Summary
A new study presented at the 2020 ASCO Annual Meeting showed that pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with brentuximab vedotin (BV) in patients with relapsed or refractory classic Hodgkin lymphoma (R/R cHL) (Abstract 8005).
In March 2017, pembrolizumab was approved by the FDA for the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after three or more prior lines of therapy. This accelerated approval was based on results of the phase II KEYNOTE-087 trial; the phase III KEYNOTE-204 trial is a confirmatory trial for pembro’s current indication in cHL.
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Original Article
Pembrolizumab Shows Significantly Improved PFS in R/R Classic Hodgkin Lymphoma
Oncology Times
By Sarah LaCorte
A new study presented at the 2020 ASCO Annual Meeting showed that pembrolizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with brentuximab vedotin (BV) in patients with relapsed or refractory classic Hodgkin lymphoma (R/R cHL) (Abstract 8005).
In March 2017, pembrolizumab was approved by the FDA for the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after three or more prior lines of therapy. This accelerated approval was based on results of the phase II KEYNOTE-087 trial; the phase III KEYNOTE-204 trial is a confirmatory trial for pembro’s current indication in cHL.
“KEYNOTE-087 was a phase II trial that led to the initial approval of pembro in relapsed/refractory Hodgkin's lymphoma. KEYNOTE-204 was designed as the successor and the randomization was to look at pembro versus brentuximab vedotin in patients that were transplant-ineligible, or patients that had relapsed following autologous stem cell transplant,” said John Kuruvilla, MD, FRCPC, Clinician Investigator at the Princess Margaret Cancer Centre, and first author on the study. “The primary endpoint was to look at progression-free survival as a whole, and the question of the trial was really to try and establish that pembrolizumab was superior to brentuximab vedotin, which had been established previously as standard of care in this patient population.”
The primary endpoints were PFS by blinded independent central review (BICR) per International Working Group (IWG) criteria including clinical and imaging data after auto-SCT or allogeneic SCT (allo-SCT) and OS. The key secondary endpoints were PFS excluding clinical and imaging data after auto-SCT or allo-SCT (PFS-secondary), and objective response rate (ORR) by BICR per IWG, PFS by investigator review per IWG, and safety.
“In all honesty, the trial performed as one would have expected based on the phase II studies. The phase II trial of brentuximab that led to its approval showed a median progression-free survival of a little under 6 months. In this trial, the PFS was around 8 months, so not that different, and you might argue that the patients that went on to the pivotal trial were a little less pretreated than the original data with brentuximab. We know from KEYNOTE-087 that the PFS of pembrolizumab in a similar but slightly more pretreated patient population was around 12 months or so. We ended up doing a little bit better than that in this trial,” said Kuruvilla.
The study included patients 18 years or older who had a post−autologous stem cell transplant (auto-SCT) or were ineligible for auto-SCT, and had measurable disease and ECOG PS 0 or 1. BV-naive and BV-exposed patients were also eligible. Subjects were randomized 1:1 to receive either pembro 200 mg IV Q3W or BV 1.8 mg/kg IV Q3W and stratified by prior auto-SCT (yes vs. no) and status after 1L therapy (primary refractory vs. relapsed <12 mo vs. relapsed ≥12 mo after end of 1L therapy). Overall, 304 patients were randomized and 300 were treated (148, pembro; 152, BV); 256 discontinued.
“With regards to the subgroups in relationship to the primary progression-free survival, the benefit extended to patients whether they had undergone prior transplant or not, whether the patient was refractory after frontline therapy, had early relapse which is defined as less than 12 months, or if patients had relapsed more than 12 months after primary treatment and was also independent of prior brentuximab exposure as well,” said Kuruvilla.
“The trial design allowed patients that had had prior brentuximab exposure into the study but there were very small numbers of patients with that pre-treatment. The treatment effect favored pembrolizumab in the vast majority of patients that had received prior BV and also favored pembro even in that small group of patients that had prior BV.”
Median (range) time on treatment was 305.0 (1-814) and 146.5 (1-794) days with pembro and BV. Statistically significant improvement was observed with pembro versus BV for primary PFS analysis (HR 0.65 [95% CI 0.48-0.88; P =0.00271]; median 13.2 vs. 8.3 mo); 12-month PFS rates were 53.9 percent versus 35.6 percent. The authors noted benefit was observed in all subgroups tested, including patients with no auto-SCT (HR=0.61), primary refractory disease (HR=0.52), prior BV (HR=0.34) and BV naive (HR=0.67). Significant improvement in PFS-secondary was observed with pembro versus BV (HR 0.62 [95% CI 0.46-0.85]; median 12.6 vs. 8.2 mo).
“The toxicity data ended up confirming what we already knew based on the other studies that have looked at these drugs in Hodgkin lymphoma; both are generally pretty well-tolerated, but they have their own unique toxicities. Brentuximab had an issue around neuropathy related to the chemotherapy payload of the antibody drug conjugate. With pembrolizumab, the common toxicities—immune mediated—are largely pretty easy to deal with such as grade 1 or 2 thyroid dysfunction,” noted Kuruvilla.
“The more worrisome toxicity that can be seen in a subset of patients, which was drug-related pneumonitis, was not that common. In the total population, 10.8 percent with 5.4 percent of patients experienced grade 3 or 4 pneumonitis, with no pneumonitis-related deaths. It essentially showed the same toxicity profile that we expected from the phase II data, but now the randomization showing the superiority in efficacy for pembro over BV.”
Per investigator assessment, PFS was longer with pembro versus BV (HR 0.49 [95% CI 0.36-0.67]; median 19.2 vs. 8.2 mo). ORR was 65.6 percent for pembro and 54.2 percent for BV; CR rates were 24.5 percent and 24.2 percent, respectively. Median (range) DOR was 20.7 months (0.0+ to 33.2+) for pembro and 13.8 months (0.0+ to 33.9+) for BV. Grade 3-5 TRAEs: 19.6 percent of patients with pembro and 25.0 percent with BV. One death due to TRAE occurred with pembro (pneumonia).
“The trial had a very rigorous statistical design, so when looking beyond progression-free survival at the other endpoints, such as overall response rate, there was a numeric difference of approximately 10 percent, favoring pembrolizumab compared to brentuximab vedotin,” said Kuruvilla. “However, that did not reach the predefined margin of statistical significance. The complete response rate was similar between the two arms so the difference in response was mainly in the number of partial responses. But when you look at the results here, progression-free survival is a far more meaningful endpoint than overall response rate. Both agents have quite good response rates as single agents, but the PFS is the telling difference.”
The authors concluded that in patients with R/R cHL, pembro was superior to BV and demonstrated statistically significant and clinically meaningful improvement in PFS across all subgroups, with safety consistent with previous reports.
“Based on this trial, we feel we accomplished a new standard with pembrolizumab now replacing brentuximab vedotin as a standard treatment in this setting in patients that were transplant ineligible or had relapsed after having autologous transplant,” said Kuruvilla. “Brentuximab remains an important treatment in R/R cHL based on the randomized AETHERA trial where BV was used as consolidation post-ASCT.
Kuruvilla said there is discussion ongoing with pembrolizumab regarding a frontline trial and that pembrolizumab is also being used in the relapsed refractory setting, and in the curative setting in some clinical trials as well.
“I think all of these studies will clearly cement the role of checkpoint inhibitors in the treatment of relapsed/ refractory Hodgkin's lymphoma. But the goal here is certainly trying to move these very active agents earlier, potentially in combination and into the curative setting. Hopefully we can replace some of the more toxic chemotherapy approaches we’ve used previously or develop novel combination approaches,” he concluded.
Sarah LaCorte is associate editor.