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Key Studies in Hematologic Malignancies: Independent Conference Coverage of the 2021 ASCO Scientific Meeting
  • CME

Ian W. Flinn, MD, PhD
Shaji K. Kumar, MD
Eunice S. Wang, MD
Released: September 13, 2021

Lymphomas

ELEVATE-RR: Background

Ian W. Flinn MD, PhD:
ASCO 2021 had numerous important presentations for patients with lymphoma, with potentially paradigm-changing treatment options, including in CLL.

Bruton tyrosine kinase (BTK) is a key driver of CLL proliferation and survival. Ibrutinib is the first irreversible BTK inhibitor approved for CLL and small lymphocytic lymphoma (SLL). Ibrutinib can bind to non-BTK kinases, and these off-target effects likely contribute to AEs.50-53 Cardiovascular and other AEs can necessitate treatment discontinuation, so next-generation BTK inhibitors more specific to BTK have been developed.54-56

Acalabrutinib is a next-generation irreversible BTK inhibitor that shows more selective binding to BTK with decreased off-target activity vs ibrutinib in vitro and is approved for adults with CLL/SLL and adults with MCL with ≥1 prior treatment.50,57

The current study reports initial results from ELEVATE-RR, the first head-to-head trial comparing the safety and efficacy of acalabrutinib vs ibrutinib in patients with previously treated CLL.58

ELEVATE-RR: Acalabrutinib vs Ibrutinib in Previously Treated CLL: Study Design

Ian W. Flinn MD, PhD:
The open-label phase III noninferiority trial ELEVATE-RR randomized 533 adults with previously treated CLL and del(17p) or del(11q) to receive acalabrutinib or ibrutinib.58

Patients could not have significant cardiovascular disease or prior exposure to BTK inhibitors or the BCL-2 inhibitor venetoclax. The primary endpoint was noninferiority of IRC-assessed PFS, and secondary endpoints included OS, any-grade atrial fibrillation/flutter, and grade ≥3 infection.

ELEVATE-RR: Baseline Characteristics

Ian W. Flinn MD, PhD:
Patients in both groups were a median 65 years of age, and 43% were 75 years of age and older.58 Patients in both arms had a similar incidence of bulky disease and Rai stage 3 or 4 disease. Cytogenic abnormalities were well balanced between the arms, although the frequency of del(17p) was notably higher compared with previous studies.

ELEVATE-RR: IRC-Assessed PFS, Acalabrutinib vs Ibrutinib (Primary Endpoint)

Ian W. Flinn MD, PhD:
The median PFS for both acalabrutinib and ibrutinib was 38.4 months (HR: 1.00; 95% CI: 0.79-1.27) at a median follow-up of 40.9 months.58 PFS was similar across patient subgroups, including age, sex, bulky disease, TP53 mutation status, complex karyotype, and number of prior therapies.

ELEVATE-RR: Secondary Endpoints

Ian W. Flinn MD, PhD:
The incidence of any-grade atrial fibrillation and flutter was significantly improved with acalabrutinib vs ibrutinib at 9.4% vs 16.0% (P = .02).58 However, the incidence of grade ≥3 atrial fibrillation and flutter was similar between the arms, affecting 4.9% of patients receiving acalabrutinib and 3.8% of patients receiving ibrutinib.

Approximately 30% of all patients in each arm developed grade ≥3 infection (P = .8777). In this analysis, median OS was not estimable in either arm (HR: 0.82; 95% CI: 0.59-1.15).

ELEVATE-RR: Safety

Ian W. Flinn MD, PhD:
Any-grade AEs affected slightly more than 97% of patients in each arm.58 The incidence of grade ≥3 AEs was slightly lower in patients receiving acalabrutinib vs ibrutinib at 68.8% vs 74.9%, respectively. There also were fewer AEs leading to treatment discontinuation in patients receiving acalabrutinib vs ibrutinib (14.7% vs 21.3%). The incidence of serious AEs and deaths due to AEs also was slightly lower with acalabrutinib vs ibrutinib. These data are in keeping with acalabrutinib having fewer off-target effects than ibrutinib.

ELEVATE-RR: Most Common AEs

Ian W. Flinn MD, PhD:
Any-grade AEs that had a significantly higher incidence in patients receiving acalabrutinib vs ibrutinib were headache (34.6% vs 20.2%) and cough (28.9% vs 21.3%).58 Headache is an AE unique to acalabrutinib that is not seen with other BTK inhibitors. The good news is that it is usually grade 1 or 2 and is generally self-limiting, resolving between 10 days and a few weeks, and sometimes treatable with caffeine.

AEs with a higher incidence with ibrutinib vs acalabrutinib were diarrhea (46.0% vs 34.6%), arthralgia (22.8% vs 15.8%), and hypertension (22.8% vs 8.6%). Overall, patients receiving acalabrutinib had fewer AEs affecting quality of life than patients receiving ibrutinib.

ELEVATE-RR: AEs of Clinical Interest

Ian W. Flinn MD, PhD:
The incidence of any-grade bleeding events and hypertension were significantly reduced with acalabrutinib vs ibrutinib (38.0% vs 51.3% and 9.4% vs 23.2%, respectively), but there was not a significant difference in infections.58

ELEVATE-RR: Cumulative Incidence of AEs of Clinical Interest, Any Grade (Acalabrutinib vs Ibrutinib)

Ian W. Flinn MD, PhD:
The cumulative incidence of atrial fibrillation, flutter, hypertension, bleeding, diarrhea, and arthralgias all favored acalabrutinib, with HRs ranging from 0.34 for hypertension to 0.63 for bleeding events.58

ELEVATE-RR: Conclusions

Ian W. Flinn MD, PhD:
The data from ELEVATE-RR show that acalabrutinib is noninferior to ibrutinib for IRC-assessed PFS in previously treated patients with CLL.58 Acalabrutinib also demonstrated a reduced incidence of multiple AEs compared with ibrutinib. Because this was a head-to-head comparison, I think these data give credence to using acalabrutinib over ibrutinib for most patients with previously treated CLL. In addition, because of acalabrutinib’s improved safety profile, healthcare professionals may choose to use this as the preferred BTK inhibitor in the frontline setting, as well.

However, it is unclear whether acalabrutinib is superior to zanubrutinib. The ALPINE study presented at the European Hematology Association 2021 Virtual Congress found that zanubrutinib had superior PFS and safety vs ibrutinib, with a minor trend toward improvement in OS.59 Currently, however, there are no head-to-head trial results of zanubrutinib with acalabrutinib. Of course, zanubrutinib does not have an FDA indication in CLL, but if zanubrutinib is approved for patients with CLL/SLL by the FDA, healthcare professionals will have another BTK inhibitor option for their patients.

ELEVATE-TN 4-Year Follow-up: Background

Ian W. Flinn MD, PhD:
Acalabrutinib received FDA approval for patients with treatment-naive CLL/SLL based on interim results of the phase III ELEVATE-TN trial comparing acalabrutinib (A) with or without the anti-CD20 antibody obinutuzumab (O) vs A alone vs O plus chlorambucil (Clb).60

After a median follow-up of 28.3 months, the trial met its primary endpoint by showing significantly prolonged IRC-assessed median PFS with A + O vs O + Clb (NR vs 22.6 months; HR: 0.10; 95% CI: 0.06-0.17; P <.0001). The current report presents an updated analysis of efficacy and safety outcomes for ELEVATE-TN with a median follow-up of 4-years.61

Acalabrutinib + Obinutuzumab vs Obinutuzumab + Chlorambucil in Untreated CLL (ELEVATE-TN) 4-Year Follow-up: Study Design

Ian W. Flinn MD, PhD:
ELEVATE-TN is an international, open-label, randomized phase III trial of A + O vs A vs O + Clb in 535 patients with untreated CLL.60-61 Acalabrutinib therapy was continued until disease progression or unacceptable toxicity. Crossover was permitted from the O + Clb arm to the A-only arm after IRC-determined disease progression.

The primary endpoint was IRC-assessed PFS for A + O vs O + Clb; after interim analysis, PFS was assessed by investigator. Secondary and other endpoints included investigator-assessed PFS, ORR, TTNT, OS, undetectable MRD (uMRD), and safety.

ELEVATE-TN 4-Year Follow-up: Baseline Characteristics

Ian W. Flinn MD, PhD:
Patients were a median of 70-71 years of age.61 In total, 12% to 14% of patients had del(17p) and/or TP53 mutation, and 17% to 18% had del(11q). As these patients are receiving initial treatment, it makes sense that the incidence of cytogenic alterations was lower than what we see in relapsed patient populations. Overall, the risk profile of these patients was similar to what has been described in previous studies of frontline CLL.

ELEVATE-TN 4-Year Follow-up: Patient Disposition and Exposure

Ian W. Flinn MD, PhD:
At a median follow up of 46.9 months, the median treatment exposure was 46.6 months with A + O vs 45.7 months with A alone.61 Exposure in the O + Clb arm was 5.6 months because it was meant as a fixed-duration therapy rather than ongoing treatment. Treatment is ongoing in 74.9% of patients in the A + O arm and 69.3% of patients in the A monotherapy arm.

ELEVATE-TN 4-Year Follow-up: PFS (Primary Endpoint)

Ian W. Flinn MD, PhD:
Median PFS in the overall population was NR with A + O (HR: 0.10; 95% CI: 0.07-0.17; P <.0001) or A (HR: 0.19; 95% CI: 0.13-0.28; P <.0001) vs 27.8 months with O + Clb. The 48-month PFS rate was 87% and 78% vs 25%, respectively.61 There was a PFS benefit with A + O or A vs O + Clb across all cytogenetic subgroups.

ELEVATE-TN 4-Year Follow-up: ORR, MRD, and OS

Ian W. Flinn MD, PhD:
ORR was 96.1% with A + O vs 89.9% with A alone and 82.5% with O + Clb.61 The CR rate in patients receiving A + O was 30.7% vs only 11.2% in patients receiving A alone and 13.0% in patients receiving O + Clb. Patients who achieved CR/CRi with A + O had a 38% rate of uMRD compared with 10% of patients receiving A alone and 9% of patients receiving O + Clb.

The 48-month OS rate was 93% with A + O vs 88% for both A and O + Clb. Median OS was NR for any of the treatment arms but was nonsignificantly prolonged with A + O.

ELEVATE-TN 4-Year Follow-up: Most Common AEs

Ian W. Flinn MD, PhD:
AEs were similar with A + O and A alone, although the incidence of any-grade neutropenia was 33.7% with A + O vs 12.3% with A and 45.0% with O + Clb. Grade ≥3 neutropenia was 30.9% vs 11.2% and 41.4%, respectively.61 Overall, the combination of A + O was well tolerated, and the most common AEs were consistent between the interim and updated analyses.

ELEVATE-TN 4-Year Follow-up: Events of Clinical Interest

Ian W. Flinn MD, PhD:
Patients who received A + O did not have a significantly increased incidence of cardiac toxicity, bleeding, hypertension, or infections compared with patients who received A alone, although all but hypertension were considerably higher than in the O + Clb arm.61

ELEVATE-TN 4-Year Follow-up: Conclusions

Ian W. Flinn MD, PhD:
In this updated analysis of the phase III ELEVATE-TN trial, A + O maintained efficacy and safety vs O + Clb in patients with treatment-naive CLL.61 Median PFS was significantly longer with A + O vs O + Clb (NR vs 27.8 months) and was consistently prolonged in patients with del(17p) and/or TP53 mutation, mutated IGHV, and unmutated IGHV. The safety profiles of A + O and A alone were consistent with previous analyses.

The estimated 48-month PFS rates favored A + O vs A alone (87% vs 78%), but at this point there is not a clear difference in OS. So, healthcare professionals may choose to continue using A alone based on patient preferences or difficulties in giving infusions.

ELEVATE-TN is an important trial for several reasons. It shows that the addition of an anti-CD20 antibody to a BTK inhibitor may improve efficacy, which is not true with the addition of rituximab to ibrutinib. Whether it is specific to obinutuzumab or acalabrutinib is unclear. But if I were to use a CD20 antibody with a BTK inhibitor, it would be obinutuzumab rather than rituximab, and I would only combine obinutuzumab with acalabrutinib.

CAPTIVATE FD Cohort: Background

Ian W. Flinn MD, PhD:
Targeted therapy with a BTK inhibitor (ibrutinib or acalabrutinib) or venetoclax is now the standard of care for patients with CLL. Oral ibrutinib has shown significant OS benefit as first-line therapy in phase III trials and is approved for patients with CLL/SLL.62-63 Venetoclax yields high rates of uMRD and is approved as a single-agent treatment or with anti-CD20 mAbs for patients with CLL/SLL.64 Preclinical and early clinical evidence suggest that ibrutinib and venetoclax have complementary and synergistic activity with nonoverlapping toxicities.65-67

The phase II CAPTIVATE trial is assessing safety and efficacy of first-line ibrutinib for 3 cycles followed by 12 cycles of ibrutinib plus venetoclax in patients with CLL/SLL.68 Patients were divided into an MRD-guided cohort and a fixed-duration cohort. Data from the MRD-guided cohort was impressive, with a 30-month PFS rate of ≥95% regardless of subsequent treatment. But it is still unclear how to incorporate MRD results into clinical decision-making, so this fixed-duration cohort is important.69

CAPTIVATE FD Cohort: Fixed Duration Ibrutinib + Venetoclax in Untreated CLL/SLL Study Design

Ian W. Flinn MD, PhD:
CAPTIVATE is an international, randomized trial that enrolled 159 patients 70 years of age and older with previously untreated CLL.69 Patients received 3 cycles of ibrutinib followed by 12 cycles of ibrutinib plus venetoclax before stopping therapy. Upon disease progression, patients could be eligible for retreatment with single-agent ibrutinib or fixed-dose ibrutinib plus venetoclax if they had a durable response.

The primary endpoint was CR/CRi rate per investigator assessment in patients without del(17p) with supporting analyses in the all-treated population. Secondary endpoints included ORR, DoR, uMRD rates, PFS, OS, and safety.

CAPTIVATE FD Cohort: Disposition and Tx Exposure

Ian W. Flinn MD, PhD:
Almost all patients completed the lead-in phase (94%) and 12 cycles of ibrutinib plus venetoclax (92%).69 The median time on study was 27.9 months, with a median treatment duration of 13.8 months and a median follow-up after treatment completion of 14.0 months.

CAPTIVATE FD Cohort: Baseline Characteristics

Ian W. Flinn MD, PhD:
As we saw with the ELEVATE-TN study in the frontline setting, the incidence of TP53 mutations is lower than what is seen in the R/R setting.61,69 Still, 17% of patients had del(17p) or TP53 mutation, and 19% had a complex karyotype, so this was a relatively high-risk population compared with the average frontline patient with CLL whom you see in the clinic. Patient baseline characteristics were consistent with the MRD-guided cohort.68

CAPTIVATE FD Cohort: Responses

Ian W. Flinn MD, PhD:
The ORR was very high in all treated patients at 96%, with a CR/CRi of 55%.69 Responses in patients with and without del(17p) were similar. The follow-up is relatively short, but a duration of CR ≥12 cycles was seen in 89% of all treated patients. The CR rate remained high across most patient subgroups, although the rate was lower with bulky disease.

CAPTIVATE FD Cohort: Supporting Analyses

Ian W. Flinn MD, PhD:
The combination of ibrutinib and venetoclax led to very high rates of uMRD.69 Patients without del(17p) had a uMRD rate of 76% in the peripheral blood vs 77% in all patients and 62% vs 60%, respectively, in the bone marrow. Patients with and without bulky disease had a uMRD rate of 77% in peripheral blood and 63% vs 59% in the bone marrow.

In addition, uMRD rates were very high across subgroups. Patients with unmutated IGHV appeared to have higher rates of uMRD in the peripheral blood vs mutated IGHV, but I suspect this is not a significant finding because biologically you would expect the opposite. Ibrutinib lead-in before combination therapy decreased the risk of tumor lysis syndrome in 94% of patients with baseline high risk, which is another secondary, but important, benefit for this regimen.

CAPTIVATE FD Cohort: PFS and OS

Ian W. Flinn MD, PhD:
The 24-month PFS rate was 96% in patients without del(17p) and 95% in all treated patients.69 The 24-month OS rate was 98% regardless of del(17p) status. The PFS rates are arguably some of the best that we have ever seen, although the follow-up was very short.

CAPTIVATE FD Cohort: Safety Summary

Ian W. Flinn MD, PhD:
No unexpected safety signals were observed with this regimen.69 Diarrhea occurred in 62% of patients but was primarily grade 1/2 and was not unexpected based on the AE profile of the single agents. Nausea, again mostly grade 1/2, occurred in 43% of patients. There was substantial incidence of neutropenia at 42%, with 33% of patients developing grade 3/4 neutropenia. However, neutropenia is a known AE associated with venetoclax, and combination therapy did not appear to increase the incidence. The other most common grade 3/4 AEs were infections and hypertension.

At 4%, the incidence of atrial fibrillation was relatively low compared with other studies with ibrutinib, and that may be due to this being a time-limited therapy. When patients receive continuous therapy with ibrutinib, it increases the cumulative incidence. So, one benefit of using time-limited therapy is that AEs may quickly correct themselves when therapy is stopped.

CAPTIVATE FD Cohort: Discontinuations/Dose Reductions

Ian W. Flinn MD, PhD:
AEs led to treatment discontinuation in 5% of patients and dose reduction in 21% of patients.69 At the time of analysis, 88% of patients who had AEs leading to dose reduction had resolution.

CAPTIVATE FD Cohort: Conclusions

Ian W. Flinn MD, PhD:
In patients with previously untreated CLL/SLL, ibrutinib plus venetoclax resulted in a CR/CRi rate of 55%.69 The uMRD rate was similar in the peripheral blood and bone marrow in patients with and without high-risk features. The uMRD rates remained high across most patient subgroups, and 2-year PFS was 95%, with a 2-year OS of 98%.

Treatment was generally well tolerated with few discontinuations. Results in the fixed-duration cohort are generally comparable with the MRD-guided cohort and suggest that this regimen can lead to durable responses.

CAPTIVATE was an important trial, and I hope these results will lead to FDA approval of the ibrutinib plus venetoclax regimen for patients with previously untreated CLL. Because this therapy is all oral and fixed duration, it is ideal for young, fit patients with CLL/SLL who prefer to receive treatment in the outpatient setting.

Many will wonder whether it is better to hold the BTK inhibitor for progression rather than use it as a frontline therapy. That question was not answered in this study, but nothing suggests that you should not use these agents alone or in combination after progression.

Venetoclax, Lenalidomide, Rituximab in Untreated MCL: Background

Ian W. Flinn MD, PhD:
There is substantial heterogeneity in the treatment of patients with MCL, but it is typically treated with chemotherapy, with more intensive regimens selected for younger, fit patients and less toxic regimens plus rituximab selected for older, unfit patients. Lenalidomide plus rituximab has shown durable efficacy as an initial treatment of MCL regardless of age, and venetoclax has shown efficacy in R/R MCL and may synergize with lenalidomide.70-72

The current phase Ib study evaluated safety and efficacy of adding venetoclax to lenalidomide and rituximab in patients with untreated MCL.73

Venetoclax, Lenalidomide, Rituximab in Untreated MCL: Study Design

Ian W. Flinn MD, PhD:
This single-arm, open-label, multicenter phase Ib trial enrolled 28 adult patients with untreated MCL to receive lenalidomide, venetoclax, and rituximab for 12 months.73 Patients who did not develop disease progression or receive transplant continued lenalidomide for 2 years, venetoclax for 1 year, and rituximab for 3 years.

The primary endpoint is safety and tolerability, and to determine the MTD. Secondary endpoints are response assessed by PET/CT scan and MRD testing after cycles 3, 6, 9, and 12.

Venetoclax, Lenalidomide, Rituximab in Untreated MCL: Baseline Characteristics

Ian W. Flinn MD, PhD:
Patients were a median of 65 years of age with good performance status and Ann Arbor stage III or IV disease, and 23 patients (93%) had bone marrow involvement.73

Because 18 patients (64%) had a high MCL International Prognostic Index score and 10 (36%) had an intermediate score, these were high-risk patients compared with the average patient with MCL.

Venetoclax, Lenalidomide, Rituximab in Untreated MCL: Exposure and Safety

Ian W. Flinn MD, PhD:
Dose reduction or delay in therapy occurred in 15 patients (53%).73 In total, 21% of patients had a dose reduction or delay due to treatment-related AEs. In 3% of cases, this was related to COVID-19, and in the remaining 18%, it was related to other causes.

As you might expect from the safety profile of venetoclax and lenalidomide, one of the most common AEs was neutropenia. In some studies, rituximab can synergize with other agents to cause neutropenia, so it is not surprising. Although neutropenia was the most common grade 3/4 AE, thrombocytopenia also was common. Fortunately, there was only 1 case each of grade 3 and grade 4 diarrhea. There were no dose limiting toxicities, so all patients were escalated to the 400-mg dose of venetoclax.

Venetoclax, Lenalidomide, Rituximab in Untreated MCL: Efficacy

Ian W. Flinn MD, PhD:
Not all patients have reached the 12-month landmark for response assessment, but the responses are impressive, with 67% of patients achieving CR at 3 months and all patients achieving CR at 12 months.73 The uMRD rate was equally impressive and shows that this regimen induces very deep remissions. At 6 months, 77% of patients had achieved uMRD, which rose to 92% at 12 months. Estimated PFS was 85.5% at the 12‑month mark.

Venetoclax, Lenalidomide, Rituximab in Untreated MCL: Conclusions

Ian W. Flinn MD, PhD:
The combination of venetoclax, lenalidomide, and rituximab was well tolerated in patients with untreated MCL, with no dose-limiting toxicities reported.73 Preliminary data suggest that the combination may be effective in a mixed MCL population, including in patients with high-risk features. No relapses occurred in patients achieving uMRD. It will be fascinating to see how these data mature, as they are some of the best results we have seen to date in any clinical trial for MCL.

ELARA: Tisagenlecleucel in Adult Patients With FL

Ian W. Flinn MD, PhD:
Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) in the United States and Western Europe.74 Disease recurs in approximately 20% of patients within 2 years of first-line therapy, and most patients experience multiple relapses and poorer clinical outcomes with each line of therapy.75-77

Tisagenlecleucel is an autologous anti-CD19 CAR T-cell therapy approved for patients up to 25 years of age with ALL that is refractory or in second or later relapse, and for adults with R/R diffuse large B-cell lymphoma (DLBCL) after ≥2 therapies.42

This trial evaluated tisagenlecleucel in adult patients with R/R FL to try to move this therapy into a broader patient population.78

Tisagenlecleucel in R/R FL (ELARA): Study Design

Ian W. Flinn MD, PhD:
ELARA is an international, single-arm phase II trial enrolling 97 adult patients with grade I, II, or IIIA R/R FL.78 Following screening apheresis and cryopreservation, patients received optional bridging therapy prior to restaging and lymphodepletion and infusion with tisagenlecleucel. Posttreatment follow-up was every 3 months for 1 year and then every 6 months until study end. The primary endpoint is CR, and secondary endpoints are ORR, DoR, PFS, OS, safety, and cellular kinetics.

ELARA: Baseline Characteristics

Ian W. Flinn MD, PhD:
Nearly 80% of patients with FL have a close to normal survival prognosis. To implement a therapy such as CAR-T cells in patients with FL, you would want to only do it in patients who are higher risk. One way of defining it is POD24, which is the group of patients who relapse within 24 months of initial therapy. In this study, 60% of patients had POD24, 78% were refractory to their last therapy, and 76% were refractory to ≥2 regimens.78 Patients had a median of 4 prior therapies, and 28% received ≥5 prior therapies.

ELARA: Efficacy

Ian W. Flinn MD, PhD:
Investigator-assessed ORR was 90.4%, with 69.1% achieving CR. IRC-assessed ORR and CR were comparable.78 This is much higher than what is seen with other drugs currently approved in this setting, such as tazemetostat and PI3K inhibitors, although it is similar to what is seen with another CAR T product, axicabtagene ciloleucel.

ELARA: Safety

Ian W. Flinn MD, PhD:
An important issue in the treatment of FL is drug safety because, as mentioned, patients with FL usually have excellent survival. It is important to be aware that there is a high incidence of neurotoxicity and CRS in large cell lymphomas, which need to be quickly identified and managed.

CRS occurred in 48.5% of patients, but all incidences were grade ≤2. The incidence of neurologic AEs was 9.3%, with 1.0% grade ≥3.78 The safety data suggest that this therapy may be a reasonable option for patients with FL, particularly patients refractory to other agents.

ELARA: Conclusions

Ian W. Flinn MD, PhD:
Tisagenlecleucel resulted in an ORR of 86% and CR of 66% in patients with R/R FL, including high-risk patients who had received multiple lines of prior therapy.78

The safety profile was acceptable and consistent with previous reports, and at least as good as what has been seen with axicabtagene ciloleucel, which is already approved for FL. One hypothesis regarding improved safety of CAR T-cells in FL is that patients with FL develop less inflammation than in some other hematologic malignancies, so they do not develop as many of the AEs seen with CAR T-cell therapy in other settings.

Overall, these exciting data show that tisagenlecleucel is a promising therapy for patients with R/R FL and will—we hope—lead to further study. If approved, I think tisagenlecleucel will be an attractive treatment option for young patients with R/R disease.

EPCORE NHL-1 Update: Background

Ian W. Flinn MD, PhD:
Despite recent treatment advances, prognosis remains poor for patients with R/R B-cell NHL. Although we have seen exciting data with CAR T-cell therapy, they are difficult and expensive to manufacture because they are unique to each patient, leading to issues in access. An off-the-shelf approach to immunotherapy for B-cell malignancies would be an important advancement.

Epcoritamab is a novel bispecific antibody targeting CD3 and CD20.79 The EPCORE NHL-1 study is an ongoing phase I/II trial evaluating single-agent SC epcoritamab in patients with R/R B-cell NHL.80 The current study reports longer follow-up from the trial and includes PFS data.81

Epcoritamab in R/R CD20+ B-cell NHL (EPCORE NHL-1) Update: Study Design

Ian W. Flinn MD, PhD:
In the phase I/II dose-escalation and dose-expansion EPCORE NHL-1 trial, 68 adults with R/R CD20+ B-cell NHL (predominantly DLBCL and FL) previously treated with anti-CD20 mAbs received epcoritamab in a dose-escalation phase and dose-expansion phase.81 Epcoritamab was given SC weekly during cycles 1 and 2, every 2 weeks for cycles 3-6, and monthly thereafter.

Primary endpoints were MTD and RP2D, and secondary endpoints were safety/tolerability and antitumor activity (per Lugano criteria).

EPCORE NHL-1 Update: Baseline Characteristics

Ian W. Flinn MD, PhD:
Patients with R/R DLBCL had received a median of 3 prior lines of therapy, with 80% refractory to their last therapy, 87% refractory to alkylating agents, and 91% refractory to anti-CD20 mAbs.81 Most patients with DLBCL had Ann Arbor stage III/IV disease.

Patients with R/R FL had received a median of 5 prior lines of therapy, and 83% were refractory to their most recent systemic therapy. In total, 75% were refractory to alkylating agents, and 83% were refractory to anti-CD20 mAbs. There were an equal number of patients with Ann Arbor stages II, III, and IV disease.

EPCORE NHL-1 Update: TEAEs

Ian W. Flinn MD, PhD:
The most common TEAE was pyrexia, affecting 63% of patients. Other common TEAEs were CRS (all grade 1/2), which affected 59% of patients, and injection site reaction, which affected 47%.81 There were various manageable AEs, including hypotension and tachycardia, which were largely related to CRS.

EPCORE NHL-1 Update: TEAEs of Special Interest

Ian W. Flinn MD, PhD:
Most patients who developed CRS did so during cycle 1.81 Neurotoxicity was limited and transient, with a median duration of 1.5 days, and was manageable with supportive therapy.

EPCORE NHL-1 Update: Efficacy

Ian W. Flinn MD, PhD:
Ten patients (91%) with R/R DLBCL who received doses of 48-60 mg responded, with 6 (55%) achieving CR and the remainder achieving PR.81 These are very exciting data because the ORR and CR are similar to what we see with CAR T-cells.

Median PFS has not been reached in patients with DLBCL who received higher doses of epcoritamab. Further follow-up will show how durable these remissions are and whether remission rates are similar to what is seen with CAR T-cell therapy.

EPCORE NHL-1 Update: Conclusions

Ian W. Flinn MD, PhD:
The longer follow-up for EPCORE NHL-1 shows manageable safety and encouraging single-agent activity with epcoritamab in R/R B-cell NHL.81 All CRS events were grade 1/2 and resolved with standard supportive care, and ORR was 50% to 91% across histologies and doses. Of the patients who achieved CR, 84% remain in remission.

The phase II expansion portion of the trial is ongoing to further evaluate epcoritamab at the RP2D of 48 mg. Single-agent epcoritamab also is being studied in the phase III EPCORE DLBCL-1 trial vs investigator choice of standard chemotherapy in R/R DLBCL.82

These early data and the data with other bispecific antibodies such as mosunetuzumab are exciting. Bispecific antibodies are showing an acceptable safety profile, high ORR, and high CR, and can be administered subcutaneously. Bispecific antibodies also are an important advance in treating B-cell malignancies, as they increase accessibility to patients with financial or logistical barriers to CAR T-cell therapy. We also need to see further follow up for epcoritamab and other bispecific antibodies.

Summary of Lymphoma Presentations at ASCO 2021

ASCO 2021 had numerous exciting presentations on the treatment of patients with lymphoma. Some of these studies are showing potentially paradigm-changing treatment options available today, with others providing early looks at promising therapies to come. For instance, the data from ELEVATE-RR clearly demonstrate that second-generation BTK inhibitors are superior to ibrutinib. The fixed-duration ibrutinib and venetoclax regimen likely will become an approved treatment option in the near future. Finally, immunotherapy with CAR T-cells or bispecific antibodies continues to expand its role in B-cell lymphomas.

Provided by Clinical Care Options, LLC

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For customer support please email: customersupport@cealliance.com

Mailing Address
Clinical Care Options, LLC
12001 Sunrise Valley Drive
Suite 300
Reston, VA 20191

Supported by educational grants from
AbbVie
AstraZeneca
Bristol-Myers Squibb
GlaxoSmithKline
Novartis Pharmaceuticals Corporation
Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc.
Sanofi Genzyme

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