CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: February 26, 2021
Expiration: February 25, 2022
Jeff P. Sharman, MD:
To begin, exciting data were presented at ASH 2020 regarding new treatments for patients with CLL/SLL. These included the phase I/II BRUIN trial of LOXO-305, the phase III UNITY-CLL trial of umbralisib plus ublituximab (U2), and the phase II CAPTIVATE study of ibrutinib plus venetoclax.
Jeff P. Sharman, MD:
BRUIN is an ongoing phase I/II first-in-human study of LOXO-305—a next-generation, noncovalent BTK inhibitor—in patients with CLL/SLL (or B-cell non-Hodgkin lymphoma NHL).1 In this dose-escalation/expansion trial, patients with previous treatment (including those with intolerance to a first-line BTK inhibitor) were treated with LOXO-305.
In phase I, patients received 25-300 mg once daily, with 200 mg/day selected as the recommended phase II dose (primary endpoint) (n = 203). In phase II, the primary endpoint was ORR with secondary endpoints including safety, survival, and pharmacokinetics (n = 120).
At ASH 2019, Mato and colleagues2 presented initial results from BRUIN and, in 2020, presented results from a much larger group with considerably longer follow-up (n = 323).1
Jeff P. Sharman, MD:
In this study, the median age was 69 years and the majority of patients had good performance status (92% Eastern Cooperative Oncology Group performance status 0/1). A key feature of this population was the percentage of patients who had already received a previous BTK inhibitor: 86%. Moreover, 27% of patients had a known BTK C481S mutation, which can confer resistance to the covalent BTK inhibitors. Similarly, the PLC-γ-2 mutation was seen in 4% of patients; this mutation has been associated with resistance to ibrutinib, acalabrutinib, and zanubrutinib. Nearly three quarters of patients had wild-type BTK.
Of note, approximately two thirds of patients had progressed on a BTK inhibitor and one third of BTK‑exposed patients had discontinued due to toxicity. In general, this group would not be expected to do well on another BTK inhibitor.
Jeff P. Sharman, MD:
The adverse event (AE) profile was impressive; this was a very well–tolerated therapy. In particular, there was minimal hypertension (5%; only 1% treatment related), bruising (50%, but no grade 3/4), and atrial fibrillation (n = 2, or < 1%).
No dose-limiting toxicities were reported and the maximum tolerated dose (MTD) was not reached; 200 mg once daily was selected as the phase II dose.
Jeff P. Sharman, MD:
The ORR in this trial was 63%, all PRs or PR with lymphocytosis. Over time, the ORR increased to 86% in 29 patients with more than 10 months of follow-up. Furthermore, a sizeable fraction of patients (94%) remain on treatment and in response at the time of data cutoff. There were very few treatment discontinuations (n = 5) at this time point.
These results suggest that among patients who have disease progression on a prior BTK inhibitor, approximately three quarters will remain progression free at 12 months with LOXO-305. That said, few patients have actually been treated that long, and I expect this Kaplan-Meier survival curve will continue to evolve with further follow-up.
John M. Burke, MD:
LOXO‑305 has excellent activity even in patients who have been previously exposed to BTK inhibitors, including those who were refractory to BTK inhibitors. I agree that, so far, the tolerability looks to be excellent. Even though it is a BTK inhibitor, the rates of bruising and minor bleeding appear to be lower than with the covalent inhibitors, and the rate of atrial fibrillation, so far, appears to be encouragingly low. Longer follow-up to gather more information on duration of response, PFS, and toxicities that may emerge with longer therapy will be important. Phase III studies of LOXO-305 for patients with CLL/SLL are planned for 2021.3
Jeff P. Sharman, MD:
The UNITY‑CLL study was the only major phase III study in CLL to report results at ASH 2020.4 In this open-label study, patients with treatment-naive or R/R CLL were randomized to receive the novel combination of umbralisib (a PI3K inhibitor) plus ublituximab (an anti-CD20 antibody; this regimen has been nicknamed “U2”) or the control combination of obinutuzumab plus chlorambucil (N = 421). In the investigational arm, patients received umbralisib 800 mg/day plus ublituximab, and those in the control arm received chlorambucil 0.5 mg/kg plus obinutuzumab. The primary endpoint was PFS, with secondary endpoints including ORR, CR, duration of response, safety and undetectable measurable residual disease (MRD).
Of interest—and different from any other clinical trial in CLL—UNITY-CLL enrolled both newly diagnosed patients and those with R/R disease. We do not have experience using obinutuzumab plus chlorambucil as a control arm in patients with R/R disease; historically, this combination has been used exclusively in the frontline setting.
Jeff P. Sharman, MD:
This study population is typical of patients with CLL: mostly older than 65 years (~ 62%) with stage III/IV disease in approximately 40%. This study did not exclude patients with deletion of chromosome 17p, and the IGHV status was evenly distributed across arms (approximately one half of the patients in each arm had IGHV-unmutated disease). In total, 57% of patients were treatment naive.
The substantial majority of patients who were previously treated (> 80%) had received CD20 antibodies. A large percentage, 85% to 90%, had received previous chemoimmunotherapy. A small number of patients (~ 15%) had previously been treated with a BTK inhibitor.
Jeff P. Sharman, MD:
In the intention-to-treat population (including both frontline and R/R patients), the median PFS was 17.9 months with control treatment, which is slightly lower than that observed in other studies of frontline obinutuzumab plus chlorambucil. However, UNITY-CLL included patients with R/R disease. By contrast, at a median follow-up of 36.7 months, the median PFS with U2 was 31.9 months (P < .0001).
Jeff P. Sharman, MD:
Looking at treatment‑naive patients, a median PFS of 38.5 months was observed with U2 vs 26.1 months with control treatment (P < .001), the latter consistent with previous studies of obinutuzumab plus chlorambucil. Of note, this is the sole phase III study to date in which patients with CLL received a PI3K inhibitor in the frontline setting. Typically, efforts to assess PI3K inhibitors in the frontline setting have been marred by the toxicity observed with this class of agents.
Jeff P. Sharman, MD:
In the R/R population, the median PFS in the control arm was just longer than 1 year. This is notable and useful because few data exist with obinutuzumab for patients with R/R CLL. The median PFS with U2 arm for patients with R/R disease was 19.5 months, which is somewhat inferior to what has been observed in trials of other novel agents such as venetoclax or BTK inhibitors that are more active in this setting.
Jeff P. Sharman, MD:
The treatment effect with U2 was mostly consistent across subgroups, favoring U2 over obinutuzumab plus chlorambucil in every group analyzed except Rai stage III/IV disease. Note that some subgroups included small numbers of patients.
Jeff P. Sharman, MD:
ORR was significantly improved with U2 (83.3% vs 68.7% with obinutuzumab plus chlorambucil; P < .001). Responses were primarily PRs, with only 5% of patients in the U2 arm and 1% in the control arm achieving a CR. In the U2 arm, the ORR for treatment-naive patients and previously treated patients was similar (84% and 82% respectively). Of note, an ORR of only 57% was observed in those with previous BTK inhibitor therapy. In the control arm, the ORR was similar to U2 for treatment-naive patients (78%) but much lower in those with previous treatment (57%) and only 25% in those with previous BTK inhibition. At 2 years, 62% of responding patients in the U2 arm maintained response. Overall, the U2 regimen was associated with a 93% disease control rate.
Jeff P. Sharman, MD:
In UNITY-CLL, the main toxicity associated with the U2 regimen was diarrhea, affecting 56% of patients, including 12% with grade 3 diarrhea. This rate is lower than that seen with other PI3K inhibitors, but all of the agents in this class are associated with substantial diarrhea. Other grade 3/4 toxicities of note in the U2 arm included infusion-related reactions (2.5%), neutropenia (31.0%), and thrombocytopenia (4.0%).
Jeff P. Sharman, MD:
The rate of grade 3/4 AEs varied somewhat based on whether patients had been previously treated. Although neutropenia was reported in 31% of patients receiving U2, it was 40% in the 90 patients with previous treatment vs 24% in the frontline patients. By contrast, diarrhea was seen in 13.8% with no previous treatment and 10.0% of those with previous treatment, which aligns with previous evidence that PI3K inhibitors are more easily tolerated in the R/R setting.
Jeff P. Sharman, MD:
Elevations in alanine aminotransferase/aspartate aminotransferase were lower than with other PI3K inhibitors but were still clinically meaningful and need to be monitored. In the U2 arm, approximately 15.0% had elevation in these enzymes (8% grade 3/4) vs 4.5% in the obinutuzumab/chlorambucil arm. Other PI3K-associated toxicities to note were rash in 13% treated with U2 vs 5% treated with obinutuzumab/chlorambucil and opportunistic infections in 14.0% vs 5.5%, respectively.
Jeff P. Sharman, MD:
I expect that results from UNITY-CLL will lead to FDA approval of the U2 combination for CLL. The question, of course, will be how best to use this regimen in this setting. U2 might be particularly suitable for patients in whom BTK inhibitors might be challenging, including those with significant preexisting cardiac disease or those on chronic anticoagulation.
I would point out that drug–drug interactions may be less of a concern with this combination, suggesting that it could be suitable for patients receiving medications that might otherwise preclude other novel agents. Early data also suggest U2 could benefit patients with R/R CLL in combination with venetoclax.
John M. Burke, MD:
The development of the U2 regimen for CLL is important for several reasons. First, it demonstrates that this particular PI3K inhibitor (umbralisib) can be given with a novel glycoengineered CD20 antibody (ublituximab) with a reasonable degree of safety in the frontline setting. However, I think it is unlikely that the U2 regimen will change the common utilization of BTK inhibitors and venetoclax plus obinutuzumab in the frontline setting, although, as Dr. Sharman said, there may be some patients for whom U2 might be a more appropriate choice, depending on comorbidities and concurrent medications. I think U2 is most likely to be utilized in the R/R setting after BTK inhibitors and venetoclax-basded therapy. The ability to add a novel anti-CD20 antibody to treatment for a patient population who had previously received obinutuzumab and/or rituximab and the relatively favorable safety profile of umbralisib make this regimen attractive in the relapsed setting.
Jeff P. Sharman, MD:
In recent years, numerous new agents have been approved for the management of CLL, and many have novel mechanisms of action. BTK inhibitors have been a significant step forward and have largely displaced chemoimmunotherapy. Venetoclax, in combination with obinutuzumab, has been also a very successful regimen in the frontline setting. Now that these agents are approved, there is interest in trying to find the optimal doublet or triplet regimen that incorporates BTK inhibitors plus venetoclax and CD20 antibodies.
At ASH 2020, updated results from the phase II CAPTIVATE study were presented.5 In this study, patients aged younger than 70 years with CLL/SLL were treated with ibrutinib 420 mg/day for 3 cycles, and then venetoclax was added and ramped up to 400 mg/day for an additional 12 cycles (N = 164). At that point, patients were randomized: Those with undetectable MRD were randomized (double blind) to ibrutinib vs placebo, and those with detectable MRD were randomized (open label) to ibrutinib vs ibrutinib plus venetoclax. CAPTIVATE was designed not as a pivotal study, but instead to help determine how to best use MRD to guide the choice of treatment with ibrutinib/venetoclax.
The primary endpoint was disease-free survival at 1 year in patients with undetectable MRD, with secondary endpoints including responses, PFS, and safety. In this study, undetectable MRD was defined as < 10-4 by flow cytometry in at least 3 consecutive cycles in both peripheral blood and bone marrow. Of note, MRD monitoring with next-generation sequencing has recently been approved and can detect MRD down to 10-6.
Jeff P. Sharman, MD:
Of note, the median patient age was 58 years and approximately one third of patients had stage III/IV disease. Many patients had high-risk markers, including 20% with del(17p) disease; this is a high percentage for a frontline study in CLL. In addition, 17% of patients had del(11q) disease and 19% had a complex karyotype.
Jeff P. Sharman, MD:
In this study, ibrutinib was effective at debulking: Before ibrutinib, 24% of patients were high risk for tumor lysis syndrome and only 2% remained high risk after 3 months of a BTK inhibitor. Similarly, only 13% of patients were considered low risk for tumor lysis syndrome, and that increased to 30% after 3 months of ibrutinib. In addition, numerous patients were able to avoid hospitalization for venetoclax initiation after the ibrutinib run-in.
Jeff P. Sharman, MD:
The rate of of undetectable MRD in the peripheral blood after after 12 cycles of ibrutinib plus venetoclax was 75% (72% in the bone marrow). In the past, venetoclax‑based regimens have demonstrated generally good MRD concordance between blood and bone marrow, and that holds true here as well. Overall, 58% of patients eligible for randomization achieved undetectable MRD in both peripheral blood and bone marrow.
Jeff P. Sharman, MD:
In the group of patients with confirmed undetectable MRD at the time of randomization, there were very similar positive outcomes regardless of whether they were switched to ibrutinib monotherapy or placebo. Those patients who continued on ibrutinib had a 100% disease-free survival rate at 1 year and those who stayed on placebo had a 95% rate, so very good outcomes with either strategy.
Jeff P. Sharman, MD:
In the MRD‑positive group (ie, detectable MRD), at a median follow-up of 31.3 months, the 30-month PFS rate was nearly identical between arms (96.7% with ibrutinib plus venetoclax vs 95.2% for ibrutinib alone).
Jeff P. Sharman, MD:
Very few patients discontinued therapy for AEs after randomization. Of course, these patients had been on therapy for 12 months, so some had already discontinued due to tolerance issues. In the group with detectable MRD after ibrutinib plus venetoclax, there were 2 discontinuations due to toxicity in the patients who received subsequent ibrutinib plus venetoclax, and 1 discontinuation in the patients who subsequently received ibrutinib.
Jeff P. Sharman, MD:
This table shows the prevalence of AEs of any grade over time by randomization group. These data confirm what is already known about the safety of these medications, particularly regarding diarrhea, arthralgias, and hypertension. Of note, the combination was associated with substantial rates of neutropenia (up to 19%), and this was associated with a rate of infections that was not trivial (25% to 50%; mostly grade 1/2). Overall, grade ≥ 3 AEs were uncommon across treatment randomization groups.
Jeff P. Sharman, MD:
In summary, the 1-year disease-free survival rate of 95.3% in patients with undetectable MRD randomized to placebo after 12 cycles of ibrutinib plus venetoclax supports a fixed-duration treatment approach. At 30 months, more than 95% of patients were progression free across all treatment arms.
In my opinion, the combination of ibrutinib plus venetoclax is likely to get approved. This is an all‑oral regimen and provides very effective disease control.
John M. Burke, MD:
I agree that this being an all‑oral regimen is attractive. Some patients would prefer to avoid intravenous treatments in the clinic, particularly in the COVID‑19 era. Another lesson from this dataset is that this combination has a manageable toxicity profile. That said, the all-oral combination of ibrutinib plus venetoclax is not devoid of neutropenia and infection risk.
This study demonstrated that stopping therapy after 1 year does not lead to a profound difference in 1-year disease‑free survival for those with undetectable MRD. In previous studies of venetoclax plus obinutuzumab in CLL, patients who achieve undetectable MRD and stopped therapy after 1 year had a low rate of progression events over the next several years. As such, it is not surprising that stopping therapy in this trial did not lead to a significant number of progression events at 1 year of follow-up. It would not surprise me if, over time, the PFS curves for ibrutinib vs placebo begin to separate. Whether that will truly translate into improved survival for patients is uncertain.
Let’s return to a question from earlier.
Jeff P. Sharman, MD:
CAR T‑cell therapy was initially demonstrated to be effective in both NHL and acute lymphoblastic leukemia. However, the development of this therapy in CLL has been considerably slower. Currently, there is no FDA-approved CAR T‑cell therapy for CLL.
Jeff P. Sharman, MD:
Lisocabtagene maraleucel will likely gain FDA approval for the treatment of CLL in 2021 or 2022. This CAR T-cell therapy differs from others in this drug class regarding the costimulatory domain as well as the fixed ratio of CD4/CD8 T-cells. At ASH 2020, Siddiqi and colleagues6 presented updated follow-up data from the phase I monotherapy cohort of the TRANSCEND CLL 004 study, which is evaluating lisocabtagene maraleucel in patients with R/R CLL/SLL (n = 23). Results showed a high rate of undetectable MRD (75% in the blood and 65% in the bone marrow), including in patients refractory to both a BTK inhibitor and venetoclax. Responses were durable, with no unexpected AEs, and the study is currently enrolling for the phase II cohort with a dose of 100 x 106 CAR T-cells.
Jeff P. Sharman, MD:
Also at ASH 2020, results from the TRANSCEND CLL 004 phase I cohort of patients who received lisocabtagene maraleucel in combination with ibrutinib (n = 19) were presented.7 Why might it be beneficial to combine lisocabtagene maraleucel with ibrutinib? One frequent feature of CLL is considerable T‑cell dysfunction. It is hypothesized that this can be reversed by ibrutinib, as T-cells collected from patients receiving ibrutinib are able to proliferate more robustly, and when the engineered T-cells are reinfused into a patient, the presence of ibrutinib helps lower rates of toxicity.
Among patients who received lisocabtagene maraleucel plus ibrutinib, 95% responded, including 9 patients who achieved a CR or CR with incomplete bone marrow recovery. In addition, lisocabtagene maraleucel was associated with manageable toxicity, with a low incidence of grade 3 cytokine-release syndrome (CRS) (n = 1) and grade 3/4 neurologic events (n = 3).
Let’s return to a question from earlier.
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