Datopotamab

Pharmacotherapeutic group: Antineoplastic agents; other monoclonal antibodies and antibody-drug conjugates, ATC code: L01FX05. Mechanism of action Brentuximab vedotin is an antibody-drug conjugate (ADC) that releases a cytotoxic agent which selectively induces apoptotic cell death in CD30-expressing tumour cells. Non-clinical 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 is then transported to the lysosomal compartment. Within the cell, proteolytic cleavage releases a single defined active species, MMAE. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest and leads to apoptotic death of the CD30-expressing tumour cell. Classical HL, sALCL and CTCL subtypes (including MF and pcALCL) express CD30 as an antigen on the surface of malignant cells. This expression is independent of disease stage, line of therapy or transplant status. These features make CD30 a target for therapeutic intervention. Owing to its CD30-targeted mechanism of action, brentuximab vedotin is able to overcome chemoresistance, since CD30 is consistently expressed in patients refractory to combination chemotherapy regardless of prior transplant status. The CD30-targeted mechanism of action of brentuximab vedotin, the consistent expression of CD30 across classical HL, sALCL and CD30+ CTCL, and the therapeutic profile and clinical evidence in CD30-positive malignancies after multiple lines of therapy provide the biological rationale for its use in patients with relapsed and refractory classical HL, sALCL with or without prior ASCT, and CD30+ CTCL after at least one prior systemic therapy. A contribution from other antibody-related functions to the mechanism of action cannot be excluded. Pharmacodynamic effects Cardiac electrophysiology Of 52 patients who received 1.8 mg/kg of brentuximab vedotin every 3 weeks in a single-arm, open-label, multicentre phase 1 cardiac safety study, forty-six (46) patients with CD30-expressing haematological malignancies were evaluable. The primary objective was to assess the effect of brentuximab vedotin on ventricular repolarisation, and the prespecified primary analysis was the change in QTc from baseline to various time points during Cycle 1. The upper limit of the 90% confidence interval (CI) for the mean effect on QTc was < 10 ms at each post-baseline time point in Cycles 1 and 3. These data indicate the absence of clinically meaningful QT prolongation with brentuximab vedotin administered at 1.8 mg/kg every 3 weeks in patients with CD30-expressing malignancies. Clinical efficacy and safety Hodgkin lymphoma Study C25003 The efficacy and safety of ADCETRIS were evaluated in a randomised, open-label, two-arm, multicentre study in 1,334 patients with previously untreated advanced HL in combination with chemotherapy (doxorubicin [A], vinblastine [V] and dacarbazine [D] [AVD]). Patients with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) were excluded from the study. All patients had histologically confirmed CD30-expressing disease. Extranodal involvement was identified in 62% of patients. Of the 1,334 patients, 664 were randomised to the ADCETRIS + AVD (A+AVD) arm and 670 to the ABVD arm (doxorubicin [A], bleomycin [B], vinblastine [V] and dacarbazine [D]). Patients were stratified by risk factors based on the International Prognostic Factor Project (IPFP) and by region. Patients were treated on Days 1 and 15 of each 28-day cycle with 1.2 mg/kg of ADCETRIS administered as a 30-minute intravenous infusion, plus 25 mg/m² doxorubicin, 6 mg/m² vinblastine and 375 mg/m² dacarbazine. The median number of cycles administered was 6 (range 1 to 6). A summary of baseline patient and disease characteristics is provided in Table 8. No significant differences in patient or disease characteristics were observed between the two arms. Table 8: Summary of baseline patient and disease characteristics in the phase 3 study in previously untreated HL Patient characteristics ADCETRIS + AVD n = 664 ABVD n = 670 Median age, years (range) 35 years (18–82) 37 years (18–83) Patients ≥ 65 years, n (%) 60 (9) 62 (9) Sex, n (%) 378 M (57) 398 M (59) 286 F (43) 272 F (41) ECOG performance status (%) 0 376 (57) 378 (57) 1 260 (39) 263 (39) 2 28 (4) 26 (4) Missing 0 2 Disease characteristics Median time from HL diagnosis to first dose (range) 0.92 mo. (0.1–21.4) 0.89 mo. (0.0–81.4) Disease stageᵃ at initial HL diagnosis, n (%) III 237 (36) 246 (37) IV 425 (64) 421 (63) Not applicable 1 (< 1) 1 (< 1) Missing 0 2 (< 1) Extranodal involvement at diagnosis, n (%) 411 (62) 416 (62) IPFPᵇ risk factors, n (%) 0–1 141 (21) 141 (21) 2–3 354 (53) 351 (52) 4–7 169 (25) 178 (27) Bone marrow involvement at diagnosis or study entry, n (%) 147 (22) 151 (23) B symptomsᵃ, n (%) 400 (60) 381 (57) ᵃ Ann Arbor classification ᵇ IPFP = International Prognostic Factor Project The primary endpoint in Study C25003 was modified PFS (mPFS) per Independent Review Facility (IRF) assessment, defined as the time from randomisation to disease progression, death, or evidence of non-complete response (non-CR) after completion of frontline therapy per IRF followed by subsequent anticancer therapy. The modified event date was defined as the date of the first PET scan after completion of frontline therapy demonstrating absence of complete response (CR), defined as a Deauville score ≥ 3. Median modified PFS per IRF was not reached in either treatment arm. Results in the intent-to-treat (ITT) population showed a statistically significant improvement in modified PFS with ADCETRIS + AVD, with a stratified hazard ratio (HR) of 0.770 (95% CI, 0.603, 0.983; p = 0.035), indicating a 23% reduction in the risk of modified PFS events with ADCETRIS + AVD versus ABVD. Efficacy results for modified PFS and overall survival (OS) in the ITT population are provided in Table 9. Table 9: Efficacy results in patients with previously untreated HL treated with 1.2 mg/kg ADCETRIS + AVD on Days 1 and 15 of a 28-day cycle (ITT) Intent-to-Treat (ITT) population ADCETRIS + AVD n = 664 ABVD n = 670 Stratified hazard ratio and p-value Number of events (%) 117 (18) 146 (22) 0.77 (95% CI [0.60, 0.98]); p-value = 0.035 Estimated mPFSᵃ per IRF at 2 years (%) 82.1 (95% CI [78.8, 85.0]) 77.2 (95% CI [73.7, 80.4]) Overall survivalᵇ Number of deaths (%) 28 (4) 39 (6) 0.73 (95% CI [0.45, 1.18]); p-value = 0.199 ᵃ At the time of analysis, the median follow-up for modified PFS in both arms was 24.6 months ᵇ Data from interim OS analysis Figure 1: Modified progression-free survival per IRF in the ITT population (ADCETRIS + AVD vs. ABVD) All other secondary endpoints, including CR rate and ORR at the end of the randomised regimen, CR rate at the end of frontline therapy, PET negativity rate at the end of Cycle 2, duration of response (DOR), duration of complete remission (DOCR), disease-free survival (DFS) and event-free survival (EFS), showed a trend favouring ADCETRIS + AVD in the ITT population. A prespecified subgroup analysis of modified PFS per IRF showed no clinically meaningful difference between the two treatment arms in the older population (patients ≥ 60 years [n = 186] [HR = 1.00; 95% CI (0.58, 1.72)] and ≥ 65 years [n = 122] [HR = 1.01; 95% CI (0.53, 1.94)]) and in patients without extranodal manifestations (n = 445) (HR = 1.04; 95% CI [0.67, 1.62]). Based on overall survival follow-up data with a median follow-up of more than 7 years, a final analysis of overall survival was performed. In the ITT population, fewer patients randomised to the ADCETRIS + AVD arm died (46 deaths, 7%) than those randomised to the ABVD arm (69 deaths, 10%; HR = 0.62; 95% CI [0.423, 0.899]); see Figure 2. In the phase III study, the proportion of deaths among patients randomised to the ADCETRIS + AVD arm (20 deaths, 8%) was similar to that among patients randomised to the ABVD arm (20 deaths, 8%) (HR = 1.01; 95% CI [0.542, 1.874]). In the phase IV study, the proportion of deaths among patients randomised to the A + AVD arm (26 deaths, 6%) was lower than among patients randomised to the ABVD arm (48 deaths, 11%; HR = 0.49; 95% CI [0.303, 0.790]). Subgroup analysis of overall survival showed no clinically meaningful difference between the two treatment arms in patients without extranodal manifestations (n = 445) (HR = 1.28; 95% CI [0.710, 2.303]). Figure 2: Final analysis of overall survival (ADCETRIS + AVD vs. ABVD) (ITT population, more than 7 years of follow-up) At the primary analysis, 33% fewer patients in the ITT population treated with ADCETRIS + AVD received subsequent salvage chemotherapy (n = 66) or high-dose chemotherapy and transplantation (n = 36) compared with the ABVD-treated population (n = 99 and n = 54, respectively). In the Stage IV population, 35% fewer patients treated with ADCETRIS + AVD received subsequent salvage chemotherapy (n = 45) than the ABVD-treated population (n = 99), and 22% fewer ADCETRIS + AVD-treated patients underwent high-dose chemotherapy and transplantation (n = 29) than ABVD-treated patients (n = 37). Study HD21 The safety and efficacy of ADCETRIS (brentuximab vedotin [Br]) were evaluated in an open-label, prospective, multicentre phase 3 study in 1,500 patients with previously untreated HL stage IIB with bulky mediastinal disease and/or extranodal lesions, or stage III or IV, in combination with chemotherapy (etoposide [E], cyclophosphamide [C], doxorubicin [A], dacarbazine [D], dexamethasone [D] [BrECADD]). Of the 1,500 patients, 751 were randomised to the BrECADD arm and 749 to the eBEACOPP arm (escalated bleomycin [B], etoposide [E], doxorubicin [A], cyclophosphamide [C], vincristine [O], procarbazine [P] and prednisone [P]), stratified by region of enrolment, age, sex and International Prognostic Score (IPS). Patients in the BrECADD arm were treated on Day 1 of each 21-day cycle with 1.8 mg/kg ADCETRIS administered as a 30-minute intravenous infusion. Patients also received chemotherapy including cyclophosphamide 1,250 mg/m², doxorubicin 40 mg/m², etoposide or etoposide phosphate 150 mg/m², dacarbazine 250 mg/m² and dexamethasone 40 mg (see section 4.2). All treated patients received primary G-CSF prophylaxis (see section 4.2). After 2 cycles of treatment, restaging was performed by PET; patients who were PET-negative received a total of 4 cycles and PET-positive patients received a total of 6 cycles. The median number of cycles administered in both arms was 4 (range 1 to 6). Table 10 provides a summary of baseline patient and disease characteristics. No significant differences in patient or disease characteristics were observed between the two arms. Table 10: Summary of baseline patient and disease characteristics in the phase 3 study in previously untreated HL Patient characteristics BrECADD n = 751 eBEACOPP n = 749 Median age, years (range) 31 years (18–60) 31 years (18–60) Patients < 45 years, n (%) 590 (79) 584 (78) Patients aged 45 to 60 years, n (%) 161 (21) 165 (22) Sex, n (%) 419 M (56) / 332 F (44) 419 M (56) / 330 F (44) ECOG performance status, n (%) 0 514 (68) 521 (70) 1 223 (30) 205 (27) 2 11 (1) 18 (2) Missing 3 (< 1) 5 (< 1) Disease characteristics Median time from HL diagnosis to randomisation (range) 0.6 mo. (0–12) 0.6 mo. (0–10) Disease stageᵃ at initial HL diagnosis, n (%) II 118 (16) 117 (16) III 298 (40) 293 (39) IV 332 (44) 334 (45) Missing 3 (< 1) 5 (< 1) IPSᵇ groups, n (%) 0–2 394 (52) 403 (54) 3–7 357 (48) 346 (46) B symptomsᵃ, n (%) 517 (69) 501 (67) ᵃ Ann Arbor classification ᵇ IPS = International Prognostic Score Study HD21 was designed with two co-primary endpoints (Treatment-Related Morbidity [TRMB] and PFS [per investigator with central confirmation]). The first co-primary endpoint was to demonstrate reduced toxicity of the BrECADD regimen compared with the eBEACOPP regimen as measured by TRMB. If reduced toxicity was demonstrated in a superiority test, the second co-primary endpoint was to further demonstrate non-inferior efficacy of BrECADD compared with eBEACOPP in terms of PFS. TRMB was defined as any grade 3 or 4 organ toxicity per the Common Terminology Criteria for Adverse Events (CTCAE) or grade 4 haematological toxicity during primary chemotherapy, including the period up to 30 days after the last dose of chemotherapy. At the time of the primary analysis, superiority of the BrECADD regimen on TRMB was achieved, with an absolute risk reduction of −16.7 percentage points and a statistically significant reduction in relative risk. For the co-primary endpoint of PFS, regardless of missed visits and regardless of initiation of new anticancer therapy, non-inferiority was met with a statistically significant reduction in risk in the BrECADD treatment arm compared with the eBEACOPP regimen (unstratified hazard ratio = 0.62 [multiplicatively adjusted 95% CI, 0.369, 1.040]) (data cut-off – 31 December 2022). The incidence of TRMB was shown to be lower in the BrECADD arm (42%) than in the eBEACOPP arm (58.7%). This was largely driven by a reduction in the incidence of grade 4 haematological toxicities (31.2% in the BrECADD arm and 52.1% in the eBEACOPP arm). TRMB by treatment arm is presented in Table 11. Efficacy results from updated analyses of PFS and overall survival (OS) are presented in Table 12 (data cut-off – 31 October 2023). Table 11: Treatment-Related Morbidity (TRMB) by treatment arm (safety population) BrECADD n = 747 eBEACOPP n = 741 Number of patients with TRMB 314 (42) 435 (59) Acute haematological toxicity; grade 4 233 (31) 386 (52) Anaemia 3 (< 1) 3 (< 1) Thrombocytopenia 227 (30) 383 (52) Infection 13 (2) 10 (1) Acute organ toxicity; grade 3 or grade 4 139 (19) 129 (17) Cardiac disorders 18 (2) 10 (1) GI disorders (excluding vomiting, nausea, mucositis) 58 (8) 32 (4) Hepatobiliary disorders 37 (5) 22 (3) Nervous system disorders 20 (3) 40 (5) Peripheral sensory neuropathy 9 (1) 17 (2) Peripheral motor neuropathy 2 (< 1) 1 (< 1) Nervous system disorders other than neuropathy 11 (2) 24 (3) Renal and urinary disorders 7 (< 1) 10 (1) Respiratory, thoracic and mediastinal disorders 25 (3) 35 (5) Difference in % (BrECADD – eBEACOPP) −16.7 Exact 95% CI −21.7, −11.5 Table 12: Efficacy results in patients with previously untreated HL treated with 1.8 mg/kg ADCETRIS on a BrECADD 21-day cycle (updated PFS analysis data cut-off – 31 October 2023) Intent-to-Treat (ITT) population BrECADD n = 751 eBEACOPP n = 749 Number of PFS events (%) 44 (5.9) 65 (8.7) PFS hazard ratio (95% CI) 0.664 (0.453, 0.973) Estimated PFSᵇ,ᶜ (95% CI) At 3 years 95.2 (93.4, 96.6) 92.4 (90.2, 94.1) At 5 years 92.8 (90.0, 94.9) 90.2 (87.5, 92.3) Overall survivalᵈ Number of deaths (%) 12 (1.6) 13 (1.7) OS hazard ratio (95% CI) 0.919 (0.419, 2.015) Estimated OS rate (95% CI) At 3 years 98.9 (97.8, 99.4) 98.9 (97.8, 99.4) At 5 years 98.1 (96.5, 98.9) 97.9 (96.4, 98.8) The PFS analysis did not account for related events such as missed visits and initiation of new anticancer therapy. PFS rate is estimated using the Kaplan-Meier method per investigator with central confirmation. At the time of analysis, the median follow-up for PFS in the ITT population was 50.8 months. Data from descriptive analysis. Duration of complete response (CR) demonstrated a clinically meaningful benefit in the BrECADD arm compared with the eBEACOPP arm in the ITT population, while other secondary efficacy endpoints, including ORR and CR rate at the end of chemotherapy, showed comparable benefit in both arms. Study SGN35-005 The efficacy and safety of ADCETRIS were evaluated in a randomised, double-blind, placebo-controlled, two-arm, multicentre study in 329 patients with HL at risk of relapse or progression after ASCT. Patients with known brain/meningeal disease, including a history of PML, were excluded from the study. Patient characteristics are shown in Table 13. Of these 329 patients, 165 were randomised to the treatment arm and 164 to the placebo arm. In this study, patients were to receive their first dose following recovery after ASCT (between 30 and 45 days after ASCT). Patients were treated with ADCETRIS 1.8 mg/kg or matching placebo intravenously over 30 minutes every 3 weeks for up to 16 cycles. Eligible patients had to have at least one of the following risk factors: HL refractory to frontline therapy, Relapsed or progressive HL occurring < 12 months from the end of frontline therapy, Extranodal involvement at the time of pre-ASCT relapse, including extranodal extension of lymph node tissue into adjacent vital organs. Table 13: Summary of baseline patient and disease characteristics in the phase 3 study in HL after ASCT Patient characteristics ADCETRIS n = 165 Placebo n = 164 Median age, years (range) 33 years (18–71) 32 years (18–76) Sex 76 M (46%) / 89 F (54%) 97 M (59%) / 67 F (41%) ECOG performance status 0 87 (53%) 97 (59%) 1 77 (47%) 67 (41%) 2 1 (1%) 0 Disease characteristics Median number of prior chemotherapy regimens (range) 2 (2–8) 2 (2–7) Median time from HL diagnosis to first dose (range) 18.7 mo. (6.1–204.0) 18.8 mo. (7.4–180.8) Disease stage at initial HL diagnosis Stage I 1 (1%) 5 (3%) Stage II 73 (44%) 61 (37%) Stage III 48 (29%) 45 (27%) Stage IV 43 (26%) 51 (31%) Unknown 0 2 (1%) Pre-ASCT PET scan status FDG-avid 64 (39%) 51 (31%) FDG-negative 56 (34%) 57 (35%) Not performed 45 (27%) 56 (34%) Extranodal involvement at pre-ASCT relapse 54 (33%) 53 (32%) B symptomsᵃ 47 (28%) 40 (24%) Best response to salvage therapy pre-ASCTᵇ Complete response 61 (37%) 62 (38%) Partial response 57 (35%) 56 (34%) Stable disease 47 (28%) 46 (28%) HL status after frontline standard chemotherapyᵇ Refractory 99 (60%) 97 (59%) Relapse occurred < 12 months 53 (32%) 54 (33%) Relapse occurred ≥ 12 months 13 (8%) 13 (8%) For refractory disease or after progression or relapse following frontline therapy. Stratification factors at randomisation. Efficacy results at the time of the primary analysis of the primary endpoint are presented in Table 14. The primary endpoint of PFS per IRF was met, with a median PFS difference of 18.8 months favouring the treatment arm. Table 14: Efficacy results in patients with HL at increased risk of relapse or progression after ASCT treated with 1.8 mg/kg ADCETRIS administered every 3 weeks (ITT, primary analysis) ADCETRIS n = 165 Placebo n = 164 Stratified hazard ratio Median per IRF 0.57 Progression-free survivalᵃ 42.9 months (95% CI [30.4, 42.9]) 24.1 months (95% CI [11.5, –]) (95% CI [0.40, 0.81]); stratified log-rank test p = 0.001 Median per investigator Not reached 15.8 months 0.5 (95% CI [26.4, –]) (95% CI [8.5, –]) (95% CI [0.36, 0.70]) Overall survivalᵇ Number of deaths (%) 28 (17) 25 (15) 1.15 (95% CI [0.67, 1.97]) At the time of the primary analysis, the median follow-up for both arms was 30 months [range, 0 to 50]. The stratified log-rank test was not performed for PFS per investigator. Prespecified subgroup analyses of PFS per IRF were performed based on patients' best response to salvage therapy pre-ASCT, HL status after frontline therapy, age, sex, baseline body weight, baseline ECOG performance status, number of prior pre-ASCT treatments, geographic region, pre-ASCT PET scan status, B symptom status after failure of frontline therapy, and pre-ASCT extranodal disease status. The analyses showed a consistent trend favouring patients who received ADCETRIS over those who received placebo, except for patients ≥ 65 years of age (n = 8). No differences in quality of life were observed between the treatment arm and the placebo arm. Medical resource utilisation (MRU) analysis showed that hospitalisations and outpatient visits, as well as workdays/other activities missed by both patients and caregivers, were lower with ADCETRIS compared with placebo in patients with HL at increased risk of relapse. An updated analysis performed 3 years after follow-up showed continued improvement in PFS per IRF (HR = 0.58 [95% CI (0.41, 0.81)]). At study closure, approximately 10 years after enrolment of the first patient, PFS per investigator continued to demonstrate benefit (HR = 0.51 [95% CI (0.37, 0.71)]). Overall survival results were consistent with those reported at the primary analysis (HR = 1.11 [95% CI (0.72, 1.70)]). Figure 3 displays PFS per investigator in the ITT population at study closure. Figure 3: Kaplan-Meier plot of PFS per investigator (ITT, study closure) Post-hoc analyses of risk factors Post-hoc analyses of the primary analysis of the primary endpoint were performed to evaluate the impact of increased risk (number of risk factors) on clinical benefit (Table 15). Representative risk factors for these analyses were: HL that occurred at < 12 months, or HL refractory to frontline therapy, Best response of PR or SD to the most recent salvage therapy on CT and/or PET assessment, 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 do not suggest any difference based on individual risk factors. No benefit on PFS or OS was observed in patients with a single risk factor for relapse or progression. Table 15: Summary of PFS per IRF and OS by number of risk factors in the phase 3 study in HL after ASCT (primary analysis) Progression-free survival per IRF Number of risk factors = 1 Number of risk factors ≥ 2 Number of risk factors ≥ 3 ADCETRIS n = 21 Placebo n = 28 ADCETRIS n = 144 Placebo n = 136 ADCETRIS n = 82 Placebo n = 84 Number of patients with disease progression or deathᵃ (%) 9 (43) 7 (25) 51 (35) 68 (50) 32 (39) 49 (58) Stratified hazard ratio 1.65 (95% CI [0.60, 4.55])ᵇ 0.49 (95% CI [0.34, 0.71]) 0.43 (95% CI [0.27, 0.68]) Overall survival Number of risk factors = 1 Number of risk factors ≥ 2 Number of risk factors ≥ 3 ADCETRIS n = 21 Placebo n = 28 ADCETRIS n = 144 Placebo n = 136 ADCETRIS n = 82 Placebo n = 84 Number of deathsᶜ (%) 5 (24) 1 (4) 23 (16) 24 (18) 15 (18) 16 (19) Stratified hazard ratio 7.94 (95% CI [0.93, 68.06])ᵇ 0.94 (95% CI [0.53, 1.67]) 0.92 (95% CI [0.45, 1.88]) Deaths without either prior progression or more than one missed assessment visit. Indicates results from an unstratified analysis. Events are deaths from any cause. At the time of the updated analysis (3-year follow-up) in 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 4 and 5). Figure 4: Kaplan-Meier plot of PFS per IRF in patients with ≥ 2 risk factors (3-year follow-up) Figure 5: Kaplan-Meier plot of PFS per investigator in patients with ≥ 2 risk factors (3-year follow-up) At study closure, approximately 10 years after enrolment of the first patient, the hazard ratio for PFS per investigator in patients with 2 or more risk factors was 0.41 (95% CI [0.29, 0.58]). The hazard ratio for PFS per investigator in patients with 3 or more risk factors was 0.38 (95% CI [0.25, 0.59]). Overall survival results remained consistent with those observed at the primary analysis. Study SG035-0003 The efficacy and safety of ADCETRIS administered as monotherapy were evaluated in a pivotal open-label, single-arm, multicentre study in 102 patients with relapsed or refractory HL. A summary of baseline patient and disease characteristics is provided in Table 16 below. Table 16: Summary of baseline patient and disease characteristics in the phase 2 study in relapsed or refractory HL Patient characteristics n = 102 Median age, years (range) 31 years (15–77) Sex 48 M (47%) / 54 F (53%) ECOG performance status 0 42 (41%) 1 60 (59%) Prior ASCT 102 (100%) Prior chemotherapy regimens 3.5 (1–13) Time from ASCT to first post-transplant relapse 6.7 mo. (0–131) Histologically confirmed CD30-expressing disease 102 (100%) Disease characteristics Primary refractory to frontline therapyᵃ 72 (71%) Refractory to most recent therapy 43 (42%) B symptoms at start of treatment 35 (33%) Stage III at initial diagnosis 27 (26%) Stage IV at initial diagnosis 20 (20%) a. Primary refractory HL is defined as failure to achieve complete remission with frontline therapy or progression within 3 months of completing frontline therapy. Eighteen (18) patients (18%) received 16 cycles of ADCETRIS; the median number of cycles administered was 9 (range 1 to 16). Response to ADCETRIS treatment was assessed by an Independent Review Facility (IRF) using the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was assessed on the basis of spiral CT of the chest, neck, abdomen and pelvis, PET imaging and clinical data. Response assessments were performed at Cycles 2, 4, 7, 10, 13 and 16, with PET imaging at Cycles 4 and 7. The objective response rate (ORR) per IRF was 75% (76 of 102 patients in the intent-to-treat [ITT] population), and tumour reduction was achieved in 94% of patients. Complete remission (CR) was achieved by 33% (34 of 102 patients in the ITT population). Median overall survival (OS) is 40.5 months (median follow-up [time to death or last contact] from first dose was 35.1 months [range 1.8 to 72.9+ months]). The estimated 5-year overall survival rate was 41% (95% CI [31%, 51%]). Investigator assessments were largely consistent with the independent assessment of images. Of the treated patients, 8 with a treatment response went on to receive allogeneic stem cell transplantation. For additional efficacy results, see Table 17. Table 17: Efficacy results in patients with relapsed or refractory Hodgkin lymphoma treated with 1.8 mg/kg ADCETRIS administered every 3 weeks Best clinical response (n = 102) IRF, n (%) 95% CI Objective response rate (CR + PR) 76 (75) 64.9, 82.6 Complete remission (CR) 34 (33) 24.3, 43.4 Partial remission (PR) 42 (41) not available Disease control rate (CR + PR + SD) 98 (96) 90.3, 98.9 Duration of response Median per IRF 95% CI Objective response rate (CR + PR)ᵃ 6.7 months 3.6, 14.8 Complete remission (CR) 27.9 months 10.8, NEᵇ Overall survival 95% CI Median 40.5 months 28.7, 61.9 Estimated 5-year overall survival rate 41% 31%, 51% Range of duration of response (DOR) was 1.2+ months to 43+ months and the median follow-up from first dose for patients who achieved objective response (OR) per IRF was 9.0 months. Not estimable. Exploratory analysis at the individual patient level showed that approximately 64% of HL patients treated with ADCETRIS in clinical study SG035-0003 experienced improved 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 study entry, all B symptoms resolved in 27 patients (77%) at a median time of 0.7 months from initiation of ADCETRIS. Data in patients with HL who are not candidates for stem cell transplantation (SCT) Study C25007 A single-arm phase 4 study was conducted in patients with relapsed or refractory HL (n = 60) who had received at least one prior chemotherapy regimen and were not considered candidates for SCT or multi-agent chemotherapy at the time of initiating ADCETRIS. Eligible patients were to have had no prior SCT. The median number of cycles was 7 (range 1 to 16). Patients were treated with ADCETRIS 1.8 mg/kg every 3 weeks. At the time of the primary analysis of the primary endpoint per IRF assessment, the objective response rate (ORR) in the ITT population was 50% (95% CI, 37, 63%). Best overall response of CR was reported in 7 patients (12%); PR was reported in 23 patients (38%). Among these 30 patients, the median time to response, defined as the time from first dose to the earliest PR or CR, was six weeks (range 5 to 39 weeks). The median time to best overall response, defined as the time from first dose to best clinical response of CR or PR, was 11 weeks (range 5 to 60 weeks). Twenty-eight patients (47%) received SCT after a median of 7 cycles (range 4 to 16) of ADCETRIS. Thirty-two patients (53%) who did not receive subsequent SCT also received ADCETRIS for a median of 7 cycles (range 1 to 16). Of the 60 patients enrolled in the study, 49 patients (82%) had received > 1 prior chemotherapy regimen and 11 patients (18%) had received 1 prior chemotherapy regimen. Per IRF, ORR was 51% (95% CI [36%, 66%]) in patients who had received > 1 prior chemotherapy regimen and 45% (95% CI [17%, 77%]) in patients who had received 1 prior chemotherapy regimen. In patients with > 1 prior chemotherapy regimen, best overall response of CR was reported in 6 patients (12%) and PR in 19 patients (39%). In patients with 1 prior chemotherapy regimen, CR was reported in 1 patient (9%) and PR in 4 patients (36%). Of the 49 patients who had received > 1 prior cycle of therapy, 22 patients (45%) received subsequent SCT; of the 11 patients who had received 1 prior therapy, 6 patients (55%) received subsequent SCT. Data were also obtained from patients (n = 15) from phase 1 dose-escalation and clinical pharmacology studies and from patients (n = 26) in the NPP with relapsed or refractory HL who had not undergone ASCT and were treated with ADCETRIS 1.8 mg/kg every three weeks. Baseline patient characteristics showed failure of multiple prior chemotherapy regimens (median number of 3 with a range of 1 to 7) before the first administration of ADCETRIS. Fifty-nine percent (59%) of patients had an initial diagnosis of advanced disease (Stage III or IV). Results from these phase 1 studies and experience gained during the NPP show that in patients with relapsed or refractory HL who have not undergone 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 treatment. Study SGN35-006 (retreatment study) The efficacy of retreatment in patients who had previously responded (CR or PR) to ADCETRIS treatment was evaluated in an open-label, multicentre phase 2 study. Twenty patients with relapsed or refractory HL received an initial dose of 1.8 mg/kg and one patient received an initial dose of 1.2 mg/kg of ADCETRIS by intravenous infusion over 30 minutes every 3 weeks. The median number of cycles administered was 7 (range 2 to 37). Of the 20 evaluable patients with HL retreated with ADCETRIS, 6 patients (30%) achieved complete remission and 6 patients (30%) achieved partial remission, 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 SGN35-014 The efficacy and safety of ADCETRIS were evaluated in a randomised, double-blind, active-controlled, multicentre clinical trial in 452 patients with previously untreated CD30+ PTCL in combination with cyclophosphamide (C), doxorubicin (H) and prednisone (P) (CHP). CD30 expression of ≥ 10% confirmed by immunohistochemical analysis was a condition for enrolment in the trial. Only patients with CD30+ PTCL who were eligible for a cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (P) [CHOP]-based regimen were enrolled. The ADCETRIS + CHP combination was not studied in all PTCL subtypes. PTCL subtypes enrolled are listed in Table 18. Of the 452 patients, 226 were randomised to ADCETRIS + CHP and 226 to CHOP. Randomisation was stratified by ALK-positive sALCL versus all other subtypes and by International Prognostic Index (IPI) score. Patients were treated with 1.8 mg/kg ADCETRIS administered as a 30-minute intravenous infusion on Day 1 of each 21-day cycle plus CHP (cyclophosphamide 750 mg/m² every 3 weeks intravenously; doxorubicin 50 mg/m² every 3 weeks intravenously; and prednisone 100 mg orally on Days 1 to 5 of each 3-week cycle) for 6 to 8 cycles. The median number of cycles administered was 6 (range 1 to 8); 70% of patients received 6 cycles and 18% received 8 cycles. Table 18 provides a summary of baseline patient and disease characteristics. Table 18: Summary of baseline patient and disease characteristics in the phase 3 study in previously untreated PTCL (ITT and sALCL) ITT population sALCL populationᵇ Patient characteristics ADCETRIS + CHP n = 226 CHOP n = 226 ADCETRIS + CHP n = 162 CHOP n = 154 Median age (range) 58.0 (18–85) 58.0 (18–83) 55.0 (18–85) 54.0 (18–83) Patients aged ≥ 65 years (%) 69 (31) 70 (31) 38 (23) 36 (23) Male sex, n (%) 133 (59) 151 (67) 95 (59) 110 (71) ECOG status, n (%) 0 84 (37) 93 (41) 58 (36) 53 (34) 1 90 (40) 86 (38) 62 (38) 61 (40) 2 51 (23) 47 (21) 41 (25) 40 (26) Disease characteristics Diagnosis by local assessment, n (%)ᵃ sALCL 162 (72) 154 (68) 162 (100) 154 (100) ALK-positive 49 (22) 49 (22) 49 (30) 49 (32) ALK-negative 113 (50) 105 (46) 113 (70) 105 (68) Peripheral T-cell lymphoma (PTCL-NOS) 29 (13) 43 (19) NA NA Angioimmunoblastic T-cell lymphoma (AITL) 30 (13) 24 (11) NA NA Adult T-cell leukaemia/lymphoma (ATLL) 4 (2) 3 (1) NA NA Enteropathy-associated T-cell lymphoma (EATL) 1 (0) 2 (1) NA NA Median time from diagnosis to first dose, months (range) 0.8 (0–19) 0.9 (0–10) 0.8 (0–19) 0.9 (0–10) Disease stage at PTCL diagnosis, n (%) Stage I 12 (5) 9 (4) 12 (7) 7 (5) Stage II 30 (13) 37 (16) 22 (14) 27 (18) Stage III 57 (25) 67 (30) 29 (18) 46 (30) Stage IV 127 (56) 113 (50) 99 (61) 74 (48) IPI score 0 8 (4) 16 (7) 7 (4) 14 (9) 1 45 (20) 32 (14) 34 (21) 18 (12) 2 74 (33) 78 (35) 58 (36) 60 (39) 3 66 (29) 66 (29) 37 (23) 40 (26) 4 29 (13) 25 (11) 22 (14) 16 (10) 5 4 (2) 9 (4) 4 (2) 6 (4) Extranodal involvement at diagnosis, n (%) ≤ 1 site 142 (63) 146 (65) 94 (58) 95 (62) > 1 site 84 (37) 80 (35) 68 (42) 59 (38) Baseline bone marrow involvement on lymphoma biopsy, n (%) Yes 30 (13) 34 (15) 15 (9) 13 (8) No 196 (87) 192 (85) 147 (91) 141 (92) Per WHO 2008 classification. In patients with locally diagnosed sALCL. The primary endpoint of Study SGN35-014 was PFS per IRF, defined as the time from randomisation to the date of first documentation of disease progression, death from any cause, or administration of subsequent anticancer therapy to treat residual or progressive disease, whichever occurred first. Administration of subsequent consolidation radiotherapy, subsequent chemotherapy for peripheral blood stem cell mobilisation, or consolidation autologous or allogeneic stem cell transplantation was not considered disease progression or initiation of new anticancer therapy. The key secondary endpoints were PFS per IRF in patients with centrally confirmed sALCL, CR rate per IRF at the end of study treatment, OS, and ORR per IRF at the end of study treatment, evaluated in a fixed-sequence testing procedure according to the statistical significance of PFS per IRF. The primary endpoint and alpha-protected key secondary endpoints, evaluated hierarchically, were met. The median PFS per IRF in the ITT population was 48.2 months in the ADCETRIS + CHP group versus 20.8 months in the CHOP group. The stratified hazard ratio was 0.71 (95% CI: 0.54, 0.93; p = 0.011), indicating a 29% reduction in the risk of PFS events with ADCETRIS + CHP versus CHOP. For overall survival, the stratified hazard ratio was 0.66 (95% CI: 0.46, 0.95; p = 0.024), representing a 34% reduction in the risk of OS events with ADCETRIS + CHP versus CHOP. PFS per IRF for patients with centrally confirmed sALCL was a prespecified key secondary endpoint. Median PFS per IRF was 55.7 months in the ADCETRIS + CHP group versus 54.2 months in the CHOP group. The stratified hazard ratio was 0.59 (95% CI: 0.42, 0.84; p = 0.024), consistent with a statistically significant 41% reduction in the risk of PFS events with ADCETRIS + CHP versus CHOP (p-value = 0.003); see Figure 6 and Table 19. Subgroup analyses were performed in patients with locally diagnosed sALCL. For overall survival, the stratified hazard ratio was 0.54 (95% CI: 0.34, 0.87), a 46% reduction in the risk of OS events with ADCETRIS + CHP versus CHOP; see Figure 7. At the end of treatment, the CR rate per IRF was 71.0% in patients in the ADCETRIS + CHP group compared with 53.2% in patients in the CHOP group, a difference of 17.7% (95% CI: 7.2%, 28.3%). At the end of treatment, the ORR per IRF was 87.7% in patients in the ADCETRIS + CHP group compared with 70.8% in patients in the CHOP group, a difference of 16.9% (95% CI: 8.1%, 25.7%). In the ALK+ sALCL and ALK- sALCL patient subgroups, the stratified hazard ratio for PFS per IRF was 0.29 (95% CI: 0.11, 0.79) and 0.65 (95% CI: 0.44, 0.95), respectively. Table 19: Efficacy results in patients with previously untreated sALCL treated with 1.8 mg/kg ADCETRIS on Day 1 of a 3-week cycle (primary analysis) ADCETRIS + CHP n = 162ᵃ CHOP n = 154ᵃ PFS per IRF Number of patients with PFS event, n (%) 56 (34) 73 (48) Median PFS, months (95% CI) 55.66 (48.20, NE) 54.18 (13.44, NE) Hazard ratio (95% CI)ᵇ 0.59 (0.42, 0.84) p-valueᶜ 0.0031 Estimated PFS (95% CI)ᵈ at: 6 months 88.0% (81.8%, 92.2%) 68.4% (60.3%, 75.2%) 12 months 78.7% (71.4%, 84.4%) 60.3% (51.9%, 67.6%) 24 months 68.4% (60.4%, 75.2%) 53.9% (45.5%, 61.5%) 36 months 65.5% (57.1%, 72.7%) 50.2% (41.6%, 58.1%) OSᵉ Number of deaths (%) 29 (18) 44 (29) Median OS, months (95% CI) NE (NE, NE) NE (NE, NE) Hazard ratio (95% CI)ᵇ 0.54 (0.34, 0.87) p-valueᶜ,ᶠ 0.0096 CR rateᵍ, % (95% CI) 71% (63.3%, 77.8%) 53% (45.0%, 61.3%) p-valueᶠ,ʰ 0.0004 ORRᵍ, % (95% CI) 88% (81.6%, 92.3%) 71% (62.9%, 77.8%) p-valueᶠ,ʰ < 0.0001 CR = complete remission; IRF = Independent Review Facility; NE: not estimable; ORR = objective response rate; PFS = progression-free survival. PFS per IRF is calculated from patients with centrally confirmed sALCL, with n = 163 patients in the A + CHP group and n = 151 in the CHOP group. OS, CR and ORR are calculated in patients with locally diagnosed sALCL. Hazard ratio (A + CHP / CHOP) and 95% confidence intervals are based on a stratified Cox proportional hazards regression model with stratification factors (ALK-positive sALCL versus all others and baseline International Prognostic Index [IPI] score). A hazard ratio < 1 favours the A + CHP group. p-value calculated using a stratified log-rank test. PFS rate is estimated using the Kaplan-Meier method and the 95% CI is calculated using the complementary log-log transformation method. Median OS follow-up was 38.5 months in the ADCETRIS + CHP group and 41.0 months in the CHOP group. p-value not adjusted for multiplicity. Response per the 2007 International Working Group criteria at the end of treatment. p-value calculated using a stratified Cochran-Mantel-Haenszel test. Figure 6: Progression-free survival per IRF in the sALCL population (ADCETRIS + CHP vs. CHOP) (primary analysis) Figure 7: Overall survival in the sALCL population (ADCETRIS + CHP vs. CHOP) (primary analysis) * The overall survival p-value is not adjusted for multiplicity. At study closure, more than 7 years after enrolment of the first patient, PFS per investigator in the ITT population showed a 30% reduction in the risk of PFS events in the ADCETRIS + CHP arm compared with CHOP-treated patients (HR = 0.70 [95% CI (0.53, 0.91)]). PFS per investigator in the sALCL population showed a 45% reduction in the risk of PFS events in the ADCETRIS + CHP arm compared with CHOP-treated patients (HR = 0.55 [95% CI (0.39, 0.79)]). At study closure, overall survival results continued to demonstrate benefit and were consistent with those reported at the primary analysis. Overall survival in the ITT population showed a 28% reduction in the risk of death in the ADCETRIS + CHP arm compared with CHOP-treated patients (HR = 0.72 [95% CI (0.53, 0.99)]). Overall survival in the sALCL population showed a 34% reduction in the risk of death in the ADCETRIS + CHP arm compared with CHOP-treated patients (HR = 0.66 [95% CI (0.43, 1.01)]); see Figure 8. Figure 8: Overall survival in the sALCL population (ADCETRIS + CHP vs. CHOP) (study closure) Study SG035-0004 The efficacy and safety of ADCETRIS as monotherapy were evaluated in an open-label, single-arm, multicentre study in 58 patients with relapsed or refractory sALCL. A summary of baseline patient and disease characteristics is provided in Table 20 below. Table 20: Summary of baseline patient and disease characteristics in the phase 2 study in relapsed or refractory sALCL Patient characteristics n = 58 Median age, years (range) 52 years (14–76) Sex 33 M (57%) / 25 F (43%) ECOG performance statusᵃ 0 19 (33%) 1 38 (66%) Prior ASCT 15 (26%) Prior chemotherapy regimens (range) 2 (1–6) Histologically confirmed CD30-expressing disease 57 (98%) Anaplastic lymphoma kinase (ALK)-negative disease 42 (72%) Disease characteristics Primary refractory to frontline therapyᵇ 36 (62%) Refractory to most recent therapy 29 (50%) Relapsed after most recent therapy 29 (50%) Baseline B symptoms 17 (29%) Stage III at initial diagnosis 8 (14%) Stage IV at initial diagnosis 21 (36%) One patient had a baseline ECOG status of 2, which was prohibited by the protocol, and is recorded as: Does not meet enrolment criteria. Primary refractory sALCL is defined as failure to achieve complete remission, or progression within 3 months of completing frontline therapy. Median time from initial sALCL diagnosis to first dose of ADCETRIS was 16.8 months. Ten (10) patients (17%) received 16 cycles of ADCETRIS; the median number of cycles administered was 7 (range 1 to 16). Response to ADCETRIS treatment was assessed by an Independent Review Facility (IRF) using the Revised Response Criteria for Malignant Lymphoma (Cheson, 2007). Treatment response was assessed on the basis of spiral CT of the chest, neck, abdomen and pelvis, PET imaging and clinical data. Response assessments were performed at Cycles 2, 4, 7, 10, 13 and 16, with PET imaging at Cycles 4 and 7. The objective response rate (ORR) per IRF was 86% (50 of 58 patients in the intent-to-treat [ITT] population), and tumour reduction (of any degree) was achieved in 97% of patients. The estimated 5-year overall survival rate was 60% (95% CI [47%, 73%]) (median follow-up [time to death or last contact] from first dose was 71.4 months). Investigator assessments were largely consistent with the independent assessment of images. Of the treated patients, 9 with a treatment response went on to receive allogeneic stem cell transplantation (SCT) and a further 9 with a treatment response went on to receive autologous SCT. For additional efficacy results, see Table 21 and Figure 9. Table 21: Efficacy results in patients with relapsed or refractory sALCL treated with 1.8 mg/kg ADCETRIS every 3 weeks Best clinical response (n = 58) IRF, n (%) 95% CI Objective response rate (CR + PR) 50 (86) 74.6, 93.9 Complete remission (CR) 34 (59) 44.9, 71.4 Partial remission (PR) 16 (28) NA Disease control rate (CR + PR + SD) 52 (90) 78.8, 96.1 Duration of response Median per IRF 95% CI Objective response (CR + PR)ᵃ 13.2 5.7, 26.3 Complete remission (CR) 26.3 13.2, NEᵇ Progression-free survival Median per IRF 95% CI Median 14.6 6.9, 20.6 Overall survival Median 95% CI Median Not reached 21.3, NEᵇ Range of duration of response (DOR) was 0.1 months to 39.1+ months, and the median follow-up from first dose for patients who achieved objective response (OR) per IRF was 15.5 months. Not estimable. Figure 9: Kaplan-Meier plot of OS Median 95% CI N Events (months) (months) ITT patients 58 25 – (21.3, –) Exploratory analysis at the individual patient level showed that approximately 69% of sALCL patients treated with ADCETRIS in clinical study SG035-0004 experienced improved 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 study entry, all B symptoms resolved in 14 patients (82%) at a median time of 0.7 months from initiation of ADCETRIS. Study C25006 The efficacy and safety of ADCETRIS administered as monotherapy were also evaluated in an open-label, single-arm, multicentre phase 4 study in 50 patients with relapsed or refractory sALCL. The objective response rate (ORR) per IRF assessment was 64% (32 of 50 patients in the intent-to-treat [ITT] population). The median duration of response (DOR) per IRF was not reached (95% CI 19.71 months, not estimable). The CR rate was 30% (15 of 50 patients in the ITT population), and tumour reduction (of any degree) was achieved in 93% of evaluable patients. The median duration of complete remission (DOCR) per IRF was not reached (95% CI 10.61 months, not estimable). Response assessments by IRF were largely consistent with investigator assessments. Of the treated patients, 13 underwent haematopoietic stem cell transplantation. Pooled data from studies C25006 and SG035-0004 (n = 108) showed an objective response rate (ORR) per IRF of 76% (82 of 108 patients in the intent-to-treat [ITT] population). The median duration of response (DOR) per IRF was 17.0 months (95% CI 12.62, 32.46). The CR rate was 45% (49 of 108 patients in the ITT population), and tumour reduction (of any degree) was achieved in 96% of evaluable patients. The median duration of complete remission (DOCR) per IRF was 26.3 months (95% CI 16.16, not estimable). Response assessments by IRF were largely consistent with investigator assessments. Study SGN35-006 (retreatment study) The efficacy of retreatment in patients who had previously responded (CR or PR) to ADCETRIS treatment was evaluated in an open-label, multicentre phase 2 study. Seven patients with relapsed sALCL received an initial dose of 1.8 mg/kg and one patient received an initial dose of 1.2 mg/kg of ADCETRIS by intravenous infusion over 30 minutes every 3 weeks. The median number of cycles administered was 8.5 (range 2 to 30). Of the 8 patients with sALCL, 3 were retreated twice for a total of 11 retreatments. Retreatment with ADCETRIS resulted in 6 patients with CR (55%) and 4 patients with PR (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 administered as monotherapy were evaluated in a pivotal open-label, randomised, multicentre phase 3 study in 128 patients with histologically confirmed CD30+ CTCL. CD30 positivity was defined as ≥ 10% of target lymphoid cells exhibiting membranous, cytoplasmic and/or Golgi staining by immunohistochemistry (Ventana anti-CD30 [Ber-H2]). Patients with a diagnosis of mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL) were eligible for enrolment. Patients were stratified by these disease types and randomised 1:1 to receive either ADCETRIS or methotrexate or bexarotene per physician's choice. Patients with pcALCL had received either prior radiation therapy or at least one prior systemic therapy, and patients with MF had received at least one prior systemic therapy. Patients with a concurrent diagnosis of systemic ALCL, Sézary syndrome or other non-Hodgkin lymphoma (other than lymphomatoid papulosis [LyP]) were excluded from the study. Patients were treated with ADCETRIS 1.8 mg/kg intravenously over 30 minutes every 3 weeks for up to 16 cycles or with the physician's choice of therapy for up to 48 weeks. The median number of cycles administered in the ADCETRIS arm was approximately 12. In the physician's choice arm, the median duration of treatment (number of cycles) was approximately 16 weeks (5.5 cycles) in patients receiving bexarotene and 11 weeks (3 cycles) in patients receiving methotrexate. A summary of baseline patient and disease characteristics is provided in Table 22. Table 22: Summary of baseline patient and disease characteristics in the phase 3 CTCL study (ITT population) Patient characteristics ADCETRIS n = 64 Physician's choice (methotrexate or bexarotene) n = 64 Median age (range) 62 years (22–83) 58.5 years (22–83) Patients ≥ 65 years, n (%) 28 (44%) 24 (38%) Sex, n (%) 33 M (52%) / 31 F (48%) 37 M (58%) / 27 F (42%) ECOG performance status, n (%) 0 43 (67) 46 (72) 1 18 (28) 16 (25) 2 3 (5) 2 (3) Disease characteristics Median number of prior therapies (range) 4 (0–13) 3.5 (1–15) Median number of skin-directed therapies (range) 1 (0–6) 1 (0–9) Median number of systemic therapies (range) 2 (0–11) 2 (1–8) MF, n (%) 48 (75) 49 (77) Early (IA–IIA) 15 (31) 18 (37) Advanced (IIB–IVBᵃ) 32 (67) 30 (61) pcALCL, n (%) 16 (25) 15 (23) Skin only 9 (56) 11 (73) Extracutaneous disease 7 (44) 4 (27) a One patient in each arm had incomplete reference data and is not included in the table The most common prior skin