Although standard therapies may provide long-lasting remissions for many patients with various subtypes of lymphoma, there is a critical need for new strategies for the sizable high-risk subset. At the 2022 Pan Pacific Lymphoma Conference, four experts in the field described future therapies for Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and peripheral T-cell lymphoma (PTCL). With cutting-edge immunotherapy and new combinations, upward of three-quarters of patients with relapsed or refractory disease are responding—suggesting that many investigative approaches may pan out.
Matt Lunning, DO, FACP
The presentations are briefly summarized here, followed by comments by session moderator Matt Lunning, DO, FACP, Associate Professor of Medicine at the University of Nebraska School of Medicine, which sponsored the conference. In an interview with The ASCO Post, Dr. Lunning provided his perspective on the most promising approaches.
Future Therapies for Hodgkin Lymphoma
Although the treatment of Hodgkin lymphoma “has been a real success story,” new developments are poised to further improve outcomes, according to Stephen M. Ansell, MD, PhD, the Dorotha W. and Grant L. Sundquist Professor in Hematologic Malignancies Research and Chair of Hematology at the Mayo Clinic, Rochester. Dr. Ansell described early-phase studies in several avenues of interest, including the targeting of T cells, natural killer (NK) cells, and macrophages and the development of combinations using older drugs that may modulate immune function.
• Targeting T Cells: T cells can be blocked, activated, redirected, or depleted—the aim being to protect them from being suppressed and to harness them to optimize the immune response. A variety of novel agents, when combined with PD-1 inhibitors, have yielded responses in about 75% of patients, with complete responses in a sizable percentage. However, as Dr. Ansell pointed out, it is difficult to tease apart the contributions of the novel agent vs those targeting PD-1.
Such high response rates, especially in PD-1–naive patients, have been reported with ipilimumab plus nivolumab1; the anti–LGA-3 agent favezelimab, plus pembrolizumab2; the histone deacetylate (HDAC) inhibitor vorinostat plus pembrolizumab3; and the JAK/STAT inhibitor ruxolitinib plus nivolumab.4 Although patients with anti–PD-1–refractory disease are less likely to respond to such combinations, he said there are enough responses to predict these approaches could be effective in patients who have failed to respond to PD-1 blockade.
Another promising avenue is the use of chimeric antigen receptor (CAR) T cells to improve antigen (CD30) recognition on the Reed-Sternberg cells, though CAR T-cell therapy is complicated in Hodgkin lymphoma, Dr. Ansell pointed out. Regardless of the barriers, when given after lymphodepleting chemotherapy, CAR T-cell therapy has yielded responses, many of them durable, in more than 70% of patients.5
Depletion of the immune-suppressing T-regulatory cells in the tumor is also an area of ongoing research. This is the mechanism by which the CD25-targeting antibody-drug conjugate camidanlumab tesirine may produce responses, some durable, in 71% of patients.6
• Natural Killer Cells, Macrophages: Targeting of NK cells is another approach under study. To this end, the anti-CD30/CD16A bispecific antibody AFM13, when paired with pembrolizumab, yielded responses in 80% of mostly PD-1–naive patients.7 Beyond this, an “off-the-shelf” version of this therapy, AFM13-complexed umbilical cord blood–derived NK cells, recently resulted in an 89.5% response rate in 19 patients.8 “The idea is that natural killer cells can be delivered with the AFM13 already attached to them, ready to seek out the Reed-Sternberg cells,” Dr. Ansell explained.
The idea is that natural killer cells can be delivered with the AFM13 already attached to them, ready to seek out the Reed-Sternberg cells.— Stephen M. Ansell, MD, PhD
Tweet this quote
A second way to potentially utilize NK cells is by blocking inhibitory receptors, thus allowing the NK cells to remain activated. The KIR family consists of activating and inhibitory checkpoint receptors that prevent NK-cell activation upon binding with their ligands. Lirilumab, a pan–KIR2D-blocking antibody, when combined with nivolumab produced responses in 76% of patients and rendered 62% progression-free at 12 months.9
Dr. Ansell was less encouraged by the modest results achieved from targeting macrophages. The aim is to turn them into tumor-destroying cells by harnessing the CD47-SIRPalpha signaling pathway.
Finally, some promise has been shown in repurposing drugs that modulate immune function. For example, when everolimus was paired with the JAK inhibitor itacitinib, the result was a 79% response rate.10
Among these strategies, Dr. Ansell said those targeting T cells look particularly promising, immune checkpoint blockade continues to be effective, CAR T-cell therapy has barriers to overcome but “will be very useful in the future.” In addition, he mentioned, the antibody-drug conjugate camidanlumab tesirine may become useful once toxicities can be better managed, NK-cell therapies are “encouraging,” macrophage blockade appears “far less effective,” and older drugs may be combined to modulate immune function and yield greater efficacy.
Future Therapies for DLBCL
“For DLBCL, there are 264 studies actively recruiting on ClinicalTrials.gov, indicating the depth of research in this malignancy,” said Christopher D’Angelo, MD, Assistant Professor of Medicine at the University of Nebraska. He said a better understanding of genomic subclassifications of this malignancy would help “to tease out the patients who aren’t going to be cured with standard chemoimmunotherapy.”
Christopher D’Angelo, MD
• Evolution of Cellular Therapies: Shifting immune therapies to the front line (before the host immune system becomes exhausted) and developing combinations to “warm up” the tumor microenvironment are potential approaches for improving outcomes in newly diagnosed patients. The CAR T-cell therapy axicabtagene ciloleucel rendered 75% of such patients progression-free at 12 months in the ZUMA-12 trial, noted Dr. D’Angelo.11
Novel cellular therapies are also tackling cold tumors and “frost-bitten hosts,” he said. One such class of drugs are “trucks”: CAR T-cell constructs that, by secreting their own cytokines, can reprogram the CAR T cell to be more proinflammatory and to recruit NK cells and other immune effectors. Trucks are now in clinical trials.
Other immune-based strategies now in development include the following:
- Allogeneic CAR T cells that are “off-the-shelf” products, including the CD52-targeting alpha2 CAR T cell (though currently on hold by the U.S. Food and Drug Administration) and CB-010 (from the ANTLER-1 trial).
- CAR-transduced NK cell–based platforms that are also off-the-shelf and can be derived from cord blood.
- Bispecific antibodies, including epcoritamab; epcoritamab plus R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) has resulted in a 100% response rate, with complete metabolic responses in 77%.12
- “Headless” CAR T-cells plus bispecific antibodies; the stimulatory domain is linked to the bispecific antibody to target multiple antigens simultaneously.
- CAR T cells that can secrete bispecific T-cell engagers.
Revised dosing allows bispecific antibodies to prime the tumor microenvironment and to be combined with other drugs. With this strategy, response rates in heavily pretreated patients were 100% with epcoritamab plus rituximab, dexamethasone, cytarabine, and oxaliplatin13 and 65% with mosunetuzumab plus polatuzumab vedotin-piiq.14
Also on the horizon for DLBCL, and particularly useful in combination therapy, are Bruton’s tyrosine kinase (BTK) degraders, CD47 antibodies, and dual-affinity retargeting molecules (DARTs). MGD 2013 is a bispecific DART that binds PD-1 and LAG-3, and magrolimab is an anti-CD47 antibody that blocks the tumor’s “don’t-eat-me” signal.
The proteolysis targeting chimera (PROTAC) is a new kind of agent that has two “heads” and a linker; one head is the target (for DLBCL it is BTK), and the other is linked to cereblon E3 ubiquitin ligase for proteasome degradation. PROTACs have advantages over BTK inhibitors in terms of increased selectivity, inhibition of all target protein functions, and potentially longer lasting effects; lower doses are sufficient, and this could result in greater safety. Early results for NX-2127 showed the drug significantly decreased BTK levels in blood.15 Finally, targeting the microbiome may offer therapeutic potential, Dr. D’Angelo said.
Future Therapies for Follicular Lymphoma
Jonathan W. Friedberg, MD, the Samuel Durand Professor of Medicine and Director of the Wilmot Cancer Institute of the University of Rochester, New York, acknowledged that many patients with follicular lymphoma fare well with standard therapies, but the small subset with early disease progression could substantially benefit from novel strategies.
The PI3 kinase inhibitors have proved to be effective in this high-risk population, but largely because of toxicity concerns, only one, copanlisib, remains available. Idelalisib, duvelisib, and umbralisib were all withdrawn from the market in the past 2 years. Newer PI3 kinases, nevertheless, may have a future in follicular lymphoma, Dr. Friedberg predicted.
A potentially “more intelligent” intermittent dosing schedule was used in a study of zandelisib. Of 121 patients who experienced disease progression or were treatment-refractory, 70% responded, 35% had complete responses, and grade 3 adverse events were rare.16 Zandelisib is now being studied in combination with rituximab in the large phase III COASTAL trial.
It’s going to be hard to know where CAR T cells fit in for follicular lymphoma.... We have no information to guide the order in which we use treatments or whether combinations will make a difference.— Jonathan W. Friedberg, MD
Tweet this quote
For the 20% of patients with EZH2 mutations, EZH2 inhibitors are in development, including tazemetostat. Tazemetostat has produced responses in 69% of patients (with some responses in wild-type tumors) and encouraging progression-free and overall survival.17 With the CD3/CD20 bispecific antibody mosunetuzumab, response rates have reached 75%, with complete responses achieved by 54%, though toxicity may be an issue.18
CAR T-cell therapy also looks to be active in follicular lymphoma. For patients with early progressive disease, 95% have responded, and 79% have been complete responses, though durability has not yet been established.19 “It’s going to be hard to know where CAR T cells fit in for follicular lymphoma…. We have no information to guide the order in which we use treatments or whether combinations will make a difference,” Dr. Friedberg commented.
Future Therapies for PTCL
Although allogeneic transplantation may be curative for many patients with PTCL, the prognosis for treatment-refractory patients is generally poor with standard chemotherapy. Novel regimens that may improve outcomes—many of them incorporating the HDAC inhibitor romidepsin, which is already approved in PTCL—were described by Neha Mehta-Shah, MD, Associate Professor of Medicine at Washington University School of Medicine, St. Louis.
The combination of romidepsin and azacitidine was shown to produce responses in 73% of patients, with 55% complete remissions. About half the patients were able to undergo allogeneic transplantation, and the drug was active in patients with TET2 mutations.20 Romidepsin in combination with lenalidomide led to responses in 53% of patients and in 100% of patients with angioimmunoblastic T-cell lymphoma (AITL).21 Paired with other active agents, therefore, romidepsin may be more effective than as monotherapy, and such combinations are now being studied upfront.
PI3 kinase inhibitors are another avenue in PTCL. Duvelisib produced responses in 50% of patients with PTCL22 and in xenograft models altered the macrophage phenotype to an immunosuppressive one. The registration study for duvelisib is the PRIMO trial, where single-agent duvelisib produced responses in 48.5% and complete responses in 34%, though progression-free survival was modest.23 When duvelisib was combined with romidepsin at the maximum tolerated dose, the response rate was 56%, with complete responses in 44%.24 Tenalisib and linperlisib are other PI3 kinase inhibitors in clinical trials.
EZH2 inhibition with oral valemetostat has shown activity, based on the phase I/II study in which responses were reported in 54.5% of patients with PTCL and 65% of patients with AITL, with complete responses in 27.3% and 47%, respectively.25 These data led to the international VALENTINE study, which recently completed accrual.
CAR T-cell therapies targeting CD5, CD30, and CD7 are in development, with still much to be learned [in PTCL].— Neha Mehta-Shah, MD
Tweet this quote
Another strategy builds upon the findings that the expression of SYK/ITK fusion protein generates lymphoproliferative disease in mice and that JAK inhibition might disrupt the tumor microenvironment in a “fruitful” way,” said Dr. Mehta-Shah. To this end, activity has been shown by the JAK/SYK inhibitor cerdulatinib26 and the JAK inhibitor ruxolitinib27; ruxolitinib was active not only in patients with activating mutations but in those with functional evidence of JAK/STAT activation, she noted.
Primarily in the extranodal NK/T-cell lymphoma subset, in whom refractory disease is difficult to treat, checkpoint inhibition has shown activity. Finally, Dr. Mehta-Shah added, CAR T-cell therapies targeting CD5, CD30, and CD7 are in development, with “still much to be learned.”
Perspective From Dr. Lunning: Which Drugs and When?
Dr. Lunning summarized key take-aways from the four presentations, highlighting the approaches he predicts to be the most impactful or the soonest to arrive in the clinic.
In Hodgkin lymphoma, he said the ability to essentially recycle older drugs, such as vorinostat, or add novel agents “to make good drugs—especially checkpoint inhibitors—work better,” is exciting. This also poses a dilemma: With most patients now cured with brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine, as shown in ECHELON-1,28 the exact setting for checkpoint inhibitors in this subtype has become unclear.
However, regardless of the better first-line choice, patients will relapse and will need effective salvage therapy. In this setting, the antibody-drug conjugate camidanlumab tesirine looks interesting, but Guillain-Barré syndrome has been a concern, and this must be addressed, he explained.
For DLBCL, Dr. Lunning said the ZUMA-12 data on axicabtagene ciloleucel are important to highlight,11 but the next new kid on the block is the emerging class of cellular therapies known as “trucks.” As previously mentioned, trucks are CAR T-cell constructs that secrete their own cytokines to produce a more inflammatory state. Also intriguing are “headless” CAR T cells with stimulatory domains linked to a bispecific antibody that can target multiple antigens.
“The class that I think will be the most impactful in the near future, however, are the bispecific antibodies, such as epcoritamab,” Dr. Lunning said. “For patients with relapsed or refractory disease, they are the furthest along in development, and they may compete with CAR T-cell therapy.”
With the availability of these new effective agents comes the question of sequencing: “When to use what agent and knowing when two drugs are complementary and when they are antagonistic—in this relapsed/refractory space where there is not a lot of head-to-head data—are considerations,” he said.
When to use what agent and knowing when two drugs are complementary and when they are antagonistic ... are considerations.— Matt Lunning, DO, FACP
Tweet this quote
For follicular lymphoma, the need for novel therapies has been less pressing because most patients respond well to standard therapy. Drug development is still active in this disease, albeit leading to fewer drugs being added to the armamentarium.
The withdrawal of the PI3 kinase inhibitors from the follicular lymphoma space was unfortunate, according to Dr. Lunning, but the newer agent zandelisib looks active, largely because its intermittent dosing strategy should reduce toxicity. Regardless of the results of the COASTAL trial, he added, zandelisib may face skepticism and excessive scrutiny based on its predecessors’ controversial history.
Bispecific antibodies such as mosunetuzumab will find a place in follicular lymphoma as well, Dr. Lunning predicted, “especially if we can find a way to use them safely and effectively in the community, where the majority of lymphoma is still treated.”
PTCL has become more challenging with the withdrawal from the market of romidepsin—although this HDAC inhibitor continues to be studied in combination with a variety of agents, such as azacitidine and PI3 kinase inhibitors (eg, duvelisib, which was withdrawn in follicular lymphoma, and tenalisib). Also, the EZH2 inhibitor valemetostat is emerging as a potential partner for other drugs as salvage therapy, as its response rate is high in both PTCL and AITL and its safety profile is acceptable. Such combinations, if proven effective, will probably be used as bridges to transplantation, he said.
DISCLOSURE: Dr. Lunning reported relationships with AbbVie, Acrotech, ADC Therapeutics, Astellas, AstraZeneca, BMS, Daiichi Sankyo, EUSA, Fate Therapeutics, Genentech, Genmab, InstilBio, Kite, MorphoSys, Novartis, Nurix Therapeutics, Sana Therapeutics, and TG Therapeutics. Dr. Ansell has received research/grant funding from numerous companies but reported no personal disclosures. Dr. D’Angelo has served as a consultant to TG Therapeutics. Dr. Friedberg reported no conflicts of interest. Dr. Mehta-Shah has served as a consultant to Genenetech, Kyowa Hakka Kirin, Karyopharm Therapeutics, C4 Therapeutics, Daiichi Sankyo, and Secura Bio.
REFERENCES
1. Ansell S, Gutierrez ME, Shipp MA, et al: A phase 1 study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). 2016 ASH Annual Meeting & Exposition. Abstract 624.
2. Johnson NA, Lavie D, Borchmann P, et al: Favezelimab (anti–LAG-3) plus pembrolizumab in patients with anti–PD-1–naive relapsed or refractory classical Hodgkin lymphoma: An open-label phase 1/2 study. 2022 ASCO Annual Meeting. Abstract 7516.
3. Herrera AF, Chen L, Budde LE, et al: Pembrolizumab plus vorinostat induces responses in patients with Hodgkin lymphoma who are refractory to prior PD-1 blockade. 2021 ASH Annual Meeting & Exposition. Abstract 234.
4. Bachanova V, Hegerova L, Cao Q, et al: Ruxolitinib plus nivolumab in patients with relapsed/refractory Hodgkin lymphoma after failure of check-point inhibitors: Preliminary report on safety and efficacy. 2019 ASH Annual Meeting & Exposition. Abstract 134.
5. Ramos CA, Grover NS, Beaven AW, et al: Anti-CD30 CAR-T cell therapy in relapsed and refractory Hodgkin lymphoma. J Clin Oncol 38:3794-3804, 2020.
6. Goldberg AD, Atallah E, Rizzieri D, et al: Camidanlumab tesirine, an antibody-drug conjugate, in relapsed/refractory CD25-positive acute myeloid leukemia or acute lymphoblastic leukemia: A phase I study. Leuk Res 95:106385, 2020.
7. Bartlett NL, Herrera AF, Domingo-Domenech E, et al: A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 136:2401-2409, 2020.
8. Nieto Y, Banerjee P, Kaur I, et al: Innate cell engager (ICR®) AFM13 combined with preactivated and expanded cord blood-derived NK cells for patients with refractory/relapsed CD30+ lymphoma. 2022 AACR Annual Meeting. Abstract CT003.
9. Armand P, Lesokhin A, Borrello I, et al: A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies. Leukemia 35:777-786, 2021.
10. Svoboda J, Barta SK, Landsburg DJ, et al: Everolimus plus itacitinib in relapsed/refractory classical Hodgkin lymphoma: Results of a phase I/II investigator initiated trial (EVITA Study). 2020 ASH Annual Meeting & Exposition. Abstract 473.
11. Neelapu SS, Dickinson M, Munoz J, et al: Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: The phase 2 ZUMA-12 trial. Nat Med 28:735-742, 2022.
12. Clausen MR, Offner F, Belada D, et al: Subcutaneous epcoritamab + R-CHOP for first-line treatment of patients with high-risk diffuse large B-cell lymphoma: Phase 1/2 update. 2022 European Hematology Association Congress. Abstract P1214.
13. Abrisqueta P, Falchi L, Phillips TJ, et al: Subcutaneous epcoritamab + R-DHAX/C in patients with relapsed or refractory diffuse large B-cell lymphoma eligible for autologous stem cell transplant: Preliminary phase 1/2 results. 2022 ASCO Annual Meeting. Abstract 7528.
14. Budde LE, Olszewski A, Assouline S, et al: Mosunetuzumab plus polatuzumab vedotin has promising efficacy and a favorable safety profile in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: Updated results from a phase Ib/II study. 2021 ASH Annual Meeting & Exposition. Abstract 533.
15. Mato A, Danilov AV, Patel MR, et al: A first-in-human phase 1 trial of NX-2127, a first-in-class oral BTK degrader with IMiD-like activity, in patients with relapsed and refractory B-cell malignancies. 2022 ASCO Annual Meeting. Abstract TPS7581.
16. Zelenetz AD, Jurczak W, Ribrag V, et al: Efficacy and safety of zandelisib administered by intermittent dosing in patients with relapsed or refractory follicular lymphoma: Primary analysis of the global phase 2 study TIDAL. 2022 ASCO Annual Meeting. Abstract 7511.
17. Morschhauser F, Tilly H, Chaidos A, et al: Tazemetostat for patients with relapsed or refractory follicular lymphoma: An open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol 21:1433-1442, 2020.
18. Budde LE, Assouline S, Sehn LH, et al: Single-agent mosunetuzumab shows durable complete responses in patients with relapsed or refractory B-cell lymphomas: Phase I dose-escalation study. J Clin Oncol 40:481-491, 2022.
19. Jacobson CA, Chavez JC, Sehgal AR, et al: Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): A single-arm, multicentre, phase 2 trial. Lancet Oncol 23:91-103, 2022.
20. O’Connor OA, Falchi L, Lue JK, et al: Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: A multicenter phase 1 study. Blood 134:1395-1405, 2019.
21. Mehta-Shah N, Lunning MA, Moskowitz AJ, et al: Romidepsin and lenalidomide-based regimens have efficacy in relapsed/refractory lymphoma: Combined analysis of two phase I studies with expansion cohorts. Am J Hematol 96:1211-1222, 2021.
22. Horwitz SM, Koch R, Porcu P, et al: Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood 131:888-898, 2018.
23. Zinzani PL, Zain J, Mead M, et al: Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma from the phase 2 PRIMO trial: Updated expansion phase analysis. 2022 European Hematology Association. Abstract P1172.
24. Horwitz SM, Moskowitz AJ, Mehta-Shah N, et al: The combination of duvelisib and romidepsin is highly active against relapsed/refractory peripheral T-cell lymphoma with low rates of transaminitis: Final results. Blood 138(suppl 1):619, 2021.
25. Morishima S, Ishitsuka K, Izutsu K, et al: First-in-human study of the EZH1/2 dual inhibitor valemetostat in relapsed or refractory non-Hodgkin lymphoma—Updated results focusing on adult T-cell leukemia-lymphoma. 2019 ASH Annual Meeting & Exposition. Abstract 4025.
26. Horwitz SM, Feldman TA, Hess BT, et al: The novel SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and clinical response in a phase 2a study in relapsed/refractory peripheral T-cell lymphoma and cutaneous T-cell lymphoma. 2018 ASH Annual Meeting & Exposition. Abstract 1001.
27. Moskowitz AJ, Ghione P, Jacobsen E, et al: A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas. Blood 138:2828-2837, 2021.
28. Ansell SM, Radford J, Connors JM, et al: Overall survival with brentuximab vedotin in stage III or IV Hodgkin’s lymphoma. N Engl J Med 387:310-320, 2022.
