ECHELON-2 data confirms new standard of care in some PTCL subtypes

Wednesday, 4 May 2022


For the past three decades, the standard of care (SOC) first-line treatment for peripheral T-cell lymphomas (PTCL) has been cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) or similar CHOP-like regimens.9  However, the ECHELON-2 five-year milestone data for brentuximab vedotin (BV) may be about to shake up the way PTCL is managed.7 The limbic spoke with Professor Miles Prince, Director for the Centre for Blood Cell Therapies and Director of Molecular Oncology and Cancer Immunology Epworth and haematologist at the Peter MacCallum Cancer Centre about the impact of ECHELON-2 and what it means for clinicians managing patients with PTCL.

“We’ve been challenged by the fact that PTCL is not one disease – the subtypes are as different as they are the same,” explained Prof. Prince. “So, getting to the underlying biology of the disease has been a slow process and, in the meantime, we’ve had to rely on chemotherapy as our standard of care, which is substantially less efficacious in T-cell lymphoma compared to B-cell lymphoma. ECHELON-2 gives us the confidence we finally have a game-changer for certain PTCL subtypes,” he said.

Challenges and unmet needs for the treatment of PTCL

PTCL is a heterogenous group of non-Hodgkin lymphoma (NHL) that are typically aggressive and account for 10-15 % of newly diagnosed cases.1-3 Over 30 subtypes have currently been identified, with PTCL not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL) amongst the most prevalent.1,2,4 With varying morphological, immunophenotypic, genetic and clinical features, diagnosis of PTCL is typically poor4-8. Once diagnosed, treatment options have historically been limited, and relapse typically occurs within 1–2 years.5-7.

The relative rarity, sheer number of disease subsets, disease heterogenicity, and the scarcity of large, randomised studies have kept the progress in management of PTCL behind other B-cell lymphoma ‘counterparts’.7 Historically, first-line therapy for PTCL was derived from treatment of aggressive B-cell NHL and included cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone (CHOEP) or infusional etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH), as well as CHOP.1  Yet CHOP or CHOP-like regimens can have limited effectiveness and may cause toxicity issues for some patient subsets.3,5,10,11 But after what has been considered years of slow progress for PTCL, there have been recent advances with novel agents.1,12

One target, CD30 – a member of the tumour necrosis factor receptor family found on the surface of activated T-cells in PTCL – has gained a lot of attention.4,13 Since 2009, four novel agents have been approved for treatment of recurrent CD30+ ALCL, including BV. (Not all CD30-targeting drugs are approved for use in Australia.)1 BV was approved by the Food and Drug Administration (FDA) in 2011, the European Medicines Agency (EMA) in 2012, and by the Therapeutic Goods Administration (TGA) in 2014.1,14

Brentuximab vedotin is a CD30-directed antibody-drug conjugate that delivers an antineoplastic agent, resulting in apoptotic cell death in CD30-expressing tumour cells, including in Hodgkin lymphoma (HL) and in both anaplastic lymphoma kinase positive and negative (ALK+ and ALK-) systemic ALCL (sALCL).7,15,16 “BV is a unique type of treatment – being an antibody-drug conjugate – and has already been recognised as a game-changer for the treatment of HL, and the ECHELON-2 study demonstrated it as the first real advancement for PTCL we’ve had since CHOP,” explained Prof. Prince.

BV has been available since 2014 as a single agent for relapsed or refractory (r/r) sALCL. In September 2021, a new listing was created for BV in combination with CHP as a frontline treatment for all CD30-expressing PTCL.17 At the same time, the PBS authority criteria was modified in r/r sALCL to allow patients who had received BV as a frontline treatment to receive BV again as monotherapy at relapse.18

 5-year ECHELON-2 data highlights the benefit for patients with sALCL7

“ECHELON-2 is an important study for us and was designed to measure some important endpoints, such as progression-free survival (PFS) and overall survival (OS),” explained Prof Prince. “When submitting the design to the FDA, they predetermined 75% of the recruited population would have sALCL and we saw some very positive results in this group. For other subtypes outside of sALCL, we need to keep in mind the trial was not powered to detect significant differences from SOC. At this stage, we cannot definitively say what the role of BV is in these subtypes like PTCL-NOS and AITL,” he said.

The ECHELON-2 trial was a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study comparing brentuximab vedotin plus cyclophosphamide, doxorubicin and prednisolone (BV+CHP) with standard-of-care CHOP in the treatment of patients with CD30-positive mature T-cell  lymphomas7. Eligible patients were aged 18 years and over, and patients with eligible histologies were those with ALK+ sALCL with an International Prognostic Index (IPI) score of 2 or above ³, ALK- sALCL, hepatosplenic T-cell lymphoma (although no patients with this histology were recruited), PTCL-NOS, adult T-cell leukaemia/lymphoma, enteropathy-associated T-cell lymphoma and AITL7.

From the primary analysis, (median follow-up 36.2 months), the 3-year PFS was 57.1% (95% confidence interval (CI): 49.9% to 63.7%) in the BV+CHP arm vs 44.4% in the CHOP arm (95% CI: 37.6% to 50.9%).7 The primary analysis also identified an OS favouring the BV+CHP arm vs CHOP, with an OS of 76.8% (95% CI: 70.4% to 82.0%) for A+CHP vs 69.1% for CHOP (95% CI: 62.3% to 74.9%).7 The 5-year analysis continued to see encouraging data with the PFS hazard ratio (HR) being 0.70 (95% CI: 0.53-0.91, p=0.0077) and a 30% reduction in progression events with BV+CHP vs CHOP.7 The median PFS was 62.3 months (95% CI: 42.0 months to not evaluable) for A+CHP and 23.8 months (95% CI: 13.6-60.8 months) for CHOP. 7 The estimated 5-year PFS was 51.4% (95% CI: 42.8% to 59.4%) for the BV+CHP arm vs 43.0% (95% CI: 35.8% to 50.0%) for the CHOP arm.7 Median OS was not reached in either arm with an HR of 0.72 (95% CI: 0.53-0.99, p=0.0424).7 The estimated OS was 70.1% (95% CI: 63.3% to 75.9%) at 5 years for A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) for CHOP.7

Patients were retreated with BV in both the BV+CHP arm (13%) and the CHOP arm (24%) after relapse or progressive disease following frontline therapy.7 In the BV+CHP arm, the median time to further treatment with BV as either a mono- or combination therapy was 15.0 months (range 3–64 months) and the median duration of treatment was 2.1 months (range 0–18 months).7 After retreatment, the BV+CHP arm saw an objective response rate (ORR) of 59%, with 17 patients achieving CR (n=11) or PR (n=6).7 Comparatively for the CHOP arm, median time to retreatment was 8.2 months (range 1–67 months) with a median duration of 2.2 months (range 0–11 months) and 27 patients (ORR: 50%) had CR (n=16) or PR (n=11).7

Trends in the sALCL subgroup7

The PFS HR was 0.55 (95% CI: 0.39-0.79; p= 0.0009) in the subset of patients with sALCL, and the estimated 5-year PFS was 60.6% (95% CI: 49.5% to 69.9%) for A+CHP and 48.4% (95% CI: 39.6% to 56.7%) for CHOP.7 The HR for OS was 0.66 (95% CI: 0.43-1.01, p=0.0529) with an OS of 75.8% (95% CI: 68.2% to 81.9%) for the BV+CHP arm versus 68.7% (95% CI: 60.5% to 75.6%) for the CHOP arm.7

What 5 years of safety data reveals about managing patients with BV7

In ECHELON-2, the safety profile remained manageable and similar to CHOP, including no increase in secondary malignancies, and the proportion of ongoing peripheral neuropathy (PN) events were reported to be similar in both arms.7 Prof. Prince pointed out that PN and monitoring patients for neutropenia are likely top of mind for many clinicians. “We’ve seen through this trial that for those few patients who develop peripheral neuropathy with frontline BV+CHP, it subsequently improved in the majority of patients and retreatment was not only possible but also effective. One reason for the low incidence of PN in ECHELON-2 is that unlike the relapsed setting – where we administer BV as a single agent for 16 cycles every 3 weeks for 12 months – in ECHELON-2, patients generally received only 6 cycles, so naturally we see less peripheral neuropathy,” said Prof. Prince.

Peripheral neuropathy events were observed in both arms, with 117 (52%) in the BV+CHP arm vs 124 (55%) in the CHOP group.7,19 From the 5-year update, the authors reported ongoing PN in 47 (21%) patients in the BV+CHP arm. For the CHOP arm PN events were identified in 42 (19%) patients.7

Adverse events were observed in the trial, for the BV+CHP arm, grade 1 and 2 events were mostly observed in 33 (70%) and 13 (28%) patients respectively, with only 1 patient (2%) experiencing a grade 3 event.7  Similarly, in the CHOP arm, mostly grade 1 and 2 events were observed, with 30 (64%) patients experiencing a grade 1 event, 11 (23%) experiencing a grade 2 event and only 1 patient (2%) with a grade 3 event.7 Indeed, for both arms, the majority of PN events either improved or resolved, including 72% of patients (84/117) in the BV+CHP vs 78% (97/124) in the CHOP arm.7

 BV is the new SOC for ALCL

BV is undoubtedly the new standard of care for sALCL,” said Prof. Prince. “For other subtypes we don’t yet have enough data and the use of BV in these circumstances will require clinical judgement. In making those decisions, it is important to note that while targeting CD30, expression of CD30 on the tumour cells can be highly variable across PTCL subtypes. Furthermore, the level of CD30 expression should not be solely relied upon to drive the decision of using BV,” he explained.

The ECHELON-2 trial continues to show improvements in both PFS and OS for BV+CHP treatment over CHOP, and with a manageable safety profile.7 The expansion of the PBS listing to allow BV in combination with traditional CHOP-like therapies for frontline treatment17 allows clinicians to enhance their first-line treatment algorithms to improve survival outcomes for candidate PTCL patients. 

Disclosure

This article was sponsored by Takeda Australia. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Adcetris product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

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    2. Lymphoma Australia. Peripheral T-cell lymphoma (PTCL) [Internet]. Queensland, Australia [Accessed: March 2022]. Available from: https://www.lymphoma.org.au/types-of-lymphoma/non-hodgkin-lymphoma/lymphoma-t-cell/peripheral-t-cell-lymphoma-ptcl/
    3. Bachy E et al. Controversies in the Treatment of Peripheral M-cell Lymphoma. HemaSphere. 2020 Oct; 4(5): e461.
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    7. Horwitz S et al. The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Annals of Oncol. 2022 Mar; 33(3): 288-98.
    8. Savage K et al ALKanaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. 2008 June; 111(12); 5496-504.
    9. Laribi K et a Recent Advances in the Treatment of Peripheral T-Cell Lymphoma. Oncologist. 2018 Sep; 23(9):1039-53.
    10. Choi EJ et al. Treatment outcomes of dose-attenuated CHOP chemotherapy in elderly patients with peripheral T cell lymphoma. Blood Res. 2017 Dec; 52(4):270-5.
    11. Bachy E et al. Romidepsin Plus CHOP Versus CHOP in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Results of the Ro-CHOP Phase III Study (Conducted by LYSA). J Clin. Oncol. 2022 Jan; 40(3):242-51.
    1. Bellei M et al. The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project. Haematologica. 2018 Jul; 103(7):1191-97
    2. Francisco JA et al. cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug; 102(4):1458-65.
    3. Therapeutic Goods Administration. Australian Government, Department of Health [Internet]. Product Information – ADCETRIS® (BRENTUXIMAB VEDOTIN). [Revised 19 May 2014; Cited March 2022]. Available from: https://www.tga.gov.au
    4. Bartlett NL et al. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J of Hematol & Oncol. 2014 Mar; 19(7).
    5. Therapeutic Goods Administration. Australian Government, Department of Health [Internet]. – Australian Product Information – ADCETRIS® (BRENTUXIMAB VEDOTIN). [Revised 14 May 2021; Cited March 2022]. Available from: https://www.ebs.tga.gov.au
    6. Pharmaceutical Benefit Scheme. Australian Government, Department of Health [Internet]. Brentuximab Vedotin [Cited March 2022]. Available from: https://www.pbs.gov.au
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