ADCETRIS Powder for concentrate for solution Ref.[6593] Active ingredients: Brentuximab vedotin

Pharmacotherapeutic group: Antineoplastic agents; other antineoplastic agents; monoclonal antibodies
ATC code: L01XC12

Mechanism of action

Brentuximab vedotin is an antibody drug conjugate (ADC) that delivers an antineoplastic agent that results in apoptotic cell death selectively in CD30-expressing tumour cells. Nonclinical data suggest that the biological activity of brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 on the cell surface initiates internalisation of the ADC-CD30 complex, which then traffics to the lysosomal compartment. Within the cell, a single defined active species, MMAE, is released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest and results in apoptotic death of the CD30-expressing tumour cell.

Classical HL, sALCL and subtypes of CTCL (including MF and pcALCL) express CD30 as an antigen on the surface of their malignant cells. This expression is independent of disease stage, line of therapy or transplant status. These features make CD30 a target for therapeutic intervention. Because of the CD30-targeted mechanism of action brentuximab vedotin is able to overcome chemo-resistance as CD30 is consistently expressed in patients who are refractory to multi-agent chemotherapy, irrespective of prior transplant status. The CD30-targeted mechanism of action of brentuximab vedotin, the consistent expression of CD30 throughout the classical HL, sALCL and CD30+ CTCL disease and therapeutic spectrums and clinical evidence in CD30-positive malignancies following multiple lines of treatment provide a biologic rationale for its use in patients with relapsed and refractory classical HL, sALCL with or without prior ASCT and CD30+ CTCL after at least 1 prior systemic therapy.

Contributions to the mechanism of action by other antibody associated functions have not been excluded.

Pharmacodynamic effects

Cardiac electrophysiology

Forty-six (46) patients with CD30-expressing haematologic malignancies were evaluable of the 52 patients who received 1.8 mg/kg of brentuximab vedotin every 3 weeks as part of a phase 1, single-arm, open-label, multicenter cardiac safety study. The primary objective was to evaluate the effect of brentuximab vedotin on cardiac ventricular re-polarization and the predefined primary analysis was the change in QTc from baseline to multiple time points in Cycle 1.

The upper 90% confidence interval (CI) around the mean effect on QTc was <10 msec at each of the Cycle 1 and Cycle 3 post-baseline time points. These data indicate the absence of clinically relevant QT prolongation due to brentuximab vedotin administered at a dose of 1.8 mg/kg every 3 weeks in patients with CD30-expressing malignancies.

Clinical efficacy

Hodgkin lymphoma

Study C25003

The efficacy and safety of ADCETRIS were evaluated in a randomised, open-label, 2-arm, multicenter trial in 1334 patients with previously untreated advanced HL in combination with chemotherapy (doxorubicin [A], vinblastine [V] and dacarbazine [D] [AVD]). All patients had a histologically confirmed CD30-expressing disease. Sixty-two percent of patients had extranodal site involvement Of the 1334 patients, 664 patients were randomised to the ADCETRIS + AVD arm and 670 patients were randomised to the ABVD (doxorubicin [A], bleomycin [B], vinblastine [V] and dacarbazine [D]) arm and stratified by number of International Prognostic Factor Project (IPFP) risk factors and region. Patients were treated on days 1 and 15 of each 28-day cycle with 1.2 mg/kg of ADCETRIS administered as an intravenous infusion over 30 minutes + doxorubicin 25 mg/m², vinblastine 6 mg/m², and dacarbazine 375 mg/m². The median number of cycles received was 6 (range, 1 to 6 cycles). Table 4 provides a summary of the baseline patient and disease characteristics. There were no relevant differences in the patient and disease characteristics between the two arms.

Table 4. Summary of baseline patient and disease characteristics in the phase 3 previously untreated HL study:

^a Per Ann Arbor Staging
^b IPFP = International Prognostic Factor Project

The primary endpoint in Study C25003 was modified PFS (mPFS) per independent review facility (IRF), defined as time from randomisation to disease progression, death, or evidence of non-complete response (non-CR) after completion of first-line therapy per IRF followed by subsequent anticancer therapy. Timing of the modified event was the date of the first PET scan post completion of first-line therapy demonstrating the absence of complete response (CR), defined as Deauville score of ≥3. The median modified PFS by IRF assessment was not reached in either treatment arm. The results in the intent-to-treat (ITT) population showed a statistically significant improvement in modified PFS for ADCETRIS+ AVD, with a stratified hazard ratio of 0.770 (95% CI, 0.603; 0.983, p=0.035), indicating a 23% reduction in the risk of modified PFS events for ADCETRIS+ AVD versus ABVD.

A pre-specified subgroup analysis of mPFS by disease stage showed that patients with Stage IV disease had a larger effect compared with the ITT population, with an unstratified hazard ratio of 0.71 (95% CI, 0.53; 0.96), compatible with a 29% reduction in the risk of modified PFS events for ADCETRIS+ AVD versus ABVD. Of the ITT population, 846 patients (64%) had Stage IV disease.

Table 5 provides the efficacy results for modified PFS and overall survival (OS) in the ITT population and patients with Stage IV disease.

Table 5. Efficacy results for previously untreated HL patients treated with 1.2 mg/kg of ADCETRIS + AVD on days 1 and 15 of a 28-day cycle (ITT and Stage IV):

^a At the time of analysis, the median modified PFS follow-up time for both arms was 24.6 months
^b Data from an interim OS analysis

Figure 1. Modified progression-free survival per IRF in the ITT population (ADCETRIS + AVD vs. ABVD):

Figure 2. Modified progression-free survival per IRF in patients with Stage IV disease (ADCETRIS + AVD vs. ABVD):

Other secondary efficacy endpoints including CR rate and ORR at the end of randomisation regimen, CR rate at the end of first-line therapy, and the rate of PET negativity at the end of Cycle 2, duration of response (DOR), duration of complete remission (DOCR), disease-free survival (DFS,) and event-free survival (EFS) all trended in favour of ADCETRIS + AVD in both the ITT and Stage IV population.

Pre-specified subgroup analyses of modified PFS per IRF were performed for the ITT population including age, region, cancer stage at baseline, baseline extranodal sites, number of IPFP risk factors, baseline B symptoms, Cycle 2 PET assessment, Cycle 2 PET Deauville score, and receipt of alternative first-line medication (AFM). The analyses showed a consistent trend towards benefit for patients who received ADCETRIS + AVD compared with patients who received ABVD in most subgroups. The efficacy in elderly patient population (patients ≥60 years of age [n=186] [HR=1.00, 95% CI (0.58, 1.72)] and ≥65 years of age [n=122] [HR=1.01, 95% CI (0.53, 1.94)]) and patients with no extranodal sites (n=445) (HR=1.04, 95% CI [0.67, 1.62]) showed no clinically meaningful difference between the two arms.

Post-hoc subgroup analyses of modified PFS per IRF for patients with Stage IV disease were performed including age, region, baseline extranodal sites, number of IPFP risk factors, baseline B symptoms, baseline ECOG status and gender. The analyses showed a consistent trend towards benefit for patients who received ADCETRIS + AVD compared with patients who received ABVD in most subgroups. Patients with Stage IV disease for whom extranodal disease was reported ([n=722] [HR=0.69, 95% CI (0.50, 0.94)]) showed an mPFS (per IRF) benefit. In patients with Stage IV disease for whom no extranodal disease was reported, no benefit has been shown at time of analysis ([n=85] [HR=1.49, 95% CI (0.51, 4.31)]). The significance of this finding in stage IV HL patients with no extranodal disease is not established due to small patient numbers and low event rates (14 events). The efficacy in elderly patients with Stage IV disease in the A + AVD arm (patients ≥ 60 years of age [n=118] [HR=0.80, 95% CI (0.42, 1.53)] and ≥ 65 years of age[n=78] [HR=0.78, 95% CI (0.36, 1.67)]) showed better benefitcompared with elderly patients in ITT population.

In the ITT population, 33% fewer patients treated with ADCETRIS + AVD in the ITT population received subsequent salvage chemotherapy (n=66) and high-dose chemotherapy and transplant (n=36) compared with those treated with ABVD (n=99 and n=54, respectively). In the Stage IV population, 35% fewer patients treated with ADCETRIS + AVD received subsequent salvage chemotherapy (n=45) compared with those treated with ABVD (n=69) and 22% fewer patients treated with ADCETRIS + AVD received high-dose chemotherapy and transplant (n=29) compared with those treated with ABVD (n=37).

The European Organization for Research and Treatment of Cancer Quality of Life 30-Item Questionnaire (EORTC-QLQ-C30) showed no clinically meaningful difference between the two arms in both the ITT and Stage IV population.

Study SGN35-005

The efficacy and safety of ADCETRIS were evaluated in a randomised, double-blind, placebo-controlled, 2-arm multicenter trial in 329 patients with HL at risk of relapse or progression following ASCT. Patients with known cerebral/meningeal disease, including history of PML were excluded from the study. See Table 6 for patient characteristics. Of the 329 patients, 165 patients were randomised to the treatment arm and 164 patients were randomised to the placebo arm. In the study, patients were to receive their first dose after recovery from ASCT (between days 30-45 following ASCT). Patients were treated with 1.8 mg/kg of ADCETRIS or matching placebo intravenously over 30 minutes every 3 weeks for up to 16 cycles.

Eligible patients were required to have at least one of the following risk factors:

• HL that was refractory to frontline treatment
• Relapsed or progressive HL that occurred <12 months from the end of frontline treatment
• Extranodal involvement at time of pre-ASCT relapse, including extranodal extension of nodal masses into adjacent vital organs

Table 6. Summary of baseline patient and disease characteristics in the phase 3 HL post-ASCT Study:

^a For refractory disease, or upon progression or relapse after frontline therapy.
^b Stratification factors at randomisation.

The efficacy results are shown in Table 7. The primary endpoint of PFS was met and showed a difference in median PFS of 18.8 months in favour of the treatment arm.

Table 7. Efficacy results in HL patients at increased risk of relapse or progression following ASCT treated with 1.8 mg/kg of ADCETRIS every 3 weeks:

^a At the time of the primary analysis, the median follow-up time for both arms was 30 months (range, 0 to 50).
^b Stratified log-rank test was not performed for PFS per Investigator.

Pre-specified subgroup analyses of PFS per IRF were performed by patients' best response to pre-ASCT salvage therapy, HL status after frontline therapy, age, gender, baseline weight, baseline ECOG performance status, number of treatments pre-ASCT, geographic region, pre-ASCT PET status, B symptom status after failure of frontline therapy, and pre-ASCT extranodal disease status. The analyses showed a consistent trend towards benefit for patients who received ADCETRIS compared with patients who received placebo with the exception of patients ≥65 years of age (n=8).

No differences were observed in quality of life between the treatment and placebo arms. Medical resource utilization (MRU) analysis showed that hospitalizations and outpatient visits, as well as working days/other activities missed by patients and caregivers were lower with ADCETRIS compared with placebo in patients with HL at increased risk of relapse.

An updated analysis conducted after 3 years of follow-up showed a sustained PFS improvement per IRF (HR=0.58 [95% CI (0.41, 0.81)]).

Post-hoc Risk Factor Analyses

Post-hoc analyses were performed to evaluate the impact of increased risk (number of risk factors) on clinical benefit (Table 8). Representative risk factors for these analyses were:

• HL that occurred <12 months or HL that was refractory to frontline therapy
• Best response of PR or SD to most recent salvage therapy as determined by CT and/or PET scanning
• Extranodal disease at pre-ASCT relapse
• B symptoms at pre-ASCT relapse
• Two or more prior salvage therapies.

The results of these post-hoc analyses suggest increased clinical benefit for patients with two or more risk factors but no difference based on any of the individual risk factors. No benefit in terms of PFS or OS has been observed in patients with one risk factor for relapse or progression.

Table 8. Summary of PFS per IRF and OS by number of risk factors in the phase 3 HL post-ASCT Study:

^a Death without either prior progression or more than one missed assessment visit.
^b Indicates results from non-stratified analysis.
^c Events are death due to any cause.

At the time of the updated analysis (3 years of follow-up) for patients with 2 or more risk factors, the hazard ratio for PFS per IRF was 0.49 (95% CI [0.34, 0.71]) and the hazard ratio for PFS per investigator was 0.41 (95% CI [0.29, 0.58]) (see Figures 3 and 4).

Figure 3. Kaplan-Meier Plot of PFS per IRF in Patients with ≥2 Risk Factors:

Figure 4. Kaplan-Meier Plot of PFS per Investigator in Patients with ≥2 Risk Factors:

Study SG035-0003

The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal open-label, single-arm, multicenter study in 102 patients with relapsed or refractory HL. See Table 9 below for a summary of baseline patient and disease characteristics.

Table 9. Summary of baseline patient and disease characteristics in the phase 2 relapsed or refractory HL study:

^a Primary refractory HL is defined as a failure to achieve a complete remission to, or progressed within 3 months of completing frontline therapy.

Eighteen (18) patients (18%) received 16 cycles of ADCETRIS; and the median number of cycles received was 9 (ranging from 1 to 16).

Response to treatment with ADCETRIS was assessed by Independent Review Facility (IRF) using the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was assessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Response assessments were performed at cycles 2, 4, 7, 10, 13, and 16 with PET at cycles 4 and 7. The objective response rate (ORR) per IRF assessment was 75% (76 of 102 patients in the intent-to-treat [ITT] set) and tumour reduction was achieved in 94% of patients. Complete remission (CR) was 33% (34 of 102 patients in the ITT set). The median overall survival (OS) is 40.5 months (the median observation time (time to death or last contact) from first dose was 35.1 months (range 1.8 to 72.9+ months). The estimated overall survival rate at 5 years was 41% (95% CI [31%, 51%]). The investigator assessments were generally consistent with the independent review of the scans. Of the patients treated, 8 responding patients went on to receive an allogeneic SCT. For further efficacy results see Table 10.

Table 10. Efficacy results in relapsed or refractory Hodgkin lymphoma patients treated with 1.8 mg/kg of ADCETRIS every 3 weeks:

^a The range of DOR was 1.2+ months to 43+ months and the median follow-up time from first dose for patients who achieved objective response (OR) per IRF was 9.0 months.
^b Not estimable.

An exploratory intra-patient analysis showed that approximately 64% of the HL patients treated with ADCETRIS as part of the SG035-0003 clinical study experienced an improvement in clinical benefit as measured by longer progression free survival (PFS) compared with their most recent prior line of therapy.

Of the 35 patients (33%) who had B symptoms at baseline, 27 patients (77%) experienced resolution of all B symptoms at a median time of 0.7 months from initiation of ADCETRIS.

Data in HL Patients Who Are Not Stem Cell Transplant (SCT) Candidates

Study-C25007

A phase 4 single-arm study was conducted in patients with relapsed or refractory HL (n=60) who had received at least one prior chemotherapeutic regimen and at the time of treatment initiation with ADCETRIS were not considered candidates for SCT or multiagent chemotherapy. The median number of cycles was 7 (range 1 to 16 cycles). Patients were treated with 1.8 mg/kg of ADCETRIS every 3 weeks. Per IRF, the objective response rate (ORR) in the ITT population was 50% (95% CI, 37; 63%). A best overall response of CR was reported for 7 patients (12%); PR was reported for 23 patients (38%). Among these 30 patients, the median time to response, defined as the time from first dose to the soonest of PR or CR, was 6 weeks (range, 5 to 39 weeks). The median time to best overall response, defined as the time from first dose to the clinical best response of CR or PR, was 11 weeks (range, 5 to 60 weeks). Twenty-eight patients (47%) went on to receive SCT after a median of 7 cycles (range, 4 to 16 cycles) of ADCETRIS treatment. The 32 patients (53%) who did not receive subsequent SCT also received ADCETRIS for a median of 7 cycles (range, 1 to 16 cycles).

Of the study’s 60 patients, 49 patients (82%) received >1 prior cancer-related treatment and 11 patients (18%) received 1 prior cancer-related treatment. Per IRF, the ORR was 51% (95% CI [36%, 66%]) for the patients who had received >1 prior cancer-related treatment and 45% (95% CI [17%, 77%]) for the patients who had received 1 prior cancer-related treatment. For the patients who received >1 prior cancer-related treatment, a best overall response of CR was reported for 6 patients (12%); PR was reported for 19 patients (39%). For the patients who received 1 prior cancer-related treatment, CR was reported for 1 patient (9%) and PR was reported for 4 patients (36%). Out of the 49 patients receiving >1 line of prior treatment, 22 patients (45%) received subsequent SCT; of the 11 patients who had received 1 prior treatment, 6 patients (55%) received subsequent SCT.

Data were also collected from patients (n=15) in phase 1 dose escalation and clinical pharmacology studies, and from patients (n=26) in a NPP, with relapsed or refractory HL who had not received an ASCT, and who were treated with 1.8 mg/kg of ADCETRIS every 3 weeks.

Baseline patient characteristics showed failure from multiple prior chemotherapy regimens (median of 3 with a range of 1 to 7) before first administration with ADCETRIS. Fifty nine percent (59%) of patients had advanced stage disease (Stage III or IV) at initial diagnosis.

Results from these phase 1 studies and from the NPP experience showed, that in patients with relapsed or refractory HL without prior ASCT, clinically meaningful responses can be achieved as evidenced by an investigator-assessed, objective response rate of 54% and a complete remission rate of 22% after a median of 5 cycles of ADCETRIS.

Study SGN35-006 (Retreatment Study)

The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Twenty patients with relapsed or refractory HL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycles was 7 (range, 2 to 37 cycles). Of the 20 evaluable patients with HL, 6 patients (30%) achieved a CR and 6 patients (30%) achieved a PR with ADCETRIS retreatment, for an ORR of 60%.

The median duration of response was 9.2 and 9.4 months in patients who achieved OR (CR+PR) and CR, respectively.

Systemic anaplastic large cell lymphoma

Study SG035-0004

The efficacy and safety of ADCETRIS as a single agent was evaluated in an open-label, single-arm, multicenter study in 58 patients with relapsed or refractory sALCL. See Table 11 below for a summary of baseline patient and disease characteristics.

Table 11. Summary of baseline patient and disease characteristics in the phase 2 relapsed or refractory sALCL study:

^a One patient had a baseline ECOG status of 2, which was prohibited by protocol and is captured as Inclusion Criteria Not Met.
^b Primary refractory sALCL is defined as a failure to achieve a complete remission to, or progressed within 3 months of completing frontline therapy.

The median time from initial sALCL diagnosis to first dose with ADCETRIS was 16.8 months.

Ten (10) patients (17%) received 16 cycles of ADCETRIS; the median number of cycles received was 7 (range, 1 to 16).

Response to treatment with ADCETRIS was assessed by Independent Review Facility (IRF) using the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was assessed by spiral CT of chest, neck, abdomen and pelvis; PET scans and clinical data. Response assessments were performed at cycles 2, 4, 7, 10, 13 and 16 with PET at cycles 4 and 7.

The ORR per IRF assessment was 86% (50 of 58 patients in the ITT set). CR was 59% (34 of 58 patients in the ITT set) and tumour reduction (of any degree) was achieved in 97% of patients. The estimated overall survival at 5 years was 60% (95% CI [47%,73%]). The median observation time (time to death or last contact) from first dose was 71.4 months. The investigator assessments were generally consistent with the independent review of the scans. Of the patients treated, 9 responding patients went on to receive an allogeneic stem cell transplant (SCT) and 9 responding patients went on to autologous SCT. For further efficacy results, see Table 12 and Figure 5.

Table 12. Efficacy results in relapsed or refractory sALCL patients treated with 1.8 mg/kg of ADCETRIS every 3 weeks:

^a The range of DOR was 0.1 months to 39.1+ months and the median follow-up time from first dose for patients who achieved objective response (OR) per IRF was 15.5 months.
^b Not estimable.

Figure 5. Kaplan-Meier Plot of OS:

An exploratory intra-patient analysis showed that approximately 69% of the sALCL patients treated with ADCETRIS as part of the SG035-0004 clinical study experienced an improvement in clinical benefit as measured by longer progression free survival (PFS) compared with their most recent prior line of therapy.

Of the 17 patients (29%) who had B symptoms at baseline, 14 patients (82%) experienced resolution of all B symptoms in a median time from initiation of ADCETRIS of 0.7 months.

Study SGN35-006 (Retreatment study)

The efficacy of retreatment in patients who had previously responded (CR or PR) to treatment with ADCETRIS was evaluated in a phase 2, open-label, multicenter trial. Seven patients with relapsed sALCL received a starting dose of 1.8 mg/kg and one patient received a starting dose of 1.2 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks. The median number of cycles was 8.5 (range, 2 to 30 cycles). Of the 8 sALCL patients, 3 were retreated twice for a total of 11 retreatment experiences. Retreatment with ADCETRIS resulted in 6 CRs (55%) and 4 PRs (36%), for an ORR of 91%. The median duration of response was 8.8 and 12.3 months in patients who achieved OR (CR+PR) and CR, respectively

Cutaneous T-cell lymphoma

Study C25001

The efficacy and safety of ADCETRIS as a single agent was evaluated in a pivotal phase 3, openlabel, randomised, multicentre study in 128 patients with histologically confirmed CD30+ CTCL. CD30 positivity was defined as ≥10% target lymphoid cells demonstrating membrane, cytoplasmic, and/or Golgi staining pattern based on an immunohistochemistry assay (Ventana anti-CD30 [Ber-H2]). Patients with a diagnosis of mycosis fungoides [MF] or primary cutaneous anaplastic large cell lymphoma [pcALCL] were considered eligible for the study. Patients were stratified by these disease types and randomised 1:1 to receive either ADCETRIS or the physician’s choice of either methotrexate or bexarotene. Patients with pcALCL received either prior radiation therapy or at least 1 prior systemic therapy and patients with MF received at least 1 prior systemic therapy. Patients with a concurrent diagnosis of systemic ALCL, Sezary syndrome and other nonHodgkin lymphoma (except for lymphomatoid papulosis [LyP]) were excluded from this study. Patients were treated with 1.8 mg/kg of ADCETRIS intravenously over 30 minutes every 3 weeks for up to 16 cycles or physician’s choice for up to 48 weeks. The median number of cycles was approximately 12 cycles in the ADCETRIS arm. In the physician’s choice arm, the median duration of treatment (number of cycles) for patients receiving bexarotene was approximately 16 weeks (5.5 cycles) and 11 weeks (3 cycles) for patients receiving methotrexate. Table 13 provides a summary of the baseline patient and disease characteristics.

Table 13. Summary of baseline patient and disease characteristics in the phase 3 CTCL Study (ITT Population):

^a One patient in each arm had incomplete staging data and are not included in the table.

The most common prior skin directed therapies in the ITT population were radiotherapy (64%), phototherapy (48%) and topical steroids (17%). The most common prior systemic therapies in the ITT population were chemotherapy (71%), immunotherapy (43%) and bexarotene (38%).

The primary endpoint was objective response rate that lasts at least 4 months (ORR4) (duration from first response to last response ≥4 months), as determined by an independent review of the Global Response Score (GRS) consisting of skin evaluations (modified severity weighted assessment tool [mSWAT] as assessed per investigator), nodal and visceral radiographic assessment, and detection of circulating Sézary cells (Olsen 2011). Table 14 includes the results for ORR4 and other key secondary endpoints.

Table 14. Efficacy results in CTCL patients treated with 1.8 mg/kg of ADCETRIS every 3 weeks (ITT population):

^a Calculated from a weighted Holm’s procedure

Pre-specified subgroup analyses of ORR4 per IRF were performed by patients' CTCL subtype, physicians' choice of treatment, baseline ECOG status, age, gender, and geographic region. The analyses showed a consistent trend towards benefit for patients who received ADCETRIS compared with patients who received physician’s choice. ORR4 was 50% and 75% in the ADCETRIS arm versus 10.2% and 20% in the physician’s choice arm for MF and pcALCL, respectively.

No meaningful differences in quality of life (assessed by the EuroQol five dimensions questionnaire [EQ-5D] and Functional Assessment of Cancer Therapy-General [FACT-G]) were observed between the treatment arms.

The efficacy and safety of ADCETRIS were evaluated in two additional open-label studies in 108 patients with relapsed CD30+ CTCL (including MF and pcALCL as well as SS, LyP and mixed CTCL histology), regardless of CD30 expression level. Patients were treated with ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles. The safety and efficacy results in these studies were consistent with results in Study C25001. Overall response rates for MF were 54-66%; pcALCL, 67%; SS, 50%; LyP, 92%; and mixed CTCL histology, 82-85%.

Paediatric population

The safety, pharmacokinetics and anti-tumour activity of ADCETRIS in 36 paediatric patients (7-17 years of age) with r/r HL and sALCL (children aged 7-11 years, n=12 and adolescents aged 12 to 17 years, n=24) were evaluated in a phase ½ open-label, single-agent, multicentre doseescalation study (C25002). Phase 1 of the study assessed the safety profile (see section 4.8), determined the paediatric maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and assessed the pharmacokinetics of ADCETRIS (see section 5.2). Phase 1 included 3 r/r HL patients treated at 1.4 mg/kg and 9 patients (7 r/r HL and 2 sALCL) treated at 1.8 mg/kg. The MTD was not reached. The RP2D was determined to be 1.8 mg/kg. Across the study, a total of 16 patients with r/r HL and 17 patients with r/r sALCL, of whom 10 were in first relapse, were treated with 1.8 mg/kg of ADCETRIS. The best overall response rate (ORR) per independent review facility (IRF) was analysed across both study phases at the RP2D. Of these 33 patients who received the RP2D, 32 were evaluable for response. The ORR was 47% in response-evaluable patients with r/r HL, 53% in patients with r/r sALCL and 60% in sALCL patients in first relapse. Eight HL patients and 9 sALCL patients went on to receive SCT following treatment with ADCETRIS.

The European Medicines Agency has deferred the obligation to submit the results of studies with ADCETRIS in one or more subsets of the paediatric population in the treatment of Hodgkin lymphoma and treatment of anaplastic large cell lymphoma (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.