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Hematologic Malignancies: A Review of Key Clinical Studies

Ian W. Flinn, MD, PhD
Shaji K. Kumar, MD
Farhad Ravandi, MD
Released: September 23, 2020


Phase III KEYNOTE-204: Pembrolizumab vs Brentuximab Vedotin in Relapsed/Refractory Classical Hodgkin Lymphoma

Ian W. Flinn, MD, PhD
Now we will discuss pembrolizumab and nivolumab, 2 immune checkpoint inhibitors that have been approved for patients with R/R Hodgkin lymphoma (HL).[35,36] Brentuximab vedotin (BV), a CD30-targeted antibody–drug conjugate chemotherapy, is also approved for relapsed HL and in other settings, such as consolidation after an ASCT.[37,38] Because BV was approved before checkpoint inhibitors in this setting, many physicians integrated BV into their practice. Prior to this trial, however, there were no head-to-head trials comparing checkpoint inhibitors as a class vs BV in R/R HL. To address this, the KEYNOTE-204 study compared the safety and efficacy of pembrolizumab vs BV in patients with R/R classical HL who relapsed after treatment or were ineligible for ASCT.[39] The primary endpoints were PFS by blinded independent central review (BICR) and OS. Secondary endpoints included ORR, PFS (per investigator review), DoR, and safety.

The baseline characteristics were well balanced in the pembrolizumab and BV arms. In the pembrolizumab arm, participants had a median of 2 previous therapies vs 3 in the BV arm; overall, however, the characteristics were similar.

KEYNOTE-204: Disposition of Treated Patients

Ian W. Flinn, MD, PhD
In this trial, 20.3% of patients in the pembrolizumab arm and 22.4% in the BV arm had had an ASCT, and 9.5% of patients in the pembrolizumab arm and 8.6% in the BV arm had had an allogeneic SCT. The median number of days on therapy was 2-fold greater for patients who received pembrolizumab (305 days) vs BV (147 days), and there was a higher discontinuation rate in the BV arm (96.1%) vs the checkpoint inhibitor arm (74.3%).

KEYNOTE-204: PFS by BICR With Post-SCT Clinical and Imaging Data (Primary Endpoint)

Ian W. Flinn, MD, PhD
Pembrolizumab was associated with a significantly longer PFS (13.2 vs 8.3 months; HR: 0.65; P = .00271). The investigator assessment showed a longer estimated PFS than the IRC, but both favored pembrolizumab over BV.

KEYNOTE-204: PFS in Key Subgroups

Ian W. Flinn, MD, PhD
The improvement in PFS held true across all key subgroups. Pembrolizumab was favored regardless of transplant status and whether patients were refractory to primary treatment or not. Pembrolizumab was favored in the 15 patients who were previously treated with BV (HR: 0.34; 95% CI: 0.04-3.10) and in patients who had not received BV (HR: 0.67; 95% CI: 0.49-0.92). OS was not reported in this presentation.

KEYNOTE-204: Objective Response Rate by BICR

Ian W. Flinn, MD, PhD
The secondary endpoint of ORR was also superior with pembrolizumab vs BV (65.6% vs 54.2%); the estimated difference of 11.3 was statistically significant (P = .0225). Approximately 24% of patients in each study arm had a CR, but more achieved a PR with pembrolizumab (41.1%) than with BV (30.1%);this powered the overall response difference. The DoR was also higher with pembrolizumab (62.4% vs 50%).

KEYNOTE-204: Safety

Ian W. Flinn, MD, PhD
Overall, the number of AEs was similar in both arms. The patient discontinuation rate due to treatment-related AEs was 16.4% in the BV cohort vs 12.8% with pembrolizumab; 8.8% of patients discontinued pembrolizumab because of serious AEs compared with 3.9% of patients in the BV arm.

KEYNOTE-204: Treatment-Related AEs in ≥ 10% of Patients

Ian W. Flinn, MD, PhD
BV is associated with peripheral neuropathy, peripheral sensory neuropathy, and nausea; pembrolizumab is associated with immune‑related events such as hypothyroidism, fatigue, and fever. The difference in AEs is an important consideration when selecting a drug for a particular patient. For example, pembrolizumab should be considered for patients who already have an underlying peripheral neuropathy, because an AE of hypothyroidism is easily corrected.

KEYNOTE-204: Immune-Mediated AEs

Ian W. Flinn, MD, PhD
It is important to keep in mind when considering therapies that pembrolizumab has immune‑mediated AEs that are not seen with BV. The incidence of many of those AES, however, is very low, with myocarditis, pancreatitis, thyroiditis, myositis, and nephritis, for example, occurring at a rate of ≤ 1.4%.

Conclusions: KEYNOTE-204

Ian W. Flinn, MD, PhD
This study is practice changing, given that it showed in a head-to-head trial that the immune checkpoint inhibitor pembrolizumab was superior to BV for ORR and PFS in R/R HL. These results encourage the use of pembrolizumab before BV in this setting. The choice of regimen, however, depends on the patient’s previous treatment.

CheckMate-744: Nivolumab Plus Brentuximab Vedotin in Younger Patients With R/R Classical Hodgkin Lymphoma

Ian W. Flinn, MD, PhD
Younger patients with R/R classical HL have poor outcomes, and the achievement of complete metabolic remission (CMR) before hematopoietic ASCT is associated with better outcomes. The standard approach to patients with relapsed HL is salvage chemotherapy followed by an ASCT. Many clinicians have wondered, however, whether some of the newer drugs are better than the standard chemotherapy drug combination of ifosfamide, carboplatin, and etoposide.

CheckMate 744 is an open-label, single-arm phase II study (N = 44) of the safety and efficacy of combining the immune checkpoint inhibitor nivolumab with BV for induction therapy in young patients (children and young adults) with R/R classical HL. If the patients have a CMR, they can then receive a transplant.

During induction, nivolumab 3 mg/kg every 3 weeks and BV 1.8 mg/kg every 3 weeks were administered for up to 4 21-day cycles. Patients achieving CMR during this period went on to high-dose chemotherapy then had an autologous transplant. Patients who did not achieve CMR after 4 cycles of this induction received the combination of bendamustine at 90 mg/m2 on Days 1 and 2 for up to four 21-day cycles and BV at 1.8 mg/kg every 3 weeks to help them achieve CMR then receive an autologous transplant. The primary endpoint was CMR (Deauville score ≤ 3) by BICR achieved any time before consolidation. Secondary endpoints were ORR after 4 cycles of induction, CMR any time before consolidation, PFS, DoR, and safety.

Patient baseline characteristics included a median age of 16 years. A total of 55% were refractory to first-line therapy; I consider them a very high-risk population. None of the patients had received an ASCT or BV previously.

CheckMate 744: Efficacy

Ian W. Flinn, MD, PhD
Efficacy was assessed by BICR and by investigator, and the results were slightly different but very consistent. Approximately 60% of patients achieved a CMR with 4 cycles of nivolumab plus BV induction, and the percentage that achieved CMR increased to 88% before consolidation therapy. The majority of patients in this trial achieved CMR during induction; only 11 patients underwent intensification. The 1-year PFS was 91%; the median DoR was not reached.

CheckMate 744: Safety

Ian W. Flinn, MD, PhD
Safety was a secondary endpoint in CheckMate 744. No new and unexpected safety signals emerged in this cohort of patients. The majority of treatment-related AEs were low grade: 1 treatment-related AE led to discontinuation due to grade 3 anaphylaxis. No severe pulmonary toxicity was seen.

CheckMate 744: Conclusions

Ian W. Flinn, MD, PhD
The results of CheckMate 744 call into question the current treatment paradigm of giving patients salvage chemotherapy followed by autologous transplant. There has been a debate in the transplant community about the need to demonstrate chemosensitivity before providing an autologous transplant. BV is a targeted chemotherapy, but nivolumab is not. Also, must patients be given chemotherapy to demonstrate efficacy? Or is achieving remission, no matter which drug is used, sufficient to take patients on to autologous transplant?

Although this study does not address these questions directly, it highlights the need for a better understanding of this issue. Study follow-up data and confirmation of the results outside of pediatric and young adult populations will provide clarity regarding the optimal treatment paradigm. We must keep in mind, of course, the need to be careful when extrapolating the results of this study to older patients with R/R HL.

ASPEN: Phase III Trial of Zanubrutinib vs Ibrutinib in Waldenström Macroglobulinemia

Ian W. Flinn, MD, PhD
B-cell receptor/BTK signaling is constitutively activated in Waldenström macroglobulinemia, and > 90% of patients with this disorder have MYD88 mutations.[40,41] Zanubrutinib was recently approved by the FDA for mantle cell lymphoma.[42] It is a next-generation selective, irreversible BTK inhibitor with reduced off-target inhibition of EGFR, ITK, JAK3, HER2, and TEC kinases.[43,44] The randomized, open-label phase III ASPEN trial compared zanubrutinib with the first-generation BTK inhibitor ibrutinib in patients with MYD88-mutated Waldenström macroglobulinemia.[45]

In the ongoing trial, 201 patients with a MYD88 mutation in cohort 1 were stratified by CXCR4 status (CXCR4WHIM vs CXCR4WT vs missing) and the number of lines of previous therapy (0 vs 1-3 vs > 3) then randomized to ibrutinib 420 mg PO once daily or zanubrutinib 160 mg PO twice daily until disease progression. The primary endpoint in cohort 1 was CR or VGPR. The secondary endpoints were DoR, PFS, safety, and QoL. (Patients who with the MYD88 wild‑type gene [cohort 2] received zanubrutinib 160 mg PO BID. The results in cohort 2 were not discussed in the current presentation.)

The median age in this trial was 70 years. The majority of patients in both treatment arms carried wild-type CXCR4 and had an intermediate or high IPSS.

ASPEN: Response in ITT Population

Ian W. Flinn, MD, PhD
The IRC analysis showed that the combination of CR and VGPR was higher in the zanubrutinib arm vs the ibrutinib arm, with a CR plus VGPR difference of 10.2 (-1.5 to 22.0; P = .0921); this difference was not statistically significant. The investigator review showed that the best overall response was similar, with a CR plus VGPR difference of 12.1 (0.5-23.7; P = .0437). The rate difference was driven by the VGPR rate of 28% in the zanubrutinib arm vs 19.2% in the ibrutinib arm. In general, response rates by IRC with either BTK inhibitor were similar across subgroups; these include CXCR4 status, baseline hemoglobin, and extramedullary disease 

ASPEN: IgM Reduction and Survival

Ian W. Flinn, MD, PhD
There was a greater IgM reduction (AUC over time) with zanubrutinib vs ibrutinib (P = .037). The PFS and OS data demonstrate that the 2 BTK inhibitors had similar event-free rates and that zanubrutinib is not less active than ibrutinib.

ASPEN: Safety

Ian W. Flinn, MD, PhD
The percentage of AEs was similar in the zanubrutinib (97%) vs ibrutinib (99%) arms, but fewer deaths were reported for patients taking zanubrutinib compared with ibrutinib (1.0% vs 4.1%, respectively). The treatment discontinuation rate associated with AEs was 4.0% with zanubrutinib vs 9.2% with ibrutinib. Overall, more patients were able to continue taking zanubrutinib and tolerate this therapy than compared with ibrutinib.

ASPEN: Most Common AEs

Ian W. Flinn, MD, PhD
The improved tolerability of zanubrutinib compared with ibrutinib was apparent on inspection of all grades of the most common AEs. Fewer patients treated with zanubrutinib had edema (9% vs 19%), atrial fibrillation (2% vs 14%), pneumonia (2% vs 12%) or muscle spasm (10% vs 24%) compared with the ibrutinib arm, but more patients receiving zanubrutinib experienced frequent neutropenia (25% vs 12%).

ASPEN: BTK Inhibitor Class AEs of Interest

Ian W. Flinn, MD, PhD
Regarding AEs of interest in the BTK inhibitor class, atrial fibrillation/flutter (any grade) was reported in 3% of patients receiving zanubrutinib vs 18.4% receiving ibrutinib; grade ≥ 3 atrial fibrillation/flutter was seen in 0% of patients receiving zanubrutinib vs 7.1% receiving ibrutinib. This is a significant finding as you avoid issues regarding antiarrhythmics and using anticoagulants in patients who already are at increased risk of bleeding if a patient does not develop atrial fibrillation. The incidence of major hemorrhaging and hypertension was lower with zanubrutinib; although the neutropenia rate was higher compared with ibrutinib, it did not translate into a higher infection rate.

Conclusions: ASPEN

Ian W. Flinn, MD, PhD
The primary endpoint of the ASPEN study was not met, but it was a considerably safer drug to give than ibrutinib. This may also have implications for other diseases such as chronic lymphocytic leukemia (CLL). The results of trials involving head-to-head comparisons with BTK inhibitors in other malignancies are much anticipated. The improved safety and similar efficacy between zanubrutinib and ibrutinib in this study is an important finding and is reason enough to consider zanubrutinib for patients in this setting.

Acalabrutinib Monotherapy in Hematologic Malignancies: Background

Ian W. Flinn, MD, PhD
Acalabrutinib is a second-generation BTK inhibitor that was recently approved for frontline and second-line therapy in CLL.[46,47]

In this section, I discuss acalabrutinib results based on the final analysis of the phase III ASCEND trial,[48] the long-term safety and efficacy of acalabrutinib monotherapy in the phase II ACE-CL-001 trial,[49] and the pooled safety analysis of acalabrutinib in B-cell malignancies.[50]

The ASCEND trial was a randomized, open-label phase III trial comparing acalabrutinib to either the PI3 kinase inhibitor idelalisib plus rituximab or chemoimmunotherapy with bendamustine and rituximab in R/R CLL. The median PFS was not reached with acalabrutinib vs 16.8 months for the combined idelalisib/rituximab and bendamustine/rituximab arm (HR: 0.27; P < .0001). The median PFS with acalabrutinib was significantly better than the median PFS of 16.2 months for idelalisib/rituximab treatment (HR: 0.27; P < .0001) or the median PFS of 18.6 months for the bendamustine/rituximab treatment (HR: 0.29; P < .0001). The ASCEND trial clearly established that acalabrutinib is an effective therapy for patients in a second‑line setting.

ASCEND: Final PFS in Prespecified Subgroups and AEs of Clinical Interest

Ian W. Flinn, MD, PhD
This table shows the PFS outcomes analysis according to TP53 mutation and IGHV status subgroups. In all cases, PFS was longer for acalabrutinib compared with either idelalisib/rituximab or bendamustine/rituximab across all prespecified subgroups, including age, sex, ECOG PS, Rai stage, number of previous therapies, and complex karyotype.

Investigators reported that acalabrutinib was generally better tolerated than the control regimens and that the discontinuation rate due to AEs was lower with acalabrutinib. These results have implications for the development of PI3 kinase inhibitors—improvements in the safety profile and tolerability are crucial. Given the results of this study, most clinicians may consider switching to a BTK inhibitor as frontline therapy rather than using it in the relapsed setting in these patients.

ACE-CL-001: Long-term Efficacy of Acalabrutinib in Treatment-Naive CLL/SLL

Ian W. Flinn, MD, PhD
These are the results of the long‑term follow-up of the ACE-CL-001 trial, which was a single-arm, open-label phase II expansion study of acalabrutinib in a treatment‑naive cohort of 99 patients.[49] The ORR was 97%, with 90% PR. The 53-month follow-up allows a glimpse at the durability of remissions and long‑term safety profile of this patient population.

ACE-CL-001: Long-term Safety

Ian W. Flinn, MD, PhD
The long-term AE profile is consistent with earlier AE reports for such AEs as diarrhea, headache, upper respiratory infections, arthralgias, and contusions. Most AEs were grade ≤ 2. Very little atrial fibrillation (5%) and no ventricular tachyarrhythmias were reported. While it is difficult to do cross-trial comparisons, the results of the ACE-CL-001 trial support claims that acalabrutinib is a better tolerated BTK inhibitor with fewer serious AEs than with ibrutinib. The atrial fibrillation rate is low in this patient population (5%), and there are fewer cases of major hemorrhage. Hypertension was present in 22% of patients. Of note, headache is a unique AE of acalabrutinib, but it is usually very low grade and improves within a few weeks. The results of the randomized ELEVATE-RR trial that is currently underway comparing acalabrutinib and ibrutinib in patients with previously treated CLL will delineate the differences in safety profiles between these 2 drugs.

Pooled Safety Analysis of Acalabrutinib in B-Cell Malignancies

Ian W. Flinn, MD, PhD
This next study is a pooled safety analysis across 9 trials that included > 1000 patients with different B-cell malignancies who were treated with acalabrutinib.[50] The median follow-up was 26.4 months and the median duration of acalabrutinib exposure was 24.6 months. Similar to what was seen in the phase II ACE-CL-001 trial, headache (35%) and diarrhea (26%) were the most common AEs. Headache generally occurred early, ie, within the first 6 months of treatment. Grade ≥ 3 AEs occurred in 54% of patients, with anemia, neutropenia, and pneumonia being the most common.

Pooled Safety Analysis of Acalabrutinib in B-Cell Malignancies: AEs of Clinical Interest

Ian W. Flinn, MD, PhD
This analysis showed that the risk of grade ≥ 3 infections was 17.6% and the risk of any grade of atrial fibrillation was 4.4%. The rate of hypertension (any grade) was 7.6%, which is far less than the rate of 22% observed in the ACE-CL-001 trial. Most of the other AEs in the long‑term follow-up study occurred at a low percentage rate and were consistent with the notion that acalabrutinib, being a more specific inhibitor of BTK than ibrutinib, results in fewer off‑target AEs.

Pooled Safety Analysis of Acalabrutinib: Cumulative Incidence of Hemorrhage and Atrial Fibrillation

Ian W. Flinn, MD, PhD
These graphs depicting the cumulative incidence of hemorrhage and atrial fibrillation are very different from an analysis of ibrutinib.[51] With acalabrutinib, the risk of atrial fibrillation was very low and did not increase substantially over the course of the study. By contrast, the incidence of any grade of hemorrhage increased during the first year of therapy but stabilized thereafter. These results are consistent with the notion that acalabrutinib may be a safer BTK inhibitor than ibrutinib.

Conclusions: Acalabrutinib Monotherapy in B-Cell Malignancies

Ian W. Flinn, MD, PhD
Preclinically, acalabrutinib had less off‑target kinase inhibition than ibrutinib. In clinical settings, this appears to have translated into fewer patients discontinuing therapy because of AEs while being treated with acalabrutinib compared with ibrutinib. Acalabrutinib seems to result in fewer serious AEs (eg, atrial fibrillation) and fewer incidences of major bleeding than other BTK inhibitors. These results suggest that acalabrutinib may be a better BTK inhibitor than ibrutinib in terms of safety, although not necessarily in terms of efficacy. However, the results of already accrued randomized trials comparing these 2 drugs will be very important to our understanding of the magnitude of these differences

Phase I/II Trial of CD3 x CD20 Bispecific Antibody Epcoritamab (GEN3013) in R/R B-Cell NHL

Ian W. Flinn, MD, PhD
Epcoritamab is a novel bispecific mAb that targets CD3 and CD20.[52] CAR T-cells are effective in many different forms of relapsed B‑cell lymphomas, but they are very expensive and very difficult to produce. By using bispecific antibodies, we hope to have an off-the-shelf product that can be administered quickly and with high efficacy.

Two of the major issues with CAR T-cells are neurotoxicity and CRS, and this means that they often must be administered in the hospital and only to a subset of patients that you really think that can withstand these issues.  We hope that any improvements in immunotherapy strategies, perhaps with this new class of drugs, the bispecific antibodies, will alleviate cytokine release and neurotoxicity while showing efficacy.

The current analysis updates dose-escalation data on efficacy and safety of epcoritamab in patients with R/R B-cell non-Hodgkin lymphoma (NHL) enrolled on this ongoing phase I/II trial. Eligible patients with R/R B-cell NHL included those previously treated with anti-CD20 mAbs or CAR T-cell therapy. Split dosing was used to decrease the incidence of CRS and to allow for safer administration of the drug. The primary objectives were to determine the recommended phase II dose and the maximum tolerated dose. Secondary objectives included an evaluation of antitumor activity (investigator-assessed ORR per Lugano criteria) and tolerability.

The baseline characteristics of the R/R B-cell NHL patients are typical of this heavily pretreated population, with a median of 3 previous therapies in patients with large‑cell lymphoma and a median of 5 previous therapies in patients with follicular lymphoma. All patients had been exposed to chemoimmunotherapy. Nearly 75% of patients with large-cell lymphoma were refractory to their last therapy; this is important to remember when interpreting the results.

Epcoritamab in R/R B-Cell NHL: Safety and Disposition

Ian W. Flinn, MD, PhD
The most important safety issue for this class of agent is the number of patients who had CRS. In this study, 57% of patients had grade 1/2 CRS, but none had grade ≥ 3 CRS. The neurotoxicity was also favorable, with only 4 patients (6.9%) developing neurotoxicity: 2 with grade 1 neurotoxicity and 2 with grade 3.

Epcoritamab in R/R B-Cell NHL: Antitumor Activity

Ian W. Flinn, MD, PhD
This table summarizes the response in a subset of patients who received what the investigators considered the lowest efficacious doses: 12 mg or higher. In patients with diffuse large B-cell lymphoma (DLBCL), the ORR was 50%: 5 of 8 patients (62.5%) in the de novo diffuse DLBCL group and 2 of 5 patients (33.3%) in the groups with transformed DLBCL. Some patients achieved CR, which, despite the small numbers of patients in this study, is exciting and provocative in the sense that these patients, including some who had failed CAR T-cell therapy, are responding so well.

Conclusions: Epcoritamab in R/R B-Cell NHL

Ian W. Flinn, MD, PhD
This study is one more step toward a more readily useable, off-the-shelf therapy for patients who have refractory large‑cell lymphoma. The use of CAR T-cells is generally restricted to large medical centers that have the cellular therapy infrastructure to administer them; thus, such therapy is not accessible to many patients. For this reason, the development of new therapies such as epcoritamab—which has high efficacy and a tolerable safety profile—is important.

The drawback with epcoritamab is that the CR rate is not as high as with CAR T-cell therapy. Clearly, more work needs to be done. Epcoritamab needs to be combined with other therapies, such as checkpoint inhibitors and other immune modifiers, which might improve efficacy.

ASCO 2020: Key Takeaways on Lymphoma

Ian W. Flinn, MD, PhD
ASCO 2020 presented very important emerging practice-changing data that are relevant to several settings for lymphoma. In HL, the advantages of pembrolizumab over BV are important findings with clinical implications. Data suggesting, at the least, safety superiority of the next-generation BTK inhibitors zanubrutinib and acalabrutinib over ibrutinib in various types of B‑cell malignancies is exciting. Finally, there are promising early data with immunotherapies, such as epcoritamab in DLBCL and follicular lymphoma and nivolumab combined with BV in classic HL, which will be a growing field of interest for patients with multiple lymphomas in coming years. All of these advances show great promise for improved patient outcomes.

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