CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: August 25, 2023
Expiration: August 24, 2024
SWOG S1826: Study Design
Jeffrey Sharman, MD:
One of the most compelling datasets presented at ASCO 2023 is from the SWOG S1826 trial. SWOG S1826 is a randomized phase III study of doxorubicin/vinblastine/dacarbazine (AVD) plus either nivolumab or brentuximab vedotin (BV) in patients with newly diagnosed stage III-IV classical Hodgkin lymphoma (cHL).18 The study included 994 patients aged 12 years and older with adequate kidney function and an LVEF of ≥50%. The primary endpoint was PFS.
Doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) was the SoC for patients with cHL for many years, but based on the ECHELON-1 trial results,19 bleomycin was replaced with BV, so BV plus AVD has been the SoC for the past several years.
SWOG S1826 investigated the addition of either nivolumab or BV to AVD.
SWOG S1826: Baseline Characteristics
The baseline characteristics were well balanced between the 2 treatment arms. The median age was 27 years in the nivolumab plus AVD arm and 26 years in the BV plus AVD arm. The majority of patients were aged 18 60 years, with approximately 25% younger than 18 years and approximately 10% older than 61 years. The International Prognostic Score (IPS) was representative of what we typically see, with approximately two thirds of patients with an IPS score of 0-3 and approximately one third with a score of 4-7.
SWOG S1826: PFS
The 1‑year PFS rate was 94% with the addition of nivolumab to AVD vs 86% with the addition of BV to AVD (HR: 0.48; 95% CI: 0.27-0.87; P = .005). This very robust data including 976 evaluable patients favored the addition of nivolumab to AVD.
SWOG S1826: PFS in Patient Subgroups
There seemed to be an advantage of nivolumab vs BV in most subgroups examined, regardless of age, IPS category, disease stage, and presence or absence of B symptoms.
SWOG S1826: OS
The OS curve looks very encouraging in both treatment arms. There was a slight imbalance in deaths, with more deaths on the BV arm (n = 11) compared with the nivolumab arm (n = 4). The causes of death on both arms included infection and sepsis, whereas cardiac arrest, pneumonitis, and dehydration/vomiting were noted on the BV arm only.
SWOG S1826: AEs in ≥10% of Patients
There was a higher rate of neutropenia in the nivolumab arm, but neuropathy was higher with BV. Of importance, part of that likely was due to the design of the study, where growth factors were required for patients on the BV arm but not for those on the nivolumab arm. Indeed, only approximately one half of patients on the nivolumab arm received prophylactic growth factors.
SWOG S1826: Clinical Implications
This phase III study of AVD in combination with either BV or nivolumab for patients with newly diagnosed advanced-stage cHL demonstrated statistically significant and clinically meaningful improvements in PFS for patients who received nivolumab plus AVD compared with those who received BV plus AVD. It is impressive that the experimental regimen resulted in an HR of 0.48 in a disease where treatment is already highly effective.
There were lower rates of neuropathy with nivolumab but higher rates of neutropenia. Therefore, if the nivolumab regimen is used, strong consideration should be given to using growth factors.
The improvements associated with nivolumab likely will result in the combination becoming a standard treatment regimen for patients with advanced-stage cHL, although some healthcare professionals would like to see longer follow-up data to exclude higher rates of late relapse with the nivolumab combination.
KEYNOTE-667 High-Risk Group Update: Study Design
The nonrandomized phase II KEYNOTE-667 trial is evaluating the efficacy and safety of pembrolizumab plus chemotherapy for 340 children, adolescents, and young adults with newly diagnosed cHL and a slow early response (SER) to initial chemotherapy. At ASCO 2023, updated results (after a median follow-up of 16.8 months) from an interim analysis in the subgroup of patients with high-risk cHL and SER were reported.20
Patients with high-risk cHL received 2 cycles of vincristine, etoposide, prednisone/prednisolone, and doxorubicin as induction therapy, after which early response was assessed, followed by consolidation therapy with 4 cycles of cyclophosphamide, vincristine, prednisone/prednisolone, and dacarbazine (COPDAC-28) plus pembrolizumab. Patients with PET-positive cHL after consolidation therapy received radiation therapy, whereas radiation therapy was omitted in those with PET-negative disease. All patients with cHL and SER received maintenance pembrolizumab.
The primary endpoint was ORR, and the secondary endpoints included PET negativity after consolidation and safety of COPDAC-28 plus pembrolizumab.
KEYNOTE-667 High-Risk Group Update: Baseline Characteristics
At data cutoff, 62 patients with high-risk cHL and SER to initial chemotherapy were included in the report. The median age was 14 years (range: 5-22), 29 (47%) patients had bulky disease, and 41 (66%) patients had Ann Arbor stage IV disease. In total, 34 (55%) patients had completed treatment, and 23 (37%) patients still were receiving consolidation/maintenance therapy. The median time receiving pembrolizumab was 11.0 months (range: 1 day to 11.8 months).
KEYNOTE-667 High-Risk Group Update: Late Response Assessment
The total number of patients who achieved a late response was the same when assessed by blinded independent central review or the investigator. Of these, approximately 70% were PET negative and 30% were PET positive.
More patients who achieved PET negativity had mixed-cellularity cHL (20%), whereas 6% of patients with this subtype were PET positive.
KEYNOTE-667 High-Risk Group Update: AEs With ≥5% Incidence
All-cause AEs occurred in 54 (87%) patients, with 38 (61%) patients experiencing a treatment-related AE (TRAE). Grade 3/4 AEs occurred in 21 (34%) patients, and 13 (21%) patients experienced a serious AE.
Grade 3/4 TRAEs occurred in 10 (16%) patients, and 4 (6%) experienced a serious TRAE. The AEs of clinical interest included grade 1/2 hypothyroidism (n = 4), grade 2 colitis (n = 1), and grade 2 pneumonitis (n = 1).
KEYNOTE-667 High-Risk Group Update: Conclusions
In this interim analysis of children, adolescents, and young adults with high-risk cHL and SER to initial chemotherapy, the addition of pembrolizumab to COPDAC-28 as consolidation therapy led to durable responses. After a median follow-up of 16.8 months, approximately 70% of patients achieved PET-negative disease for whom radiation therapy was omitted.
It appears that the addition of pembrolizumab to COPAC-28 may augment treatment responses in this group of patients with SER to initial chemotherapy.
Glofitamab in R/R LBCL: Background
Glofitamab is a unique CD20-directed CD3 T-cell‒engaging bispecific antibody. Its unique 2:1 configuration and superior CD20 binding lends it an extended half-life. Glofitamab recently received accelerated FDA approval for patients with R/R DLBCL, NOS, or LBCL arising from FL after ≥2 lines of systemic therapy. One of its unique characteristics is that it is administered as a fixed course of 12 three‑week cycles. In a phase II study, it demonstrated high CR rates with a manageable safety profile in patients with R/R LBCL.21
At ASCO 2023, data from extended follow-up and landmark analyses of the phase II study were presented.22
Glofitamab in R/R LBCL: Study Design
Patients with DLBCL, NOS, HGBCL, transformed FL, or primary mediastinal B-cell lymphoma were eligible to enroll on the single-arm phase II expansion trial (N = 155). The eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and previous treatment with ≥2 systemic lines, including an anti‑CD20 antibody and an anthracycline. All patients received a pretreatment dose of obinutuzumab 7 days before the first dose of glofitamab to help mitigate AEs. Glofitamab was administered intravenously using a step-up dosing schedule in cycle 1, followed by the 30-mg full dose from cycles 2-12 in 21-day cycles.
The primary endpoint was CR rate by an independent review committee (IRC). Post hoc analyses of PFS and OS were performed as landmark analyses to assess outcomes in patients who experienced CR in response to glofitamab.
Glofitamab in R/R LBCL: Response
After a median follow-up of 18.2 months, the ORR was 52%, including 40% of patients who achieved a CR. It is encouraging that the majority of patients (68%) who achieved a CR continued to maintain it. Indeed, 70% of patients who achieved a CR at any time remained in remission at 18 months. Considering that this is a heavily pretreated, highly refractory patient population with very aggressive disease kinetics, these results are impressive.
Glofitamab in R/R LBCL: PFS, OS Landmark Analyses by Response at End of Treatment
Landmark analyses of PFS and OS appear to be highly contingent on the type of response achieved at cycle 3. Patients who achieve a CR have very durable responses, whereas those who achieve a partial response (PR) tend to have less durable responses. Patients without a response at cycle 3 have poor survival outcomes.
Glofitamab continues to show durable responses in patients with heavily pretreated LBCL after a median of 18.2 months of follow-up, and most patients who achieve a CR at the end of treatment remain in remission. Based on these results, it is very exciting to see that glofitamab is now approved by the FDA.
Glofitamab in R/R LBCL: Safety Profile
In terms of safety, cytokine-release syndrome (CRS) is a notable AE associated with bispecific antibodies. With this class of agents, grade 1 CRS tends to be fever, grade 2 tends to be fever and/or hypoxia requiring oxygen or hypotension requiring fluids, and grades 3/4 tend to require vasopressors. With glofitamab, grades 1 and 2 CRS were the most common (60%), but 3% of patients experienced grade 3 CRS. Therefore, although few patients (4%) experienced grade 3/4 CRS, it is important to be prepared by having systems in place to appropriately manage CRS if it does occur.
EPCORE NHL-1 Update: Background
Despite recent treatment advances, prognosis remains poor for patients with R/R B-cell NHL. This is particularly true if they have double-hit or triple-hit lymphoma, have progressed while receiving a CAR T‑cell therapy, or have multiply relapsed disease requiring later-line therapy.
Epcoritamab is another CD20-directed CD3 T-cell‒engaging bispecific antibody with a more conventional 1:1 binding configuration. Epcoritamab recently received accelerated FDA approval for patients with R/R DLBCL, NOS, including DLBCL arising from indolent lymphoma, and HGBCL after ≥2 lines of systemic therapy. A key distinguishing feature of epcoritamab is that it is administered subcutaneously.
A previous analysis of the EPCORE NHL-1 trial after 10.7 months of follow-up demonstrated an ORR of 63.1%.23 At ASCO 2023, updated data after a median follow-up of 20 months were presented.24
EPCORE NHL-1 Update: Study Design
EPCORE NHL-1 is an open-label phase II study. The dose-expansion study included patients with R/R CD20-positive B-cell NHL who have received ≥2 previous lines of therapy, including ≥1 anti‑CD20 monoclonal antibody. Patients who had previously received CAR T-cell therapy were allowed on the trial.
SC epcoritamab initially was administered by step‑up dosing with corticosteroid prophylaxis to mitigate CRS. Thereafter, patients in the dose-expansion cohort received the recommended phase II dose: 48-mg full doses in 28-day cycles. The dose-expansion cohort included 157 patients with LBCL and 148 patients with DLBCL or HGBCL. The primary endpoint was ORR by IRC.
EPCORE NHL-1 Update: Baseline Characteristics and Patient Disposition
The baseline characteristics were generally well-balanced between patients with DLBCL/HGBCL and LBCL. Of importance, the median time from initial diagnosis of disease was 19 months, and there was a median of 3 prior lines of therapy (range: 2-11). Furthermore, approximately 60% of patients had primary refractory disease, and approximately 80% were refractory to their most recent line of therapy. Approximately 40% of patients had received CAR T-cell therapy. Therefore, this patient population had difficult-to-treat B-cell NHL.
The mean number of treatment cycles received was 9, and 23% of patients still are receiving treatment. Although 77% of the patients discontinued therapy, only approximately 10% of patients discontinued treatment due to AEs.
EPCORE NHL-1 Update: Efficacy
The ORR was 63% among 99 patients with LBCL and 61% among 90 patients with DLBCL/HGBCL. In either of the subgroups, the CR rate was 39%, with a median time to CR of 2.7 months and a median time to response of 1.4 months. In addition to the quick response observed, the median DoR was 15.5 months.
Among those who achieved a CR, the median DoR was 20.8 months, and the median PFS and median OS were not reached in either of the patient subgroups.
EPCORE NHL-1 Update: TEAEs in Patients With LBCL
Among the 157 patients with LBCL, TEAEs included CRS (grade 1/2: 48%; grade 3: 3%). Neutropenia was associated with treatment (grade 1/2: 8%; grade 3: 7%; grade 4: 10%). Fatal TEAEs occurred in 15 patients, including 1 death associated with COVID-19 pneumonia and 1 related to immune effector cell–associated neurotoxicity syndrome (ICANS).
EPCORE NHL-1 Update: CRS
Among the 157 patients with LBCL, 51% experienced CRS, and anticytokine therapy was administered in 15%. This means that approximately 15% of patients had either grade ≥2 CRS or prolonged fevers.
Typically, CRS occurs after the first full dose; therefore, for the bispecific antibodies epcoritamab and glofitamab, hospitalization is recommended at the time of the first dose, as patients are likely to experience CRS. With epcoritamab, CRS primarily occurs after administration on cycle 1, Day 15.
In the EPCORE NHL-1 trial, the median time to onset of CRS after the first full dose of epcoritamab was 20 hours. This further supports the recommendation to observe these patients in the hospital after the first full dose is administered.
Glofitamab and Epcoritamab in R/R LBCL and HGBCL: Clinical Implications
Both glofitamab and epcoritamab are recently approved by the FDA for patients with R/R LBCL and/or HGBCL, and both trigger an immune response against lymphoma. The results from the phase II trial of glofitamab in R/R LBCL and the EPCORE NHL-1 trial of epcoritamab in R/R B-cell NHL are very similar and impressive. These results indicate that these 2 CD20-directed CD3 T-cell‒engaging bispecific antibodies are very exciting new drugs for patients with heavily pretreated B-cell lymphomas.
Glofitamab is administered intravenously, whereas epcoritamab is given subcutaneously. Both agents employ a step-up dosing schedule to minimize AEs. In addition, patients receiving glofitamab get a pretreatment dose of obinutuzumab. Another difference in the dosing schedule is that glofitamab is administered as a “fixed-duration therapy” given once every 3 weeks after the full dose is reached, whereas epcoritamab is given more frequently within each cycle and taken until disease progression.
Both agents have remarkable efficacy in this heavily pretreated patient population, with an ORR of approximately 50% to 60% and a CR rate of approximately 40%. In my experience, patients who achieve a CR with either of these agents can have very durable disease control, whereas patients who achieve only a PR tend to progress early. Those without response have very poor outcomes.
Both bispecific antibodies were associated with CRS in approximately 50% to 60% of patients, with grade 3/4 observed in <5% of these patients. With both agents, hospitalization for optimal monitoring of CRS is recommended at different times.
This class of agents is among the most active treatments seen in the heavily pretreated LBCL/HGBCL space. Epcoritamab and glofitamab can have a significant impact on treatment outcomes. They have novel mechanisms of action and a toxicity profile with which healthcare professionals will need to familiarize themselves. At present, there is no rigorous answer to the question of how to choose between these 2 agents. Both were developed in parallel, with similar findings. Regarding the difference in modes of administration, it is unlikely that patients will have a preference because, oftentimes, they are really quite ill at this stage. The bigger challenge that I foresee is being able to monitor and appropriately manage CRS associated with these bispecific antibodies. Outside of academic medicine, treating healthcare professionals in the community setting are updating their systems to be able to deal with this toxicity. Of note, future studies may support moving these agents earlier in the treatment algorithm for patients with R/R LBCL or HGBCL.
BRUIN 2-Year Update: Background
MCL is another type of B-cell lymphoma. In MCL, covalent BTK inhibitors such as acalabrutinib and zanubrutinib are highly active with manageable AE profiles. However, the utility of these agents in MCL is limited by acquired resistance and treatment intolerance. Once the disease progresses on a covalent BTK inhibitor, survival outcomes are dismal.
Pirtobrutinib is a next-generation, highly selective noncovalent (reversible) BTK inhibitor. It recently received accelerated FDA approval for patients with R/R MCL after ≥2 previous lines of systemic therapy, including a covalent BTK inhibitor. At ASCO 2023, updated efficacy and safety results from the BRUIN trial of pirtobrutinib in patients with MCL were presented.25
BRUIN 2-Year Update: Study Design
The phase I/II BRUIN trial examined the efficacy and safety of pirtobrutinib in previously treated patients with NHL or CLL/SLL.25 The study included patients with MCL who had received ≥2 prior therapies including a covalent BTK inhibitor. Patients had an ECOG PS of 0-2. The primary endpoint was maximum tolerated dose and recommended phase II dose for the phase I portion of the trial and ORR for the phase II portion.
BRUIN 2-Year Update: Baseline Characteristics
The MCL patient population included 90 patients with prior exposure to a covalent BTK inhibitor and 14 patients with BTK inhibitor‒naive disease. The patient population is very typical of what is seen normally in MCL, including mostly older patients and an overwhelming representation of male patients. Of note, molecular characteristics were not available for approximately 60% of patients. For those with available molecular characteristics, approximately 20% of patients had MCL harboring TP53 mutations, and approximately 30% of patients had a Ki-67 index of ≥30%.
BRUIN 2-Year Update: Prior Therapy
The median number of previous lines of therapy was 3 (range: 1-8) for patients who had received a prior BTK therapy. For patients who were BTK inhibitor naive, the median number of previous lines of therapy was 2 (range: 1-3). Prior therapies received include an anti-CD20 antibody, chemotherapy, an IMiD, stem cell transplant, anti-BCL2 therapy, CAR T-cell therapy, and a PI3 kinase inhibitor. These prior therapies are representative of those typically used for patients with R/R MCL.
BRUIN 2-Year Update: Efficacy Summary
After a median follow-up of approximately 2 years, the ORR was 56.7%, including a CR rate of 18.9% among the 90 patients who had previously received a covalent BTK inhibitor. In the subgroup of 14 patients without any prior exposure to a covalent BTK inhibitor, the ORR was 85.7%, including a CR rate of 42.9%.
For patients with previous exposure to a covalent BTK inhibitor, the median DoR, PFS, and OS were 17.6, 7.4, and 23.5 months, respectively.
In the cohort of patients with covalent BTK-naive MCL, however, the median DoR, PFS, and OS were not reached at the time of data cutoff. The 18‑month DoR, PFS, and OS rates in this patient cohort were 100%, 92%, and 92.3%, respectively, which are quite high.
BRUIN 2-Year Update: Efficacy in Subgroups
The ORR and median DoR appear to be similar regardless of the Ki-67 index category. The median PFS was numerically better among patients with TP53 mutation‒negative MCL (7.4 months) compared with those harboring the TP53 mutation (5.2 months). Overall, the ORR was 71% in patients who have received >3 lines of therapy and 49.2% in those who have received ≤3 prior lines of therapy.
BRUIN 2-Year Update: Safety
Pirtobrutinib is a well-tolerated noncovalent BTK inhibitor. Fatigue is relatively common in this patient population, but bruising, rash, and arthralgias are class effects that occur at a lower rate than would be expected for the approved covalent BTK inhibitors.
BRUIN 2-Year Update: Clinical Implications
Pirtobrutinib has a novel mechanism of inhibiting BTK, which—unlike the available covalent BTK inhibitors—does not require irreversible binding to the kinase. The patient population in the BRUIN trial included patients who both had and had not previously received a covalent BTK inhibitor.
The ORR was 56.7% for those who had previously received a covalent BTK inhibitor, with a median DoR of 17.6 months. For patients without any prior exposure to a covalent BTK inhibitor, the ORR was 85.7%, with a median DoR that has not yet been reached. These results are impressive. However, the median PFS of 7.4 months demonstrated in the group of patients with previous exposure to a covalent BTK inhibitor is modest. For these patients, it will be difficult to determine the next line of treatment, especially for those who have previously received a covalent BTK inhibitor and an IMiD.
The ongoing phase III BRUIN-MCL-321 trial is a head-to-head study investigating the efficacy and safety of pirtobrutinib vs investigator’s choice of covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) for patients with MCL who have received ≥1 prior line of therapy, including those with BTK inhibitor‒naive disease (NCT04662255). This phase III study aims to move pirtobrutinib earlier in the MCL treatment landscape. We eagerly await the results from the BRUIN-MCL-321 trial to confirm the observations made in the phase I/II BRUIN trial, especially in patients with covalent BTK inhibitor‒naive MCL.
TRANSCEND CLL 004: Study Design
The phase I/II TRANSCEND CLL 004 study evaluated lisocabtagene maraleucel (liso-cel), an autologous CD19-directed CAR T-cell therapy, in 117 patients with R/R CLL/SLL after ≥2 previous lines of therapy, including those who were ineligible for or failed prior BTK inhibitor therapy.
Eligible patients received liso-cel at either of 2 dose levels. Patients received a target dose of either 50 x 106 CAR T-cells (dose level 1) or 100 x 106 CAR T-cells (dose level 2) after lymphodepletion with or without bridging therapy. The primary endpoint was the rate of CR/ and CR with incomplete marrow recovery (CRi) by IRC per the 2018 International Workshop on CLL criteria.
At ASCO 2023, the key datasets that were reported were on patients treated at the full dose and patients who already had experienced treatment failure of both a BTK inhibitor and a BCL2 inhibitor, as these are currently some of the most challenging patients with CLL/SLL seen in clinical practice.26,27
TRANSCEND CLL 004: Baseline Characteristics
Among the 70 patients who had experienced treatment failure of both a BTK inhibitor and a BCL2 inhibitor (venetoclax), the median age was 66 years, and the median number of previous lines of therapy received was 5 (range: 2-12). Of these patients, 46% had bulky lymph nodes, and 79% received bridging therapy.
TRANSCEND CLL 004: Efficacy
The IRC-assessed CR/CRi rate was 18% in the full study population of 87 evaluable patients and in the 49 evaluable patients with progression on a BTK inhibitor and venetoclax failure. In the latter subgroup of patients, the IRC-assessed ORR was 43%, the PR/near PR rate was 24%, and the rate of undetectable MRD (uMRD) was 63% in the blood and 59% in the bone marrow. Although liso-cel is active in this patient population, a higher ORR is desirable. Of note, liso-cel was not given concurrently with any BTK inhibitor in this study.
TRANSCEND CLL 004: PFS by Best Overall Response
The median PFS is highly contingent on the type of response achieved. For patients who achieved a CR, the response is durable, and the median PFS is longer. After a median follow-up of 20.8 months, the median PFS in patients with disease progression on a BTK inhibitor and venetoclax failure who achieved a CR was not reached. For those who achieved a PR, the median PFS was 11.9 months, whereas it was very poor (3.7 months) for nonresponders. Therefore, achieving a CR is very important for patients for whom liso-cel is administered.
TRANSCEND CLL 004: OS by Best Overall Response
A similar pattern was observed regarding OS. After disease progression on a BTK inhibitor and venetoclax failure, the median OS was not reached for patients who achieved a CR to liso-cel. For those who achieved a PR, the median OS was 30.3 months, whereas it was only 10.7 months for nonresponders. These results confirm that the management of the disease in nonresponders can be very challenging.
TRANSCEND CLL 004: TEAEs of Special Interest
CRS is a fairly prominent TEAE observed in 85% of the full study patient population (grade 1: 37%; grade 2: 39%; grade 3: 9%). The median time to the first onset or resolution of CRS was 7 days. Neurologic events also are notable with liso-cel, affecting 45% of patients (grade 1: 11%; grade 2: 15%; grade 3: 18%; grade 4: 1%). No grade 4/5 CRS or grade 5 neurotoxicities were reported. Other TEAEs of special interest included prolonged cytopenia (54%) and grade ≥3 infections (17%).
TRANSCEND CLL 004: Conclusions
CAR T-cell therapy has transformed the management of several lymphoproliferative conditions, but it has not yet been approved in CLL/SLL. Ironically, CLL was one of the first disease states where CAR T-cell therapy responses were first documented. TRANSCEND CLL 004 investigated liso-cel in patients with CLL who had previously received a BTK inhibitor and a BCL2 inhibitor. This is a patient population with a considerable unmet clinical need and for whom no strong SoC exists. These patients often receive PI3 kinase inhibitors or chemoimmunotherapy, but the DoR with these approaches has been disappointing.
For patients who achieved a CR, the median PFS and OS results are very impressive. For those who achieved a PR, it appears that many had early relapse followed by a “plateau on the curve,” suggesting that a subset of these patients also may achieve very durable responses. In the case of nonresponding patients, the median PFS was very limited at <4 months, with OS of <1 year. These results highlight the acuity of the disease in this patient population.
A041702: Study Design
The randomized phase III A041702 study examined the efficacy and safety of response-based fixed-duration or continuous ibrutinib in combination with obinutuzumab with or without venetoclax in 465 patients aged 65 years and older with previously untreated intermediate-risk or high‑risk CLL with an ECOG PS of 0-2. Patients who achieved any response on the triplet arm continued ibrutinib. On the doublet arm, patients who achieved uMRD discontinued ibrutinib, and those with any other response continued ibrutinib. The primary endpoint was PFS.
At ASCO 2023, survival outcomes and treatment safety were reported.28
A041702: Baseline Characteristics
The inclusion criterion of 65 years of age and older mirrors that of the GLOW trial, where the combination of ibrutinib and venetoclax was studied and noted to be somewhat challenging in older patients.29 This contrasts with the more favorable results achieved for patients 70 years of age and younger in the CAPTIVATE study.30
A041702: PFS
The probability of PFS in the overall population was similar in both treatment arms; the triplet combination was not superior to the doublet (HR: 1.12; 95% CI: 0.70-1.79).
A041702: PFS With COVID-19 Deaths Censored
Regarding PFS after censoring deaths due to COVID-19, there was no significant difference in PFS between treatment arms (HR: 0.82; 95% CI: 0.70-1.79).
A041702: Grade 3-5 AEs
Of note, the A041702 trial was conducted during the COVID-19 pandemic, and there seemed to be an imbalance of toxicity, with more patients in the experimental triplet arm experiencing COVID‑19‒related AEs. In addition, rates of hematologic toxicity were higher among patients who received the triplet regimen (61%) vs those who received the doublet regimen (48%; P = .006).
A041702: Conclusions
The A041702 trial results are similar to those obtained in the randomized phase III GAIA/CLL13 study for fit patients with previously untreated CLL, in which the PFS advantage with the triplet regimen containing ibrutinib, obinutuzumab, and venetoclax vs the doublet regimen containing obinutuzumab and venetoclax was modest, and this advantage was offset by increased toxicity.31
The A041702 trial addresses the question of whether a triplet combination of ibrutinib, obinutuzumab, and venetoclax is superior to a doublet combination of ibrutinib and obinutuzumab as first-line therapy for patients aged 65 years and older with CLL/SLL. In summary, this triplet combination was not superior to ibrutinib plus obinutuzumab in older patients with CLL/SLL, and there was a higher incidence of hematologic toxicities and COVID-19 infection among patients who received the triplet regimen. These results further suggest that although some datasets may demonstrate benefit with the addition of obinutuzumab to a BTK inhibitor, the optimal combination approach for the inclusion of obinutuzumab and a BTK inhibitor remains unknown.
TRANSCEND CLL 004 and A041702: Clinical Implications
The treatment of CLL/SLL continues to evolve as more novel agents—such as noncovalent BTK inhibitors and BTK degraders, as well as new approaches including cellular therapies—are being developed. In addition, the field is still seeking to develop novel approaches for the optimization of already available agents, including BTK inhibitors, BCL2 inhibitors, and anti-CD20 antibodies.
To this end, several ongoing trials are evaluating multiple treatment combinations in the upfront and R/R CLL settings. The randomized phase III CLL17 study is investigating ibrutinib alone or in combination with venetoclax vs obinutuzumab plus venetoclax for patients with previously untreated CLL/SLL (NCT04608318). Also, the randomized phase III MAJIC trial is evaluating venetoclax in combination with either acalabrutinib or obinutuzumab for patients with previously untreated CLL/SLL (NCT05057494). For patients with R/R CLL/SLL, the randomized phase III BRUIN-CLL-322 trial is investigating venetoclax in combination with rituximab with or without pirtobrutinib (NCT04965493). These ongoing trials will help identify optimal treatment combinations to maximize efficacy without additional toxicities in the management of patients with CLL/SLL.
JACKPOT8 Part B: Study Design
JACKPOT8 is an open-label, multipart phase II study assessing the efficacy and safety of golidocitinib, an orally available, highly selective JAK1 inhibitor, in patients with R/R peripheral T-cell lymphoma (PTCL) and an ECOG PS ≤2. The primary endpoint was IRC-assessed ORR based on CT images per Lugano 2014 criteria.
At ASCO 2023, primary results from part B of the study in 112 patients with R/R PTCL who received a daily dose of golidocitinib (150 mg) were reported.32
JACKPOT8 Part B: Baseline Characteristics
The median age was 58 years (range: 20-79), 34.8% of patients were female, and 19.6% of patients had bone marrow involvement at baseline. The median number of prior lines of therapy was 2 (range: 1-3). Previous treatments received include chemotherapy (98.2%), a histone deacetylase inhibitor (45.5%), and a CD30-directed therapy (16.1%). The majority of patients had PTCL, NOS (45.5%). Other histologic subtypes included angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large-cell lymphoma (ALCL) (14.3% and 9.8%, respectively).
JACKPOT8 Part B: Response
Among 88 efficacy-evaluable patients, the ORR was 44.3%, and 23.9% achieved a CR. A reduction in tumor size from baseline was observed in the majority of patients. After a median follow-up of 6.3 months, the median DoR was not reached.
JACKPOT8 Part B: Response by Histology Subtype
The ORR varied by histologic subtype, and two thirds of patients with natural killer T-cell lymphoma (NKTCL) achieved a response. Of 50 evaluable patients with PTCL, NOS, 46% achieved a response, and the ORR among 16 patients with AITL was 56.3%. Of interest, of the 10 patients with ALCL, only 1 (10%) was responsive to treatment.
In general, antitumor efficacy was observed across all subgroups evaluated, including age, ECOG PS, and baseline bone marrow involvement.
JACKPOT8 Part B: Duration of Treatment and Dose Intensity
The median duration of treatment was 1.6 months, and the median actual dose intensity was 150 mg/day. The median relative dose intensity was 100%. The majority of patients (61.6%) received treatment for >3 months, whereas only approximately 9% of patients received treatment for ≥12 months.
JACKPOT8 Part B: Safety Summary
The most common grade ≥3 TRAEs were hematologic, including neutrophil count decreased (24.1%), WBC count decreased (23.2%), platelet count decreased (17%), and lymphocyte count decreased (16.1%). TRAEs leading to dose interruption, reduction, and discontinuation occurred in 37.5%, 8.0%, and 6.3% of patients, respectively. One death due to TRAEs was reported.
JACKPOT8 Part B: Clinical Implications
T-cell lymphoma remains an area of considerable unmet clinical need. It is unlikely that the field will advance forward by a reshuffling of existing conventional cytotoxic agents; therefore, novel therapies are urgently needed. In the JACKPOT8 study, golidocitinib yielded impressive results, with an ORR of 44.3% after a median follow-up of 6.3 months. The ORR for patients with PTCL, NOS; AITL; and NKTCL ranged from 46% to 66.7%. If these ORRs are durable with additional follow-up, golidocitinib is likely to gain further traction in the field.
Lymphomas/CLL/SLL: Overall Conclusions
These are exciting times in the lymphoma field. Several drugs have recently received FDA approval, and data updates for numerous drugs were presented at ASCO 2023.
This year at ASCO, several important updates from studies of lymphoid malignancies coincided with recent FDA approvals, including pirtobrutinib in MCL and epcoritamab and glofitamab in DLBCL. The nivolumab plus AVD results from the SWOG S1826 trial were quite surprising and will change the frontline treatment landscape for cHL.
The current momentum in lymphoid malignancies is remarkable. Standards of care for frontline DLBCL have evolved for the first time in approximately 20 years. Bispecific antibodies have been approved in R/R FL and DLBCL, and we expect to see this class of agents move into earlier lines of treatment. Cellular therapies are evolving, and they continue to have a meaningful impact on patients with lymphoid malignancies.
Finally, regarding CLL/SLL, this field has been completely upended by novel agents, and the space continues to be refined by important datasets.
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