Although considerable progress has been made in treating diffuse large B-cell lymphoma since the advent of chemoimmunotherapy, approximately 33% of patients still develop relapsed/refractory disease, which is associated with considerable morbidity and mortality.
Grzegorz S. Nowakowski, MD
Although considerable progress has been made in treating diffuse large B-cell lymphoma (DLBCL) since the advent of chemoimmunotherapy, approximately 33% of patients still develop relapsed/refractory (R/R) disease, which is associated with considerable morbidity and mortality.1 Several treatment options exist for this patient population including high-dose therapy and transplant, as well as chimeric antigen receptor (CAR) T-cell therapy. However, as patients progress through treatments, options in subsequent lines of therapy dwindle, particularly if they are ineligible for transplant. This dilemma has led to the search for novel therapeutic approaches for patients whose disease fails to respond to currently available therapies.
During a recent OncLive Peer Exchange®, a panel of hematologic cancer experts discussed several emerging treatment approaches, including new chemotherapy combinations, combination immunotherapy after autologous stem cell transplantation (ASCT), and the use of monoclonal antibodies and bispecific antibodies in those who may not be candidates for CAR T-cell therapy. The panelists also discussed the importance of enrolling patients in clinical trials, making clear this is an extremely rapidly changing field. “I think in the next several years, we’ll see some major changes,” panelist Grzegorz S. Nowakowski, MD, said.
Chemotherapy and Immunotherapy
One approach that can be considered for patients with R/R DLBCL is bendamustine—rituximab (BR) in combination with the novel antibody-drug conjugate polatuzumab vedotin-piiq (Polivy). The regimen was granted accelerated approval by the FDA on June 10, 2019, making it the first chemoimmunotherapy approved for these patients.2
Approval was based on the results of Study GO29365 (NCT02257567), which included 80 patients with R/R DLBCL who were randomly assigned to BR plus polatuzumab vedotin or BR alone. The study showed a complete response (CR) rate of 40% with BR plus polatuzumab vedotin versus 18% with BR alone. Of the 25 patients who achieved a CR or partial response (PR) in the BR plus polatuzumab vedotin arm, 16 (64%) had a duration of response (DOR) of ≥6 months and 12 (48%) had a DOR of ≥12 months. BR plus polatuzumab vedotin is currently indicated for adult patients with DLBCL that has progressed or returned after ≥2 prior therapies.2
Peter Martin, MD, said another novel combination showing promise is ibrutinib (Imbruvica)—lenalidomide (Revlimid)–rituximab (Rituxan) (iR2 regimen). This triplet is being evaluated in the ongoing, multicenter, open-label, phase II PCYC-1123 study (NCT02077166), which is evaluating 89 patients with R/R nongerminal center B-cell—like (non-GCB) DLBCL who are ineligible for stem cell transplantation. Participants receive oral lenalidomide 20 mg (n = 55) or 25 mg (n = 34) on days 1 to 21 of each 28-day cycle plus ibrutinib 560 mg orally once daily and rituximab 375 mg/m2 intravenously on day 1 of cycle 1 to 6.3 The median time to response was 2.7 months. Of the 85 response-evaluable patients with follow-up response assessment, the overall response rate (ORR) was 47%, including 28% CRs and 19% PRs. “This regimen clearly has activity,” Martin said, noting that he has occasionally used it off-label.
When trying to offer patients palliation of symptoms, Martin said he sometimes uses single-agent chemotherapy, such as gemcitabine or bendamustine. “Anecdotally, I think that we’ve also tried a variety of things, including HDAC [histone deacetylase] inhibitors, demethylating agents. Periodically, people get responses to some of these things, and although it’s hard to say that that’s the right thing to do all the time, we will always have examples of somebody who does well,” he said. “Some of these patients with large cell lymphoma seem to have a lymphoma that does not explode but rather trickles. Those are opportunities to try creative things. My bias is always to do that in the context of a clinical trial, but it’s not always feasible,” he added.
Novel approaches to maintain disease control in ASCT candidates with more aggressive disease is another area of need. Use of immunotherapy following ASCT is being explored, as patients with high-risk disease often progress within the first 18 months after ASCT, and maintenance strategies have thus far failed to demonstrate benefit.4 The ongoing CPIT-001 trial is assessing the safety and efficacy of combined checkpoint inhibition with ipilimumab (Yervoy) and nivolumab (Opdivo) as consolidation following ASCT for patients with high-risk hematological malignancies, including primary refractory DLBCL or relapse <12 months after completion of induction.4
It’s a small number of patients—15 primary refractory patients or early relapse. The patients with EFS [event-free survival] at 18 months is 83%,” moderator Andre Goy, MD, said. He noted that a challenge with immunotherapy is the toxicity. Among the entire study population, which also included patients with multiple myeloma and peripheral T-cell lymphoma, 65% of patients developed immune-related adverse effects (irAEs) grade ≥2, requiring treatment with systemic steroids. The most common irAEs included colitis, rash, thrombocytopenia, anemia, and transaminitis. There was 1 death from treatment- related pneumonitis.4 Although steroid use is thought to compromise the efficacy of immunotherapy, neither its use nor the length of its use affected progression-free survival or overall survival (OS).
Tafasitamab and the L-MIND Study
An exciting study that the panelists discussed is the ongoing, open-label, singlearm, phase II L-MIND trial (NCT02399085), which is assessing tafasitamab (MOR208) plus lenalidomide in patients with R/R DLBCL treated with ≤3 prior lines of therapy, including at least 1 anti-CD20 therapy, who were ineligible for stem cell transplantation.5 Tafasitamab is an Fc-enhanced, humanized, anti-CD19 monoclonal antibody that has previously shown single-agent activity in this patient population.6
“Interestingly, there were a few complete responses—complete remissions in diffuse large B-cell lymphoma—which you don’t typically see with antibody therapy alone,” panelist Kami J. Maddocks, MD, said. These promising data led to the L-MIND study, which assessed the efficacy of tafasitamab and lenalidomide combination therapy for 1 year, with patients allowed to continue tafasitamab alone thereafter if they achieved stable disease or better.5 The study’s primary end point was independent review committee-assessed ORR as per Cheson 2007 criteria.5,7 “The ORR in these 80 patients was 60%, with a 42% complete remission rate. The median duration of response was 22 months,” Maddocks said.
Overall, the tafasitamab and lenalidomide combination was well tolerated. “The toxicity was primarily what you see with lenalidomide alone,” Maddocks said. The most commonly reported adverse effects (AEs) were infusion reactions, and serious treatment-related AEs were usually infections and neutropenic fever.5 “About 50% of patients had dose reductions in the lenalidomide, but 70% of them were maintained at a dose of 20 mg or higher,” she said, noting that once the lenalidomide was stopped after 12 months, the toxicity significantly decreased.
Subgroup analyses of the L-MIND trial showed a trend for better outcomes among patients with 1 prior line of therapy versus those with ≥2 prior lines, with an ORR of 70% versus 50%, respectively, and a 12-month OS rate of 86.9% and 60.1%, respectively.7 However, the number of prior lines of therapy did not affect DOR. As was also expected, patients with a low or low- intermediate International Prognostic Index score had better outcomes than those with an intermediate-high or high score, with an ORR of 70.0% versus 50.0%, respectively; a 12-month DOR rate of 86.5% versus 50.4%, respectively; and a 12-month OS rate of 87.0% versus 59.9%, respectively.7 “This was done in a transplant-ineligible population and in a non-GC [nongerminal center subtype] compared to the GC subtype, but the GC subtype still had a 50% overall response rate,” Maddocks said.
There has been some concern that tafasitamab may interfere with the effectiveness of subsequent use of CD19-targeted CAR T-cell therapy due to competition for CD19 binding. “We don’t have great data [on this],” Maddocks said, but noted that an abstract presented at the 2019 American Society of Hematology Annual Meeting (2019 ASH) outlining in vitro assessments suggests CAR T-cell therapy is still effective in cells that have been treated with tafasitamab.8 “There are also a few patients who were treated on trial who went on to get CAR T and have done well on that therapy. But, certainly, using it either before or even after the CAR T is something that we’ll have to have more patients treated with to understand the effects,” she said.
The panelists discussed when they may consider using tafasitamab in clinical practice versus CAR T-cell therapy. “There are some patients who I would not be too comfortable giving CAR T [-cell] therapy, especially patients with some type of organ dysfunction. That would be a very nice population that you would still want to consider something like this for,” panelist Nathan H. Fowler, MD, said. Maddocks also pointed out that there are parts of the United States where it would be challenging for patients to receive CAR T-cell therapy, such as those who live in rural settings and cannot easily travel, and that a tafasitamab regimen could be considered for such patients as well.
One class of agent with numerous promising drugs in various stages of clinical development are bispecific antibodies, which combine ≥2 antigen-recognizing elements into a single construct that can bind to ≥2 targets.9 Because of this mechanism, “[bispecific antigens] potentially could do similar things that we see with CAR T cells,” panelist Nathan H. Fowler, MD, said, noting that he is particularly excited by T-cell redirecting bispecific antibodies. “They’re using your own CAR T cells, drawing them to the tumor, and hopefully inducing this T-cell response,” he said.
A bispecific antibody that has received a great deal of attention recently is REGN1979, which targets both CD20 and CD3. At 2019 ASH, a very high response rate was reported in patients with relapsed or refractory DLBCL who received ≥80 mg of REGN1979.10 The ORR was 57.9% and the CR rate was 42.1%. When examining response based on prior CAR T-cell exposure, patients who did not receive prior CAR T-cell therapy had an ORR of 71.4%, all of which were CRs. In contrast, patients who received prior CAR T-cell therapy had an ORR of 50.0%; 25% had CRs and 25% had PRs.
The lower response rates in heavily pretreated patients, particularly in those who have received previous CAR T-cell therapy, are not surprising because bispecific antibodies rely on patients’ T cells, which are more likely to be compromised in this patient population than in those who have received few or no prior treatments.11 Nevertheless, it is promising that some CRs were still observed in the more heavily pretreated patients.
Another exciting bispecific antibody is mosunetuzumab, which has also yielded some CRs in patients with heavily pretreated relapsed or refractory DLBCL, including disease progression after CAR T-cell therapy.12 Mosunetuzumab targets CD3 on the surface of T cells and CD20 on the surface of B cells. Among 16 patients who were efficacy evaluable and had prior CAR T-cell therapy (7 DLBCL, 5 transformed follicular lymphoma [FL], 4 FL), the ORR and CR rates were 43.8% (n = 7) and 25% (n = 4; 2 DLBCL and 2 FL), respectively.12
Importance of Clinical Trials
Throughout the Peer Exchange, the panelists emphasized the importance of enrolling patients into clinical trials. “There are over 2000 new drugs in the pipeline of lymphoma, so we have a lot of work in front of us. Please enroll and refer patients for clinical trials,” Goy said. “This is the way we move the needle,” he added.
Martin emphasized that patients who participate in clinical trials often have superior outcomes. “I think that we have to make more of an effort as a research community to bring clinical trials to populations that historically have not had access to them. I think that all of us have looked recently at a funding opportunity from the Leukemia & Lymphoma Society, which rightfully perceives this as a weakness,” he said.
Fowler identified some problems regarding how clinical research is being performed. “We are incredibly inefficient in the way we conduct clinical research across the world. Right now, there’s a major gap in the biological understanding of these diseases and what we do in clinical practice…I think some of that has to do with the lack of mechanistic and correlative studies that occur in our clinical trials,” he said.
The panelists acknowledged, however, that it is currently difficult to enroll some patients into trials, such as individuals who relapse after CAR T-cell therapy. “The problem is [these patients] usually have other issues like thrombocytopenia, and they are not eligible for trials,” panelist Julio Chavez, MD, MS, said. Nowakowski concurred. “I think you nailed it because this is a very difficult population to deal with. But we are living in a post—CAR T-cell world—they are here, and they’re probably going to be around for some time—so we need to learn how to deal with those patients who are relapsing post–CAR T-cell [therapy]. Since we are developing our future clinical trials, we must be open-minded when defining the inclusion criteria,” he concluded.