Standard-of-Care Drugs Provide Strong Foundation For Effective Combinations in Hematologic Malignancies

Commentary
Article

Catherine C. Coombs, MD, discusses future directions for BTK inhibitors in chronic lymphocytic leukemia and combination therapies in myelofibrosis.

Catherine C. Coombs, MD

Catherine C. Coombs, MD

Bruton tyrosine kinase (BTK) inhibitors in combination with BCL2 inhibitors may represent the future of improved treatment regimens for patients with chronic lymphocytic leukemia (CLL), according to Catherine C. Coombs, MD, who noted that combination strategies are also making strides in myelofibrosis and acute myeloid leukemia (AML).

“I hope in the future, we will have an oral doublet for our patients [with CLL] and will continue to improve the outcomes of patients,” Coombs said in an interview with OncLive® following an OncLive Institutional Perspectives in Cancer (IPC) webinar on leukemia and lymphoma, which she chaired.

In the interview, Coombs highlighted key points from the webinar regarding leukemia and myelofibrosis, including future directions with BTK inhibitors in CLL, key findings from trials investigating the addition of novel agents to standard ruxolitinib (Jakafi) in myelofibrosis, and the significance of the FDA approval of quizartinib (Vanflyta) for a subset of patients with FLT3-ITD–mutated AML.

In particular, Coombs noted recent data readouts from the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, including extended follow-up findings from the phase 3 ALPINE trial (NCT03734016). These findings showed, at a median study follow-up of 39.0 months, that patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) who received zanubrutinib (Brukinsa; n = 327) achieved a progression-free survival benefit compared with those who received ibrutinib (Imbruvica; n = 325; HR, 0.68; 95% CI, 0.53-0.86; 2-sided descriptive P = .0011).1 She also offered insights regarding the future implications of the phase 3 MANIFEST-2 trial (NCT04603495), whose data demonstrated that patients with myelofibrosis who received pelabresib (CPI-1610) plus ruxolitinib (n = 214) achieved a mean change in spleen volume at week 24 of –50.6 (95% CI, –53.2 to –48.0) vs –30.6 (95% CI, –33.7 to –27.5) in those who received placebo plus ruxolitinib (n = 216).2

Coombs is an associate professor in the Division of Hematology/Oncology in the Department of Medicine at the University of California, Irvine (UCI) School of Medicine.

OncLive: Regarding your presentation on new directions and combination studies in CLL, which combination regimens are of interest for this patient population?

Coombs: Our main 2 standards of care for a patient needing frontline therapy are either a continuous BTK inhibitor or the combination of venetoclax [Venclexta] and obinutuzumab [Gazyva]. However, I think our standards will change. A prelude to this is the success we’ve seen with the combination studies of ibrutinib with venetoclax.

[During the IPC webinar, I presented] some of the recent data, including those from the exciting FLAIR trial [ISRCTN01844152] presentation from [Cancer Research UK] that investigated the combination of ibrutinib plus venetoclax, which, instead of being given as a fixed duration for all patients [with previously untreated CLL], can be given for between 2 and 6 years depending on when patients attain minimal residual disease negativity. This was a positive trial. [Findings] published in the New England Journal of Medicine [showed that] patients who received ibrutinib plus venetoclax performed drastically better than those who received FCR [fludarabine, cyclophosphamide, and rituximab], the comparator regimen. However, I don’t necessarily see [ibrutinib plus venetoclax] becoming our standard in the US, because we’ve largely moved past ibrutinib.

[Additionally, I presented data from] the different trials that have led to the US moving past ibrutinib, [including] the phase 3 ELEVATE-RR trial [NCT02477696] that showed acalabrutinib [Calquence] is a safer treatment alternative with similar efficacy [to ibrutinib in patients with previously treated CLL]. ELEVATE-RR had a noninferiority design. [I also discussed findings from] the ALPINE trial, which was the head-to-head trial of zanubrutinib vs ibrutinib, which showed that zanubrutinib was safer [than ibrutinib in patients with relapsed/refractory CLL], specifically [regarding its] lower rates of atrial fibrillation and cardiac events, as well as more efficacious. We saw the 3-year update of this presentation at the 2023 ASH annual meeting.

I’m eagerly awaiting the results of some ongoing trials. The trial that is closest to being read out is the phase 3 AMPLIFY trial [NCT03836261] comparing acalabrutinib plus venetoclax vs acalabrutinib plus venetoclax and obinutuzumab vs chemoimmunotherapy [in patients with previously untreated CLL]. Hopefully this trial, if positive, will lead to registrational approval of the acalabrutinib/venetoclax combination. I’m interested to see whether there’s a benefit of a triplet regimen over a doublet regimen. I’m a bit of a skeptic, but we have to see those results. That’ll be interesting.

However, [chemoimmunotherapy is] not a relevant comparator arm in the US. We don’t use a lot of chemoimmunotherapy, so the other trial I’m excited about is the phase 3 MAJIC trial [NCT05057494], where acalabrutinib plus venetoclax is being stacked head-to-head against venetoclax plus obinutuzumab, which I’m using a lot of in my practice, [in patients with previously untreated CLL or SLL]. Similar to MAJIC, BeiGene is doing their own phase 3 trial [NCT06073821] against venetoclax/obinutuzumab, but instead of using venetoclax as the partner to zanubrutinib, they’re using their own BCL2 inhibitor, sonrotoclax [BGB-11417]. [There is] a lot to look forward to.

Your colleague, Angela G. Fleischman, MD, of UCI, discussed the ways in which standard myelofibrosis therapies have been challenged in recent years. Which clinical data are most likely to impact myelofibrosis management over the next few years?

Myelofibrosis is a challenging malignancy because it affects patients in many different ways. Some patients have cytopenias, many patients have constitutional symptoms, and we always have to think about splenomegaly. It’s important to recognize that not all myelofibrosis is the same, and we need to individualize treatment goals based on how a patient is affected by their disease.

Now we have several different JAK inhibitors that are FDA approved, so we’re not still in the ruxolitinib-only days. Fedratinib [Inrebic] was FDA approved in 2019 [for patients with intermediate-2 or high-risk primary or secondary myelofibrosis]. However, 2 newer additions [to the treatment paradigm] are primarily helpful for patients with cytopenic myelofibrosis. Pacritinib [Vonjo] was approved in February 2022 [for patients with intermediate- or high-risk primary or secondary myelofibrosis] and momelotinib [Ojjaara] was approved in September 2023 [for patients with myelofibrosis with anemia]. Pacritinib is useful in patients with thrombocytopenic myelofibrosis, and momelotinib is helpful in patients with anemic myelofibrosis.

That’s not where the drug development stopped—we’re always continuing to work on improving matters for patients. A few interesting, randomized trials [have investigated] add-on therapy in patients receiving ruxolitinib.

First was the phase 3 TRANSFORM-1 trial [NCT04472598], a randomized, double-blind, placebo-controlled, multicenter trial. [TRANSFORM-1 was] a well-conducted trial that evaluated ruxolitinib plus placebo vs ruxolitinib plus navitoclax in patients with untreated myelofibrosis. Findings from this trial were presented by Naveen Pemmaraju, MD, [of The University of Texas MD Anderson Cancer Center in Houston], at the 2023 ASH annual meeting.

The rationale to use navitoclax in myelofibrosis is that navitoclax is an oral inhibitor of BCL2 and BCLxL. Data from preclinical studies indicate that the combination of a JAK2 inhibitor with this agent could overcome acquired resistance to single-agent JAK2 treatment. [In TRANSFORM-1], patients were randomly assigned [and then] stratified based on their risk features of either intermediate-2 vs high-risk disease, and their platelet counts of [either] above 200 x 109/L or below 200 x 109/L.

A significantly higher number of patients achieved spleen volume reduction of at least 35% [(SVR35) at week 24] in the combination arm compared with patients who received placebo. [At week 24, the SVR35 rates were] 63.2% in the navitoclax plus ruxolitinib arm and 31.5% in the placebo plus ruxolitinib arm. This is the first randomized trial in JAK inhibitor–naive myelofibrosis that showed an improvement in SVR35 with the combination compared with ruxolitinib plus placebo. Patients had similar symptom responses [to those seen in previous trials with ruxolitinib monotherapy], despite receiving a lower average dose of ruxolitinib.

The main adverse effects [AEs] to watch out for [with navitoclax plus ruxolitinib] are cytopenias, specifically thrombocytopenia, anemia, and neutropenia. However, these AEs [adverse events] were reported to be manageable with dose modification without any clinically significant sequelae. These preliminary data are encouraging.

Another randomized trial in myelofibrosis was the MANIFEST-2 trial, [which studied] pelabresib in combination with ruxolitinib in treatment-naive patients with myelofibrosis. Patients were randomly assigned 1:1, and this random assignment was double blind. There was a significantly greater response in patients treated with the combination of pelabresib plus ruxolitinib vs [those who received] placebo plus ruxolitinib. At the 24-week mark, there was a significantly reduced spleen size, a similar difference [to that seen between the navitoclax and placebo arms in TRANSFORM-1, at] 65.9% vs 35.2%. Patients overall seemed to do well. I look forward to further studies. The [treatment armamentarium] for patients with myelofibrosis will hopefully continue to improve for all the ways in which patients can be affected by this disease.

Joshua F. Zeidner, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, presented updated treatment options for patients with AML. How has the addition of quizartinib to the AML treatment paradigm influenced treatment decisions for patients with this disease?

[The management of] AML has been interesting and we have exciting new therapeutics. However, we also have different [AML] classification systems. [During the IPC], we walked through our old classification system, the World Health Organization classification system, as well as newer criteria based on the International Consensus Classification.

There are pros and cons to having different classification systems. One of the main cons is that it is confusing for providers and patients. I hope in the future, we can have a unified classification system to help simplify matters for all of us and for clinical trial purposes.

We have new therapeutics [for patients with AML including] a new FLT3 inhibitor, quizartinib. This is not a new drug—it’s been around for a long time—however, we finally saw the results of the phase 3 QuANTUM-First trial [NCT02668653], which were published in The Lancet in 2023. As a result of this trial, quizartinib was FDA approved in July 2023 to be used in combination with 7 + 3 chemotherapy [for patients with newly diagnosed, FLT3-ITD–positive AML]. The prior FDA-approved agent [for patients with AML], midostaurin [Rydapt], is still on the market. However, quizartinib is only used for patients with FLT3-ITD mutations, whereas midostaurin can also be used for patients with FLT3-TKD mutations.

In the QuANTUM-First trial, patients were randomly assigned to receive either 7 + 3 [chemotherapy] plus placebo or 7 + 3 plus quizartinib. The median overall survival was significantly prolonged for patients who received quizartinib [vs those who received] placebo, which supported the FDA’s approval. When evaluating patient subgroups, this trial allowed patients who were up to the age of 75 years, which many think may be on the older end [for being able to tolerate] chemotherapy. [When patients were stratified by age]––younger than 60 years vs older than 60 years––the benefit with quizartinib was much more notable among the younger patients. Among the older patients, the curves largely overlapped between quizartinib and placebo.

AML remains a complicated disease to treat. It’s important to incorporate molecular data prior to starting therapeutics, and data from real-world studies have demonstrated that [most patients have] time to wait [for biomarker testing results]. It’s wonderful to have an extra tool in our toolbox, specifically because quizartinib seems like an effective agent in patients with FLT3-ITD–positive disease.

References

  1. Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Blood. 2023;142(suppl 1):202. doi:10.1182/blood-2023-174289
  2. Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naive patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141
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