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Brentuximab vedotin for the treatment of Hodgkin lymphoma

Jul 21, 2021
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In May 2018, the Lymphoma Hub reported the FDA approval of brentuximab vedotin (BV) for the frontline treatment of patients with advanced-stage (Stages III or IV) classical Hodgkin lymphoma (cHL). This decision was based on a the randomized phase III ECHELON-1 trial (NCT01712490), in which superior efficacy and a lower risk of progression was identified in patients treated with BV in combination with doxorubicin, vinblastine, and dacarbazine (BV+AVD), compared with those treated with AVD + bleomycin (ABVD). This was a significant development for patients with cHL, who at that point had seen no significant changes in treatment choices for four decades.

Here, we summarize the 5-year updated ECHELON-1 trial data, presented by Martin Hutchings during the European Hematology Association (EHA)2021 Virtual Congress1 and published in Lancet Haematology by David Straus and colleagues2. In addition, we summarize work from Anita Kumar and colleagues published in the Journal of Clinical Oncology,3 describing their experience of using BV and chemotherapy in patients with early-, as opposed to advanced-stage HL.

ECHELON-1 study: Updated results and findings 5 years on1,2

The ECHELON-1 study was a randomized, multicenter, phase III clinical trial conducted over a 4-year period between 2012 and 2016, enrolling >1,200 patients with Stage III or IV cHL across 21 countries.

Survival data

Table 1 shows the 5-year progression-free survival (PFS) data for all patients, as well as for patients with either a negative or positive interim positron emission tomography (PET) scan after two cycles of therapy (PET-2). The median follow-up was 60.9 months (interquartile range, 52.2-67.3 months).

Table 1. The 5-year PFS across the treatment groups*

Patient group

5-year PFS, % (95 CI)

HR (95% CI)

p value

BV+AVD

ABVD

All patients

82.2 (79.0–85·0)

75.3 (71.7–78.5)

0.68 (0.53–0.87)

0.002

PET-2-negative

84.9 (81.7–87.6)

78.9 (75.2–82.1)

0.66 (0.50–0.88)

0.004

PET-2-positive

60.6 (45.0–73.1)

45.9 (32.7–58.2)

0.70 (0.39–1.26)

0.229

ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AVD, doxorubicin, vinblastine, and dacarbazine; BV, brentuximab vedotin; CI, confidence interval; HR, hazard ratio; PET-2, positron emission tomography scan after two cycles of therapy; PFS, progression-free survival.
*Data from Hutchings et al.1

Toxicity data

Patients receiving either BV+AVD or ABVD who experienced peripheral neuropathy (85% vs 86%) saw improvements in their symptoms over time, with persistence of peripheral neuropathy observed in more patients treated with BV+AVD compared with those treated with ABVD (19% vs 9%).

Fewer secondary malignancies were found in patients receiving BV+AVD compared with those receiving ABVD (3% vs 4%), and more live births were reported among patients and their partners in the BV+AVD group (n = 75) compared with the ABVD group (n = 50).

Conclusion

The 5-year follow-up data builds on the superior efficacy of BV+AVD identified in the original study. BV+AVD demonstrates sustained improvement for the PFS of patients with advanced-stage, untreated cHL 5 years after the completion of treatment, and this superiority is independent of PET‑2 positivity. The data also show that BV+AVD is well tolerated and causes less frequent adverse effects relative to ABVD.

Martin Hutchings provides his expert opinion on these updated trial results here: 

Phase III ECHELON-1 study: Updated results of brentuximab vedotin + chemotherapy for untreated cHL

BV+AVD for the treatment of patients with early-stage, unfavorable risk Hodgkin Lymphoma3

At present, BV is not approved for the frontline treatment of newly diagnosed early-stage HL. Anita Kumar and colleagues conducted a pilot, cohort study of BV+AVD for the treatment of early-stage unfavorable risk HL, across four sites within the USA (NCT01868451). The goal of the study was to determine if radiation can be omitted from patients treated with BV+AVD who have become PET‑negative, without compromising their outcomes and survival data.

Study design

All patients received two courses of BV+AVD, with PET-computed tomography (CT) reassessment, followed by a further two courses of BV+AVD, and further PET-CT reassessment. Those that were PET-CT-positive, but biopsy-negative, and those that were PET-CT-negative were then assigned to one of four radiotherapy cohorts:

  • Cohort 1: 30-Gy involved-site radiotherapy
  • Cohort 2: 20-Gy involved-site radiotherapy
  • Cohort 3: 30-Gy consolidation-volume radiotherapy
  • Cohort 4: no radiotherapy

Patients who were PET-CT-positive and biopsy-positive were excluded from the study. The inclusion criteria included early-stage, unfavorable-risk HL. In addition, Cohorts 1 and 2 has no diagnosis of bulky disease. Whereas Cohorts 3 and 4 had a diagnosis of bulky disease, defined by Memorial Sloan Kettering criteria (>7 cm in maximal transverse or coronal diameter on computed tomography). The primary endpoint was to evaluate PET-negative complete response rates at the end of treatment for Cohorts 2–4 and to evaluate safety for Cohort 1.

Results

A total of 117 patients were recruited; one did not complete chemotherapy. The overall rate of PET-negativity was 87% at first reassessment, 88% at second reassessment, and 85% at end of treatment. With a median follow-up of 3.8 years, the 2-year PFS and 2-year overall survival were 94% (95% confidence interval, 89.7–98.3) and 99% (95% confidence interval, 97.3–1.0), respectively, for all patients. Table 2 shows the response and survival outcomes according to treatment cohort.

Table 2. Response and outcome data across different treatment cohorts*

Variable

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Number of patients

30

29

29

29

Median follow-up, years

5.9

4.5

2.5

2.2

2-year PFS, % (95% CI)

93.1 (83.9–1.0)

96.6 (89.9–1.0)

89.7 (78.5–1.0)

96.6 (89.9–1.0)

EOT complete remission rate, %

93

100

93

97

CI, confidence interval; EOT, end of treatment; PFS, progression-free survival.
*Data from Kumar et al.3

Safety data

All 117 patients experienced ≥1 adverse event. In total, 84 patients (72%) experienced a Grade ≥3 adverse event, the most common of which was neutropenia, occurring in 45 patients. There were 41 treatment-related hospitalizations for 24 patients. The most common toxicities (any grade) were neutropenia in 52 patients (44%), peripheral sensory neuropathy in 63 patients (54%), constipation in 81 patients (69%), and fatigue in 93 patients (80%).

Conclusion

This pilot study demonstrates that BV+AVD is a well-tolerated and efficacious treatment regimen with or without consolidative radiotherapy for patients with newly diagnosed, early-stage, unfavorable HL, including those with bulky disease. Clinical outcomes for patients in Cohorts 1–3 were similar, despite differences in their radiotherapy strategy. Patients in Cohort 4, treated with chemotherapy alone, had an excellent 2-year PFS of 96.6%, suggesting that consolidative radiotherapy could be eliminated in patients with a complete metabolic response after four cycles of BV+AVD. These data need to be confirmed in larger, randomized studies.

Summary

These studies provide further evidence that BV+AVD is both safe and effective for the treatment of patients with newly diagnosed cHL, including those with either advanced-stage or unfavorable risk early-stage disease. In particular, further work is needed in early-stage disease to determine the efficacy of the treatment within this patient group.

  1. Hutchings M, Radford J, Długosz-Danecka M, et al. Brentuximab vedotin with chemotherapy for patients with previously untreated, stage III or IV classical Hodgkin lymphoma: A 5-year update of the phase 3 ECHELON-1 study (NCT01712490). Oral abstract #S205. European Hematology Association (EHA)2021 Virtual Congress; June 11, 2021; Virtual.
  2. Straus DJ, Długosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021;8(6):e410-e421. DOI: 10.1016/S2352-3026(21)00102-2
  3. Kumar A, Casulo C, Advani RH, et al. Brentuximab vedotin combined with chemotherapy in patients with newly diagnosed early-stage, unfavorable-risk Hodgkin lymphoma. J Clin Oncol. 2021;39(20):2257-2265. DOI: 10.1200/JCO.21.00108

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