Pembrolizumab extends PFS in relapsed or refractory classical Hodgkin lymphoma
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Pembrolizumab extended PFS compared with brentuximab vedotin for patients with relapsed or refractory classic Hodgkin lymphoma, according to study results presented during the ASCO20 Virtual Scientific Program.
The results — from an interim analysis of the randomized phase 3 KEYNOTE-204 study — suggest pembrolizumab (Keytruda, Merck) monotherapy should be the standard of care for this population, researchers concluded.
“Both of these agents clearly have a role in this disease,” John Kuruvilla, MD, hematologist and associate professor of medicine at Princess Margaret Cancer Centre and University of Toronto, told Healio. “Brentuximab vedotin initially established itself in this setting, and this randomized study shows pembrolizumab is superior, but I don’t look at it as if brentuximab vedotin has gone away. We just have another generation of active treatments. We already have refined where we can use brentuximab vedotin by moving it earlier, and I think this will show the same strategy needs to be taken with checkpoint inhibitors.”
An estimated 15% to 20% of patients with classical Hodgkin lymphoma — the most common type of Hodgkin lymphoma — do not achieve remission after first-line treatment, Kuruvilla said. Prognosis is poor for these patients, many of whom are young, so additional effective therapies are needed.
Pembrolizumab — an anti-PD-1 therapy — is approved in the United States for treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma who relapsed after three or more prior lines of therapy.
The international, open-label KEYNOTE-204 study compared pembrolizumab with brentuximab vedotin (Adcetris, Seattle Genetics), an antibody-drug conjugate directed at CD30, among 304 adults with relapsed or refractory classical Hodgkin lymphoma who either underwent or were ineligible for autologous stem cell transplant.
All patients had measurable disease and an ECOG performance status of 0 or 1, and 15 patients had received prior brentuximab vedotin.
Researchers assigned patients pembrolizumab dosed at 200 mg or brentuximab vedotin dosed at 1.8 mg/kg (maximum 180 mg per dose) on day 1 of each 3-week cycle. Treatment continued for up to 35 cycles.
Researchers stratified randomization by prior stem cell transplant and status after first-line therapy (primary refractory vs. relapsed within less than 12 months after completion vs. relapsed 12 months or longer after completion).
PFS by blinded independent central review per International Working Group criteria — including clinical and imaging data after autologous stem cell transplant or allogeneic stem cell transplant — and OS served as co-primary endpoints. Other endpoints included PFS secondary, which excluded clinical and imaging data after autologous or allogeneic stem cell transplant; objective response rate assessed by blinded independent central review; PFS by investigator review and safety. Duration of response assessed by blinded independent central review served as an exploratory endpoint.
Kuruvilla and colleagues presented data of 300 patients (pembrolizumab, n = 148; brentuximab vedotin, n = 152).
Median follow-up was 24.7 months (range, 0.6-42.3). Median time on treatment was 305 days (range, 1-814) in the pembrolizumab group and 146.5 days (range, 1-794) in the brentuximab vedotin group. At the time of data cutoff, 256 patients had discontinued treatment.
The primary PFS analysis showed a statistically significant PFS benefit with pembrolizumab (median, 13.2 months vs. 8.3 months; HR = 0.65; 95% CI, 0.48-0.88). A higher percentage of pembrolizumab-treated patients remained progression free at 12 months (53.9% vs. 35.6%).
Researchers observed the benefit with pembrolizumab in all evaluated subgroups, including patients who had not undergone autologous stem cell transplant (HR = 0.61), those with primary refractory disease (HR = 0.52), and patients who either received prior brentuximab vedotin (HR = 0.34) or were naive to the agent (HR = 0.67).
Researchers also reported improvement in other endpoints with pembrolizumab, including PFS secondary (median, 12.6 months vs. 8.2 months; HR = 0.62; 95% CI, 0.46-0.85), investigator-assessed PFS (median, 19.2 months vs. 8.2 months; HR = 0.49; 95% CI, 0.36-0.67), ORR (65.6% vs. 54.2%), complete response rate (24.5% vs. 24.2%) and median duration of response (20.7 months vs. 13.8 months).
Both drugs exhibited safety profiles consistent with prior reports.
A lower percentage of patients assigned pembrolizumab than brentuximab vedotin experienced grade 3 to grade 5 treatment-related adverse events (19.5% vs. 25%). One patient assigned pembrolizumab died due to treatment-related pneumonia.
Slightly more than 10% of pembrolizumab-treated patients developed pneumonitis. These patients were treated successfully with corticosteroids, and no deaths occurred due to these toxicities.
Peripheral neuropathy in the brentuximab vedotin group appeared manageable, Kuruvilla said.
Per study protocol, OS was not formally tested during the interim analysis. The study will continue so researchers can evaluate OS, and additional data could be available in the next 12 to 18 months, Kuruvilla said.
“You’re always concerned in Hodgkin lymphoma that the bar is set high. There are so many effective therapies and people can go on to other treatments and OS advantages are frequently elusive,” he told Healio. “That being said, given the large effect we saw with the drug in terms of the HR for PFS, we might actually see a survival advantage. I think that would be quite a surprise, but it would validate the benefit of checkpoint inhibitors in this disease.” – by Mark Leiser
Reference:
Kuruvilla J, et al. Abstract 8005. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Perspective
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Lee Greenberger, PhD
The performance of pembrolizumab is impressive. Given the statistically significant difference, this looks like a good option for patients with relapsed refractory Hodgkin lymphoma compared with brentuximab vedotin, at least at this point. Although the researchers provided PFS data, there are no OS data yet. It remains to be seen whether they demonstrate a difference. However, the PFS results are impressive.
The toxicity profile seems favorable. A lot of antibody-drug conjugates have toxicity. The PD-1 molecules may have some toxicities but they’re a totally different type.
I’m not so sure about a real uptake of brentuximab vedotin in the front-line setting yet. A lot of clinicians are still using traditional ABVD [doxorubicin, bleomycin, vinblastine and dacarbazine]. And if brentuximab vedotin is going to be used in the front-line setting, would it be used in the refractory setting for a patient who already received it? Probably not, so I’m not sure ABVD has really been knocked out of the first-line setting by brentuximab vedotin.
Perspective
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Joshua Brody, MD, PhD
The practice-changing results of KEYNOTE-204 will immediately impact how we think about this pressing patient problem. Although advanced-stage Hodgkin lymphoma is curable for more than 70% of patients with chemotherapy-based regimens, this leaves a large number of young patients with incurable cancer, and there is a dire need for effective therapies.
Brentuximab vedotin and anti-PD-1 antibodies both are approved in this setting and induce somewhat durable responses, but it has been unknown which yielded better long-term outcomes. KEYNOTE-204 demonstrated an impressive PFS benefit along with higher response rates and fewer high-grade toxicities. Although OS was not yet assessed, these data seemingly would solve the conundrum of how to treat these frequently chemotherapy-resistant young patients.
The moving target here is that, because of the success of the ECHELON-1 study, which showed the impressive benefit of incorporating brentuximab vedotin into first-line Hodgkin lymphoma therapy, the de facto choice might have become PD-1 blockade for relapsed/refractory patients by default — particularly given the comfort most community oncologists have with these agents, which they routinely use to treat non-small cell lung cancer, melanoma and other solid tumors. Regardless, the remarkable anti-PD-1 results in this study — with response rates three times higher than those in NSCLC — provide a tremendous opportunity to learn what tumoral and patient features predict the greatest efficacy of cancer immunotherapy.
Reference:
Straus DJ, et al. Blood. 2020;doi:10.1182/blood.2019003127.
Collapse
Kuruvilla J, et al. Abstract 8005. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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