Ryan McDonald

Interim results from the phase 3 ALPINE trial suggest that treatment with zanubrutinib (Brukinsa) may be superior to treatment with ibrutinib (Imbruvica) for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). 

In findings from the interim analysis presented during the virtual 2021 European Hematology Association (EHA) Annual Congress, the newer generation BTK inhibitor zanubrutinib demonstrated higher response and progression-free survival (PFS) rates compared with ibrutinib. 

“The treatment of CLL has been transformed by the advent of effective inhibitors of the B-cell receptor pathway such as the BTK inhibitor ibrutinib,” lead study author Peter Hillmen, MB ChB, PhD, a consultant in clinical hematology at Leeds Teaching Hospitals NHS Trust and honorary professor of hematology at University of Leeds, said during a presentation of the findings. “We hypothesized that zanubrutinib may minimize toxicities related to ibrutinib off-target inhibition, and zanubrutinib may improve efficacy outcomes.”

Hillmen and colleagues set out to conduct the phase 3 ALPINE study to assess the efficacy and safety profile of zanubrutinib compared to ibrutinib in patients with relapsed/refractory CLL/SLL who received at least 1 prior systemic therapy. The authors recruited 652 patients, of which 415 were randomized to receive either zanubrutinib at 160 mg BID (n = 207) or ibrutinib at 420 mg once daily (n = 208).

Overall response rate (ORR), comprising a partial or complete response, as assessed by investigator served as the study’s primary endpoint. Additional endpoints included duration of response (DOR), progression-free survival (PFS) and overall (OS), as well as atrial fibrillation of any grade, patient outcomes and safety.

Baseline characteristics were well balanced between the two arms. The median age for the zanubrutinib and ibrutinib arms was 67 years, and patients in both arms (68.6% vs 75.0%, respectively) were mostly male.

At a data cutoff of approximately 12 months, the ORR among patients in the zanubrutinib arm (78.3%; 95% CI, 72-83.7) was far superior than in the ibrutinib arm (62.5%; 95% CI, 55.5-69.1). When taking partial and complete responses, as well as partial response-lymphocytosis into account, Hillmen noted, ORR was 88.4% for the zanubrutinib arm and 81.3% for the ibrutinib arm.

The findings also demonstrated that patients who received zanubrutinib achieved a superior 12-month PFS rate (94.9%) than those who received ibrutinib (84%; HR = 0.4; 95% CI, 0.23-0.69; 

= .0007). The 12-month OS rate, however, was relatively similar between the two arms (97% vs 92.7%, respectively; HR = 0.54; 95% CI, 0.25-1.16; 

Regarding safety, almost all patients in both the zanubrutinib (95.6%) and ibrutinib (99%) experienced any grade adverse event (AE). Moreover, more than half of each arm (55.9% vs 51.2%, respectively) reported any grade ≥ 3 AE. Sixteen patients in the zanubrutinib arm, along with 27 patients in the ibrutinib arm had to discontinue treatment because of AEs. There were deaths associated with AEs — 8 in the zanubrutinib arm and 12 in the ibrutinib arm. Diarrhea (16.7 % vs 19.3%, respectively), neutropenia (19.6% vs (15.5%), anemia (13.2% vs 15%), upper respiratory tract infection (21.6% vs 14%) and arthralgia (9.3% vs 14%) were among some of the most frequently experienced AEs.

AEs of special interest included, but were not limited to, cardiac disorders, atrial fibrillation and flutter, hemorrhage and hypertension. Of note, atrial fibrillation and flutter of any grade was drastically reduced in the zanubrutinib (2.5%) arm compared to the ibrutinib (10.1%) arm.

Currently, 87.4% of patients in the zanubrutinib arm remain on treatment compared to 75.5% of the ibrutinib arm.

“In this interim analysis of the randomized phase 3 ALPINE study in patients with relapsed refractory CLL, zanubrutinib was shown to have a superior response rate, improved progression-free survival rates and a lower rate of atrial fibrillation (and) flutter than ibrutinib,” Hillmen concluded. “These data support that more selective BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes.”

Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: Results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 2021 European Hematology Association Congress; June 9-17, 2021; Virtual. Abstract LB1900.

Articles

Interim results from the phase 3 ALPINE trial suggest that treatment with zanubrutinib may be superior to treatment with ibrutinib for patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. 

Fewer Toxicities, Greater Efficacy Suggested With Zanubrutinib Compared With Ibrutinib in R/R CLL/SLL

In newly diagnosed, transplant-eligible (NDTE) patients with multiple myeloma, carfilzomib (Kyprolis) consolidation with cyclophosphamide and dexamethasone (KCd) conferred noninferior results compared to upfront autologous stem cell transplantation (ASCT), according to results of the CARDAMON study presented at the 2021 ASCO Annual Meeting.

Of note, the 2-year progression-free survival (PFS) was similar among the treatment arms.

Data currently support the use of ASCT in these patients; however, those trials have employed lenalidomide as maintenance therapy. The concern is that lenalidomide has been shown to mostly benefit patients with standard-risk disease. Moreover, ASCT among this patient population is associated with high MRD rates following induction and consolidation strategies.

As a result, researchers aimed to assess the effect of carfilzomib-based induction and maintenance treatments versus ASCT in this patient population.

Patients at pre-randomization received 4 cycles of 56 mg/m2 of carfilzomib in a bi-weekly regimen along with 500 mg of cyclophosphamide and 40 mg of dexamethasone weekly. Patients who achieved at least a partial response to therapy proceeded to peripheral blood stem cell harvests (PBSCH) and were then randomized 1:1 to melphalan 200 mg/m2 plus ASCT or 4 cycles of KCd consolidation. The study population then received 18 cycles of maintenance carfilzomib at 56 mg/m2 weekly.

Prior results of the CARDAMON trial evaluating very good partial response (VGPR) to therapy were previously. Here, the study’s lead author Kwee Yong, MBBS, PhD, of University College London Hospitals NHS Foundation Trust, presented results from the second co-primary endpoint of PFS. 

The trial enrolled 281 patients (median age, 59 years), of which 47.3% were aged older than 60 years. All patients received KCd induction and were then randomized. At the time of randomization, outcomes were similar between the ASCT (n =109) and KCd consolidation (n = 109) arms. 

Two hundred and twenty-eight patients proceeded to PBSCH, and 197 patients started maintenance therapy. Following induction treatment, VGPR rate was 58.5%, which increased to 77.3% after consolidation and 80% after ASCT. The MRD-negative rate after induction was 24.3%, which increased to 35.8% after consolidation and 53.1% after ASCT.

Among patients considered standard risk, VGPR rate after KCd induction (n = 207) was 58.5%, which increased to 79.5% with consolidation KCd (n = 79) and 76.8% with ASCT (n = 85). The MRD-negative rate was 25% after induction, 37.1% with consolidation and 48.1% with ASCT. The results, Yong noted, were relatively similar in the high-risk patient population. In those individuals, VGPR rate after induction (n = 52) was 59.6%, 77.3% after consolidation (n = 22) and 89.5% after ASCT (n = 19). MRD-negative rate was 24% after induction, 31.6% with consolidation and 66.7% after ASCT.

“This difference in MRD-negative rate looks striking,” Yong said. “But I would draw your attention to the relatively small patient numbers in these groups.”

As for survival outcomes, Yong noted that KCd was not non-inferior to ASCT. At a median follow-up of 37.5 months, 2-year PFS rate in the ASCT arm was 76% (95% CI, 66-83) compared with 70% (95% CI, 60-78) in the KCd consolidation arm. Patients in the ASCT arm have not yet reached a median PFS, whereas the median PFS in the consolidation group is 3.4 years (95% CI, 2.4-N/A).

In terms of genetic risks, patients with standard-risk genetics achieved a median PFS of 5.1 years while the high-risk patients achieved a median PFS of 1.7 years (HR = 2.7, 1.8-4.1; 

 < .001). Moreover, the median PFS in the ASCT arm was 4.7 years (95% CI, 3.3-N/A) compared to 1.2 years in the consolidation arm (95% CI, 0.7-N/A) among high-risk patients.

“However, this does not reach significance,” Yong explained. “And because of the high confidence intervals in neither high-risk [nor] standard-risk group, it does appear that ASCT has a benefit over consolidation.”

Following randomization, patients who were MRD-negative following PBSCH had similar PFS rates in the ASCT and consolidation arms (HR = 0.8, 0.3-2.0; 

In summary, Yong noted that induction with K56Cd produced deep responses in patients with a 24.3% MRD-negative rate. Additionally, VGPR rates were similar between the ASCT and KCd consolidation arms. However, MRD-negative rate was higher following ASCT (53%) than KCd consolidation (35.8%).

“High risk patients have inferior PFS compared to standard risk patients but in neither of these genetic risk groups is there evidence that ASCT is more effective than KCd consolidation,” she concluded. “Patients who are MRD-positive at randomization may derive more benefit from ASCT than from consolidation.”

Yong K, Camilleri M, Wilson W, et al. Upfront autologous stem cell transplantation (ASCT) versus carfilzomib-cyclophosphamide-dexamethasone (KCd) consolidation with K maintenance in transplant-eligible, newly diagnosed (NDTE) multiple myeloma (MM). 

. 2021;39(suppl 15):8000. doi: 10.1200/JCO.2021.39.15_suppl.8000

In newly diagnosed, transplant-eligible patients with multiple myeloma, carfilzomib consolidation with cyclophosphamide and dexamethasone conferred noninferior results compared to upfront autologous stem cell transplantation.

In Transplant-Eligible, Newly Diagnosed MM, KCd Consolidation Proves Noninferior to ASCT

Increased efficacy was observed with the combination of mosunetuzumab with polatuzumab vedotin (Polivy) in in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL), according to results from a phase 1b study.

The results, which were presented at the 2021 ASCO Annual Meeting, also demonstrated that the combination had an acceptable safety profile among the patient population.

Prior research has shown that treatment with mosunetuzumab — which is a full-length, humanized, IgG1 bispecific antibody — alone was safe and effective in treating relapsed/refractory B-NHL.

Additionally, recent results from a xenograft mouse model indicated that the combination induced increased efficacy compared to either agent administered as a monotherapy.

“These data supported a phase 1b/2, open-label, multicenter trial of [mosunetuzumab with polatuzumab vedotin] for relapsed-refractory B-NHL,” lead study author Elizabeth Budde, MD, PhD, of City of Hope, said during a presentation of the study results.

Here, Budde presented early clinical data from the dose-finding phase 1b cohort comprised of 22 patients (median age, 70 years; male, 50%) with either relapsed/refractory follicular lymphoma (FL) or aggressive NHL, including diffuse large B-cell lymphoma (n = 12), transformed FL (n = 4) and FL grade 3b (n = 3).

Patients were excluded from enrollment onto trial if they had received CD20-directed bispecific antibodies, as well as immunochemotherapy within 4 weeks of the first dose of study drug or radiotherapy within 2 weeks of first dose of study drug.

The study participants received a step-up dose of mosunetuzumab at 1 mg on day 1 of treatment and 2 mg on day 8 and then continued the target dose of 2 mg. That dose was given every 21 days for 8 cycles, or 17 cycles if patients achieved stable disease or a partial response after the eighth treatment cycle. Polatuzumab vedotin was administered at a dose of 1.8 mg/kg with mosunetuzumab on the first day of each treatment cycle for 6 cycles.

Determining a recommended phase 2 dose of study drug served as this cohort’s primary endpoint.

Patients had received a median 3 prior lines of therapy (range, 1-10), and 7 patients had previously received treatment with a CAR T-cell therapy.

At a median follow-up of 9.6 months (range, 0.7-23.7 months), all patients experienced at least 1 adverse event (AE). Neutropenia and nausea (40.9%, respectively), as well as fatigue and diarrhea (36.4%, respectively) were the most common treatment-related AEs (TRAEs). Two patients experienced a fatal grade 5 AE — one because of sudden cardiac death and another because of respiratory failure. Those deaths were not considered related to treatment, the study authors noted. Of note, AEs led to dose modification among 8 patients and treatment discontinuation in 3 patients.

Two cases of cytokine release syndrome occurred during the first cycle of step-up dosing; however, both were considered non-severe and were treated without the need of the immunosuppressive drug tocilizumab (Actemra), admission to the ICU or use of vasopressors.

Importantly, Budde noted, no neurotoxicity syndrome-like events occurred.

Of the study population, 15 patients achieved a best overall response (OR), of which 12 achieved a complete response (CR).

“[Mosunetuzumab with polatuzumab vedotin] showed promising efficacy in patients with relapsed/refractory NHL with predominantly aggressive histology,” Budde concluded. “Complete response rate was seen in 54.5% (of patients) and were also seen in patients who failed prior CAR Ts and patients with high-grade lymphoma.”

The phase 2 expansion cohort in patients with relapsed/refractory DLBCL is currently ongoing.

Budde E, Ghosh N, Chavez JC, et al. Promising tolerability and efficacy results from dose-escalation in an ongoing phase Ib/II study of mosunetuzumab (M) with polatuzumab vedotin (Pola) in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin’s lymphoma (B-NHL). 

Increased efficacy was observed with the combination of mosunetuzumab with polatuzumab vedotin in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Mosunetuzumab With Polatuzumab Vedotin Effective, Well Tolerated in R/R B-Cell Non-Hodgkin Lymphoma

One infusion of ciltacabtagene autoleucel (cilta-cel) lead to early and deep responses in a cohort of patients previously treated for relapsed/refractory multiple myeloma, according to findings the phase 2 CARTITUDE-2 study presented during the 2021 ASCO Annual Meeting.

Treatment with a target dose of cilta-cel at 0.75 x 106/kg resulted in an overall response rate (ORR) of 95% (95% CI, 75-100) with a stringent complete response rate (sCR) of 75% (95% CI, 51-91), and a very good partial response rate or better of 85% (95% CI, 62-97).

After a median follow-up of 5.8 months, the median time to first response with cilta-cel was 1 month (range, 0.7–3.3) and the median time to best response was 1.9 months (0.9–5.1). As of the January 2021 data cutoff, a median duration of response had not yet been reached.

Cilta-cel, formerly JNJ-68284528, is a second-generation CAR T-cell therapy with 2 BCMA-targeting, single-domain antibodies designed to confer avidity. Previous data that were published from the phase 1b/2 CARTITUDE-1 trial demonstrated that single infusion of cilta-cel was associated with deep and durable response among heavily pretreated patients with relapsed/refractory disease.

The primary objective of this cohort of the phase 2 CARTITUDE-2 trial was to assess minimal residual disease (MRD) negativity at 10–5 threshold among patients who were refractory to lenalidomide or relapsed after one to three prior lines of therapy. Additional secondary outcomes included ORR, duration of response (DOR), time and duration of MRD negativity and incidence and severity of adverse events (AEs).

Patients received the targeted dose of cilta-cel 5 to 7 days after the beginning of lymphodepletion (daily cyclophosphamide at 300 mg/m2 and fludarabine at 30 mg/m2 for 3 days).

A total of 20 patients (median age, 60 years; 65% male) received the single-infusion CAR T-cell therapy. One of the patients was treated in an outpatient setting. Twelve of the patients had received fewer than 3 lines of therapy, and the remaining 8 received 3 prior lines of therapy.

All the patients had been previously treated with a proteasome inhibitor (PI), an immunomodulatory drug (IMiD) and dexamethasone. Almost all (95%) of the patients were exposed to alkylating agents and 65% received daratumumab (Darzalex).

All patients (n = 4) with MRD-evaluable samples were MRD negative at the January 2021 cutoff and more samples are being evaluated.

In terms of safety, hematologic AEs that occurred in 20% or more of the patients included neutropenia (95%), thrombocytopenia (80%), anemia (65%), lymphopenia (60%) and leukopenia (55%). Moreover, cytokine release syndrome occurred in 85% of patients, of which 10% were considered grade 3 or 4.

“The safety profile was manageable, including in the one patient that was treated in the outpatient setting,” said study author Mounzer E. Agha, MD, director, Mario Lemieux Center for Blood Cancers, clinical director of Hematopoietic Stem Cell Transplantation, UPMC Hillman Cancer Center, during a recorded presentation of the data. “There were no cases of movement and neurocognitive adverse events.”

Agha noted that one death occurred 100 days after the infusion of cilta-cel due to COVID-19 infection and was assessed as treatment-related by the investigators.

“Early and deep responses were observed with a single infusion of cilta-cel in lenalidomide refractory patients with multiple myeloma who received one-to three prior lines of therapy,” he concluded.

The CAR T-cell therapy is being evaluated in other cohorts of the CARTITUDE-2 in earlier line settings, as well as in the phase 3 CARTITUDE-4 study in patients with one to three prior lines of therapy.

Agha ME, Cohen AD, Madduri D, et al. CARTITUDE-2: Efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in patients with progressive multiple myeloma (MM) after one to three prior lines of therapy. 

One infusion of ciltacabtagene autoleucel lead to early and deep responses in a cohort of patients previously treated for relapsed/refractory multiple myeloma, according to findings the phase 2 CARTITUDE-2 study.

Ryan McDonald | Authors

Articles

Fewer Toxicities, Greater Efficacy Suggested With Zanubrutinib Compared With Ibrutinib in R/R CLL/SLL

In Transplant-Eligible, Newly Diagnosed MM, KCd Consolidation Proves Noninferior to ASCT

Mosunetuzumab With Polatuzumab Vedotin Effective, Well Tolerated in R/R B-Cell Non-Hodgkin Lymphoma

Cilta-Cel Elicits Deep Response Early On in Patients With R/R Multiple Myeloma