Pembrolizumab After ASCT is Feasible in Peripheral T-Cell Lymphoma

Mwanasha Merrill

PD-1 blockade post autologous stem cell transplantation (ASCT) with pembrolizumab (Keytruda) demonstrated a favorable safety profile and encouraging activity when given to patients with peripheral T-cell lymphoma (PTCL), according to a phase 2 study (NCT02362997).¹

While ASCT is often used for several subtypes of PTCL as consolidation in first remission, many patients still relapse following ASCT. With no approved treatment options for post transplantation maintenance or consolidation in this patient population, researchers conducted a phase 2 study.

In the multicenter trial, pembrolizumab 200 mg was given to patients with PTCL in first remission after ASCT via intravenous infusion every 3 weeks for up to 8 cycles within 21 days from post ASCT discharge. Investigators assessed the primary end point of progression-free survival (PFS) at 18 months post ASCT.²

Of the 21 patients treated, 14 (67%) completed 8 cycles of treatment.1 Thirteen of the 21 evaluable patients were alive, and the study's primary end point of PFS at 18 months after ASCT was met with an estimated 18-month PFS of 83.6% (95% CI, 68-100). For a secondary end point of overall survival, the rate observed was 94.4% (95% CI, 84-100).

For safety, there was a similar toxicity profile observed in this trial to the known toxicity profile of pembrolizumab. No grade 5 toxicities were reported.

These data support further confirmatory studies of pembrolizumab post ASCT in this space.

Cancer cell spreading among healthy cell stem cells© catalin - stock.adobe.com

“I think this would be a very attractive subtype to investigate further to see exploring transplantation and then PD-1 blockade specifically for this subtype,” Mwanasha Merrill, told Targeted Oncology^TM, in an interview.

In the interview, Merrill, hematology oncology clinical fellow, Department of Medical Oncology, Dana-Farber Cancer Institute, discussed the implication of findings from a phase 2 trial of pembrolizumab after ASCT for the treatment of patients with PTCL.

Targeted Oncology: Can you discuss the background of this phase 2 study?

Merrill: PTCL is pretty heterogeneous, and we don't have a lot of treatment options for this. At the moment, the biggest recommendation is to give chemotherapy and then consolidate with an autologous stem cell transplant when patients go into first remission. There are no approved treatments that are given in posttransplant maintenance or consolidation in peripheral T cell lymphomas. We were thinking that if we give someone a transplant and target that post transplant setting whereby someone has minimal disease state, then it would also be a good time to target T cells, because this is a time of immune reconstitution. Using PD-1 blockade in that setting was pretty attractive to us.

What were the methods and design of this trial?

This was a phase 2 study. It was an open-label, non-randomized, multicenter study as well. We were looking at pembrolizumab given after transplant in patients with several lymphomas. Our study had 3 arms. The first arm was looking at classical Hodgkin lymphoma. The second one was looking at [diffuse large B-cell lymphoma], and the study that I was presenting on was the third arm that was looking at PTCL. Patients with PTCL in first remission were eligible for this study. As I mentioned, the rationale was that the post transplant setting is the low tumor burden, a low disease state, as well as it's also a good time to prime the immune response, given that it's a time for immune reconstitution. We thought that this would be the perfect time to use pembrolizumab in this setting.

Who was included in the study and what were the objectives?

We enrolled in a lot of the different PTCL histologies, but we did exclude cutaneous T-cell lymphoma, and our positive PTCL patients had to be eligible for transplant in order to enroll in this study as well. Patients [received] the transplant and they were supposed to receive pembrolizumab within 21 days, but this could go as much as 60 days. After that, they received pembrolizumab 200 mg [intravenously] every 3 weeks, and this was up to 8 cycles. For treatment response, we looked at PET CT that was done at different intervals throughout the study.

Our primary objective [was] the 18-month PFS, and for secondary objectives, we looked at things like overall survival, PFS, response rate, as well as safety. We chose, at least for the primary objective, 18-month PFS rate because we knew that data shows that in patients with chemosensitive PTCL, the 18-month PFS rate is about 40% to 50%. Therefore, we postulated that if we gave patients pembrolizumab, we expect this PFS rate to go up to 70%. In order for our study to be positive, we needed at least 13 of the 21 patients to be progression-free at 18 months.

Can you discuss the findings of the study?

In our study, we ended up with 21 patients and we had a few different PTCL histologies, but the most common was PTCL-NOS [not otherwise specified]. We found that at least 13 out of our 21 patients were progression-free at the 18 month post [transplant], so the study met the prespecified primary end point. We did also look at a second end point of PFS rate, and this was 83.6% when we looked at the entire cohort. We also looked at the PFS rate for the different histologies, and unfortunately, because the numbers are small, we didn't see any difference there. We also looked at the overall survival for the entire cohort that was about 94%. When we tried to look at the different histologies again, we didn't see any difference there, so we're not able to make any meaningful conclusions about that.

What are the implications of these results?

We had 21 patients and so definitely a bigger study would be interesting. There's been quite a bit of data showing that PD-1 blockade, at least in NK T cells, has shown promising results in the relapsed and refractory setting. I think this would be a very attractive subtype to investigate further while exploring transplantation and then PD-1 blockade specifically for this subtype.

Another interesting thing that can be looked at is seeing, what is the sequence? What is the ideal sequence of PD-1 blockade? Do we give it before transplant or after transplant? I say this because if we give it prior to transplant, potentially, this could act as a sensitizing agent. That's something that is worth looking at as well. Then the other thing I'll point out is just looking at combination studies. Brentuximab vedotin [Adcetris] has done so well, so looking at the combination of potentially brentuximab and PD-1 blockade with or without a transplant can be something that may be attractive as well.

What unmet needs still exist?

Because it's such a heterogeneous disease like so many subtypes, it's rare, so that makes it a bit harder to study. For us, we concentrated specifically in this post transplant maintenance setting because other lymphomas, like high-risk classic Hodgkin lymphoma, have used brentuximab as a maintenance agent; in mantle cell lymphoma we can use rituximab [Rituxan] as a maintenance agent after transplant. But in PTCL, we don't have that. Transplant is recommended after that first remission. I think trying to find something that works in this setting is important. And overall, I think just adding more agents to the treatment of this disease.

REFERENCES:

1. Merrill MH, Dahi PB, Redd RA, et al. A phase 2 study of pembrolizumab after autologous stem cell transplantation in patients with T-cell non-Hodgkin lymphoma. Blood. 2023;142(7):621-628. doi:10.1182/blood.2023020244

2. Pembrolizumab after ASCT for Hodgkin lymphoma, DLBCL and T-NHL. ClinicalTrials.gov. Updated July 27, 2023. Accessed November 2, 2023. https://tinyurl.com/bd48hkyn