of death for any cause). ●●Statistical analysis
Data were analyzed by descriptive statistics and all percentages are referred to the total Italian population of the global safety study if not otherwise stated. All analyses were performed on the safety population and included all patients who received at least one dose of vemurafenib. Estimates of PFS and OS were calculated using a Kaplan–Meier approach. Subgroup analyses on the efficacy variables were performed according to the presence of brain metastases at baseline and the metastatic stage at baseline (M1a, M1b and M1c). Results ●●Patient population
In total, 385 Italian patients were evaluated in the present subanalysis; of these, 135 received prior systemic chemotherapy (35%) and 44 (11%) ipilimumab. In total, 83 patients (22%) had brain metastasis at baseline. A total of 48 patients (12%) had stage M1a disease, 53 (14%) M1b and 280 (73%) M1c. Table 1 summarizes patient’s baseline characteristics. The median follow-up of the study was 11.5 months (95% CI: 11.2–11.8). In total, 74 (19%) patients maintained the full dosing during the entire observation period. A total of 60 patients (16%) interrupted the study for reasons other than progression of disease. At disease progression, 146 patients (38%) remained on vemurafenib and 17 (4%) were treated with ipilimumab. ●●Safety
summarizes the safety findings in the overall population. In total, 330 patients (86%) reported at least one AE; in 269 cases (70%), the AE was considered related to the study drug. Only a low proportion of patients (n = 16; 4%) had to discontinue the study due to AEs. Most frequent AEs included rash (n = 82; 21%), arthralgia (n = 73; 19%), asthenia (n = 57; 15%), alopecia (n = 49; 13%) and nausea (n = 47; Table 2
future science group
Vemurafenib in BRAFV600 mutated metastatic melanoma
Research Article
Table 1. Patient’s baseline characteristics (n = 385). Patients
n (%)
Patients with brain metastases at baseline Patients with ECOG 0–1 at baseline Patients with ECOG ≥2 at baseline Patients with unknown ECOG at baseline Patients aged ≥65 years Patients aged ≥75 years Males Patients who received prior ipilimumab Patients who received prior BRAF inhibitor Patients who received prior MEK inhibitor Patients who received prior systemic chemotherapy
83 (22) 356 (92) 20 (5) 9 (2) 89 (23) 21 (5) 208 (54) 44 (11) 0 12 (31) 135 (35)
ECOG: Eastern Cooperative Oncology Group.
12%). Squamous cell carcinoma was diagnosed in 18 patients (5%) and keratoacanthoma in 16 (4%). Two patients (1%) reported a new primary melanoma. Sixteen patients (5%) experienced serious AEs. Three serious AEs, namely one case of dysphagia and two cases of neutropenia, were considered related to vemurafenib and required treatment interruption in one case (dysphagia) and treatment discontinuation in another (neutropenia). All vemurafenib-related severe AEs were fully resolved. A total of 288 patients (75%) reported AEs during the first 3 months of vemurafenib treatment, with 12 cases (3%) requiring study discontinuation. In 219 patients (57%), these events were considered related to vemurafenib. ●●Efficacy variables
In total, 332 patients (82%) had measurable disease at baseline and at least one tumor assessment post baseline: of these, 4% (n = 14) showed a complete response, 26% (n = 87) a partial response and 54% (n = 181) stable disease, with an overall disease control rate of 84% (Table 3) . A total of 278 patients (72.2%) progressed at the cutoff date, with a median PFS of 5.9 months (95% CI: 5.4–6.8), and 132 patients (24.3%) died, with a median OS of 16.3 months (13.4–not reached) (Figure 1) . In patients with brain metastasis, median PFS was 4.3 months (95% CI: 3.6–5.4) and OS was 7.6 months (95% CI: 6.0–11.1). On the other hand, in patients without brain metastasis, the median PFS was 6.5 months (95% CI: 5.7–8.0) and OS was not reached (95% CI: 16.3–not reached) (Figure 2) . When stratifying patients according to disease stage at baseline, median PFS was 12.6 months
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(95% CI: 7.7–not reached) in patients with M1a stage of disease, 9.6 months (95% CI: 6.0–13.2) in those with M1b stage and 5.4 months (95% CI: 4.7–5.9) in subjects with M1c stage (Figure 3) . Median OS was not reached in patients with M1a and M1b stages of disease, and 12.9 months (95% CI: 11.6–16.3) in those with M1c stage (Figure 3) . Discussion In this ad interim subanalysis of the Italian cohort of the global safety study, vemurafenib appears fairly well tolerated, with no new safety concerns with respect to the global cohort. These findings were obtained in a daily practice scenario, and were collected in a mixed population of patients who present overall poorer clinical conditions than those enrolled in clinical trials [12,13] . More in detail, most common AEs were rash, arthralgia, asthenia, alopecia and nausea, and only a low incidence (
Vemurafenib in BRAFV600 mutated metastatic melanoma: a subanalysis of the Italian population of a global safety study Michele Del Vecchio*,1, Paolo Antonio Ascierto2, Mario Mandalà3, Vanna Chiarion Sileni4, Michele Maio5, Lorenza Di Guardo1, Ester Simeone2 & Paola Queirolo6
ABSTRACT Aim: We describe the ad interim analysis of the Italian cohort of the global safety study on vemurafenib in patients with metastatic melanoma. Patients & methods: A total of 385 patients received vemurafenib 960 mg twice daily. Results: In total, 330 patients (86%) reported adverse events; 16 serious adverse events were observed (three related to vemurafenib). The response rate was 30.4%. Median progression-free survival (PFS) and overall survival (OS) were 5.9 months and 16.3 months, respectively. In patients with brain metastasis (BM; n = 83), median PFS was 4.3 months and OS was 7.6 months. In patients without BM, PFS was 6.5 months and OS was not reached. Median PFS was 12.6 months in patients with M1a stage of disease, 9.6 months in those with M1b stage and 5.4 months in subjects with M1c stage. Conclusion: Vemurafenib appears safe and active in clinical practice, and seems particularly active in patients without BM and low tumor burden. Metastatic melanoma (MM) is associated with poor prognosis, with a 5-year survival rate of about 60% in patients with regional metastasis and 15% in patients with distant metastasis [1,2] . Of note, chemotherapy has only limited efficacy for the treatment of this disease [3–6] . In clinical trials, biological agents such as vemurafenib – an inhibitor of the BRAF kinase – and the anti-CTLA-4 antibody ipilimumab have been shown to prolong survival in patients with MM and are now established treatment options in clinical practice [7–9] . It is, however, widely acknowledged that clinical trial patients are not entirely comparable with those treated in daily clinical practice. For example, patients enrolled in clinical trials usually have a good performance status; more specifically, in the MM setting, patients with brain metastases are often considered not eligible, while about one out of three stage IV MM present CNS involvement [10,11] . Large, well-conducted observational studies can provide further details on data emerging from clinical trials and also help gather evidence on the safety and effectiveness of different treatment strategies in daily practice [12,13] . Expanded access and safety clinical practice studies are also important in documenting rare adverse events (AEs), such as secondary melanomas or other malignancies [14,15] . The safety and the effectiveness of vemurafenib in clinical practice has been already assessed in a very recent large global study, conducted in 44 countries [16] . Overall, at the third ad interim analysis of this study, at a median follow-up of 11.5 months, the safety and efficacy of this molecule was consistent with those reported previously. In addition, the global safety study suggested that vemurafenib may be safe and effective in patients who have poor prognosis and are typically excluded from clinical trials [16] .
KEYWORDS
• metastatic melanoma • safety • vemurafenib
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Unit of Melanoma, Cancer Immunotherapy & Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy 3 Papa Giovanni XXIII Hospital, Bergamo, Italy 4 Veneto Institute of Oncology (IOV) – IRCCS, Padua, Italy 5 Istituto Toscano Tumori, University Hospital, Siena, Italy 6 Istituto Nazionale Tumori, San Martino Hospital, Genoa, Italy *Author for correspondence: [email protected] 1 2
10.2217/FON.15.55 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(9), 1355–1362
part of
ISSN 1479-6694
1355
Research Article Del Vecchio, Ascierto, Mandalà et al. We describe the ad interim analysis of the Italian cohort of the global safety study on vemurafenib, in order to provide a picture of the results collected in a limited number of reference centers with experience in the treatment of MM; of note, the Italian cohort accounted for more than 10% of the entire study population. Patients & methods In this paper, we consider only the results achieved in the Italian cohort of the global safety study on vemurafenib (study code NCT01307397) [17] . This is the third ad interim safety analysis, with a data cutoff on 31 January 2013. The final analysis will be performed after all enrolled patients have died, withdrawn consent, have been lost to follow-up or have been followed up for secondary malignancy for 24 months after the enrollment of the last patient. The methods of this study have been described in detail elsewhere [16] . Only a synopsis of the methods is reported here. ●●Study design & patients
This was an open-label, multicenter study aimed at assessing the safety, tolerability and effectiveness of vemurafenib in untreated or previously treated patients with unresectable stage IIIC or stage IV melanoma carrying a BRAFV600 mutation. The study comprised a screening period (days -28 to -1), treatment phase, follow-up visit 28 days after the last vemurafenib dose and a safety phase lasting until 24 months after the last patient was enrolled. The study protocol was approved by the institutional review boards or independent ethics committee at each study center, and the study was performed in accordance with Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent. ●●Procedures
Patients received oral vemurafenib 960 mg twice a day until progression of disease, unacceptable toxicity, withdrawal of consent or death. Dose interruption and reduction to 720 mg twice a day and then 480 mg twice a day was allowed for intolerable grade 2 or 3 toxicity. ●●Outcomes
The primary end point was safety, with clinical assessments for safety being performed every 28 days during treatment. The main efficacy variable
1356
Future Oncol. (2015) 11(9)
was the proportion of patients with an investigator-assessed confirmed objective response according to the RECIST criteria (version 1.1). Other efficacy variables included progression-free survival (PFS; defined as the time between the first dose of vemurafenib and the date of progression or death for any cause) and overall survival (OS; time from the first vemurafenib dose to the date of death for any cause). ●●Statistical analysis
Data were analyzed by descriptive statistics and all percentages are referred to the total Italian population of the global safety study if not otherwise stated. All analyses were performed on the safety population and included all patients who received at least one dose of vemurafenib. Estimates of PFS and OS were calculated using a Kaplan–Meier approach. Subgroup analyses on the efficacy variables were performed according to the presence of brain metastases at baseline and the metastatic stage at baseline (M1a, M1b and M1c). Results ●●Patient population
In total, 385 Italian patients were evaluated in the present subanalysis; of these, 135 received prior systemic chemotherapy (35%) and 44 (11%) ipilimumab. In total, 83 patients (22%) had brain metastasis at baseline. A total of 48 patients (12%) had stage M1a disease, 53 (14%) M1b and 280 (73%) M1c. Table 1 summarizes patient’s baseline characteristics. The median follow-up of the study was 11.5 months (95% CI: 11.2–11.8). In total, 74 (19%) patients maintained the full dosing during the entire observation period. A total of 60 patients (16%) interrupted the study for reasons other than progression of disease. At disease progression, 146 patients (38%) remained on vemurafenib and 17 (4%) were treated with ipilimumab. ●●Safety
summarizes the safety findings in the overall population. In total, 330 patients (86%) reported at least one AE; in 269 cases (70%), the AE was considered related to the study drug. Only a low proportion of patients (n = 16; 4%) had to discontinue the study due to AEs. Most frequent AEs included rash (n = 82; 21%), arthralgia (n = 73; 19%), asthenia (n = 57; 15%), alopecia (n = 49; 13%) and nausea (n = 47; Table 2
future science group
Vemurafenib in BRAFV600 mutated metastatic melanoma
Research Article
Table 1. Patient’s baseline characteristics (n = 385). Patients
n (%)
Patients with brain metastases at baseline Patients with ECOG 0–1 at baseline Patients with ECOG ≥2 at baseline Patients with unknown ECOG at baseline Patients aged ≥65 years Patients aged ≥75 years Males Patients who received prior ipilimumab Patients who received prior BRAF inhibitor Patients who received prior MEK inhibitor Patients who received prior systemic chemotherapy
83 (22) 356 (92) 20 (5) 9 (2) 89 (23) 21 (5) 208 (54) 44 (11) 0 12 (31) 135 (35)
ECOG: Eastern Cooperative Oncology Group.
12%). Squamous cell carcinoma was diagnosed in 18 patients (5%) and keratoacanthoma in 16 (4%). Two patients (1%) reported a new primary melanoma. Sixteen patients (5%) experienced serious AEs. Three serious AEs, namely one case of dysphagia and two cases of neutropenia, were considered related to vemurafenib and required treatment interruption in one case (dysphagia) and treatment discontinuation in another (neutropenia). All vemurafenib-related severe AEs were fully resolved. A total of 288 patients (75%) reported AEs during the first 3 months of vemurafenib treatment, with 12 cases (3%) requiring study discontinuation. In 219 patients (57%), these events were considered related to vemurafenib. ●●Efficacy variables
In total, 332 patients (82%) had measurable disease at baseline and at least one tumor assessment post baseline: of these, 4% (n = 14) showed a complete response, 26% (n = 87) a partial response and 54% (n = 181) stable disease, with an overall disease control rate of 84% (Table 3) . A total of 278 patients (72.2%) progressed at the cutoff date, with a median PFS of 5.9 months (95% CI: 5.4–6.8), and 132 patients (24.3%) died, with a median OS of 16.3 months (13.4–not reached) (Figure 1) . In patients with brain metastasis, median PFS was 4.3 months (95% CI: 3.6–5.4) and OS was 7.6 months (95% CI: 6.0–11.1). On the other hand, in patients without brain metastasis, the median PFS was 6.5 months (95% CI: 5.7–8.0) and OS was not reached (95% CI: 16.3–not reached) (Figure 2) . When stratifying patients according to disease stage at baseline, median PFS was 12.6 months
future science group
(95% CI: 7.7–not reached) in patients with M1a stage of disease, 9.6 months (95% CI: 6.0–13.2) in those with M1b stage and 5.4 months (95% CI: 4.7–5.9) in subjects with M1c stage (Figure 3) . Median OS was not reached in patients with M1a and M1b stages of disease, and 12.9 months (95% CI: 11.6–16.3) in those with M1c stage (Figure 3) . Discussion In this ad interim subanalysis of the Italian cohort of the global safety study, vemurafenib appears fairly well tolerated, with no new safety concerns with respect to the global cohort. These findings were obtained in a daily practice scenario, and were collected in a mixed population of patients who present overall poorer clinical conditions than those enrolled in clinical trials [12,13] . More in detail, most common AEs were rash, arthralgia, asthenia, alopecia and nausea, and only a low incidence (
