Summary Basis of Decision for Adcetris

 

Clinical Pharmacology

Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) cells characteristically express the cell-surface receptor CD30. Adcetris (brentuximab vedotin) is a CD30-directed antibody-drug conjugate (ADC) consisting of three components:

• the chimeric immunoglobulin G1 monoclonal antibody cAC10, specific for human CD30;
• monomethyl auristatin E (MMAE) - a potent microtubule-disrupting agent; and
• a linker that attaches cAC10 to MMAE.

Non-clinical data suggest that Adcetris exerts its anti-cancer activity through the binding of the ADC to CD30-expressing cells, followed by the internalization of the ADC-CD30 complex and the subsequent release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic cell death of the CD30-expressing tumor cell.

Pharmacodynamics

QT Prolongation

The effect of Adcetris on the QTc interval was evaluated in an intensive, open-label, single-arm study (Study SGN35-007) in 46 evaluable patients with CD30-expressing hematologic malignancies. Patients were administered the recommended therapeutic dose (1.8 mg/kg administered as a 30 minute intravenous infusion once every 3 weeks) and were assessed on Days 1-4 of the first and third week of the 3-week treatment cycles. Electrocardiogram (ECG) measurements taken at and around the time of the maximum plasma concentration (C_max) of MMAE and the C_max of the ADC were used to evaluate whether there was an Adcetris effect on the QTc interval.

Administration of Adcetris did not prolong the QTc interval from baseline; however, small increases in QTc interval cannot be excluded because of study limitations. Adcetris was associated with small, but statistically significant, decreases in the QTcF interval (maximum mean decrease from baseline approximately 7 ms. At present, the clinical consequences of QTc shortening of this magnitude are not known. There was no convincing evidence of a treatment-related effect of MMAE on the QRS duration, the PR interval, or heart rate. Because studies to assess the levels of MMAE in subjects with hepatic or renal impairment have not yet been completed, exposure in subjects with compromised elimination is not known.

Limitations of this ECG assessment study include the lack of a placebo control arm to enable correction for background changes in the ECG intervals and lack of a positive control to verify assay sensitivity.

Pharmacokinetics

Drug-Drug Interactions

The results of the drug-drug interaction study, SGN35-008A, indicated that MMAE is unlikely to be an inducer or inhibitor, but is a substrate, of cytochrome P450 (CYP)3A4. There is also the potential that MMAE is a P-glycoprotein (P-gp) substrate; therefore, it is important to note the potential of MMAE to interact with drugs or foods that are inhibitors/inducers of CYP3A enzymes and/or P-gp as these could affect exposures to MMAE. The pharmacokinetics of ADC were not affected by co-administration of any modulators of CYP3A4/P-gp, nor did the ADC affect the pharmacokinetics of midazolam, a CYP3A substrate. This indicates that at the current dosing regimen, CYP3A enzymes are not inhibited by Adcetris or any of its components.

The clinical pharmacology program was considered appropriate and did not identify any major issues that would preclude authorization. At the time of submission, one study (Study SGN35-008B) investigating renal and hepatic impairment was underway but not complete. This study has been designated as a post-marketing commitment.

For further details on the clinical pharmacology of Adcetris, please refer to the Adcetris Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Adcetris was evaluated in two pivotal, single-arm, open-label, multicentre, Phase II studies: Study SG035-0003 (herein referred to as Study 3) and Study SG035-0004 (herein referred to as Study 4). Study 3 enrolled 102 relapsed or refractory HL patients that had undergone an autologous stem cell transplant (ASCT) and Study 4 enrolled 58 patients with relapsed or refractory sALCL. In both studies, patients were treated with Adcetris monotherapy administered every 21 days by intravenous (IV) infusion at a dose of 1.8 mg/kg for up to 16 cycles.

For both studies, the primary endpoint was the overall objective response rate (ORR), defined as the proportion of patients who achieved complete response (CR) or partial response (PR). Response was determined by an independent review facility (IRF) that assessed response using standardized response criteria for malignant lymphoma. These criteria are widely accepted for use in the measurement of response in clinical studies for malignant lymphoma.

Secondary endpoints included duration of response (DOR) per IRF, CR rate per IRF, Progression-Free Survival (PFS) per IRF, and Overall Survival (OS). The DOR was defined as the time from the first documentation of objective tumor response (CR or PR) to the first subsequent documentation of objective tumor progression or to death due to any cause, whichever came first. The CR rate per IRF was defined as the proportion of patients achieving CR according to standardized response criteria. Progression-Free Survival per IRF was defined as the time from start of study treatment to first documentation of objective tumor progression or to death due to any cause, whichever came first. Lastly, OS was defined as the time from start of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was to be censored at the last date the patient was known to be alive. Patients lacking data beyond the day of first dose were to have their survival time censored at 1 day.

The resolution rate of B symptoms was an additional endpoint in both studies, and was defined as the proportion of patients with lymphoma-related B symptoms at baseline who achieved resolution of all B symptoms at any time during the treatment period.

Hodgkin Lymphoma

An independent radiological and clinical data review that applied standardized response criteria determined that 75% [76/102; 95% Confidence Interval (CI): 64.9; 82.6] of patients achieved an objective response while receiving Adcetris monotherapy. Of these 76 patients, 33 [32% (95% CI: 23.4; 42.3)] were assessed as having a CR at one or more time-points. Forty-three patients [42% (95% CI: 32.4; 52.3)] had a best clinical response of PR. The lower bound of the 95% CI around the ORR substantially exceeded the pre-defined limit of 20% and, therefore, the ORR was considered to be both clinically and statistically significant.

The DOR (key secondary endpoint) for HL patients receiving Adcetris was considered to be durable. Overall, responders had a median DOR of 6.7 months (95% CI: 3.6; 14.8). The median duration of response was not reached in CR patients [95% CI: 10.8, NE (not estimatable)] while patients that achieved PR had a median DOR of 3.5 months (95% CI: 2.2; 4.1). The median time to objective response was 5.7 weeks (range: 5.1 - 56 weeks) and the median PFS was 5.6 months (95% CI: 5.0; 9.0). Median OS was estimated to be 27.0 months (95% CI: 23.9, NE); however, in the absence of a comparator arm, it is difficult to put the results of time-to-event endpoints, such as PFS and OS, into context. Therefore, it is imperative that confirmatory studies are adequately designed to properly characterize these key endpoints.

The resolution of B-symptoms was investigated as an additional endpoint. Thirty-five patients had B-symptoms at baseline. Of these, 27 (77%) had complete resolution of B-symptoms at some time after the initiation of treatment.

Systemic Anaplastic Large Cell Lymphoma (sALCL)

Patients treated with Adcetris demonstrated an ORR per IRF of 86% (50/58 patients; 95% CI: 74.6; 93.9). Fifty-nine percent (59%) (34/58 patients; 95% CI: 44.9; 71.4) of patients had a CR and 28% (16/58 patients; 95% CI: 16.7; 40.9) had a PR. The lower bound of the 95% CI for ORR substantially crossed the pre-specified limit of 20%, therefore the ORR was considered to be statistically and clinically meaningful.

The median DOR per IRF was 13.2 months (95% CI: 5.7, NE). The responses were durable for CR responders (not reached, 95% CI 13.0, NE), but not for PR responders (2.0 months, 95% CI 0.1, 21+); however, these results should be interpreted with caution as patients who achieved a CR may have pre-treatment characteristics that favour a longer duration of response compared to PR responders.

The ORR per IRF was consistent with that per investigator and among most of the subgroups. The median time to objective response was 5.9 weeks (range 4.3-14 weeks). The estimated median PFS per IRF was 14.3 months (95% CI: 6.9, NE) and the median OS was not reached. At the time of the study closure, 55% of patients had progressed or died, and 33% of the patients had died. In the absence of a comparator arm, these results are difficult to interpret. In addition, 14 out of 17 patients (82%) had resolution of their B symptoms, but this result should be interpreted with caution as only a small proportion of patients had B symptoms at baseline (17 patients; 29.3%). Confirmatory studies are warranted to assess the true clinical benefit of Adcetris.

Supportive Studies

Data from one single-arm, open-label, multi-centre, first-in-human, Phase I dose-escalation study (Study SG035-0001 - herein referred to as Study 1) provided support for the efficacy of Adcetris in patients with CD30-positive haematological malignancies. The study enrolled 45 patients. The primary objective of the study was to characterize the safety of Adcetris monotherapy and to determine the maximum-tolerated dose (MTD) of Adcetris when administered once every three weeks. Secondary objectives were to characterize the efficacy and pharmacokinetics for Adcetris and for the cytotoxic portion of Adcetris, MMAE.

For patients receiving a dose of 1.8 mg/kg (n = 12), the ORR was 50%. This level of response was supportive of the high rates of response (75%) observed in the pivotal studies.

Overall Analysis of Efficacy

In conclusion, both pivotal studies met their primary endpoint by achieving a high ORR in the indicated populations. Furthermore, a Phase I study (Study 1) in which a limited number (12 of 45 subjects who took part in the study) of patients with CD30 positive haematological malignancies received Adcetris monotherapy at a dose of 1.8 mg/kg every 3 weeks also detected a high rate of response. Duration of response was a key secondary efficacy endpoint in both pivotal studies, and responses were considered to be durable in both the HL and sALCL populations. Other measures of efficacy common to both pivotal trials included PFS and OS; however, in the absence of a comparator arm, time-to-event endpoints [that is (i.e.) PFS, OS,] are difficult to interpret and no definite conclusions on these efficacy results can be drawn.

Based on the primary endpoint (ORR) results, in combination with the demonstration of durability of response, Adcetris therapy is considered likely to be efficacious in the population in which it was tested. Confirmatory studies are warranted to assess the true clinical benefit of Adcetris and are required in order to fulfill commitments agreed upon with the sponsor.

The original indications proposed with the New Drug Submission were as follows:

• Treatment of patients with HL after failure of ASCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.
• Treatment of patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.

Following review of the submission, Health Canada revised the indication to include the following statement:

• The indications were approved based on promising response rates demonstrated in single-arm trials. No data demonstrate increased survival with Adcetris.

For more information, refer to the Adcetris Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Adcetris was evaluated in the pivotal and supportive studies described in the Clinical Efficacy section.

Hodgkin Lymphoma

Of the 102 patients in the safety evaluable set, 100 (98%) experienced at least one treatment-emergent adverse event (TEAE) that was considered related to study drug by the investigator. A total of 41 patients (40%) experienced a Grade 3 TEAE; 14 patients (14%) had a Grade 4 TEAE; and 1 patient had a Grade 5 (fatal) TEAE. There were 94 patients (92%) who had at least one adverse event (AE) considered related to study drug by the investigator.

The key TEAEs that occurred in ≥20% of patients were neutropenia (54%), peripheral sensory neuropathy (52%), fatigue (46%), nausea (42%), upper respiratory tract infection (47%), diarrhea (36%), pyrexia (29%), thrombocytopenia (28%), vomiting (22%), and cough (21%). Infusion reactions were observed in 12% of patients, but were generally mild (all ≤ Grade 2). One case of Stevens-Johnson syndrome (Grade 3) was reported. The patient developed the AE approximately 2 weeks after the first dose of Adcetris. The AE resolved within 1 month; however, the patient discontinued treatment due to the AE. The risk of Stevens-Johnson syndrome is included as a warning in the Product Monograph for Adcetris. Monomethyl auristatin E (MMAE), one of the components of Adcetris, is a microtubule disrupting agent, and this AE profile is consistent with the profiles of other microtubule disrupting agents.

Twenty patients (20%) had an AE that led to treatment discontinuation. Serious adverse events (SAEs) were experienced by 25 patients (25%); 14 of these patients (14%) had an SAE that was considered related to study drug by the investigator. The most commonly experienced SAEs by System Organ Class were 'Infections and Infestations' (9%); 'Respiratory, Thoracic, and Mediastinal Disorders' (8%); 'Gastrointestinal Disorders' (5%); and 'Nervous System Disorders' (4%). Notably, no cases of neutropenia were considered to be SAEs, and a total of 3 cases of peripheral neuropathy were considered serious.

No deaths occurred within 30 days of the last dose of Adcetris. The single death reported during the study was related to disease progression. On Study Day 13 this patient had an SAE (endobronchial tumor as a result of recurrent HL). The patient died >30 days after receiving the last dose of Adcetris; however, as the initial event occurred during the study, the death is captured in the database as an AE with an outcome of death.

Systemic Anaplastic Large Cell Lymphoma

In Study 4, the safety population included all 58 patients enrolled in the trial. All patients experienced at least 1 TEAE. The most common TEAEs occurring in ≥20% included fatigue (38%), pyrexia (34%), nausea (40%), diarrhea (29%), constipation (22%), rash (24%), and most importantly infections, peripheral neuropathy, and hematological toxicity. Peripheral neuropathy was observed in 33/58 patients (57%), and was unresolved in several patients at the end of the treatment or during follow-up period. Thirty-seven patients (64%) experienced neutropenia and of these, 14 patients had ≥ Grade 3 neutropenia. One incidence of Tumour Lysis Syndrome (Grade 3) was also observed. Infusion reactions occurred in five patients (9%; all of ≤ Grade 2 in severity).

Sixteen patients (28%) discontinued treatment due to AEs. The most common AE leading to treatment discontinuation was peripheral sensory neuropathy (6/16 patients; 28%). Thirty-six patients (62%) experienced ≥ Grade 3 AEs and 25 patients (43%) had SAEs. The System Organ Classes with the greatest incidences of SAEs were 'Nervous System Disorders' (7 patients - 12%) and 'Infections' (7 patients - 12 %).

A total of six deaths occurred within 30 days of the last dose of Adcetris. Four deaths were due to disease progression (such as recurrent ALCL in 3 patients and respiratory failure in 1 patient), one death was due to myocardial infarction and acute renal failure (the patient had pre-existing conditions), and one death was due to sudden death (unknown cause, but the patient had a pre-existing disease-related tracheal disorder).

Supportive Studies

The safety profile observed in Study 1 was relatively consistent with the profile observed in the pivotal trials in terms of incidence and type of events experienced.

Study SG035-0002 (herein referred to as Study 2) was a single-arm, open-label, multicentre, Phase I dose-escalation in patients with relapsed/refractory CD30-positive hematologic malignancies. Study 2 included 44 patients in the safety population, most of whom had HL (86%) and only 5 of whom had sALCL (11%). The results of this study determined that the maximum tolerated dose was 1.2 mg/kg. Due to the single-arm nature of this study and differences in study design and protocol, as well as patient populations, a direct comparison of the safety results with the pivotal studies was not feasible; however, the safety profile appears to be fairly consistent with that of both pivotal trials.

QT shortening was observed in CD30-positive patients treated with Adcetris in a clinical pharmacology study. The clinical significance of QT shortening is unknown.

Post-Marketing Experience

Three cases of progressive multifocal leukoencephalopathy (PML) (2 confirmed, 1 suspected) have been reported since the authorization of Adcetris in the United States. One of these cases occurred in a patient enrolled in Study SG35-010 while the other two occurred in subjects that received commercial Adcetris (1 sALCL patient and 1 HL patient). One of these patients died. The other two were in hospice care at the time of the submission; however, both patients' neurological states were worsening. The occurrence of PML in these patients prompted the United States Food and Drug Administration (FDA) to add a Black Box Warning to the United States Prescribing Information (USPI).

Progressive multifocal leukoencephalopathy is the result of an infection of the brain with John Cunningham (JC) virus that is fatal in approximately 30-50% of cases. Those that survive are often left with severe neurological disabilities. John Cunningham virus is carried by most healthy individuals; however, in those that have lowered immune defenses it is able to proliferate in the white matter of the brain. Patients with HL that have had multiple rounds of multi-modal chemotherapies, radiation, and ASCTs are already at risk for the development of this disease. Based on the single-arm pivotal studies submitted, Adcetris also has a suppressive effect on the immune system (lowered neutrophil counts, lymphopenia); therefore, at this time, it would be prudent to assume that Adcetris treatment may increase the risk of PML in HL patients.

One case of Tumour Lysis Syndrome (TLS) was reported in a patient receiving commercial Adcetris. The incident occurred in a patient diagnosed with diffuse large B-cell lymphoma. The event resolved. This was the second case of TLS observed in patients receiving Adcetris and the first spontaneous report.

One case of Steven-Johnson syndrome was reported in a 28-year old female with HL. This is the second case and the first spontaneous report. The first case was reported in Study 3. The patient has recovered.

Appropriate warnings and precautions are in place in the approved Adcetris Product Monograph to address the identified safety concerns. A Black Box Warning describing serious warnings and precautions for PML has been included in the Product Monograph for Adcetris. John Cunningham (JC) virus infection resulting in PML and death can occur in Adcetris-treated patients. Contributing factors may include prior therapies and underlying disease that may cause immunosuppression. Healthcare professionals should monitor patients on Adcetris for any new sign or symptom that may be suggestive of PML. Further treatment with Adcetris should be withheld immediately at the first sign or symptom suggestive of PML.

Overall Analysis of Safety

In summary, the safety database for Adcetris included data from 6 completed clinical studies. These included 357 patients, with CD30-positive hematological malignancies that received at least one dose of Adcetris. One hundred and sixty (160) of these were enrolled in the Phase II, pivotal studies (102 in Study 3; 58 in Study 4). Both Phase II studies were carried out using the authorized dose and schedule, which is 1.8 mg/kg every 21 days for up to 16 cycles. An additional 6 Phase I - III studies were ongoing at the time of authorization. The number of patients exposed and the extent of exposure in the current clinical safety database are considered adequate to characterize the safety profile.

For more information, refer to the Adcetris Product Monograph, approved by Health Canada and available through the Drug Product Database.