Brentuximab Vedotin Plus Chemotherapy in North American Subjects with Newly

Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2435 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly

Diagnosed Stage III or IV Hodgkin Lymphoma

Radhakrishnan Ramchandren,1 Ranjana H Advani,2 Stephen M Ansell,3 Nancy L Bartlett,4 Robert Chen,5 Joseph M Connors,6 Tatyana Feldman,7 Andres Forero-Torres,8 Jonathan W Friedberg,9 Ajay K Gopal,10 Leo I Gordon,11 John Kuruvilla,12 Kerry J Savage,6 Anas Younes,13 Gerald Engley,14 Thomas J Manley,14 Keenan Fenton,14 and David J Straus13 1Department of Hematology/Oncology, Barbara Ann Karmanos Cancer Center, Detroit, MI, USA; 2Department of Medicine, Stanford University, Palo Alto, CA, USA; 3Division of Hematology, Mayo Clinic, Rochester, MN, USA; 4Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO; 5Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA; 6University of British Columbia and the Department of Medical Oncology, British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, BC, Canada 7John Theurer Cancer Centre, Hackensack University Medical Center, Hackensack, NJ, USA; 8Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 9James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; 10Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA; 11Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA; 12Division of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, ON, Canada; 13Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 14Seattle Genetics, Inc., Bothell, WA, USA Running Title: Brentuximab Vedotin for Hodgkin Lymphoma in North America

Correspondence: Radhakrishnan Ramchandren, MD 4100 John R, Detroit, MI 48201 Phone: (313) 576-8746 Fax: (313) 576-8767 Email: [email protected]

Disclosure of conflicts of interest: RR serves as a consultant for Seattle Genetics. RA reports Advisory Board membership with AstraZeneca, Autolus, Bayer Healthcare Pharmaceuticals, Bristol Myers Squibb, Cell Medica, Gilead/Kite, Kyowa, Pharmacyclics, Roche/Genentech, Seattle Genetics, and Takeda; and receives research funding grants from Agensys, Bristol Myers Squibb, Celgene, Forty Seven, Inc., Genentech/Roche, Infinity, Janssen, Kura, Merck, Millenium, Pharmacyclics, Regeneron, and Seattle Genetics. SMA receives research funding grants from Affimed, Bristol Myers Squibb, Regeneron, Seattle Genetics, and Trillium. NLB reports Advisory Board membership with Acerta and Pfizer and receives research funding grants from Affimed, Bristol-Meyers Squibb, Celgene, Forty Seven, Genentech, Gilead, Immune

Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2435 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Design, Janssen, Merck, Millenium, and Pharmacyclics. RC reports Advisory Board membership with and serves as a consultant for Bristol Myers Squibb, Merck, and Seattle Genetics; receives research funding from Bristol Myers Squibb and Seattle Genetics; and is on the Speaker’s Bureau for Merck and Seattle Genetics. JMC reports honoraria and travel expenses from Seattle Genetics and receives research funding from Amgen, Bayer Healthcare, Bristol Myers Squibb, F Hoffmann-La Roche, Genentech, Janssen, Merck, NanoString Technologies, Roche Canada, Seattle Genetics, and Takeda. TF receives research funding from Seattle Genetics and is on the Speaker’s Bureau for Abbvie, Celgene, Janssen, Johnson and Johnson, KITE, Pharmacyclics, and Seattle Genetics. AF receives research funding from and is on the Speaker’s Bureau for Seattle Genetics. JWF reports receiving honoraria from Astellas and Bayer. AKG reports Advisory Board membership, consultancy, and honoraria from Bristol Myers Squibb, Janssen, Seattle Genetics, and Takeda; and receives research funding from Bristol Myers Squibb, Janssen, Merck, Seattle Genetics, Spectrum, Takeda, and Teva. JK serves as a consultant to Abbvie, Bristol Myers Squibb, Gilead, Janssen, Merck, Roche, and Seattle Genetics; reports honoraria from Amgen, Bristol Myers Squibb, Celgene, Gilead, Janssen, Karyopharm, Lundbeck, Merck, Roche, and Seattle Genetics; reports Advisory Board membership with Lymphoma Canada; and receives research funding from Leukemia and Lymphoma Society Canada, Princess Margaret Cancer Foundation, Roche, and Janssen. KJS reports Advisory Board membership with Bristol Myers Squibb; consultancy with Abbvie, Bristol Myers Squibb, Merck, Seattle Genetics, and Verastem; and honoraria with Abbvie, Bristol Myers Squibb, Merck, Seattle Genetics, Verastem, and Takeda. GE, TJM, and KF are employed by and own stock in Seattle Genetics. DJS serves as a consultant for Bayer, DAVA, InPractice Elselvier, JUNO, Millenium (Takeda), Onco Tracker, and Seattle Genetics; and is on the Speaker’s Bureau for ROCH China and Medical Crossfire. AY reports honoraria from Bayer, Bristol Myers Squibb, Celgene, Incyte, Janssen, Sanofi, Seattle Genetics, Takeda Millenium, Genentech, and Merck; and receives research funding from Bristol Myers Squibb, Curis, Johnson and Johnson, Novartis, and Roche.

Translational Relevance For over 40 years, the standard of care for frontline Hodgkin lymphoma in North America has

been chemotherapy with ABVD or an ABVD-like regimen. The novel A+AVD regimen

incorporates a targeted agent, the CD30-directed antibody-drug conjugate brentuximab vedotin

(ADCETRIS®), into a backbone of AVD chemotherapy. The phase 3, ECHELON-1 trial established A+AVD as the first frontline regimen with a targeted agent to demonstrate a modified progression-free survival benefit in comparison to ABVD for Stage III or IV classical

Hodgkin lymphoma (cHL). A preplanned subgroup analysis of ECHELON-1 revealed regional variation with a trend towards greater efficacy in North America; we present the efficacy, safety, and disease management of subjects in North America to better understand A+AVD as a

frontline treatment option for patients with Stage III or IV cHL. While these findings are

hypothesis-generating, they may provide meaningful information for managing patients with

A+AVD and influence future cHL studies.

ABSTRACT Purpose: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study

treated in North America (NA).

Experimental Design: ECHELON-1 is a global, open-label, randomized phase 3 study

comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin

(A+AVD) versus ABVD (AVD+bleomycin) as frontline therapy in subjects with Stage III or IV

classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive

A+AVD or ABVD intravenously on Days 1 and 15 of each 28-day cycle for up to 6 cycles.

Results: The NA subgroup consisted of 497 subjects in the A+AVD (n=250) and ABVD (n=247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary

endpoint (modified progression-free survival [PFS] per independent review) demonstrated an

improvement among subjects who received A+AVD compared with ABVD (HR=0.60; P=.012).

For PFS, the risk of progression or death was also reduced (HR=0.50; P=.002). Subsequent

anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were

more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as

compared to ABVD. Noted differences between arms included higher rates of febrile

neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of

pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD.

Conclusions: The efficacy benefit and manageable toxicity profile observed in the NA subgroup

of ECHELON-1 support A+AVD as a frontline treatment option for Stage III or IV cHL patients.

INTRODUCTION Approximately 8,200 cases of classical Hodgkin lymphoma (cHL) are diagnosed annually in the

United States (1). For over 40 years, the frontline standard of care for cHL in North America

(NA) has been chemotherapy with ABVD (2-4). Despite high response rates, approximately 30% of advanced stage HL patients are refractory or relapse following frontline treatment with ABVD

(5-7).

ECHELON-1 is an international, phase 3 trial comparing doxorubicin, vinblastine, and dacarbazine (AVD) in combination with brentuximab vedotin (ADCETRIS®) (A+AVD) versus

ABVD (AVD+bleomycin) as frontline therapy in subjects with Stage III or IV cHL (8). The primary endpoint was modified progression-free survival (PFS) per independent review facility

(IRF), defined as progression, death, or the receipt of additional treatment for subjects not achieving complete response (CR) at the completion of frontline therapy. It showed that A+AVD was superior to ABVD (hazard ratio [HR]=0.77, P=.035) with 2-year modified PFS rates of

82.1% and 77.2%, respectively, with no significant difference in overall survival (OS) at the OS interim analysis. Treatment with A+AVD was associated with higher rates of febrile neutropenia and peripheral neuropathy, and lower rates of pulmonary-related toxicity compared to ABVD.

A+AVD is the first treatment regimen utilizing a targeted agent to show superior efficacy in terms of modified PFS compared to ABVD while also eliminating the need for bleomycin in subjects with previously untreated Stage III or IV cHL. For the ECHELON-1 primary endpoint of modified PFS, assessment by region of the world was among the preplanned subgroup analyses, and consistent with the primary analysis showed an improvement in modified PFS for subjects randomized to A+AVD compared to those randomized to ABVD within the NA region

(Canada and the United States). Here we present additional safety and efficacy outcomes for

subjects on the ECHELON-1 study treated in NA.

METHODS

Trial Design ECHELON-1 is a global, open-label, randomized phase 3 study of A+AVD versus ABVD as

frontline therapy in subjects with Stage III or IV cHL (NCT01712490). Subjects were randomly

assigned in a 1:1 ratio, stratified by region (Americas [39%], Europe [50%], and Asia [11%]) and

international prognostic score (IPS), to receive A+AVD or ABVD intravenously on Days 1 and

15 of each 28-day cycle for up to 6 cycles. A detailed study design and the results of the entire

intent-to-treat (ITT) population have been published previously (8). The NA subset consisted of subjects enrolled at 85 sites across the United States and Canada.

Subjects Subjects 18 years of age or older with histologically confirmed Stage III or IV cHL, according to the World Health Organization pathology classification system (9), who had not been previously treated with systemic chemotherapy or radiotherapy, were eligible. Subjects were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and

satisfactory lab results (absolute neutrophil count, platelet count, hemoglobin level, markers of

liver and kidney function). Subjects were ineligible for the study if they had nodular lymphocyte

predominant HL, peripheral sensory or motor neuropathy, any evidence of residual disease from

another cancer, diagnosis of another cancer within 3 years before the first dose, or clinically relevant cardiovascular conditions.

Disease Assessments Modified PFS by independent review facility (IRF) was the primary objective of the

ECHELON-1 trial. Regional analysis of modified PFS per IRF, including North America, was a

prespecified sensitivity analysis. All additional analyses for the regional subgroups were

exploratory. Disease progression was evaluated in accordance with the Revised Response

Criteria for Malignant Lymphoma (Cheson 2007) (10) by both a blinded IRF and investigator

(INV) assessment.

Modified PFS per IRF was defined as time from randomization to first documentation of

progressive disease (per Cheson 2007), death due to any cause, or confirmed non-response (End

of Treatment [EOT] Deauville score ≥3) for subjects who received additional anti-cancer

therapy. Modified PFS per INV was defined as time from randomization to first documentation

of progressive disease (per Cheson 2007), death due to any cause, or confirmed non-response

(per Cheson 2007) for subjects who received additional anti-cancer therapy. PFS per INV was

defined as time from randomization to first documentation of progressive disease (per Cheson

2007) or death due to any cause.

An additional secondary endpoint was rate of CR defined as best overall response achieved at the

end of randomized regimen per IRF assessment (10). Subject disease status, following Cycle 2 and at EOT, by PET scan (using the Deauville criteria) was also assessed by IRF.

All survival endpoints were summarized using the Kaplan–Meier method and evaluated with the

use of a log-rank test. A Cox regression model was used to estimate the HR and the 95%

confidence interval (CI) for the treatment effect.

Safety evaluations included incidence of adverse events (AEs), as well as severity and type of

AE defined according to the Medical Dictionary for Regulatory Activities (MedDRA), version

19.0, with grading of AEs defined according to the National Cancer Institute Common

Terminology Criteria for Adverse Events [NCI-CTCAE], version 4.03.

Oversight The ECHELON-1 trial was conducted in accordance with regulatory requirements; the protocol

(previously-described (8)) was approved by institutional review boards and ethics committees at individual sites, and adhered to Good Clinical Practice guidelines (as defined by the International

Council for Harmonisation). A steering committee and an independent data and safety monitoring committee oversaw the conduct of the trial, and all the subjects provided written informed consent. Data were analyzed by sponsor statisticians and interpreted by academic authors and sponsor representatives. All the authors vouch for the completeness and accuracy of the data and adherence of the trial to the protocol.

RESULTS

Demographics The NA subgroup of the ECHELON-1 study consisted of 497 subjects (37% of the entire study population), 250 in the A+AVD arm and 247 in the ABVD arm. In the A+AVD arm, 214 subjects (86%) were from the United States and 36 (14%) were from Canada; whereas in the

ABVD arm, 225 subjects (91%) were from the United States and 22 (9%) were from Canada.

Baseline demographics and disease characteristics were consistent between treatment arms

(Table 1), and were generally comparable to the overall ITT population.

Efficacy At a median follow-up of 24.7 months, there was a clinically meaningful improvement in modified PFS per IRF in subjects treated with A+AVD versus ABVD, corresponding to a 40% reduction in the risk of progression, death, or modified progression events (HR=0.60; 95% CI,

0.40 to 0.90; P=.012) (Figure 1A). The 2-year modified PFS per IRF (95% CI) was 84.3% (78.7 to 88.5%) in the A+AVD arm and 73.7% (67.3 to 79.1%) in the ABVD arm, an absolute difference of 10.6 percentage points. The A+AVD and ABVD arms reported a total of 38 and

57 events, respectively. The majority of events reported in both arms were disease progression

(28 in the A+AVD arm versus 39 in the ABVD arm) followed by deaths (6 events in the

A+AVD arm versus 10 events in the ABVD arm). Modified progression accounted for 4 events in the A+AVD arm versus 8 events in the ABVD arm (Table 2). As previously reported, the HR for modified PFS per IRF in the European region was 0.83 (95% CI, 0.59 to 1.17; P=.281) and

0.91 (95% CI = 0.43 to 1.93; P=.810) in the Asian region (8). Modified PFS per investigator was generally consistent with these results by region (Supplemental Table 1).

Modified PFS per IRF showed a consistent trend towards improvement among NA subjects treated with A+AVD versus ABVD across all subgroups that were prespecified in the primary analysis (Figure 2). In addition, there was an advantage for A+AVD versus ABVD in subjects who were PET-negative at Cycle 2 (HR=0.60; 95% CI, 0.37 to 0.97; P=.034), with a 2-year modified PFS of 87.9% (82.5 to 91.6%) versus 78.3% (71.7 to 83.5%), respectively. Subjects who were PET2-positive showed a trend towards a greater benefit with A+AVD (HR=0.52; 95%

CI, 0.21 to 1.27; P=.139), with a 2-year modified PFS rate on the A+AVD arm of 58.2% (33.5 to

76.5%) versus 36.6% (16.7 to 56.9%) on the ABVD arm.

Though the prespecified event count for assessing the key secondary endpoint of OS has not been reached for the ITT population, an interim analysis of OS in subjects treated in NA showed a trend in favor of the A+AVD arm versus the ABVD arm (HR=0.51; 95% CI, 0.23 to 1.14;

P=.094). The interim 2-year OS rates (95% CI) were 97.0% (93.7 to 98.6%) in the A+AVD arm and 93.2% (88.8 to 95.8%) in the ABVD arm.

Modified PFS was the predefined primary endpoint of the ECHELON-1 trial; however, an

assessment of traditional PFS defined as time to either progression or death, was also performed

in NA subjects. The results from this analysis demonstrate a similar benefit for A+AVD versus

ABVD as was observed for the modified PFS endpoint. At a median follow-up of 24.7 months,

there was an improvement in PFS per investigator assessment in subjects treated with A+AVD

versus ABVD, corresponding to a 50% reduction in the risk of progression or death (HR=0.50;

95% CI, 0.32 to 0.79; P=.002) (Figure 1B). The 2-year PFS per investigator (95% CI) was 88.1%

(83.1 to 91.7%) in the A+AVD arm and 76.4% (70.1 to 81.5%) in ABVD arm, an absolute

difference of 11.7 percentage points.

A benefit was also seen in NA subjects who were PET2-negative at Cycle 2 (HR=0.439; 95% CI,

0.25 to 0.77; P=.003), with a 2-year PFS rate of 91.9% (87.0 to 95.0%) in the A+AVD arm

versus 81.1% (74.7 to 86.0%) with ABVD; for PET2-positive subjects, 2-year PFS rates of

54.5% (32.1 to 72.4%) versus 48.0% (26.0 to 67.0%) were seen (HR=0.901; 95% CI, 0.38 to

2.12; P=.810).

Response rates as determined by IRF demonstrated a consistent benefit for A+AVD compared to

ABVD and are summarized in Supplemental Table 2. The CR rates following frontline therapy

(per the Revised Response Criteria for Malignant Lymphoma (10)) were 72% in the A+AVD

arm and 67% in the ABVD arm. At the Cycle 2 PET scan, 88% of subjects in the A+AVD arm

and 83% of subjects in the ABVD arm had a Deauville score ≤3; at the EOT PET scan, the rates

of Deauville Score ≤3 were 86% and 78%, respectively. A summary of the rates of Deauville

Scores per IRF at the Cycle 2 and EOT PET scans is presented in Supplemental Table 2.

Subjects treated with A+AVD required fewer subsequent anti-cancer therapies than subjects treated with ABVD. In the A+AVD arm, 30 subjects (12%) received at least one subsequent

anti-cancer therapy (some subjects received more than one subsequent treatment): 12 subjects

received one or more cycles of chemotherapy, 12 received high dose chemotherapy plus

transplant, 9 received radiation, and 3 received a checkpoint inhibitor. In the ABVD arm, 52

subjects (22%) received at least one subsequent anti-cancer therapy. Of these, 41 subjects

received one or more cycles of chemotherapy, 22 received high dose chemotherapy plus

transplant, 11 received radiation, 10 subjects received a checkpoint inhibitor alone or in combination, and 3 received radiation with chemotherapy.

Dose Delivery There were noted differences in the management of drug dosing and administration for each

treatment regimen; the greatest differences were with brentuximab vedotin and bleomycin (Table

3). Subjects who received at least one dose of study drug were included in the safety population,

which comprised 489 subjects (249 in the A+AVD arm and 240 in the ABVD arm). Alteration of

the dose or administration of any individual drug was most common for brentuximab vedotin

(61%) in the A+AVD arm and bleomycin (53%) in the ABVD arm. The most frequent

alterations of brentuximab vedotin in the A+AVD arm were dose delay and dose reduction; 35%

and 32% of subjects in the A+AVD arm had at least one brentuximab vedotin dose delay or dose

reduction, respectively. The most frequent alterations for bleomycin in the ABVD arm were dose

delay and dose discontinuation; 27% and 26% of subjects in the ABVD arm had at least one

bleomycin dose delay or dose discontinuation, respectively.

Regional rates of dose modifications for brentuximab vedotin and bleomycin are presented in

Supplemental Table 3. Notably, dose reductions for brentuximab vedotin were more common in

NA than in Europe or Asia (32%, 21%, 26%, respectively); however, dose delays were less

common (35%, 55%, 59% respectively). In the ABVD arm, bleomycin discontinuation was more common in NA (26%) compared to Europe (9%), or Asia (18%).

In all, a full 6 cycles of brentuximab vedotin were received by 70% of subjects in the A+AVD arm, whereas 6 cycles of bleomycin were received by 63% of subjects in the ABVD arm. For the remaining drugs in both regimens (doxorubicin, vinblastine, and dacarbazine), 83-90% of subjects received all 6 cycles in NA (Table 3); similar rates of doxorubicin, vinblastine, and dacarbazine dose delivery were observed in Europe and Asia (data not shown).

Safety Treatment-emergent adverse events (TEAEs) are summarized in Supplemental Table 4. In the

A+AVD arm, all subjects in the NA safety population experienced at least one TEAE, 81% had

Grade 3 or higher TEAEs, 77% had drug-related Grade 3 or higher TEAEs, and 15% had TEAEs that resulted in study drug discontinuation or dose alterations. Similarly, with ABVD all subjects experienced at least one TEAE, 67% had Grade 3 or higher TEAEs, 56% had drug-related Grade

3 or higher TEAEs, and 24% had TEAEs that resulted in study drug or dose discontinuation. The most common AEs in both arms were nausea, constipation, fatigue, and neutropenia

(Supplemental Table 5).

For the ECHELON-1 safety population, there were noted differences between treatment arms in select TEAEs of interest, including febrile neutropenia, peripheral neuropathy, and pulmonary toxicity; similar differences were noted in the NA population.

Neutropenia occurred in 62% of subjects receiving A+AVD and 54% of subjects receiving

ABVD (Table 4). The incidence of Grade 3 or higher neutropenia was higher in subjects treated with A+AVD (59%) compared with subjects receiving ABVD (45%). The incidence of febrile neutropenia was also higher in A+AVD arm (20%) compared to the ABVD arm (9%). Among

subjects in the A+AVD arm, 35 (14%) received granulocyte-colony stimulating factor (G-CSF)

primary prophylaxis; of these, 3 subjects (9%) experienced febrile neutropenia on-study. Among

subjects in the ABVD arm, 11 (5%) received G-CSF primary prophylaxis; none experienced

febrile neutropenia on-study.

Peripheral neuropathy was reported by the investigators in 80% of subjects receiving A+AVD

and 56% of subjects receiving ABVD (Table 4). While the incidence of Grade 1 peripheral neuropathy was similar between treatment arms, the incidence of Grade 2 and Grade 3 peripheral neuropathy was higher in subjects treated with A+AVD (21% and 17%, respectively) compared

with subjects treated with ABVD (12% and <1%, respectively). The incidence of peripheral

neuropathy in the A+AVD arm was similar between NA (79.5%) and Asia (75.7%) and was

lower in Europe (55.4%) (Supplemental Table 6). The incidence of peripheral neuropathy in the

ABVD arm was lower in Europe (35.1%) and Asia (42.3%), compared with NA (55.8%).

Of the 198 NA subjects in the A+AVD arm who experienced peripheral neuropathy during the

study, 149 subjects (75%) showed improvement or resolution at last follow-up: 42% had complete resolution and 33% showed improvement by at least one grade. Ongoing events at last

follow-up related to peripheral neuropathy were Grade 1 (37%), Grade 2 (15%), or Grade 3

(6%). Similarly, 74% of the 134 subjects who experienced peripheral neuropathy in the ABVD

arm showed improvement or resolution: 60% had complete resolution and 13% showed

improvement by at least one grade. Ongoing events at last follow-up related to peripheral

neuropathy were Grade 1 (27%), Grade 2 (12%), or Grade 3 (<1%).

Pulmonary-related toxicity was reported in 3% of subjects in the A+AVD arm versus 10% of

subjects in the ABVD arm (Table 4). Pulmonary-related toxicity events of Grade 3 or higher

were reported in 2% of subjects in the A+AVD arm and 6% of subjects in the ABVD arm. In

subjects who received primary prophylaxis with G-CSF, pulmonary-related toxicity was observed in 1 of the 35 subjects in the A+AVD arm (Grade 3) and 3 of the 11 subjects in the

ABVD arm (2 were ≥ Grade 3).

There were 9 deaths that occurred within 30 days of last treatment (i.e., on-study deaths). In the

A+AVD arm, there were 2 on-study deaths; 1 of these was related to febrile neutropenia in a subject who did not receive primary prophylaxis with G-CSF. There were 7 on-study deaths in the ABVD arm; 6 of these subject deaths were associated with pulmonary-related toxicity.

DISCUSSION The international phase 3 ECHELON-1 trial demonstrated an improvement in modified PFS for subjects with previously untreated Stage III or IV cHL treated with A+AVD as compared to

ABVD. Prespecified subgroup analyses of the primary endpoint of the study, modified PFS per

IRF, showed evidence of benefit (HR of less than 1) across the majority of subgroups. The analyses presented here further assessed the safety and efficacy observed in subjects treated within the NA region of the phase 3 ECHELON-1 trial.

ECHELON-1 was prospectively designed to compare the safety and efficacy of A+AVD to

ABVD with subject randomization stratified by region, as geographic differences in treatment of

HL patients (such as the application of consolidative radiotherapy) and access to supportive care therapies vary globally. Regional variations in the outcomes of large multi-national randomized trials have been reported in other settings (11-13). As baseline demographics and disease characteristics were comparable between the NA subset and other regions, other potential factors for the regional differences need to be considered, including regional variation in patient management. Dose reductions for brentuximab vedotin were more common in NA than in

Europe or Asia; however, dose delays were less common. In the ABVD arm, bleomycin

discontinuation was more common in NA compared to Europe and Asia. It is possible that these regional differences in dosing of brentuximab vedotin and bleomycin may have contributed to the differential results in the NA subgroup. However, other factors including the potential for population differences in drug metabolism and/or sensitivity are possible alternative considerations.

For subjects treated in NA, modified PFS by IRF and investigator assessment demonstrated a consistent improvement in favor of A+AVD versus ABVD, with differences in 2-year rates of

10.6 and 12.8 percentage points and corresponding HRs of 0.60 (P=.012) and 0.52 (P=.002), respectively. For patients with incomplete response at EOT, additional therapy for active disease before radiographic evidence of progression (new lesions or tumor increase >50%) was considered an event for the modified PFS endpoint. Thus, modified PFS may be a more clinically relevant surrogate for primary treatment failure. An analysis of a more traditional PFS endpoint can provide further confirmation of the primary endpoint and further context with regards to historical efficacy assessments. Thus, an analysis of PFS, defined as time to disease progression or death from any cause per investigator assessment, was performed. Similar to the modified PFS results, a PFS difference of 11.7 percentage points at 2-years and a HR of 0.50

(P=.002) in favor of A+AVD was observed among subjects treated in NA. While differences in response across regions were noted, these differences were not significant from those observed in

NA.

In the primary analysis of the ECHELON-1 trial, there was an increased incidence of febrile neutropenia and peripheral neuropathy in the A+AVD arm, and an increase in pulmonary-related toxicity in the ABVD arm. In the NA region, febrile neutropenia rates were similar to those observed in the entire safety population. Rates in the A+AVD arm were reduced and comparable

(9%) to the rates in the ABVD population among the 35 subjects in the A+AVD arm who received G-CSF primary prophylaxis beginning with Cycle 1. These results highlight the importance of G-CSF primary prophylaxis for all subjects treated with A+AVD.

The incidence of peripheral neuropathy was higher in the NA subset than in Europe for both treatment arms. Per the ECHELON-1 protocol (Supplemental Table 7), management of Grade 2 neuropathy required brentuximab vedotin dose reduction while Grade 3 neuropathy required withholding brentuximab vedotin until symptoms improved to Grade 2 or better, followed by dose reductions. Rates of resolution or improvement by last follow-up visit were also higher in

NA (approximately 75% of subjects in both arms) than rates in the overall safety population

(approximately 66% in both arms).

Recently, several HL trials have assessed the safety and efficacy of response-adapted strategies intended to maintain efficacy and minimize the risk of both short-term (i.e., bleomcyin-induced pulmonary toxicity) and long-term toxicities (i.e., secondary malignancies, infertility). While direct comparisons between studies are difficult due to protocol differences in subject population and treatment approaches, relating the data from ECHELON-1 in the context of the PET-adapted

RATHL trial may be an important consideration (14). In addition to subjects with Stage III or IV disease, RATHL also enrolled 42% of subjects with Stage II disease, which differed from the

ECHELON-1 trial which only enrolled subjects with Stage III or IV disease. Subjects treated in

RATHL received 2 cycles of ABVD followed by de-escalation to AVD versus continuation of

ABVD for the PET2-negative patients or escalation to BEACOPP for the PET-2 positive patients. Both ECHELON-1 and RATHL reduced pulmonary toxicity by completely eliminating or limiting the exposure to bleomycin. In the subset of the RATHL subjects with Stage III or IV disease who were ≤60 years old, the 3-year PFS rates for the PET2-negative subjects were the

same for the AVD and ABVD subsets at 82.1%. For subjects who were PET-positive at cycle 2,

the 3-year PFS rate was 63.9% following BEACOPP. In the ECHELON-1 NA subset (which

included 12.7% of subjects ≥60 years old), the 2-year PFS for PET2-negative A+AVD versus

ABVD subjects was 91.9% versus 81.1%, respectively; 2-year PFS for PET2- positive A+AVD

versus ABVD subjects was 54.5% and 48%, respectively. When focusing on PET2-negative

subjects, the ECHELON-1 NA subset demonstrated an increase in PET2-negative rate at 88% for

A+AVD compared with 83.7% in RATHL. Furthermore, this higher PET2-negative rate in the

ECHELON-1 NA subset was also paired with an increase in 2-year PFS to 91.9% which

compares favorably to the 3-year PFS of 82.1% in RATHL for subjects treated with ABVD or

ABVD de-escalated to AVD. Longer follow-up will determine if the 2-year estimates remain

stable at later time points. Overall, the ECHELON-1 NA subset data supports that A+AVD compares favorably to the treatment approach of RATHL without the need for additional

treatment decisions (including escalation to BEACOPP) predicated on real-time PET2 disease

assessment, which can be challenging in certain clinical settings.

Identifying specific drivers of regional variation in randomized multinational trials has often

proven challenging. Trials are typically not designed with an objective of detecting potential

regional differences in efficacy; however, results from specific regions help establish the

reliability of primary results and are important to better inform patient care decisions made

within the regions of interest. Further, the availability of this regional data will better inform

cost-effectiveness analysis models, where understanding regional safety and efficacy results, as

well as transitions in care, are important modeling considerations. While the improvements in

modified PFS and PFS were not as pronounced in Europe and Asia when compared with NA, it

is notable, that there were more brentuximab vedotin and bleomycin dose delays and less

bleomycin dose discontinuations in Europe and Asia which may be important considerations.

The results of the ECHELON-1 NA subgroup analyses are consistent with those of the primary analyses, indicating a benefit in the subjects who received A+AVD compared to those who received ABVD.

ACKNOWLEDGMENTS The authors wish to acknowledge Matt Blahna of Seattle Genetics, Inc. and Elizabeth O’Connor of MMS Holdings, Inc. for assistance in manuscript preparation. Research support was provided by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical

Company Limited, and Seattle Genetics.

REFERENCES 1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61(4):212-36 doi caac.20121 [pii] 10.3322/caac.20121. 2. Carde P, Johnson P. Principles of Chemotherapy in Hodgkin Lymphoma. In: Engert A, Horning SJ, editors. Hodgkin Lymphoma A Comprehensive Update on Diagnostics and Clinics. Berlin, Heidelberg: Springer- Verlag Berlin Heidelberg,; 2011. p online resource. 3. NCCN. *RETIRED* NCCN Guidelines Version 1.2017: Hodgkin Lymphoma. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Volume Version 1.2017 - March 1, 2017: National Comprehensive Cancer Network; 2017. p 1-83. 4. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 1975;36(1):252-9. 5. Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol 2013;31(6):684-91 doi 10.1200/JCO.2012.43.4803. 6. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 1992;327(21):1478-84 doi 10.1056/NEJM199211193272102. 7. Carde P, Karrasch M, Fortpied C, Brice P, Khaled H, Casasnovas O, et al. Eight cycles of ABVD versus four cycles of BEACOPPescalated plus four cycles of BEACOPPbaseline in stage III to IV, international prognostic score >/= 3, high-risk Hodgkin lymphoma: first results of the phase III EORTC 20012 Intergroup trial. J Clin Oncol 2016;34(17):2028-36 doi 10.1200/JCO.2015.64.5648. 8. Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med 2018;378(4):331-44 doi 10.1056/NEJMoa1708984. 9. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood 2011;117(19):5019-32 doi 10.1182/blood-2011-01-293050. 10. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-86 doi JCO.2006.09.2403 [pii] 10.1200/JCO.2006.09.2403.

11. Mayer J, Arthur C, Delaunay J, Mazur G, Thomas XG, Wierzbowska A, et al. Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics. BMC cancer 2014;14:69 doi 10.1186/1471-2407-14-69. 12. Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo- controlled phase III study. J Clin Oncol 2011;29(30):3968-76 doi 10.1200/jco.2011.36.2236. 13. Swain SM, Im YH, Im SA, Chan V, Miles D, Knott A, et al. Safety profile of pertuzumab with trastuzumab and docetaxel in patients from Asia with human epidermal growth factor receptor 2-positive metastatic breast cancer: results from the phase III trial CLEOPATRA. Oncologist 2014;19(7):693-701 doi 10.1634/theoncologist.2014-0033. 14. Johnson P, Federico M, Kirkwood A, Fossa A, Berkahn L, Carella A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma. N Engl J Med 2016;374(25):2419-29 doi 10.1056/NEJMoa1510093.

TABLES Table 1 Demographics and disease characteristics for North American subgroup A+AVD ABVD (N=250) (N=247) Subject demographics Sex, n (%) Male 146 (58) 148 (60) Female 104 (42) 99 (40) Age, mean (SD) 38.2 (16) 40.5 (15) Age categories (years)a, n (%) <45 171 (68) 162 (66) 45-59 50 (20) 51 (21) 60-64 11 (4) 14 (6) ≥65 18 (7) 20 (8) Country, n (%) United States 214 (86) 225 (91) Canada 36 (14) 22 (9) Race, n (%) White 213 (85) 204 (83) Black or African American 15 (6) 16 (6) Not reported 9 (4) 15 (6) Asian 7 (3) 7 (3) Other 6 (2) 5 (2) Disease characteristics, n (%) Ann Arbor stage at initial diagnosis Stage III 99 (40) 115 (47) Stage IV 150 (60) 132 (53) IPS score 0-1 50 (20) 55 (22) 2-3 123 (49) 119 (48) 4-7 77 (31) 73 (30) ECOG performance status 0 118 (47) 118 (48) 1 121 (48) 118 (48) 2 11 (4) 11 (4) Extranodal involvement at initial diagnosis None 74 (30) 92 (37) 1 site 74 (30) 79 (32) >1 site 78 (31) 63 (26) B symptomsb 146 (58) 139 (56) aAge at date of informed consent. bSubjects who present with B symptoms (general malaise [fever, night sweats, weight loss, etc]) for at least one visit prior to the start of study drug administration.

Table 2 Summary of end of treatment Deauville scores and subsequent therapies for subjects modified PFS events per IRF A+AVD ABVD N=250 N=247 Number with events per IRF, n (%) 38 (15) 57 (23) Reason leading to modified PFS event, n (%) Progressive disease 28 (11) 39 (16) Death due to any cause 6 (2) 10 (4) Receipt of additional therapy after non-CRa, n (%) 4 (2) 8 (3) Salvage chemotherapy 3/4 (75) 7/8 (88) Deauville score at end of treatmentb 3 0 0 4 2/3 (67) 2/7 (29) 5 1/3 (33) 5/7 (71) Radiation 1/4 (25) 1/8 (13) Deauville score at end of treatmentb 3 1/1 (100) 0 4 0 1/1 (100) 5 0 0 aConfirmed non-complete responders (Deauville 3, 4, or 5) with receipt of additional anticancer treatment after completion of frontline therapy bEvidence of a non-CR required an EOT Deauville score ≥3.

Table 3 Dose Modification, delay, or discontinuation of study drug in North America A+AVD ABVD (N=249) (N=240) Action, n (%) BV Doxorubicin Vinblastine Dacarbazine Bleomycin Doxorubicin Vinblastine Dacarbazine No action taken 98 (39) 144 (58) 134 (54) 147 (59) 114 (48) 156 (65) 149 (62) 158 (66) Action on study druga 151 (61) 105 (42) 115 (46) 102 (41) 126 (53) 84 (35) 91 (38) 82 (34) Dose reduced 79 (32) 9 (4) 26 (10) 10 (4) 2 (<1) 8 (3) 20 (8) 6 (3) Dose heldb 28 (11) 1 (<1) 4 (2) 0 22 (9) 1 (<1) 4 (2) 1 (<1) Dose delayedc 86 (35) 93 (37) 92 (37) 88 (35) 65 (27) 70 (29) 73 (30) 70 (29) Dose discontinued 30 (12) 14 (6) 18 (7) 14 (6) 63 (26) 4 (2) 9 (4) 4 (2) No alternative frontline regimen 243 243 243 243 238 238 238 238 6 cycles randomized regimen 175 (70) 213 (86) 207 (83) 216 (87) 150 (63) 215 (90) 211 (88) 212 (88) aSubjects recording the same action on study drug multiple times within a cycle or overall will be counted only once in the respective summary. bHold indicates a dose that was skipped before restarting in the subsequent treatment round. cDelay indicates doses administered after the protocol-specified treatment window for a cycle. BV=brentuximab vedotin

Table 4 Neutropenia, neuropathy, and pulmonary toxicity in North America A+AVD ABVD Adverse event category, n (%) (N=249) (N=240) Neutropeniaa Incidence of neutropenia (any grade) 154 (62) 130 (54) Grade 3 or higher neutropenia 146 (59) 109 (45) Incidence of febrile neutropeniab 51 (20) 22 (9) Peripheral neuropathyc Incidence of peripheral neuropathy (any grade) 198 (80) 134 (56) Grade 1 peripheral neuropathy 102 (41) 104 (43) Grade 2 peripheral neuropathy 53 (21) 28 (12) Grade 3 peripheral neuropathy 43 (17) 2 (<1) Pulmonary toxicityd Incidence of pulmonary toxicity (any grade) 7 (3) 25 (10) Grade 3 or higher pulmonary toxicity 4 (2) 14 (6) aNeutropenia includes preferred terms of neutropenia and neutrophil count decreased. bA total of 35 subjects received A+AVD and G-CSF primary prophylaxis. Of these, 3 subjects (9%) experienced febrile neutropenia. cIncludes the preferred terms of peripheral motor neuropathy, peripheral sensorimotor neuropathy, peroneal nerve palsy, muscular weakness, hypotonia, or muscle atrophy. dIncludes adverse events in the Interstitial lung disease Standardized MedDRA Query, MedDRA dictionary Version 19.0. G-CSF = granulocyte-colony stimulating factor

FIGURE LEGENDS Figure 1 Kaplan-Meier analysis of modified PFS per IRF (A) and PFS per investigator assessment (B) by treatment group in North America

Figure 2 Forest plot of modified PFS per IRF by baseline risk factor subgroups

Figure 1 A 1.0

0.8

0.6

0.4

ProbabilityModified of 0.2 Events

Progression-FreeSurvival N Progression Death Modified Total A+AVD 250 28 6 4 38 Log-rank test p-value: 0.012 ABVD 247 39 10 8 57 Hazard ratio (95% CI): 0.596 (0.395, 0.899) 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Time (Months) from Randomization Number at Risk: A+AVD 250 240 238 227 208 203 196 185 173 165 129 123 117 72 68 62 35 30 30 13 11 10 3 3 3 0 0 ABVD 247 231 226 210 185 173 164 156 147 141 109 102 99 63 57 54 28 24 23 8 7 7 1 1 1 0 0

B 1.0

0.8

0.6

0.4 Probability of

0.2 Events

Progression-FreeSurvival N Progression Death Total A+AVD250 24 5 29 Log-rank test p-value: 0.002 ABVD 247 43 10 53 Hazard ratio (95% CI): 0.500 (0.318, 0.786) 0.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Time (Months) from Randomization Number at Risk: A+AVD 250 241 238 229 213 207 202 189 176 171 137 129 124 77 72 65 38 31 31 14 12 11 3 3 3 0 0 ABVD 247 233 228 216 191 182 174 167 159 155 123 113 109 66 60 58 31 27 25 8 7 7 2 2 2 0 0 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Censored subjects are represented by a solid circle (A+AVD) or triangle (ABVD).Research. Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2435 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Figure 2 Event / N (%) Hazard Ratio Subgroup A+AVD ABVD (95% CI) Overall 38/250 (15.2) 57/247 (23.1) 0.596 (0.395, 0.899) Age <60 years 30/221 (13.6) 49/213 (23.0) 0.534 (0.339, 0.841) ≥60 years 8/29 (27.6) 8/34 (23.5) 0.974 (0.360, 2.634) <45 years 22/171 (12.9) 33/162 (20.4) 0.565 (0.330, 0.970) ≥45 years 16/79 (20.3) 24/85 (28.2) 0.668 (0.355, 1.257)

IPS Score 0–1 9/ 50 (18.0) 12/ 55 (21.8) 0.789 (0.332, 1.874) 2–3 17/123 (13.8) 20/119 (16.8) 0.733 (0.384, 1.400) 4–7 12/77 (15.6) 25/73 (34.2) 0.396 (0.199, 0.789)

Baseline cancer stage Stage III 14/ 99 (14.1) 24/115 (20.9) 0.640 (0.331, 1.237) Stage IV 24/150 (16.0) 33/132 (25.0) 0.554 (0.327, 0.937)

Baseline B symptoms Present 24/146 (16.4) 32/139 (23.0) 0.664 (0.391, 1.127) Absent 14/104 (13.5) 25/108 (23.1) 0.509 (0.265, 0.980)

Baseline extra nodal sites 0 12/74 (16.2) 24/92 (26.1) 0.556 (0.278, 1.112) 1 12/74 (16.2) 11/79 (13.9) 0.966 (0.426, 2.190) >1 14/78 (17.9) 20/ 63 (31.7) 0.569 (0.287, 1.127)

Baseline ECOG status 0 16/118 (13.6) 24/118 (20.3) 0.618 (0.328, 1.163) 1 19/121 (15.7) 30/118 (25.4) 0.554 (0.312, 0.984) 2 3/ 11 (27.3) 3/11 (27.3) 0.692 (0.139, 3.451)

Gender Male 20/146 (13.7) 34/148 (23.0) 0.537 (0.309, 0.934) Female 18/104 (17.3) 23/ 99 (23.2) 0.679 (0.366, 1.258)

0.1 0.5 1 Favors A+AVD Hazard Ratio Favors ABVD Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Subgroups analyses presented are those which were conductedResearch. for the primary analysis Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2435 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Brentuximab Vedotin Plus Chemotherapy in North American Patients with Newly Diagnosed Stage III or IV Hodgkin Lymphoma

Radhakrishnan Ramchandren, Ranjana H. Advani, Stephen M Ansell, et al.

Clin Cancer Res Published OnlineFirst January 7, 2019.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-18-2435

Supplementary Access the most recent supplemental material at: Material http://clincancerres.aacrjournals.org/content/suppl/2019/01/07/1078-0432.CCR-18-2435.DC1

Author Author manuscripts have been peer reviewed and accepted for publication but have not yet been Manuscript edited.

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/early/2019/01/07/1078-0432.CCR-18-2435. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.