Findings Continue to Show Brentuximab Vedotin Plus CHP Offers Survival Advantage in PTCL

Andrew M. Evens, DO, MSc, associate director for Clinical Services, director, Lymphoma Program, Rutgers Cancer Institute and medical director, Oncology Service Line at RWJBarnabas Health, considered the data supporting brentuximab vedotin (Adcetris) with chemotherapy for the treatment of a patient with peripheral T-cell lymphoma (PTCL).

Targeted OncologyTM: Can you comment on these poll results and how the National Comprehensive Cancer Network (NCCN) guidelines should be factored into deciding treatment for this patient?

EVENS: I think [the chosen options are] fair because, if you’re [going] by the data, this patient might not fit into [treatment with brentuximab vedotin with chemotherapy]. The reason I chose brentuximab vedotin plus CHP [cyclophosphamide, doxorubicin, prednisone], unlike [in] Hodgkin lymphoma, where you’re already starting at 70% to 80%, [is that] you’re starting at 30% 3-year progression-free survival PFS]. If I can get someone any kind of bump, I’m trying it.

Now, by the letter of the law, [this case] didn’t fit ECHELON-1 [NCT01712490]. The [population with] PTCL was a small subgroup in ECHELON-2 [NCT01777152], but the confidence interval crossed 1.00. So officially, it wasn’t significant there. I would say the alternative is not great, and I would take this patient to an [autologous stem cell transplant], and for complete remission [CR], I want to use whatever my best [option is] to get them into remission. However, I think you can make an argument either way.

[The NCCN guidelines] say the preferred regimen in category 1 is [brentuximab vedotin plus CHP] for anaplastic large cell lymphoma [ALCL] and systemic ALCL. [The brentuximab vedotin plus CHP]…is an option [for PTCL], as are CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] and CHOEP [cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone].¹

Can you discuss the study design of the ECHELON-2 trial, which looked at the safety and efficacy of brentuximab vedotin plus CHP combination therapy?

It was a randomized study [that included] all histologies, as long as they had 10% of CD30 on the tumor cells. The standard treatment was 6 to 8 cycles of CHOP versus brentuximab vedotin plus CHP.

Can you discuss the efficacy and safety results of this trial and any updates?

[ECHELON-2] had better results and efficacy [for this patient population] compared with those with Hodgkin lymphoma.² Part of those results come from [some patients] starting at 40% 3-year survival, so it’s a little easier to go up, but there was significant improvement in PFS.

You could argue [that patients with ALCL] were favorable toward treatment on CHOP, although there were small numbers, whereas patients with PTCL favored brentuximab vedotin plus CHP, which crossed a confidence interval of 1.00. However, updated findings show more definitively that patients with ALCL favored brentuximab vedotin plus CHP [TABLE].³

This was the first study in the world in PTCL [whose results have] shown an overall survival advantage. Other studies—not many—have shown a PFS [advantage], so we can say we are curing more patients, not just achieving a higher remission rate. Now, would we like it to be higher? Of course we would, but I think [these data are] why it was published in Lancet and made it a game changer.²

[Looking at] CR rates, they were not surprisingly higher overall for patients treated on brentuximab vedotin plus CHP versus [patients on] CHOP, 68% [n = 153] compared with 56% [n = 126], respectively.

There really was no difference in overall neuropathy— 45% grade 3/4 adverse events versus 3%—and I think that is important. Maybe a lesson learned for [treating patients with] Hodgkin lymphoma is there should be a future study where we drop the vinblastine, maintain the efficacy, and decrease the toxicity in the future.

If this patient achieved a CR to frontline therapy, would you consider transplant?

[ECHELON-2 had] an interesting abstract because a transplant was left up to the investigator’s decision. About a third of patients on ECHELON-2 went on to transplant. There’s always some selection bias when you look at transplant studies because usually healthier patients with CR go on to it. But at least when they looked at patients with CR, they tried to take CR out of the equation. It looked, not surprisingly, as if there was a benefit to transplant for patients in ECHELON-2. At a 3-year follow-up, 76% went with transplant and 53% [went] without.⁴

I want to acknowledge that of course there’s going to be some bias here in selection. But I think, until we have data that say it’s not helpful, I agree that for most patients with PTCL—not ALCL ALK positive—[there’s] a good prognosis. For pretty much everyone else, you at least want to think about an autologous stem cell transplant.

Are there other treatment options to consider for this patient population?

[Yes.] They are active, but they’re not home runs by any stretch. Everything [is] right around a 30% response rate, with duration of response around 9 to 12 months. On almost every one of these studies, you see a tail to the curve of about 10% of patients staying in long-term, many-years remission with any of these [other treatments]. Unfortunately, with any of these, we don’t have any biomarkers to tell us who are these 26% to 27% of patients. I think it’s definitely an unmet need we have in all of lymphoma, but especially PTCL.

There are some other [treatments] that aren’t FDA approved: bortezomib [Velcade], lenalidomide [Revlimid], anecdotally bendamustine can also work. Ultimately, we still need more therapy [options] even though brentuximab vedotin is a breakthrough.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. T-cell lymphomas, version 1.2021. Accessed February 19, 2021. https://bit.ly/2G0YfBi}

_{2. Horwitz S, O’Connor OA, Pro B, et al; ECHELON-2 Study Group. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240. doi:10.1016/S0140-6736(18)32984-2}

_{3. Horwitz S, O’Connor OA, Pro B, et al. The Echelon-2 trial: 5-year results of a randomized, double-blind, phase 3 study of brentuximab vedotin and CHP (A+CHP) versus CHOP in frontline treatment of patients with CD30-positive peripheral T-cell lymphoma. Blood. 2020;136(suppl 1):3-5. doi:10.1182/blood-2020-134398}

_{4. Savage KJ, Horwitz SM, Advani RH, et al. An exploratory analysis of brentuximab vedotin plus CHP (A+CHP) in the frontline treatment of patients with CD30+ peripheral t-cell lymphomas (ECHELON-2): impact of consolidative stem cell transplant. Blood. 2019;134(suppl 1):464. doi:10.1182/blood-2019-122781}