By Mwanasha Merrill, MD
How can Pembro (MK-3475) help patients with with -cell non-hodgkin lymphoma? I'm excited about this phase 2 Pembro (MK-3475) study, Pembrolizumab after autologous stem cell transplant in patients with T-cell lymphoma. As most rare for T-cell lymphomas have a poor prognosis and it's really hard for developing new therapies given the heterogeneous nature of this disease and currently high dose chemotherapy and consolidation with an autologous stem-cell transplant is recommended in first remission. And however, at the moment we also do not have any options for post-transplant maintenance and consolidation in PTCL.
So that's where our Pembro (MK-3475) study comes in because we wanted to look at using PD-1 blockade after transplant to see if that would improve the outcomes of these patients. And in particular, we chose this post-transplant setting without, this would be an ideal time because one, this is a time of minimal disease state. It's also a time of immune reconstitution, which would be the ideal time to stimulate the T-cells.
And then, so for this study, so this was a phase 2 study Pembro (MK-3475). It was open label, it was non randomized ENT study, and we ended up enrolling about 21 patients. And in the study you got the transplant and then you received pembrolizumab at 200 milligrams IV every 3 weeks for up to 8 cycles, and then response was gauged by using a PET CT.
I was done at cycles 4 and 7, and at 12 and 18 months after transplant. And our main primary objective was the 18 month PFS and the secondary end point objectives we were looking at things like overall survival, PFS and safety as well. So for this study, we for the study to be interesting. Based on our statistical study results, we needed 13 out of the 21 patient.
Because our sample size is 21 to be progressive, at the 18 month follow up and the study met that primary endpoint. So it was a positive study in that regard.
Pembrolizumab, also known as Pembro (MK-3475), is a humanized monoclonal anti-PD-1 antibody that is currently in the experimental stage of development. Its purpose is to reactivate antitumor immunity by inhibiting the interaction between PD-1 on T-cells and its ligands, PD-L1 and PD-L2. Through a process known as dual-ligand inhibition, pembrolizumab is able to suppress the PD-1 pathway.
Pembrolizumab is now being researched as a potential treatment for more than 30 different types of cancer, both as a monotherapy and in combination with other drugs. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to include more than 24 clinical trials spanning 30 unique types of tumors, recruiting over 6,000 patients at approximately 300 clinical trial sites across the globe, including additional Phase 3 studies.
Other things that we noted in this study was that for some of the baseline characteristics we had the most common histology was PTCL NOS in the study. And we also saw that we looked at the EBV status, which is available for about 13 of the patients, and 6 of them had EBV positive disease and the most commonly used prior regimen was choag.
And in prior to, at least for the disease status, before transplant, about 90% of the patient were in CMR and after transplant, 95% of the patient were in CMR. And just talking about some of the treatment outcomes and adverse events we did see that most of the common adverse events that we observed.
Quite similar to what has been observed with pembrolizumab was mostly grade 1 and grade 2 events. And some of the grade 3 events that we saw were colitis, abdominal pain and diarrhea that happened in one patient. And then we had transaminitis as well as headache in in our, in 2 other patients. Otherwise, we did not see any grade 4 or grade 5 toxicities in the study.
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Except for ALK+ anaplastic large cell lymphoma, peripheral T cell lymphomas (PTCL) are a heterogeneous category of malignancies with a dismal prognosis (ALCL). Most institutions consider autologous stem cell transplantation (ASCT) in first remission to be standard of care to improve progression-free survival (PFS). Despite this, more than fifty percent of patients who undergo ASCT will relapse.
A phase II, multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab administered following ASCT for multiple subtypes of lymphoma. Arm C enrolled PTCL patients in their initial remission. The anticipated 18-month PFS rate with ASCT in chemosensitive T-NHL is between 40 and 50%. We expected that consolidation therapy with pembrolizumab would increase PFS at 18 months to 70%. With a sample size of 21, the treatment would be deemed encouraging if at least 13 patients remained alive and progression-free 18 months after ASCT.
From January 2017 to July 2020, twenty-one participants were registered. The median age was 58. PTCL NOS was the most common histology (52%). Angioimmunoblastic T-cell lymphoma (19%), extranodal NK/T-cell lymphoma, nasal type (14%), ALK- ALCL (10%), and monomorphic epitheliotropic intestinal T-cell lymphoma (5%). The median number of previous treatments was one. 90% of patients were in complete metabolic response prior to ASCT (CMR).
The toxicity evaluation (n = 21) comprised all patients who received at least one dosage of the study's therapy. During the course of the trial, at least 17 patients encountered toxicity, including grade 1 (n = 5/21; 24), grade 2 (n = 8/21; 38), and grade 3 (n = 3/21; 14). The most prevalent toxicities of any grade were nausea (n = 5/21; 24%), alkaline phosphatase elevation (n = 4/21; 19%), diarrhea (n = 4/21; 19%), abdominal pain (n = 3/21; 14%), hypothyroidism (n = 3/21; 14%), alanine aminotransferase (ALT) elevation (n = 2/21; 10%), anemia (n = 2/21; 10%), arth The most prevalent grade 3 adverse reactions were abdominal discomfort (n = 1/21), colitis (n = 1/21), diarrhea (n = 1/21), ALT elevation (n = 2/21), AST elevation (n = 1/21), and headache (n = 1/21).
Consolidation therapy with pembrolizumab after ASCT is feasible and led to a good PFS, satisfying the primary objective of the research. This is the first trial to suggest that PD-1 blocking may have a role in PTCL consolidation therapy. Due to the likelihood that sensitivity to this therapy varies between PTCL histologic or molecular subgroups, additional research may designate a subpopulation most likely to benefit from this strategy and warrant a larger confirmatory investigation.
I think this is very, obviously PTCLs are a very heterogeneous group of diseases, so sometimes hard with the sample sizes. And as I mentioned, our end was 21 in the study. But I think a next step after this would be looking. Which subtypes in particular benefit more from this strategy that we're using PD-1 blockade after transplant?
There's been data about, with NK/T-cell lymphomas that seems to be promising in the relapsed and refractory setting, so that's something that could be explored further, as well as also thinking about using PD-1 blockade. Could we use this before transplant? Could we to act as a priming agent? So that's something that also of interest and worth exploring as well.
Mwanasha Merrill, MD - About The Author, Credentials, and Affiliations
Mwanasha Hamuza Merrill, MD is a medical oncology clinical Fellow in Medicine at the Dana-Farber Cancer Institute. She holds a Doctor of internal medicine degree. focusing on Non-Lymphoma Hodgkin's while participating in clinical studies.
Merck Sharp & Dohme LLC is a global leader in health care seeking to improve global health. MSD is the name used for Merck outside of the United States and Canada. Through our prescription medications, vaccines, biological treatments (e.g. medical oncology), consumer care, and animal health products, we collaborate with customers in over 140 countries to provide innovative health solutions. Merck Sharp & Dohme LLC also demonstrate our dedication to expanding access to healthcare through comprehensive policies, programs, and collaborations.
Merck - Merck Announces Generic Name for MK-3475, Merck’s Investigational anti-PD-1 Antibody: Pembrolizumab. Merck, May 30, 2014
ASH Publications - A Phase 2 Study of Pembrolizumab (MK-3475) after Autologous Stem Cell Transplantation in Patients with T-Cell Non-Hodgkin Lymphoma. ASH Publications, NOVEMBER 15, 2022