MEETING HIGHLIGHT

Evolution in the treatment of CD30-positive lymphomas: The role of brentuximab vedotin

30 Apr 2019
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Prof. Connors, Joseph M.

Emeritus Professor,
University of British Columbia,
Vancouver, BC, Canada

At a meeting organized by the Hong Kong Society of Hematology (HKSH), Professor Joseph M. Connors of the University of British Columbia shared his insights into the evolution in the treatment of CD30-positive lymphomas. With advances being made in understanding CD30 biology and therapeutic targeting, the crucial role of brentuximab vedotin as a CD30-specific antibody-drug conjugate (ADC) was discussed.

Overview of standard chemotherapy regimens for HL treatment

Over the past 20 years, the standard treatment for Hodgkin’s lymphoma (HL) has revolved around the use of multidrug chemotherapy regimens.1 The mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid chemotherapy was found to be effective in producing a high rate of complete remission (CR) in patients with advanced HL, but a randomized trial by Duggan et al. found that the use of ABVD (ABV plus dacarbazine) was as effective as MOPP/ABV, albeit with lesser toxicity.1 “It turned out that the real work horse was ABVD, and in comparison, ABVD performed just as well as the 7-drug combination MOPP/ABV,” Prof. Connors said.

Although findings from the GHSG HD9 study on escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) challenged the position of ABVD as standard of care in treating patients with advanced-staged HL,2 subsequent reports from various studies (GISL HD2000, GSM-HD, LYSA H34, and EORTC [HD8]) found similar overall survival (OS) rate between the two chemotherapy regimens.3-6 As shown in an article by Prof. Connors,7 this generalized improvement in outcomes with ABVD could be because “we became better at delivering ABVD, and we’re able to achieve more with that 4-drug recipe.”

It was difficult to achieve a better efficacy with the chemotherapy regimens, and therefore the development of treatment strategies was aimed toward reducing toxicity via treatment de-escalation: 1) eBEACOPP for 6 cycles, then dropping the last 2 cycles if PET2 is negative, or 2) ABVD for 6 cycles, then dropping bleomycin in the last 4 cycles if PET2 is negative.8,9 Additionally, there is the possibility to escalate treatment if PET2 is positive, for example by changing the last 4 cycles of a 6-cycle ABVD into eBEACOPP.10 Nonetheless, Prof. Connors noted that either escalation of ABVD or de-escalation of eBEACOPP only reduced toxicity, but did not improve the survival of HL patients who were treated.

Brentuximab vedotin for HL treatment

Since none of the aforementioned strategies is clearly superior to 6-cycle ABVD, a new approach was developed with the use of brentuximab vedotin. In its open-label, phase 2 study, patients with relapsed/refractory HL after failed autologous stem-cell transplantation who received brentuximab vedotin had an objective response rate (ORR) of 75% and a CR rate of 34%.11 These patients were followed up for 5 years, and the survival outcomes are shown in Figure 1.12 “By definition they had [ABVD and high-dose chemotherapy (HDCT)] resistant disease, yet 5-6 years later they’re behaving that they were cured,” Prof. Connors commented, when referring to the tail of the survival curves.

 

 

Subsequent report from AETHERA, a randomized, double-blind, placebo-controlled, phase 3 trial, provides further evidence.13 The trial randomized 329 patients with unfavorable-risk relapsed or primary refractory classic HL who had undergone ASCT (and had CR, partial remission, or stable disease after pre-transplantation salvage chemotherapy) to receive placebo or brentuximab vedotin as consolidation therapy.13

With the introduction of brentuximab vedotin, more patients appear potentially cured from HL.13 As shown in Figure 2, the results showed that almost a third of patients, who were not curable with ABVD or intensified chemotherapy, were cured with brentuximab vedotin.13 “It’s the use of novel agents based on the novel understanding of biology that has led to actual improvement for our patients with HL,” Prof. Connors said.

 

Of note, brentuximab vedotin plus AVD were compared against ABVD as frontline therapy for stage III/IV HL in the phase 3 ECHELON-1 trial, which has been published in The New England Journal of Medicine.14

Brentuximab vedotin for PTCLs treatment

The use of brentuximab vedotin has also been investigated in peripheral T-cell lymphomas (PTCLs).15 Systemic anaplastic large cell lymphoma (sALCL), in particular, is a CD30-expressing subtype of PTCL with high rates (approx. 40-65%) of disease recurrence after frontline treatment with anthracycline-based chemotherapy regimens.15

Pro et al. conducted a single-arm, open-label, multicenter, phase 2 study in 58 patients with relapsed/refractory sALCL (with at least 6 months of follow-up) and found an ORR of 86% and CR rate of 57% with the use of brentuximab vedotin.15 Remarkably, those who achieved CR continued to demonstrate improved outcomes with median progression-free survival (PFS) not being reached after 5 years of follow-up.15 Figure 3 shows PFS curves for all patients as well as stratified by best response.15 “With long-term follow-up, the curve flattens out and at least some of these patients did not receive anything further – they’re behaving like they’re actually being cured by brentuximab vedotin,” Prof. Connors said.

 

 

The phase 3 ECHELON-2 trial further investigated the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in previously untreated subjects with CD30-expressing PTCLs, and the results have been published in The Lancet.16 This data is also pending review by the Hong Kong Department of Health.

Brentuximab vedotin for CTCLs treatment

As for cutaneous T-cell lymphomas (CTCLs), a rare group of non-HL with mycosis fungoides and Sézary syndrome being the most common forms, the prognosis is generally good with chemotherapy, but without durable and reliable disease control.17,18 In ALCANZA, an open-label, randomized, phase 3 trial that enrolled 131 patients with CD30-positive mycosis fungoides or primary cutaneous ALCL (pcALCL) who had been previously treated, brentuximab vedotin was compared against physician’s choice (oral methotrexate or oral bexarotenze).18 The primary endpoint of the study was an objective global response lasting at least 4 months per independent review facility (ORR4).18 “The response to treatment had to be more than evanescent, that is, not just there for a few weeks and then gone,” Prof. Connors explained.

The proportion of patients achieving ORR4 in ALCANZA was much higher with brentuximab vedotin versus physician’s choice (56.3% vs. 12.5%; between-group difference of 43.8% [95% CI: 29.1-58.4; p<0.0001]).18 This translates into a greater survival benefit in patients receiving brentuximab vedotin, as shown in Figure 4.18 In regard to the proportion of patients experiencing serious adverse events, it was similar between the two groups (29% for both).18 Peripheral neuropathy of any grade was more common (45%) in patients receiving brentuximab vedotin, whereas hypertriglyceridemia of any grade was more common (30%) in patients receiving bexarotene.18 After follow-up for almost 2 years, most (82%) patients in the brentuximab vedotin arm had an improvement or resolution of peripheral neuropathy.18

 

 

Conclusion

More evidence shows the role of brentuximab vedotin in the treatment of CD30-positive lymphomas. Presenting itself as a treatment that further improves survival outcomes, brentuximab vedotin holds promise as an important addition to the treatment of the disease.

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