New BTK Agents and Combinations Are on the Horizon for B-cell Malignancies

Ian W. Flinn, MD, PhD

The bruton tyrosine kinase (BTK) plays a key role in B-cell receptor signaling, regulating cellular proliferation and survival in patients with B-cell malignancies.¹ In 2013, the FDA approved the first BTK inhibitor, ibrutinib (Imbruvica), which has since redefined the standard of care for many B-cell malignancies; however, its off-target activities on non-BTK kinases limits its use in certain populations.^1,2 Now the field is packed with novel agents and combinations that are setting the stage for further advancements.

During a recent OncLive Peer Exchange^®, a panel of leukemia and lymphoma experts discussed 2 emerging BTK inhibitors: acalabrutinib (Calquence), which was approved in October 2017 for previously treated mantle cell lymphoma (MCL) and received a breakthrough therapy designation in August 2019 for chronic lymphocytic leukemia (CLL), and zanubrutinib (Brukinsa), which was approved in November for patients with MCL who have received at least 1 prior therapy.^3-5

The panelists examined key studies assessing these second-generation BTK inhibitors as a treatment for CLL, MCL, and Waldenström macroglobulinemia (WM). They also discussed the promise of new and emerging BTK combinations, including ibrutinib/venetoclax (Venclexta) in patients with CLL.

Studies assessing BTK inhibitor combinations are adding to the evidence that positive synergistic effects occur when BTK inhibitors are correctly combined with other active agents, which may be particularly important for certain patient subsets, including older adults and high-risk patients. “I think this is a very exciting time in B-cell malignancies. We have a lot of new tools available to us. Most agents were developed as single agents, but I think combinations are particularly exciting,” Matthew S. Davids, MD, MMSc, said.

CLL Studies

The panelists discussed several studies assessing acalabrutinib in CLL, including the phase III ASCEND and ELEVATE-TN trials, which led to acalabrutinib receiving FDA breakthrough therapy designation as a monotherapy for CLL.^4,6 “Assuming acalabrutinib does get an indication in CLL, I could easily see it being my preferred BTK inhibitor when I’m opting for a BTK inhibitor,” Brad S. Kahl, MD, said.

The panelists also discussed 3-year follow-up study findings that showed acalabrutinib in combination with obinutuzumab (Gazyva) to have benefit in treatment-naïve and relapsed/refractory (R/R) CLL, provided insights on where zanubrutinib is in clinical development for CLL, and examined various ibrutinib combinations.^7-11 They were particularly excited by ibrutinib/venetoclax, which recently showed good efficacy in previously untreated high-risk and older patients with CLL.¹¹

Acalabrutinib

Acalabrutinib is a highly selective, potent, covalent BTK inhibitor. The ASCEND trial randomly assigned 310 previously untreated patients 1:1 to acalabrutinib monotherapy or physician’s choice of rituximab (Rituxan) plus either idelalisib (Zydelig) or bendamustine.⁴

“Comparing acalabrutinib [with] idelalisib/ rituximab or bendamustine/rituximab, acalabrutinib was superior in terms of progression-free survival [PFS] and response rates,” Davids said. “Particularly striking in this trial was the tolerability of acalabrutinib.”

He said that half the idelalisib-treated patients had to stop therapy due to toxicities and that the bendamustine/rituximab regimen resulted in anticipated adverse effects (AEs), including infections and cytopenia. In contrast, acalabrutinib was mostly associated with headaches (~20% of patients, significantly lower than the almost 40% seen in some early-phase studies), with very little atrial fibrillation or major bleeding events. John M. Pagel, MD, PhD, concurred with Davids’ assessment, saying, “I think the ASCEND trial message to me wasn’t so much that it was better than idelalisib, as we kind of anticipated that, [but] the biggest message was the tolerability of acalabrutinib.”

The ELEVATE-TN trial randomly assigned 535 previously untreated patients 1:1:1 to chlorambucil/obinutuzumab, acalabrutinib/ obinutuzumab, or acalabrutinib monotherapy.^4,6 The primary end point is independent review committee (IRC)—assessed PFS in the acalabrutinib/obinutuzumab arm compared with the chlorambucil/obinutuzumab arm. A key secondary end point is IRC-assessed PFS in the acalabrutinib monotherapy arm compared with the chlorambucil/ obinutuzumab arm.

As with the ASCEND trial, ELEVATE-TN met its end points early.⁶ Pagel said he was not surprised that acalabrutinib/obinutuzumab showed better efficacy than the chemoimmunotherapy regimen, because that was also expected, but that it will be important to see if adding obinutuzumab provides benefit over acalabrutinib alone. “I think it’s important to know because giving people an expensive drug, an IV [intravenous] infusion—if it’s not needed, we shouldn’t be doing it,” he said. Data from the ELEVATE-TN trial will be presented at the 2019 American Society of Hematology Annual Meeting and Exposition (2019 ASH).¹²

Acalabrutinib/Obinutuzumab

Although it remains unclear whether adding obinutuzumab to acalabrutinib is beneficial, the panelists noted that the combination showed good efficacy in a small, single-arm study including 19 treatment-naïve and 26 R/R patients.⁷

The study’s primary end points were overall response rate (ORR) and safety. The ORR was 95% in treatment-naïve patients, with 6 (32%) achieving a complete response (CR) and 12 (63%) achieving a partial response (PR); the ORR was 92% in the R/R patients, with 2 (8%) achieving a CR and 22 (85%) achieving a PR. The most common AEs included upper respiratory tract infections (71%), increased weight (71%), maculopapular rash (67%), cough (64%), diarrhea (62%), headache (56%), nausea (53%), arthralgia (51%), and dizziness (47%).⁷

Davids said an interesting finding was that responses appear to have deepened over time, indicating that the treatment-naïve cohort’s initially reported CR rate was ~15% but reached almost 33% at 3-year follow-up. “Whether that’s relevant or not, I’m not so sure, because this is still given as a continuous therapy. So, do you need to get to CR? Maybe that does predict for progression-free survival, but I think time will tell,” he said, adding that the ELEVATE-TN results will help tease out whether the addition of a CD20- directed agent provides benefit.

Zanubrutinib

Zanubrutinib, a next-generation BTK, is still in clinical development for CLL. Because that drug was almost exclusively assessed in clinical trials outside the United States, the panelists acknowledged having limited experience with it. Davids, who has treated some patients with CLL with this agent, said it appears similar to acalabrutinib. Studies are ongoing, including the phase III ALPINE trial (NCT03734016), which is comparing zanubrutinib with ibrutinib in patients with R/R CLL and small lymphocytic lymphoma (SLL).⁸

Ibrutinib Combinations

Ibrutinib, which is approved as monotherapy in CLL/SLL, has been assessed in various combinations in patients with CLL, such as being paired with obinutuzumab, rituximab, and venetoclax.

In January 2019, the FDA approved ibrutinib/ obinutuzumab for treatment-naïve patients with CLL/SLL based on data from the phase III iLLUMINATE trial, making it the first approval of a nonchemotherapy combination for untreated CLL.⁹

At a median follow-up of 31 months, the combination showed a significant improvement in IRC-evaluated PFS compared with chlorambucil plus obinutuzumab. The median PFS with the ibrutinib regimen was not evaluable versus 19 months with the chlorambucil- containing combination (HR, 0.23; 95% CI, 0.15-0.37; P <.0001), which translated into a 77% reduction in the risk of progression or death.⁹

In contrast, ibrutinib/rituximab, the first nonchemotherapy treatment approved by the FDA for WM, showed no significant difference in PFS between ibrutinib/rituximab and ibrutinib alone in untreated patients with CLL aged ≥65 years in results from a phase III trial (NCT01886872).¹⁰

Findings from a second phase III E1912 trial (NCT02048813) involving patients aged <70 years with previously untreated CLL demonstrated the superiority of the ibrutinib/rituximab combination versus immunochemotherapy. At a median follow-up of 33.6 months, the PFS favored the combination at 89.4% versus 72.9% with a hazard ratio for progression or death of 0.35 (95% CI, 0.22-0.56; P <.001). Reported overall survival was 98.8% for the combination arm versus 91.5% in the immunochemotherapy arm (HR for death, 0.17; 95% CI, 0.05-0.54; P <.001).¹³

Based on these results, the manufacturer submitted a supplemental new drug application (NDA) to the FDA to expand the indication to include the combination with rituximab for the first-line treatment of patients with CLL or SLL.¹⁴ Updated data are planned for presentation at 2019 ASH.¹⁵

Recently, ibrutinib/venetoclax showed promising results in a phase II study (NCT02756897) that included previously untreated high-risk patients, defined as those with chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, and older patients (aged ≥65 years) with CLL.

Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily), with combination therapy administered for 24 cycles.¹¹

After 12 cycles of combined treatment, 88% of the patients had a CR or CR with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were observed in older adults and across all high-risk subgroups.

“I think getting to a state of undetectable minimal residual disease, which you can get with these combinations—particularly with this combination of ibrutinib and venetoclax— is an important end point for many patients, particularly because it enables us to stop therapy,” Pagel said. “One of the unappealing things for many patients who are taking oral targeted therapies is this long duration of treatment.”

MCL Studies

In patients with MCL, ibrutinib is approved for patients who have received at least 1 prior therapies. Acalabrutinib and zanubrutinib are emerging options for patients with R/R disease. “Like CLL, I think the landscape is ever changing in MCL,” noted moderator Ian W. Flinn, MD, PhD. “The natural history of this disease has been dramatically changed over the last 15 to 20 years.”

Kahl noted that response patterns are different in MCL than they are in CLL. “An important thing to remember about any BTK inhibitor in relapsed MCL is [that] the data [aren’t] like CLL data. The response rates aren’t 90%. They’re more like 70%. The complete response rates are quite low, and the median progression-free survival is often around a year—maybe 18 months, at best—so there is a significant problem in relapsed MCL of patients who break through their BTK inhibition, and it happens at a much higher and faster rate than in does in CLL,” Kahl explained.

For that reason, Davids said, there is a great need to develop approaches combining BTK inhibitors with other active agents, as is being done in other settings.

Acalabrutinib

In the ACE-LY-004 study (NCT02213926), 124 patients with R/R MCL (median of 2 previous therapies) received oral acalabrutinib (100 mg twice daily) until disease progression or unacceptable toxicity.¹⁶ The primary end point was ORR according to Lugano classification. At a median follow-up of 15.2 months, 100 patients (81%) achieved an ORR and 49 (40%) achieved a CR. “That’s the best single-agent data we’ve ever seen in relapsed MCL,” Pagel said.

Acalabrutinib was well tolerated. The most common AEs were primarily grade 1 or 2 and included headache (38%), diarrhea (31%), fatigue (27%), and myalgia (21%). The most common grade ≥3 AEs were neutropenia (10%), anemia (9%), and pneumonia (5%).16 There were no cases of atrial fibrillation, and there was 1 case of grade ≥3 hemorrhage.

The panelists emphasized that these acalabrutinib data cannot be directly compared with those observed with ibrutinib because the patient populations and methods for assessing response were different. “It’s important to understand that both [acalabrutinib and ibrutinib] in a relapsed patient are very important and valuable, and I think we’ll see that with zanubrutinib, as well,” Pagel said.

Kahl concurred. “There’s no question that BTK inhibition gives you the best response rates in relapsed MCL, so usually that is my preferred strategy, whether it be ibrutinib or acalabrutinib,” he said. “Efficacy-wise, the 2 drugs are very comparable—there may be no difference, quite honestly.” However, he said that he often favors acalabrutinib because he has observed it to be better tolerated.

Zanubrutinib

In November 2019, the FDA granted an accelerated approval for zanubrutinib in patients with MCL who have received ≥1 prior therapy.⁵ The decision, which occurred after the Peer Exchange program took place, was based on findings from 2 single-arm studies.

In a phase I/II study (NCT02343120), zanubrutinib demonstrated an ORR of 84% (95% CI, 67%-95%), including a 22% CR, and a median duration of response (DOR) of 18.5 months (95% CI, 12.6 months-not estimable [NE]). In a phase II study (NCT03206970), the ORR also was 84% (95% CI, 74%-91%) in 86 patients, with 59% achieving a CR and a median DOR of 19.5 months (95% CI, 16.6 months-NE).⁵

Although the data for zanubrutinib are still sparse, Kahl said, they look comparable to acalabrutinib and ibrutinib. “Whether it has some therapeutic advantage over the earlier BTK inhibitors, I honestly can’t tell yet, but I’m glad to see zanubrutinib being developed. It’ll be great to see more mature, larger data sets. It’s always good to have options. I’ll never complain about having too many choices,” he said.

WM Studies

Acalabrutinib and zanubrutinib both appear promising in WM as single agents, with studies including untreated and R/R patients and those with MYD88 and CXCR4 mutation status. Ibrutinib has been approved for patients with WM since 2015.

Acalabrutinib

Acalabrutinib was assessed in a small, singlearm, phase II study that included patients with treatment-naive (n = 14) or R/R (n = 92) WM.¹⁷ Patients received 100 mg of acalabrutinib twice daily (or 200 mg once daily [n=6], later switched to 100 mg once daily) in 28-day cycles until progressive disease or intolerance.

Investigator-assessed ORR, the primary end point, was 93% in untreated patients and 94% in R/R patients. The major response rates were 79% and 78%, respectively. There were no CRs, but a very good PR was observed in 1 untreated patient (7%) and 29 R/R patients (32%). Common AEs included headaches (39%), diarrhea (31%), contusion (29%), and dizziness (25%). Common grade 3/4 AEs included neutropenia (16%), pneumonia (7%), anemia (5%), increased alanine aminotransferase levels (5%), and hyponatremia (5%).

“[The data look] very consistent with everything we know about acalabrutinib from an efficacy and toxicity standpoint,” Pagel said. Because the study did not have an ibrutinib arm, he said that it is unclear whether acalabrutinib offers an advantage over ibrutinib, but he anticipates a future role for acalabrutinib in patients with WM. The panelists speculated that the role may end up being as a combination therapy with rituximab, because ibrutinib/rituximab is already approved in this setting; thus, this pairing would be logical, but definitive data are needed.

Zanubrutinib

Zanubrutinib is being assessed versus ibrutinib in the head-to-head phase III ASPEN study (NCT03053440) in patients with WM, including those with MYD88 and CXCR4 mutation status.

Updated data on the MYD88 wild-type population was presented at the 24th European Hematology Association Congress in June 2019. The BTK inhibitor demonstrated clinical activity in the group typically associated with poor prognosis and response. Among the 26 patients enrolled, 5 were treatment naïve and 21 were R/R. The ORR was 80.8%, with 53.8% of patients having a response of PR or better. The time to PR or better was 2.9 months (range, 1.9-7.4).¹⁹

“Whether [zanubrutinib] offers advantages over ibrutinib or acalabrutinib remains to be seen. There are some theoretical reasons why zanubrutinib might have some advantages in getting into [lymph node tissue], although that has yet to be proven definitively, but it will be a nice option to have,” Kahl said.