American Society of Hematology Review on Frontline Large B Cell Lymphoma Trials 2021 PDF

American Society of Hematology 2021 L Street NW, Suite 900, Washington, DC 20036 Phone: 202-776-0544 | Fax 202-776-0545 [email protected] The curre...

American Society of Hematology 2021 L Street NW, Suite 900, Washington, DC 20036 Phone: 202-776-0544 | Fax 202-776-0545 [email protected] The current landscape of frontline large B cell lymphoma trials Tracking no: BLD-2023-023789-CR1 David Qualls (Dana-Farber Cancer Institute, United States) Philippe Armand (Dana-Farber Cancer Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 Institute, United States) Gilles Salles (Memorial Sloan Kettering Cancer Center, United States) Abstract: At least 25-35% of patients with large B cell lymphoma (LBCL) are not cured with frontline treatment, with generally poor subsequent outcomes. This motivates ongoing and intense interest in improving the frontline treatment of this disease. R-CHOP has remained the standard of care for 20 years despite dozens of trials aiming to improve upon this regimen, and only recently has a novel regimen (Pola-R-CHP) challenged its supremacy. Fortunately, at least 15 promising randomized trials evaluating new treatments in frontline LBCL treatment are underway. They differ not only in the therapy evaluated in the experimental arm, but in the choice of control arm, primary endpoint, and patient selection strategy, with some targeting specific biologic subtypes, some focusing on specific high-risk patient populations, and others enrolling older or frail patients. Novel response-adapted strategies leveraging circulating tumor DNA are also underway. While this variety of approaches provides a welcome increase in the overall likelihood of success, it will also present challenges if several of these trials are successful and we must choose among multiple potential treatment options that were not all tested in the same fashion. In this review, we summarize the main ongoing frontline randomized trials and discuss some of the questions that we will face in interpreting and applying their results in clinical practice in the next few years. Conflict of interest: COI declared - see note COI notes: D.Q. has received financial compensation for advisory board participation from Genmab. P.A. reports consultancy for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, AstraZeneca, Genentech/Roche, Xencor, Foresight, and ATB Therapeutics; received research funding from Kite; received research funding (institutional) from Merck, Bristol Myers Squibb, Affimed, Adaptive, Tensha, Otsuka, Sigma Tau, Genentech/Roche, IGM Biosciences, AstraZeneca; and reports honoraria from Merck and Bristol Myers Squibb. G.S. has received financial compensation for advisory boards or consulting roles from Abbvie, Atbtherapeutics, Beigene, BMS, Genentech/Roche, Genmab, Innate Pharma, Incyte, Ipsen, Janssen, Kite/Gilead, Merck, Modex, Molecular Partners, Nurix, Orna Therapeutics, Treeline. He is also a shareholder of Owkin. He received research support from Abbvie, Genentech, Genmab Janssen, Ipsen, and Nurix, which was managed by his institution. Preprint server: No; Author contributions and disclosures: D.Q, P.A. and G.S. designed and performed the research, and all wrote and approved the manucript Non-author contributions and disclosures: No; Agreement to Share Publication-Related Data and Data Sharing Statement: Clinical trial registration information (if any):  1 The current landscape of frontline large B cell lymphoma trials 2 3 David Qualls1, Philippe Armand1, and Gilles Salles2 4 5 Short title: first line LBCL trials 6 7 1. Dana-Farber Cancer Institute, Boston, MA, USA 8 2. Memorial Sloan Kettering Cancer Center, New York, NY, USA 9 Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 10 Word count: 11 Text: 4378 (max 4000) 12 Abstract: 218 (max 250) 13 Refs: 95 (max 100) 14 Tables: 5 15 Figures: 2 16 17 18 19 20 1  1 Abstract 2 At least 25-35% of patients with large B cell lymphoma (LBCL) are not cured with frontline 3 treatment, with generally poor subsequent outcomes. This motivates ongoing and intense 4 interest in improving the frontline treatment of this disease. R-CHOP has remained the 5 standard of care for 20 years despite dozens of trials aiming to improve upon this regimen, and Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 6 only recently has a novel regimen (Pola-R-CHP) challenged its supremacy. Fortunately, at least 7 15 promising randomized trials evaluating new treatments in frontline LBCL treatment are 8 underway. They differ not only in the therapy evaluated in the experimental arm, but in the 9 choice of control arm, primary endpoint, and patient selection strategy, with some targeting 10 specific biologic subtypes, some focusing on specific high-risk patient populations, and others 11 enrolling older or frail patients. Novel response-adapted strategies leveraging circulating tumor 12 DNA are also underway. While this variety of approaches provides a welcome increase in the 13 overall likelihood of success, it will also present challenges if several of these trials are 14 successful and we must choose among multiple potential treatment options that were not all 15 tested in the same fashion. In this review, we summarize the main ongoing frontline 16 randomized trials and discuss some of the questions that we will face in interpreting and 17 applying their results in clinical practice in the next few years. 18 2  1 Introduction 2 R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) has been the 3 standard of care in large B cell lymphoma (LBCL) for nearly two decades, despite multiple 4 attempts to improve on this regimen.1 Recently, the POLARIX trial demonstrated a progression- 5 free survival (PFS) benefit for Pola-R-CHP (with polatuzumab vedotin replacing vincristine) over R-CHOP, heralding a possible change in standard of care.2 Currently, at least 15 randomized Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 6 7 clinical trials, which will ultimately enroll over 9,000 patients, are underway (Tables 1-3). How 8 are these trials different from their predecessors? And how will we manage LBCL if, as may be 9 hoped, several of these trials are positive? In this review, we discuss key ongoing frontline 10 randomized trials in LBCL. We do not aim to predict their outcomes, but rather to consider how 11 their designs will impact the interpretation and implementation of their results. 12 13 14 A Brief Recent History of Frontline LBCL Therapy 15 In the early 2000s, the addition of rituximab to CHOP chemotherapy revolutionized the 16 treatment of LBCL.3,4 Since then, dozens of clinical trials, enrolling over 10,000 patients, have 17 aimed to improve upon R-CHOP.1,5 Attempts to intensify R-CHOP overall did not improve 18 survival and added toxicity.6–9 The combination of rituximab with doxorubicin, 19 cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) is an exception as it 20 improved PFS and overall survival (OS) compared to R-CHOP in young patients with age- 21 adjusted International Prognostic Index (IPI) score of 1.10 However, given the complexity of 22 administration, toxicity,11 and unavailability of vindesine in some countries, its adoption outside 23 of Europe has been limited. Maintenance therapies after R-CHOP using everolimus,12 24 enzastaurin,13 and rituximab14 did not improve PFS. Lenalidomide maintenance improved PFS in 25 patients aged 60-80, but a lack of OS benefit and lenalidomide-associated toxicities limited its 26 adoption.15 27 28 The addition or substitution of novel agents to the R-CHOP regimen, commonly referred to as 29 “R-CHOP + X,” has been evaluated in many studies.16–19 Results to date have been mostly 3  1 disappointing, but subset analyses in some have provided interesting avenues for further 2 research. In the PHOENIX trial, while ibrutinib (a Bruton Tyrosine Kinase inhibitor, or BTKi) did 3 not improve event-free survival (EFS) for the overall population, a significant EFS and OS benefit 4 was suggested in patients younger than 60.17 Further analysis using molecular profiling found 5 that young patients with specific molecular subsets (specifically the LymphGen-defined MCD 6 and N1 subsets, representing less than 20% of patients with non-germinal center B-cell Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 phenotype enrolled in that study) might benefit from the addition of ibrutinib.20 Likewise, 8 further analysis by gene expression profiling (GEP) in the ReMoDL-B trial revealed that 9 bortezomib addition to R-CHOP yielded a significant benefit in activated B-cell (ABC) and 10 molecular high-grade lymphomas.21 These subset analyses have been useful in planning 11 subsequent studies, but have not yet changed standard practice. 12 13 Unique among such studies, the POLARIX trial evaluating Pola-R-CHP (polatuzumab vedotin, 14 rituximab, cyclophosphamide, doxorubicin, and prednisone) reached its primary endpoint and 15 changed the treatment approach for many patients (Table 4).2 In so doing, this trial also raised 16 important questions that are relevant to the design and interpretation of ongoing and future 17 trials. First, Pola-R-CHP improved PFS compared to R-CHOP but not OS.22 Second, a post hoc 18 subset analysis of POLARIX using GEP suggested a significant benefit within the ABC subtype of 19 DLBCL, but no discernible benefit for Germinal Center B-cell (GCB)-type DLBCL.5,23. Together 20 with the subset analysis from PHOENIX and ReMoDL-B mentioned above, this strongly supports 21 the possibility that more individualized therapies, rather than a one-size-fits-all approach, may 22 ultimately succeed in improving survival for patients with LBCL. 23 24 25 LBCL Biology: Is Personalized Treatment the Key to Success? 26 LBCL is a heterogeneous disease which can be categorized using biologic characteristics, 27 including histologic subtype, gene expression profile, genomic alterations, or tumor 28 microenvironment.24–27 Different classifications have been proposed which intersect but are not 29 identical, highlighting both the significant biological variability in this disease and the difficulty 4  1 of defining reproducible subsets for clinical trial inclusion.28 Some trials, such as GUIDANCE-02 2 and ESCALADE (see below), are already using genomic criteria for patient or treatment 3 selection (Table 2). This raises many challenges in both interpretation and implementation. 4 5 Challenges in defining biologic subgroups of LBCL 6 The application of biologically targeted therapies would require the adoption of the same Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 classification tools that are used in the trial. Many classification systems currently exist, with 8 important differences and limitations. LBCL can be classified by its “cell of origin” (COO), divided 9 into GCB and ABC subtypes. While optimally this is performed using GEP, in clinical practice this 10 is usually done using immunohistochemistry and the Hans algorithm29, which may misclassify 11 10-20% of patients.30 Genomically, at least 5 subtypes of LBCL have been proposed; several 12 classifiers exist, although the subtype delineation and proportions of classifiable tumors vary. 13 Hence, none have been incorporated into routine practice.25,26,31 Each genomic subset 14 represents a relatively small proportion of all LBCL cases, and many patients remained 15 unclassified in recent trials using genomic classifiers (Figure 1). Splitting patient populations 16 into biologic subtypes would require large sample sizes to detect significant differences for a 17 given subtype. Finally, LBCL classification is rapidly evolving, and a system used at the outset of 18 a multi-year trial may not be optimal by the time the trial reads out. 19 20 Despite these challenges, it is plausible that obtaining significant therapeutic benefits in the 21 future will indeed require more granularity in patient and treatment selection than current all- 22 comers studies, forcing us to find acceptable ways to implement molecularly based selection in 23 clinical trials. Ongoing efforts in this direction are summarized below. 24 25 Molecular subtype-driven trials 26 The GUIDANCE-01 randomized phase 2 trial compared standard R-CHOP chemotherapy with R- 27 CHOP-X, where drug “X” was assigned based on genomic subtype.32 This trial reported a 28 significant improvement in all outcomes with R-CHOP-X. This presents an exciting concept, 29 proposing personalized therapy based on real-time molecular characterization. However, many 5  1 questions remain. The genomic classifier is not a standard assay and was unable to categorize 2 39% of patients. The significant benefit across all subtypes was surprising for a phase 2 study, 3 with unusually low toxicity and drop-out rates compared to other trials with similar therapies, 4 raising the possibility that the results may not be fully replicated in a broader context.33,34 Many 5 of these questions should be answered by the confirmatory phase 3 GUIDANCE-02 trial. In it, 6 1100 patients will undergo genomic characterization and will be assigned to receive R-CHOP Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 (control arm) or R-CHOP combined with orelabrutinib, lenalidomide, or decitabine, assigned 8 based on genomic subgroup. 9 10 Three other studies aim to revisit the possible benefit of BTK inhibition in LBCL. Acalabrutinib, a 11 second-generation BTKi, demonstrated safety and encouraging outcomes in combination with 12 R-CHOP.35 A randomized phase 2 trial, REMoDL-A, is comparing acalabrutinib-R-CHOP (A-R- 13 CHOP) to R-CHOP.36 Patients are randomized 2:1 to A-R-CHOP vs R-CHOP, with a primary 14 endpoint of PFS and a secondary endpoint of PFS within specific GEP-defined subsets. 15 Additionally, a phase 3 trial, ESCALADE, evaluates A-R-CHOP versus R-CHOP specifically in non- 16 GCB-type DLBCL.37 All patients initially receive one cycle of R-CHOP to avoid treatment delays 17 while GEP is performed. Those with ABC- or non-GCB-type DLBCL are then randomized to either 18 five cycles of R-CHOP cycles plus two cycles of rituximab or to the same regimen plus 19 acalabrutinib. This trial could provide the first approved COO-specific therapy in DLBCL. The 20 phase 3 BELIEVE-01 (NCT05234684) study similarly evaluates the addition of orelabrutinib38 to 21 R-CHOP in patients with the MCD LymphGen subtype of DLBCL, following post hoc results from 22 the PHOENIX trial.20 23 24 Two other trials evaluate R-CHOP + X strategies in LBCL with specific biologic characteristics. 25 The addition of tucidinostat, a histone deacetylase inhibitor, to R-CHOP showed promising 26 efficacy in DLBCL with both MYC and BCL2 overexpression39, prompting a phase 3 trial in this 27 specific population (NCT04231448).40 The ENGINE1 study evaluates the addition of enzastaurin 28 to R-CHOP in patients with an IPI score ≥3, with the primary endpoint being OS in patients with 29 a specific germline DGM1 polymorphism, which was previously associated with enzastaurin 6  1 benefit in a randomized phase 2 study.41,42 This study is unique in that all DLBCL patients are 2 eligible, but the primary outcome only considers those patients with the biomarker of interest, 3 which will be retrospectively determined. This allows for more rapid enrollment, with the 4 tradeoff that patients without this biomarker will not contribute to the primary analysis and are 5 (potentially unnecessarily) exposed to the toxicity of the additional agent. 6 Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 8 Enrolling Higher-Risk Populations 9 R-CHOP therapy is curative for the majority of patients with LBCL, and very effective for 10 patients with low-risk disease. Prior clinical trials, such as the Alliance/CALGB 50303 study 11 comparing dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine, 12 cyclophosphamide, and doxorubicin) to R-CHOP, showed no significant difference in PFS, 13 though subset analyses suggested there may be an R-EPOCH benefit restricted in those with 14 higher IPI score, while low-risk patients, overrepresented in the study, did no better with R- 15 EPOCH.9 Therefore, many trials recruit higher-risk patients, usually defined by their IPI score. 16 Since these patients have a higher risk of R-CHOP failure, it will be easier to demonstrate the 17 benefit of a novel treatment in this patient population. 18 19 Published in 1993, the IPI has served as a reliable, validated prognostic index in LBCL, yet may 20 not be optimal even as a clinical score to identify truly high-risk patients.43,44 For example, a 21 recent multi-trial validation of IPI found that Eastern Cooperative Oncology Group Performance 22 Status (ECOG PS), LDH, and stage were most strongly associated with survival, while age and 23 extranodal sites factors were less predictive.44 This means that outcomes are still variable in 24 patients with the same score; for instance, patients who are over 60 with an IPI score of 2 (only 25 one additional risk factor) may have a better prognosis than younger patients with 2 higher-risk 26 factors. The age-adjusted IPI (aaIPI), which uses only LDH, Stage, and ECOG PS, may better 27 identify high-risk patients under the age of 60.43 Another recent evaluation of IPI 1-2 disease 28 revealed that higher LDH (≥1.3 times the upper limit of normal) and/or tumor bulk >7 cm 7  1 identifies a higher-risk population with outcomes similar to IPI 3.45 Based on these findings, 2 some trials are expanding beyond IPI to enroll these higher-risk populations. 3 4 Beyond prognostic indices, LBCL trials historically had prolonged delays from diagnosis to 5 treatment initiation (DTI), which likely resulted in the exclusion of higher-risk patients who 6 require urgent therapy.46 This important insight led some modern trials to adapt inclusion Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 criteria accordingly. Several trials now allow one cycle of standard chemoimmunotherapy prior 8 to trial enrollment, providing an easier path for inclusion of patients with high-risk features. 9 Others, like the frontMIND trial, exclude patients with a DTI longer than 28 days. While this 10 approach likely does exclude some lower-risk patients who do not require urgent treatment, it 11 may also exclude patients who cannot complete trial screening in a timely manner due to their 12 illness, and might exclude another distinct high-risk population. 13 14 Finally, frail patients have a poor prognosis, with higher risks of toxicity with standard 15 chemoimmunotherapy.47,48 Mechanisms to identify these patients have been developed, and 16 trials using novel therapies are underway in the hopes of improving efficacy while mitigating 17 toxicity. 18 19 Bringing effective tools for relapsed/refractory (R/R) disease to frontline high-risk patients 20 Several novel therapies were recently approved for R/R LBCL and are now being tested in 21 frontline treatment, using inclusion criteria meant to select for patients with higher-risk LBCL. 22 23 Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of R/R LBCL, 24 with 3 commercially available products.49–51 Axicabtagene ciloleucel (axi-cel) is being evaluated 25 as a frontline treatment approach in particularly high-risk patients with LBCL. The phase 2 26 ZUMA-12 study enrolled patients with IPI≥3 or double/triple-hit cytogenetics and a positive 27 positron emission tomography [PET] CT after 2 initial cycles of chemoimmunotherapy, and 28 administered axi-cel instead of completing R-CHOP.52 Based on the promising PFS observed in 29 this trial,53 the ZUMA-23 phase 3 trial will randomize patients with high-risk disease, defined as 8  1 IPI score 4-5, to axi-cel therapy or standard chemoimmunotherapy (NCT05605899).54 ZUMA-23 2 allows for 1 cycle of standard chemoimmunotherapy prior to enrollment, which should allow 3 enrollment of high-risk, short DTI patients. 4 5 Three CD3xCD20 bispecific antibodies (BsAbs), epcoritamab, glofitamab, and odronextamab, 6 yielded favorable results in patients with R/R LBCL, resulting in regulatory approvals of Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 epcoritamab and glofitamab in the R/R setting55–57 and paving the way for their evaluation in 8 upfront therapy. All 3 are now being tested in frontline randomized trials.58–60 Frontline phase 9 1/2 studies of chemoimmunotherapy plus epcoritamab or glofitamab have demonstrated high 10 response rates.61,62,63 In the EPCORE DLBCL-2 trial, patients are randomized to R-CHOP with or 11 without epcoritamab (NCT05578976).58 Interestingly, patients with IPI score 2-5 are eligible, 12 although the primary efficacy endpoint will be PFS in patients with IPI score 3-5. In the 13 randomized phase 3 OLYMPIA-3 trial, patients with IPI score 2-5 will receive either R-CHOP or 14 odronextamab-CHOP (NCT06091865).64 Finally, the ongoing SKYGLO trial, which evaluates the 15 addition of glofitamab to Pola-R-CHP, is the only actively recruiting phase 3 trial using Pola-R- 16 CHP as the control arm (NCT06047080). 17 18 Tafasitamab, an anti-CD19 monoclonal antibody, combined with the immunomodulator 19 lenalidomide (Tafa/Len), received approval for R/R LBCL in transplant-ineligible patients.56 20 Tafa/Len + R-CHOP was evaluated in a phase 1b trial of previously untreated DLBCL, with 21 sufficient safety and efficacy to open a phase 3 trial.65 The frontMIND trial compares 6 cycles of 22 R-CHOP alone or with Tafa/Len in patients with an IPI score of 3-5, or age-adjusted IPI 2-3 if age 23 ≤60 (NCT04824092).66 24 25 Finally, the new phase 3 GOLSEEK-1 trial evaluates the addition of golcadomide to R-CHOP 26 (NCT06356129). Golcadomide is a novel cereblon E3 ligase modulator that has demonstrated 27 preliminary activity in R/R LBCL67 and safety in a phase 1b study of frontline treatment with R- 28 CHOP.68 The ongoing phase 3 trial is enrolling patients with IPI ≥3, or “high-risk” IPI 1-2 with 29 higher LDH or tumor bulk.45 9  1 2 Response-adapted therapy: a dynamic means of risk identification 3 Rather than focusing on specific biological subsets or broad markers of high-risk disease at the 4 time of diagnosis, it may be possible to identify high-risk patients based on their initial response 5 to standard frontline therapy. Historically PET-CT has been used for response assessment, and 6 PET-adapted approaches have been used to reduce or escalate treatment intensity in LBCL.69–71 Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 More recently, the use of circulating tumor DNA (ctDNA) has garnered significant interest. 8 Multiple ctDNA assays have been developed in LBCL with varying methods and performance 9 characteristics (reviewed in depth elsewhere72). 10 11 Phase 1 and 2 trials, and at least one phase 3 trial, are evaluating response-adapted therapies 12 using ctDNA.72 Quantitatively, ctDNA can act as a surrogate of LBCL burden and its response to 13 therapy, allowing stratification into risk categories that may be more robust and dynamic than 14 IPI. Additionally, ctDNA allows qualitative assessment of genomic alterations, facilitating 15 biologic characterization. Recent studies demonstrated the feasibility of prospective ctDNA- 16 based approaches. In one, patients with less than a 2-log reduction in plasma ctDNA after 2 17 cycles of R-CHOP, a threshold which has been associated with inferior outcomes, received 18 glofitamab added to R-CHOP.62 The SAKK 38/19 phase 2 trial evaluates the use of a PET-CT and 19 ctDNA-guided approach, where both qualitative ctDNA analysis to assess for MCD genomic 20 subtype, and quantitative ctDNA assessment of response to initial therapy, determine whether 21 acalabrutinib is added to R-CHOP therapy (NCT04604067).73 22 23 Phased variant enrichment and detection sequencing (PhasED-seq) has shown particular 24 promise, with high sensitivity for minimal residual disease detection and favorable performance 25 characteristics compared to PET-CT.74–76 The ALPHA3 trial uses PhasED-seq to randomly assign 26 patients with MRD-positive disease at the end of standard frontline treatment to consolidation 27 with cemacabtagene ansegedleucel, an allogeneic CD19 CAR T-cell product.77 Other trials 28 leveraging these technologies are anticipated in the near future. 29 10  1 Focusing on older and frail populations 2 Approximately one-third of patients diagnosed with DLBCL are over 75, with cases expected to 3 rise as the population ages.14,78 Dose-attenuated therapy, such as R-mini-CHOP, is currently a 4 standard of care for patients who are not candidates for full-dose R-CHOP, particularly those 5 aged over 80 or with extensive comorbidities.79 Ongoing trials are evaluating approaches that 6 build on or replace R-mini-CHOP in these patients. Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 8 Similar to POLARIX, the POLAR BEAR (NCT04332822) study80 randomizes patients to R-mini- 9 CHOP or R-Pola-mini-CHP, with polatuzumab vedotin replacing vincristine. Patients over 80 10 years old, or 75-80 years old and frail by simplified Comprehensive Geriatric Assessment (CGA), 11 are eligible. Initial safety data showed similar safety and tolerability between the arms.80 Two 12 other studies are currently evaluating the addition of either oral azacitidine (NCT04799275)81 or 13 acalabrutinib (NCT05820841)82 to R-mini-CHOP. 14 15 Another phase 3 trial compares R-mini-CHOP to the chemotherapy-free combination of 16 zanubrutinib, lenalidomide, and rituximab (ZR2) in patients age ≥80 or 70-79 with CGA 17 unfit/frail status (NCT05179733). Preliminary phase 1/2 data with ZR2 in R/R LBCL, along with 18 retrospective data in the frontline setting, showed promising activity; however, with limited 19 follow-up, questions about the long-term curative potential of this combination remain.83,84 20 21 There are unique challenges in trials for older, unfit or frail patients. The first is how we define 22 these populations. Different criteria for fitness and frailty exist, but uniform standards are 23 needed to properly interpret, compare and apply trial results. Another important concern is 24 toxicity. To reduce toxicity, R-mini-CHOP is given in lieu of R-CHOP, but adding another agent 25 will invariably add toxicity. Since trial-eligible patients must meet rigorous inclusion criteria, 26 patients who are unfit or frail but are trial-eligible may not be fully representative of unfit or 27 frail patients in the “real world” setting, who may have more comorbidities, poorer 28 performance status, and less ability to tolerate these therapies. Further follow-up and 29 population-based studies will be needed to ensure tolerability and efficacy across these 11  1 populations. Lastly, such trials may force us to wrestle with the concept of cure. It is plausible 2 that regimens will emerge that have less curative potential but greater tolerability or short- 3 term efficacy than R-mini-CHOP, with improved survival in the short-term that is not sustained 4 in the long-term. How to weigh this trade-off for individual patients will require a nuanced, 5 personalized approach and careful consideration of life expectancy and patient preferences. 6 Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 8 Trial design: are the comparators and endpoints meaningful? 9 10 Choosing the control arm 11 For a randomized trial to be relevant to our practice, the control arm should be considered an 12 acceptable standard therapy for the disease. An important implication of the POLARIX study is 13 that R-CHOP may be considered an obsolete control arm when EFS or PFS are the primary 14 endpoint. At this time, all ongoing trials except SKYGLO use R-CHOP as a control arm, which will 15 complicate their interpretation. If an OS benefit is observed over R-CHOP in one of these trials, 16 this would provide a strong rationale to favor that regimen over Pola-R-CHP (which has not to 17 date shown an OS benefit over R-CHOP). However, if a PFS benefit alone is demonstrated, two 18 (or more) options may then be available for the same patient population. In the absence of a 19 direct comparison of efficacy, other factors must be considered. If the novel regimen is more 20 toxic, expensive, or logistically challenging than Pola-R-CHP, it is less likely to be adopted. If 21 benefits are seen with a specific regimen in a distinct biologic subtype, it will be tempting to use 22 that regimen according to those biologic characteristics, although this will risk over- 23 interpretation of subgroup analyses. 24 25 Optimal study endpoints 26 In nearly all of the phase 3 trials discussed, the primary endpoint is either PFS or EFS. Adopting 27 PFS or EFS may be problematic when therapies known to be highly effective in R/R disease are 28 added to the frontline treatment for LBCL, such as axi-cel in ZUMA-23. The primary endpoint of 29 this study is EFS; however, EFS will not capture the benefit of 2nd line CAR T-cell in patients with 12  1 frontline chemoimmunotherapy failure. Even if the study is positive, whether treating high-risk 2 disease with CAR T-cell in the frontline setting is superior to initial chemoimmunotherapy with 3 CAR T-cell as backup in the 2nd line will remain an open question. The ALPHA3 study (discussed 4 above), which uses an allogeneic CD19-directed CAR T-cell product as consolidation therapy, 5 also uses EFS as a primary endpoint and raises similar questions; of additional concern in this 6 case is the fact that the product under study is not an approved treatment for R/R LBCL, and Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 could in theory compromise the future efficacy of standard CD19-directed CAR T-cell products. 8 9 An additional concern relates to the surrogacy of PFS for OS in LBCL. As noted above, the 10 POLARIX study has not (so far) shown an OS benefit. If a PFS benefit comes with little added 11 toxicity (as was the case in POLARIX), and without a significant impact on the efficacy of salvage 12 therapy, the absence of OS benefit may not be an impediment to adoption. But if there is a 13 large increase in toxicity burden, including financial toxicity, or if upfront use of an agent is 14 likely to have an important impact on its later use (as with CAR T-cell or BsAb), it will be harder 15 to accept a PFS benefit not accompanied by a concomitant OS benefit to change standard 16 practice. 17 18 OS should therefore be a very closely watched endpoint across these trials. Even in cases of OS 19 benefit, attention to post-protocol therapy in the event of treatment failure is needed. 20 Whether crossover is permitted, and whether effective 2nd-line therapies such as CAR T-cells 21 are available, may significantly impact OS. Attention to long-term toxicities, such as 22 cardiomyopathy, infections, and secondary malignancies, and their impact on long-term 23 survival, will also be necessary. 24 25 26 Beyond PFS: quality of life, costs, and diversity 27 While efficacy is a key factor in selecting a given therapy, toxicity, logistics, and costs, all of 28 which contribute to patients’ quality of life, will also ultimately determine its uptake in practice. 13  1 For instance, aside from cost, adopting Pola-R-CHP is rather simple since it follows the same 2 schedule and has similar toxicity as R-CHOP. 3 4 Almost all trials mentioned above are adding therapy to R-CHOP or Pola-R-CHP, which will 5 almost certainly result in greater toxicity (Table 5). For example, BsAb and CAR T-cell therapies 6 have been associated with increased infection risk, highlighted during the COVID-19 Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 pandemic.85,86 In the phase 1/2 trial of tafasitamab/lenalidomide-R-CHOP, high rates of grade 3- 8 4 neutropenia, thrombocytopenia and infections were observed.65 While this did not appear to 9 significantly impact R-CHOP dose intensity, these toxicities could be magnified in the real-world 10 setting, where such regimens will be considered for patients with comorbidities and without 11 the rigorous monitoring used in clinical trials. In some cases, increased toxicity may outweigh 12 the benefit of anti-tumor efficacy, and a full appreciation of this trade-off necessitates 13 consolidated long-term trial results. 14 15 Some of the regimens under investigation significantly increase the frequency and number of 16 required visits (Figure 2). Going from visits and infusions every 3 weeks to every 1 week 17 significantly inflates the burden of treatment on patients and the healthcare system generally. 18 Additional burdens are incurred with the use of complex therapies such as CAR T-cell (and, to 19 some extent, BsAbs), which may require hospitalization and are often restricted to specialized 20 treatment centers. This may lead to geographic and socioeconomic disparities in the availability 21 of novel combinations. 22 23 Given the ballooning economic burden of healthcare, the cost of novel therapies must also be 24 considered. There is ongoing debate about the cost-effectiveness of Pola-R-CHP.87,88 When one 25 considers regimens with multiple novel therapies like glofitamab-pola-R-CHP and 26 tafasitamab/lenalidomide-R-CHOP, or CAR T-cell therapy, hundreds of thousands of dollars may 27 be added to the price of frontline therapy. Ultimately, whether the reduction in disease 28 progression and death justifies the costs of these agents will require careful analyses involving 29 patients and multiple stakeholders, with evaluation of long-term data. 14  1 2 Advances in LBCL therapy unfortunately do not benefit all patients equally, with disparities in 3 outcomes based on geography, socioeconomic status, race, ethnicity, and gender.89,90 This is 4 reflected in the underrepresentation of Black, Hispanic, and female patients in clinical trials.91 5 While major factors, including geography and economics, contribute to these disparities, 6 seemingly minor decisions, like laboratory value cutoffs for eligibility, may affect racial Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 representation and must be considered when designing trials today.92 While these disparities 8 are not limited to LBCL, every effort should be made to ensure that patients enrolled in trials 9 reflect the population affected by LBCL, and we should appraise these ongoing trials based on 10 their ability to include diverse and representative populations. Ultimately, the therapies that 11 are effective for, and accessible to, the most people will be the ones that make the greatest 12 difference in LBCL. 13 14 15 Looking further into the future: Chopping Off Chemotherapy 16 Could R-CHOP be replaced altogether by combinations of novel agents? The ZR2 study in older 17 patients is the only phase 3 study asking this question, but encouraging early-phase studies may 18 motivate future trials. Based upon favorable results in the “Smart Start” trial93, the “Smart 19 Stop” phase 2 trial is evaluating frontline therapy with lenalidomide, tafasitamab, rituximab and 20 acalabrutinib (uLTRA).94 In Part A, patients received initial uLTRA therapy, then, according to 21 depth of response, received R-CHOP for 2 to 6 cycles. Encouraged by high response rates to 22 uLTRA, a second cohort where R-CHOP is excluded entirely in complete responders is 23 underway. 24 25 Removing chemotherapy entirely from frontline LBCL treatment raises many questions. The 26 first is whether the new regimen is curative. We have decades of follow-up with CHOP and will 27 need extended time to demonstrate if obtaining a complete response with novel therapies 28 translates into a cure. It is also plausible that the outcome of R-CHOP in a salvage setting after 29 patients have already received novel therapies may be compromised, in which case the strategy 15  1 overall may be harmful. If this type of treatment is indeed curative, another question will be 2 whether such a regimen avoids some of the long-term CHOP-associated risks, particularly 3 secondary malignancies and cardiac toxicity, and whether new long-term toxicities occur. 4 Overall, chemotherapy-free approaches are attractive, but we will need definitive evidence of 5 benefit and safety before abandoning chemotherapy entirely in the frontline treatment of LBCL. 6 Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 7 8 Conclusions 9 While improving the frontline treatment of LBCL has been a daunting challenge over the last 20 10 years, many exciting novel therapies are under investigation in ongoing trials. In the best-case 11 scenario, in which several of those trials succeed, differences in design, patient population, 12 control arm, endpoints, toxicity, and costs will inform the interpretation and application of 13 results. We hope that through careful methodological evaluation and vigorous discussions, 14 even before the trials read out, we will be able to optimally apply their findings to improve 15 patient outcomes, and to develop the next generation of early-phase and randomized trials. 16 17 18 Acknowledgements: 19 D.Q. has received training support and funding from the Lymphoma Research Foundation. 20 This research was funded in part through the NIH/NCI. Cancer Center support grant P30 21 CA008748. PA most gratefully acknowledges the support of the Leukemia and Lymphoma 22 Society and the Harold and Virginia Lash Foundation. 23 24 Authorship: 25 D.Q, P.A. and G.S. designed and performed the research, and all wrote and approved the 26 manucript 27 28 Conflicts of Interest: 29 D.Q. has received financial compensation for advisory board participation from Genmab. 30 P.A. reports consultancy for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, 31 ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, 32 Enterome, Regeneron, Epizyme, AstraZeneca, Genentech/Roche, Xencor, Foresight, and ATB 33 Therapeutics; received research funding from Kite; received research funding (institutional) 34 from Merck, Bristol Myers Squibb, Affimed, Adaptive, Tensha, Otsuka, Sigma Tau, 16 1 Genentech/Roche, IGM Biosciences, AstraZeneca; and reports honoraria from Merck and 2 Bristol Myers Squibb 3 G.S. has received financial compensation for advisory boards or consulting roles from Abbvie, 4 Atbtherapeutics, Beigene, BMS, Genentech/Roche, Genmab, Innate Pharma, Incyte, Ipsen, 5 Janssen, Kite/Gilead, Merck, Modex, Molecular Partners, Nurix, Orna Therapeutics, Treeline. He 6 is also a shareholder of Owkin. He received research support from Abbvie, Genentech, Genmab 7 Janssen, Ipsen, and Nurix, which was managed by his institution. 8 Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 9 17  1 Table 1. Features of pivotal phase 3 clinical trials in 1L LBCL treatment. 2 Name Trial ClinicalTrial.gov Enrollment Patients Eligible histologies Lead-in treatment Primary Outcome Blinding ID goal permitted? General POLARIX2,22 R-Pola-CHP NCT03274492 1000 Age 18-80 Included: DLBCL, TCHRLBL, EBV+ LBCL, ALK+ Steroid prephase only PFS (Investigator) Double-Blind vs. IPI 2-5 LBCL, HHV8+ LBCL, HGBCL R-CHOP ECOG 0-2 Excluded: PMBCL, FL3B, hx indolent, Grey Zone, PEL, leg type, CNSL, Richter, transformed iNHL frontMIND66 R-CHOP + NCT04824092 880 Age 18-80 Included: DLBCL, TCHRLBL, EBV+ LBCL, ALK+ Steroid prephase only PFS (Investigator) Double-Blind Tafasitamab + IPI 3-5 (if >60 years) LBCL, HHV8+ LBCL, HGBCL (DH/TH), Lenalidomide aaIPI 2-3 (if ≤60 years) transformed iNHL, FL3B vs. Diagnosis to treatment Excluded: PMBCL, Grey Zone, PEL, leg type, R-CHOP interval 80, or >60-80 w: Included: DLBCL, PMBCL, leg type, Steroid/rituximab/vincristine PFS (Investigator) Open label Acalabrutinib -ADL 12% were reported; in FIRST-MIND, >10%; ZUMA-12, ≥15%; Aza-R-CHOP, ≥20% or grade 3-4 in ≥5%. For the other studies (1L Glofitamab + R-CHOP, 1L Glofitamab + Pola-R-CHP, EPCORE NHL-2, ACCEPT, CC-220-DLBCL-001), data has been reported only in abstract form, without declared reporting thresholds. Abbreviations: IPI, international prognostic index; ORR, overall response rate; CRR, complete response rate; PFS, progression-free survival; OS, overall survival; AE, adverse event; R-Pola-CHP, rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; DS, Deauville score; NP, neutropenia; F&N, febrile neutropenia; TCP, thrombocytopenia; ICANS, immune effector cell associated neurotoxicity syndrome; CRS, cytokine release syndrome; 21 Table 5. Toxicities observed in selected trials. Other notable Grade 5 Trial Treatment Grade 3-4 toxicity* toxicities* AE rate NP 31% Anemia 8% Neuropathy 54% R-CHOP 2.3% F&N 8% (G3-4 1%) POLARIX 2 Infection 13% Phase 3 NP 28% Neuropathy 53% Anemia 12% (G3-4 2%) R-Pola-CHP 3.0% F&N 14% Diarrhea 31% (G3- Infection 15% 4 4%) 1L Glofitamab + ICANS 0% NP 48% R-CHOP62 Glofitamab-R-CHOP CRS 11% (G3-4 7.1% Infection 22% Phase 1b 0%) Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 1L Glofitamab + Glofitamab-Pola-R- NP 63% ICANS 0% Pola-R-CHP63 4.2% CHP Infection 17% CRS 8% (G3-4 0%) Phase 1b CRS 60% (G3-4 NP 62% EPCORE NHL-261 Epcoritamab-R- 2%) F&N 13% N/A Phase 1/2 CHOP ICANS 4% (G3-4 Anemia 28% 0%) NP 58% Anemia 21% Tafasitamab + Hypokalemia 21% TCP 12% 9.1% R-CHOP (G3-4 9%) F&N 18% FIRST-MIND65 Infection 21% Phase 1b NP 85% Diarrhea 33% (G3- Tafasitamab + TCP 36% 4 6%) Lenalidomide + 6.1% F&N 18% Hypokalemia 30% R-CHOP Infection 27% (G3-4 6%) NP 37% ACCEPT35 Acalabrutinib + Diarrhea (G3-4 F&N 13% N/A Phase 1b/2 R-CHOP 11%) Infection 7% NP 77% CC-220-DLBCL- Venous Golcadomide + TCP 32% 00168 thromboembolism N/A R-CHOP F&N 14% Phase 1 8% Infection 15% NP 53% CRS 100% (G3-4 Axi-Cel (in patients ZUMA-1252,53 Anemia 30% 8%) with DS 4-5 after 2 2.5% Phase 2 TCP 15% Neuro AE 73% cycles chemo) Infection 15% (G3-4 23%) Diarrhea 56% (G3- NP 63% 4 7%) Aza-R-CHOP95 Oral azacitidine + Anemia 17% Pulmonary 1.7% Phase 1 R-CHOP TCP 14% embolism (G3-4 F&N 25% 7%) *Available data on adverse events included, though cutoffs for reporting vary by study. For POLARIX, events occurring in >12% were reported; in FIRST-MIND, >10%; ZUMA-12, ≥15%; Aza-R-CHOP, ≥20% or grade 3-4 in ≥5%. For the other studies (1L Glofitamab + R-CHOP, 1L Glofitamab + Pola-R-CHP, EPCORE NHL-2, ACCEPT, CC-220-DLBCL-001), data has been reported only in abstract form, without declared reporting thresholds. Abbreviations: IPI, international prognostic index; ORR, overall response rate; CRR, complete response rate; PFS, progression-free survival; OS, overall survival; AE, adverse event; R-Pola-CHP, rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; DS, Deauville score; NP, neutropenia; F&N, febrile neutropenia; TCP, thrombocytopenia; ICANS, immune effector cell associated neurotoxicity syndrome; CRS, cytokine release syndrome; 22 Figure 1. Relative frequencies of LBCL subtypes represented in selected clinical trials, with cell of origin based on gene expression profiling in the top row and genomic subtype based on DNA sequencing in the bottom row. Abbreviations: GEP, gene expression profiling; ABC, activated B cell; GCB, germinal center B cell. MCD, N1, A53, BN2, ST2, and EZB are genetic subtypes, explained in detail in Wright et al., Cancer Cell 2021).20 *In the PHOENIX trial, only patients with non-GCB cell of origin by immunohistochemistry Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 were included. When the LymphGen classifier was applied, only “core” subtype cases with a high probability (≥90%) of DLBCL subtype membership were classified as such. Additionally, the A53 subtype could not be identified due to lack of DNA copy number data. Figure 2. Treatment schemas for selected ongoing phase 3 trials. In R-CHOP and R-Pola-CHP protocols, rituximab monotherapy in cycles 7 and 8 may not be included at all sites. Of note, BsAb are administered in the initial cycle(s) using a step-up dosing scheme. *In OLYMPIA-3, one additional odronextamab dose is given on day 8 in cycle 5, and one on day 15 in cycle 6. Abbreviations: R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-Pola-CHP, rituximab, polatuzumab vedotin, cyclophosphamide, doxorubicin, prednisone 23 References 1. Lue JK, O’Connor OA. A perspective on improving the R-CHOP regimen: from Mega-CHOP to ROBUST R-CHOP, the PHOENIX is yet to rise. Lancet Haematol. 2020;7(11):e838–e850. 2. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. New England Journal of Medicine. 2021; 3. Coiffier B, Lepage E, Brière J, et al. CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma. 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Blood. 2022;139(8):1147– 1159. 30  Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 REMoDL-B Trial (NCT01324596) FigurePOLARIX 1Cell Trial (NCT03274492) of Origin by GEP PHOENIX Trial* (NCT01855750) Cell of Origin by GEP Cell of Origin by GEP n = 668 n = 747 n = 918 Unclassi Unclassi fied Unclassi fied 7% fied 14% 22% GCB ABC ABC 17% 33% 26% ABC GCB GCB 76% 53% 52% POLARIX Trial (NCT03274492) PHOENIX Trial* (NCT01855750) GUIDANCE-01 Trial (NCT04025593) LymphGen Classifier LymphGen Classifier NGS-Based Classifier n = 594 n = 773 n = 128 N1 1% A53 MCD 3% MCD 9% BN2 14% 6% MCD-like BN2 N1 Undeter Undeterm 20% 9% 4% mined ST2 ined 46% 5% Composit [PERCENT e BN2-like Undeterm AGE] 2% 18% ined EZB [PERCENT 24% AGE] TP53 mut Composi 17% N1-like te EZB-like 4% 3% 2%  Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 Figure 2 Cycle 1 Cycle 2 Cycle 3 - Cycle 4 Cycle 5 - Cycle 6 Cycle 7 - Cycle 8 Cycle 9+ Day 1 2-7 8 9-14 15 16-21 1 2-7 8 9-14 15 16-21 1 2-7 8 9-14 15 16-21 1 2-7 8 9-14 15 16-21 1 2-7 8 9-14 15 16-21 1-21 R-CHOP R-CHOP Standard of care POLARIX R-Pola-CHP NCT03274492 R-CHOP frontMIND Tafasitamab NCT04824092 Lenalidomide (PO) D1-D10 D1-D10 D1-D10 D1-D10 EPCORE DLBCL-2 R-CHOP NCT05578976 Epcoritamab OLYMPIA-3 CHOP NCT06091865 Odronextamab * * SKYGLO Pola-R-CHP NCT06047080 Glofitamab ESCALADE R-CHOP NCT04529772 Acalabrutinib (PO) Key R-CHOP infusion in clinic Rituximab infusion in clinic Pola-R-CHP infusion in clinic Novel drug infusion/injection in clinic Novel drug taken PO at home  Downloaded from http://ashpublications.org/blood/article-pdf/doi/10.1182/blood.2023023789/2244048/blood.2023023789.pdf by guest on 01 October 2024 Timeline of Ongoing Frontline Trials in Large B Cell Lymphoma (LBCL). Conclusions: At least 15 ongoing phase 3 clinical trials may impact the frontline treatment of LBCL. Differences in inclusion criteria, interventions, primary outcomes, and generalizability may inform how these trials are implemented. Qualls et al. DOI: 10.xxxx/blood.2024xxxxxx