Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma

This article is featured in Highlights of This Issue, p. 1691

Approximately 8,200 cases of classical Hodgkin lymphoma (cHL) are diagnosed annually in the United States (1). For over 40 years, the first-line standard of care for cHL in North America (NA) has been chemotherapy with ABVD (2–4). Despite high response rates, approximately 30% of patients with advanced stage Hodgkin lymphoma are refractory or relapse following first-line treatment with ABVD (5–7).

ECHELON-1 is an international, phase III trial comparing doxorubicin, vinblastine, and dacarbazine (AVD) in combination with brentuximab vedotin (ADCETRIS; A+AVD) versus ABVD (AVD + bleomycin) as first-line 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 first-line therapy. It showed that A+AVD was superior to ABVD (HR = 0.77, P = 0.035) 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 with ABVD. A+AVD is the first treatment regimen utilizing a targeted agent to show superior efficacy in terms of modified PFS compared with 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 with 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.

ECHELON-1 is a global, open-label, randomized phase III study of A+AVD versus ABVD as first-line 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 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.

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; ref. 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 nonresponse [End of Treatment (EOT) Deauville score ≥3) for subjects who received additional anticancer 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 nonresponse (per Cheson 2007) for subjects who received additional anticancer 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.

The ECHELON-1 trial was conducted in accordance with regulatory requirements; the protocol (previously described ref. 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.

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 with the overall ITT population.

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, 0.40–0.90; P = 0.012; Fig. 1A). The 2-year modified PFS per IRF (95% CI) was 84.3% (78.7%–88.5%) in the A+AVD arm and 73.7% (67.3%–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 vs. 39 in the ABVD arm) followed by deaths (6 events in the A+AVD arm vs. 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, 0.59–1.17; P = 0.281) and 0.91 (95% CI, 0.43–1.93; P = 0.810) in the Asian region (8). Modified PFS per investigator was generally consistent with these results by region (Supplementary Table S1).

Modified PFS per IRF showed a consistent trend toward improvement among NA subjects treated with A+AVD versus ABVD across all subgroups that were prespecified in the primary analysis (Fig. 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, 0.37–0.97; P = 0.034), with a 2-year modified PFS of 87.9% (82.5%–91.6%) versus 78.3% (71.7%–83.5%), respectively. Subjects who were PET2-positive showed a trend toward a greater benefit with A+AVD (HR = 0.52; 95% CI, 0.21–1.27; P = 0.139), with a 2-year modified PFS rate on the A+AVD arm of 58.2% (33.5%–76.5%) versus 36.6% (16.7%–56.9%) on the ABVD arm.

Although 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, 0.23–1.14; P = 0.094). The interim 2-year OS rates (95% CI) were 97.0% (93.7%–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, 0.32–0.79; P = 0.002; Fig. 1B). The 2-year PFS per investigator (95% CI) was 88.1% (83.1%–91.7%) in the A+AVD arm and 76.4% (70.1%–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, 0.25–0.77; P = 0.003), with a 2-year PFS rate of 91.9% (87.0%–95.0%) in the A+AVD arm versus 81.1% (74.7%–86.0%) with ABVD; for PET2-positive subjects, 2-year PFS rates of 54.5% (32.1%–72.4%) versus 48.0% (26.0%–67.0%) were seen (HR = 0.901; 95% CI, 0.38–2.12; P = 0.810).

Response rates as determined by IRF demonstrated a consistent benefit for A+AVD compared with ABVD and are summarized in Supplementary Table S2. The CR rates following first-line therapy (per the Revised Response Criteria for Malignant Lymphoma; ref. 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 Supplementary Table S2.

Subjects treated with A+AVD required fewer subsequent anticancer therapies than subjects treated with ABVD. In the A+AVD arm, 30 subjects (12%) received at least 1 subsequent anticancer therapy (some subjects received more than 1 subsequent treatment): 12 subjects received 1 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 1 subsequent anticancer therapy. Of these, 41 subjects received 1 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.

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 1 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 1 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 1 bleomycin dose delay or dose discontinuation, respectively.

Regional rates of dose modifications for brentuximab vedotin and bleomycin are presented in Supplementary Table S3. 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 with Europe (9%) or Asia (18%).

In all, 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% to 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).

Treatment-emergent adverse events (TEAEs) are summarized in Supplementary Table S4. In the A+AVD arm, all subjects in the NA safety population experienced at least 1 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 1 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 (Supplementary Table S5).

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 with the ABVD arm (9%). Among subjects in the A+AVD arm, 35 (14%) received 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). Although 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%; Supplementary Table S6). 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 1 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 1 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.

The international phase III 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 with 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 III 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 patients with Hodgkin lymphoma (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 with 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 = 0.012) and 0.52 (P = 0.002), 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 = 0.002) in favor of A+AVD was observed among subjects treated in NA. Although 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%) with 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 (Supplementary Table S7), management of grade 2 neuropathy required brentuximab vedotin dose reduction, whereas 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., bleomycin-induced pulmonary toxicity) and long-term toxicities (i.e., secondary malignancies, infertility). Although 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 deescalation to AVD versus continuation of ABVD for the PET2-negative patients or escalation to BEACOPP for the PET2-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 deescalated 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 with 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. Furthermore, 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. Although 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 with those who received ABVD.

R. Ramchandren and N.L. Bartlett is a consultant/advisory board member for Seattle Genetics. R.H. Advani is a consultant/advisory board member for Seattle Genetics and Takeda. R. Chen and J.M. Connors report receiving speakers bureau honoraria from and are consultant/advisory board members for Seattle Genetics. T. Feldman reports receiving commercial research grants from Amgen, Bristol-Myers Squibb, Cell Medica, Eisai, Genentech, Idera Pharmaceutical, Janssen, Kyowa, Millennium, Pfizer, Portola, Roche, Seattle Genetics, Viracta, and Trillium, speakers bureau honoraria from Takeda (Millenium), Seattle Genetics, Abbvie, Pharmacyclics, Janssen, Celgene, and Kite Pharma, is a consultant/advisory board member for Bristol-Myers Squibb and Seattle Genetics. A. Forero is an employee of and holds ownership interest (including patents) in Seattle Genetics. J.W. Friedberg is a consultant/advisory board member for Bayer and Astellas. A.K. Gopal reports receiving commercial research grants from Seattle Genetics, Teva, Bristol-Myers Squibb, Pfizer, Merck, Takeda, Janssen, and Gilead, and is a consultant/advisory board member for Seattle Genetics, Janssen, Takeda, Pfizer, Amgen, Sanofi, Gilead, Acerta, and Aptevo. L.I. Gordon reports receiving commercial research grants from Juno, and is a consultant/advisory board member for Juno and Bayer. J. Kuruvilla reports receiving speakers bureau honoraria from Seattle Genetics, Bristol-Myers Squibb, Merck, Roche, Amgen, Astra Zeneca, Janssen, and Karyopharm, and is a consultant/advisory board member for Seattle Genetics, Bristol-Myers Squibb, Merck, Roche, Abbvie, Gilead, Janssen, and Karyopharm. K.J. Savage is a consultant/advisory board member for Seattle Genetics, Bristol-Myers Squibb, Merck, Verastem, and Abbvie. A. Younes reports receiving speakers bureau honoraria from Takeda, Roche, Epizyme, Bristol-Myers Squibb, Merck, Curis, Janssen, Accerta, and Abbvie, and is a consultant/advisory board member for Xynomics. G. Engley, T.J. Manley, and K. Fenton hold ownership interest (including patents) in Seattle Genetics. D.J. Straus reports receiving speakers bureau honoraria from Oncotracker and Medical Crossfire, and is a consultant/advisory board member for Seattle Genetics and InPractice (Elsevier). No potential conflicts of interest were disclosed by the other authors.

Conception and design: S.M. Ansell, R. Chen, J.M. Connors, J.W. Friedberg, A.K. Gopal, A. Younes, G. Engley, T.J. Manley

Development of methodology: S.M. Ansell, R. Chen, J.M. Connors, A.K. Gopal, G. Engley

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): R. Ramchandren, R.H. Advani, N.L. Bartlett, R. Chen, J.M. Connors, T. Feldman, A. Forero-Torres, A.K. Gopal, J. Kuruvilla, K.J. Savage, A. Younes, D.J. Straus

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): R. Ramchandren, R.H. Advani, S.M. Ansell, N.L. Bartlett, R. Chen, J.M. Connors, A.K. Gopal, J. Kuruvilla, K.J. Savage, G. Engley, T.J. Manley, K. Fenton, D.J. Straus

Writing, review, and/or revision of the manuscript: R. Ramchandren, R.H. Advani, S.M. Ansell, N.L. Bartlett, R. Chen, J.M. Connors, A. Forero-Torres, J.W. Friedberg, A.K. Gopal, L.I. Gordon, J. Kuruvilla, K.J. Savage, G. Engley, T.J. Manley, K. Fenton, D.J. Straus

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): T. Feldman

Study supervision: R. Ramchandren, R.H. Advani, S.M. Ansell, A. Younes, G. Engley

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.