BTK Inhibitors Stretch Frontline Approaches in Mantle Cell Lymphoma

Michael Wang, MD

Martin Dreyling, MD

The expansion of Bruton tyrosine kinase (BTK) inhibitors in the treatment of patients with mantle cell lymphoma (MCL) has led to unique combinations that have resulted in improved progression-free survival (PFS) compared with standard-of-care therapy. These novel combinations have demonstrated promising efficacy in patients who have significant unmet needs. At the same time, BTK inhibitors have refined the use of autologous stem cell transplant (ASCT). Recent findings that stratify the use of BTK inhibitors in combination with ASCT were explored during major medical conferences in 2022.

In younger, fit patients, standard of care for patients with MCL consists of cytarabine, followed by ASCT and rituximab (Rituxan) maintenance.¹ In patients who are less fit, the standard-of-care regimen consists of less intense immunotherapy, such as the combination of bendamustine-rituximab, followed by rituximab maintenance therapy.²

Now recent findings from the phase 3 TRIANGLE study (NCT02858258) presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition have suggested that adding the BTK inhibitor ibrutinib (Imbruvica) to standard chemoimmunotherapy induction, followed by ASCT and maintenance with ibrutinib for 2 years improved outcomes compared with chemoimmunotherapy and ASCT alone.³

“Based on failure-free survival, the combination of ASCT plus ibrutinib is significantly superior to ASCT alone,” lead author Martin Dreyling, MD, said during a presentation of the data. “ASCT is not superior to ibrutinib without ASCT. Currently, there [are] no decisions about whether autologous stem cell transplant adds to ibrutinib, but certainly right now toxicity favors ibrutinib only.” Dreyling is a professor of medicine and head of the Lymphoma Program in Medical Clinic III at Grosshadern Clinic at Ludwig-Maximilians-University in Munich, Germany. The open-label 3-arm trial (N = 870) randomly assigned patients to arm A, arm B, and arm C. All 3 arms received 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine [Oncovin], and prednisone)/R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin).

In arm A (n = 288) following R-CHOP/R-DHAP, patients underwent ASCT and observation. In arm B (n = 292), patients underwent ASCT, followed by 2 years of ibrutinib maintenance and observation. The third arm (n = 290) was treated with 2 years of ibrutinib and observation. Patients in all 3 arms received rituximab maintenance (58% in arm A, 57% in arm B, and 54% in arm C). The trial was designed to detect an HR of 0.60 and 1-sided α of 0.01665, powered at 90%.

The median age of patients was 57 years (range, 27-68), and most patients (76%) were male. Overall, baseline characteristics were balanced across all 3 arms.

The 3-year failure-free survival rate was 72% with standard induction and ASCT vs 88% with ibrutinib added to induction, ASCT, and 2 years of ibrutinib maintenance (HR, 0.52; P = .0008). Investigators reported that the 3-year overall survival rate (OS) was 86% in arm A, 91% in arm B, and 92% in arm C.³

The objective response rate (ORR) after induction therapy was determined to be 94% in arm A, and patients had a complete response (CR) rate of 36%. When combining the findings from both arm B and arm C (n = 559), the ORR was 98% and the CR rate was 45%.³

Dreyling said the CR rates were comparable to other US-based trials and noted that, “This [study] is CT based. It is not PET [positron emission tomography]–CT based. It is in line with previously published data [using this method], and when we looked at other induction regimens, this is highly comparable.”

SHINE Study

To further refine the use of ASCT, in the phase 3 SHINE study (NCT01776840), older patients with MCL who were not candidates for intensive chemotherapy or ASCT because of toxicities received ibrutinib with bendamustine-rituximab and rituximab maintenance.⁴ The patients were stratified by low-, intermediate-, or highrisk disease based on the MCL International Prognostic Index and randomly assigned to receive ibrutinib (560 mg daily) or placebo, plus 6 cycles of bendamustine (90 mg/m²) and rituximab (375 mg/m²).

During the 2022 American Society of Clinical Oncology Annual Meeting, Michael Wang, MD, reported on data showing that at a median follow-up of 84.7 months, treatment with the ibrutinib-based regimen (n = 261) induced a median PFS of 6.7 years (80.6 months) compared with a median of 4.4 years (52.9 months) in the placebo-based arm (HR, 0.75; 1-sided P = .011). This was a 50% improvement compared with placebo and standard of care, Wang noted.

“I think this is huge progress [in the MCL landscape],” Wang, lead study author and Puddin Clarke Endowed Professor, Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with Targeted Therapies in Oncology™.

“Transplant will not be replaced totally, but I think its use will decrease dramatically based on this study.”

The median age of the patients at study entry was 71 years (range, 65-87). Additional results demonstrated a CR rate of 65.5% in the ibrutinib arm and 57.6% in the placebo arm (P = .0567). However, there was no statistical significance in OS between the 2 treatment arms (P = .648).⁴

Wang said that based on findings from SHINE, in the frontline setting for patients older than 65 years, the combination of ibrutinib, bendamustine, and rituximab will be useful.

Resistance to Ibrutinib

Despite its benefits, patients treated with BTK inhibitors will eventually experience resistance, so the search for next-generation BTK inhibitors continues. Clinicians can look towards the approval of pirtobrutinib (Jaypirca) for relapsed or refractory MCL after at least 2 lines of systemic therapy.⁵ Efficacy was based on findings from the phase 1/2 BRUIN study (NCT03740529), which also explored unique combinations explored during the 2022 ASH meeting.

Updated findings from the BRUIN study demonstrated durable efficacy for pirtobrutinib.⁶ Previously treated patients with B-cell malignancies were eligible to participate in which pirtobrutinib monotherapy was given in either the dose-escalation or dose-expansion portion of the multicenter study.

In 90 heavily pretreated patients with MCL, 77 (86%) received the recommended phase 2 dose of pirtobrutinib (200 mg once daily). The ORR was 58% (95% CI, 47%-88%) and included 18 CRs (20%) and 34 partial responses (PRs; 38%).⁶

The median duration of response (DOR) at the 12-month follow-up was 22 months (95% CI, 7.5-not estimable [NE]), according to investigators. The 12-month and 18-month estimated DOR rates were 57% (95% CI, 39%-72%) and 52% (95% CI, 34%68%), respectively.⁶

In the safety cohort that included all patients treated with pirtobrutinib (n = 725), study investigators reported that the most common treatment-emergent adverse event (TEAE) of grade 3 or higher was neutropenia (20%; n = 143). The most common any-grade treatment-emergent AEs, regardless of attribution, were fatigue (26%; n = 191), diarrhea (22%; n = 160), and contusion (19%; n = 16). Neutropenia was the most common grade 3 or greater TEAE, according to Wang et al. They concluded that the agent was well tolerated with few drug-related toxicities.⁶

Another noncovalent BTK inhibitor, CG-806 (luxeptinib), is undergoing evaluation in early-phase clinical trials for patients with relapsed/refractory (R/R) hematologic malignancies, including MCL, chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma. Investigators demonstrated that the agent disrupts B-cell receptor signaling and induces metabolic reprogramming and apoptosis in MCL. The investigators noted that targeting BCL2 using CG-806 warrants further exploration.⁷

BTK Inhibitors in Unique Combinations

Ibrutinib and Zilovertamab

The combination of ibrutinib with zilovertamab (NCT03088878) was explored in patients with MCL and CLL in data presented during the 2022 ASH meeting. Results from the dose-finding and dose- expansion cohorts revealed ORRs of 89.3% and 91.2%, respectively, in patients with MCL (n = 25) and CLL (n = 31).⁸

“We are excited [to see these data] in patients with MCL and CLL who were treated with this combination,” lead author Hun Ju Lee, MD, an assistant professor of medicine in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, said in an interview with Targeted Therapies in Oncology™.

In the MCL population, investigators reported a median DOR of 34.1 months (95% CI, 13.67-NE).

At the 6-month, 12-month, and 26-month follow-ups, the CR rate was 29.6%, 37%, and 40.7%, respectively.

The median PFS was 35.9 months (95% CI, 17.3-NE) after a median follow-up of 15.1 months, and the landmark PFS rate was approximately 70% at 30 months.⁸

In a subpopulation of patients with tumors harboring TP53 mutations, the ORR was 83.3% (with 1 CR and 4 PRs), median DOR was 13.84 months (95% CI, 11.3-NE), median PFS was 17.3 months (95% CI, 2.85NE), and landmark PFS rate at 12 months was greater than 80%. In patients whose Ki67 index score was 30% or greater (n = 14), the ORR was 85.7%, with 5 CRs and 7 PRs.⁸

Ibrutinib and Ixazomib

The combination of ibrutinib and ixazomib (Ninlaro) was evaluated in patients with relapsed/refractory (R/R) MCL.⁹

In the phase 1 portion, patients could be either ibrutinib naïve or ibrutinib pretreated. In phase 2, patients were divided into 2 cohorts: ibrutinib naïve or ibrutinib pretreated. Investigators noted that the ibrutinib-pretreated cohort was closed early because of slow enrollment.

In the phase 1 portion (n = 12), 2 dose levels of ixazomib were evaluated (3 mg and 4 mg on days 1, 8, and 15 of a 28-day cycle) with ibrutinib at 560 mg daily. Treatment continued until disease progression or unacceptable toxicity.

Thirty-five patients who were ibrutinib-naïve were enrolled in phase 2. The CR rate was 42.9% (95% CI, 26.3%-60.6%), and the ORR was 77.1% (95% CI, 59.9%-89.6%).

Median DOR was 8 cycles (range, 1-23), with 23% of patients remaining on treatment after a median of 12 cycles (range, 6-19). Twenty-seven patients discontinued treatment because of AEs (n = 13), progression (n = 9), death due to an AE (n = 1), physician discretion (n = 1), and treatment delay (n = 1).

The primary end point for the phase 2 portion was CR within the first year of the study treatment.⁹

Grade 3 AEs including hypertension, lymphopenia, neutropenia, thrombocytopenia, rash, syncope, and atrial fibrillation were reported in 1 patient or more. AEs leading to treatment discontinuation included rash (n = 2), atrial fibrillation (n = 2), and hepatic failure, sepsis, fatigue/anorexia, peripheral neuropathy, muscle spasms, arthralgia, thrombocytopenia, diarrhea, and heart failure (n = 1 each).⁹

Acalabrutinib and Umbralisib/ Ublituximab-xiiy

Twelve patients with previously untreated MCL were enrolled in a phase 2 study (NCT04783415).¹⁰ Acalabrutinib (Calquence) 100 mg was given twice daily, umbralisib (Ukoniq) 800 mg was given daily, and ublituximab-xiiy (Briumvi) 900 mg was given intravenously on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles. After 6 cycles, patients continued maintenance with oral agents and ublituximab every 2 cycles (planned for 24 cycles).

The primary end point was efficacy as determined by CR rate, and the secondary end point was safety. Enrollment was suspended by the FDA in February 2022 due to general safety concerns with umbralisib and other PI3K inhibitors.¹¹

Because the first 2 patients who enrolled developed grade 3 and 4 aspartate aminotransferase and alanine transaminase levels, the trial design was amended so that umbralisib was given on days 1 through 14 of cycle 1 and days 1 through 7 of subsequent cycles. Four patients were unable to continue taking acalabrutinib because of elevated aspartate aminotransferase and alanine transaminase levels and continued on umbralisib/ublituximab alone.¹⁰

All 12 patients achieved CR (ORR, 100%; CR, 100%). As of data presented at the 2022 ASH meeting, 10 patients remained on therapy. Danilov et al concluded that the combination of continuous umbralisib and acalabrutinib resulted in liver function abnormalities but that intermittent dosing of umbralisib was well tolerated.¹⁰

Cellular Therapies

BTK inhibitors in combination with cellular therapies such as chimeric antigen receptor (CAR) T-cell therapy are under evaluation in ongoing trials. Whether to use these agents sequentially or concomitantly remains to be determined.¹² The TABLE^13-16 summarizes a sample of trials that explore the combination of CAR T-cell therapy with BTK inhibitors.

Conclusion

The evolution of BTK inhibitors in MCL has established this class of agent as a mainstay in the R/R setting, and their potential for further benefit continues to be explored. Unique combinations—including those that pair BTK inhibitors with targeted therapies or cellular therapies— and second-generation agents further enhance the efficacy of BTK inhibitors, and their use remains a backbone approach moving forward.

REFERENCES

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