A Review of Selected Presentations From the 63rd ASH Meeting and Exposition
• December 11-14, 2021 • Atlanta, Georgia
Three-Year Follow-Up of the ASCEND Trial: Acalabrutinib vs Rituximab Plus Idelalisib or Bendamustine in Relapsed/Refractory Chronic Lymphocytic Leukemia
Acalabrutinib is a second-generation inhibitor of Bruton tyrosine kinase (BTK) approved for the treatment of chronic lymphocytic leukemia (CLL).1 The phase 3 ASCEND trial evaluated acalabrutinib vs the investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab. Eligible patients were adults with a diagnosis of CLL (as defined by the International Workshop on CLL [iwCLL]) who had received at least 1 prior systemic therapy. The trial enrolled 310 patients. Stratification factors included presence of the 17p deletion (del[17p]), Eastern Cooperative Oncology Group (ECOG) performance status, and number of prior therapies. Patients were randomly assigned to receive acalabrutinib (100 mg, twice daily) vs idelalisib (150 mg, twice daily) plus rituximab or bendamustine (70 mg/m2) plus rituximab. The primary endpoint was investigator-assessed progression-free survival (PFS). Patients with disease progression in the rituximab arm were allowed to cross over into the acalabrutinib arm.
The patients’ median age was 67 years (range, 32-90 years). They had received a median of 2 prior therapies (range, 1-10 prior therapies). Bulky disease (≥5 cm) was noted in 48.7% of patients, and 41.6% had Rai stage III/IV disease. Cytogenetic abnormalities included unmutated immunoglobulin heavy chain (IGHV) in 78.4%, complex karyotype in 31.0%, del(11q) in 26.8%, and del(17p) in 15.8%. The median time on study was similar for all 3 treatment regimens (range, 34.2-36.0 months).2 The median duration of exposure was 35.0 months with acalabrutinib, 11.5 months with idelalisib plus rituximab, and 5.6 months with bendamustine plus rituximab. Treatment was discontinued by 19% of patients in the bendamustine arm, 43% of patients in the acalabrutinib arm, and 85% of patients in the idelalisib arm.
The median PFS was not reached with acalabrutinib vs 16.8 months with pooled data from the 2 rituximab cohorts (hazard ratio [HR], 0.29; 95% CI, 0.21-0.41; P<.0001). The 3-year PFS was 63% vs 21%, respectively. Acalabrutinib also yielded superior PFS vs idelalisib plus rituximab (HR, 0.31; 95% CI, 0.22-0.43; P<.0001) or bendamustine plus rituximab (HR, 0.25; 95% CI, 0.16-0.40; P<.001; Figure 1). The median PFS was higher with acalabrutinib vs the investigator’s choice of therapy among patients with del(17p) (HR, 0.13; 95% CI, 0.06-0.30; P<.0001) or without del(17p) (HR, 0.34; 95% CI, 0.24-0.48; P<.0001; Figure 2). Similar improvements in median PFS were reported for patients with unmutated IGHV (HR, 0.30; 95% CI, 0.21-0.42; P<.0001) or with mutated IGHV (HR, 0.32; 95% CI, 0.14-0.70; P<.0027). Treatment with acalabrutinib yielded a superior median PFS compared with the rituximab combinations in all prespecified subgroups, including those based on number of prior therapies, Rai stage at screening, bulky disease, and complex karyotype. The median overall survival (OS) was not reached in either arm. At 2 years, however, the Kaplan-Meier curves showed separation between patients treated with acalabrutinib vs the investigator’s choice. The 3-year OS rates were 80% with acalabrutinib vs 73% with the rituximab-containing therapies (HR, 0.69; 95% CI, 0.43-1.10; P=.1184). The objective response rate was similar for acalabrutinib vs the investigator’s choice of therapy (83% vs 85%, respectively; P=.62).
Adverse events (AEs) of grade 3 or higher were observed in 62% of patients in the acalabrutinib arm, 92% in the idelalisib plus rituximab arm, and 49% in the bendamustine plus rituximab arm. Grade 5 AEs were observed in 9%, 7%, and 6% of patients, respectively. AEs led to treatment discontinuation in 21%, 65%, and 17%. Serious AEs associated with acalabrutinib therapy included pneumonia (8%), pyrexia (2%), and diarrhea (1%).
References
1. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.
2. Jurczak W, Pluta A, Wach M, et al. Three-year follow-up of the ASCEND trial: acalabrutinib vs rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia [ASH abstract 393]. Blood. 2021;138(suppl 1).
A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib to Ibrutinib in Patients With Chronic Lymphocytic Leukemia: A Minimal Residual Disease–Driven, Time-Limited Approach
A phase 2 trial evaluated induction with ibrutinib monotherapy, followed by ublituximab plus umbralisib (U2), in patients with detectable minimal residual disease (MRD).1 The multicenter, open-label trial enrolled patients who were receiving ongoing ibrutinib as any line of therapy for at least 6 months. Patients had detectable residual CLL in the peripheral blood according to flow cytometry, with a cutoff of 10-4. For patients with detectable MRD, U2 was added to ibrutinib therapy. Patients were serially monitored for MRD starting on day 1 of cycle 3. Patients who remained MRD-free for 4 weeks underwent treatment-free observation. Patients with detectable MRD continued with combination therapy for up to 24 cycles. The primary endpoint was the rate of undetectable MRD.
Twenty-eight patients were evaluable for safety and 27 for efficacy. The patients were a median age of 64 years (range, 48-81 years). The median duration of ibrutinib monotherapy at study entry was 21 months (range, 7-67 months). Sixty-eight percent of patients were receiving ibrutinib monotherapy as their first-line therapy, and all of the patients had achieved a partial response (PR) as their best response during treatment with ibrutinib. Cytogenetic features included unmutated IGHV in 67%, del(11q) in 21%, and del(17p) in 7%. Two patients discontinued study therapy owing to AEs consisting of rash and/or arthralgia. Grade 3/4 treatment-emergent AEs included hypertension (7%), diarrhea (4%), elevated transaminases (4%), and COVID-19 (4%). One patient died of COVID-19 complications 103 days after discontinuing the U2 regimen and was not included in the efficacy evaluations.
Seventy-seven percent of patients achieved undetectable MRD. Nineteen percent of patients had detectable MRD and were continuing therapy, and 1 patient had completed 24 cycles of therapy and had detectable MRD. The median time to undetectable MRD was 7.4 months (95% CI, 4.6-10.2 months; Figure 3). At the time of the report, only 1 patient had developed progressive disease.
Reference
1. Roeker LE, Leslie L, Soumerai J, et al. A phase 2 study evaluating the addition of ublituximab and umbralisib to ibrutinib in patients with chronic lymphocytic leukemia: a minimal residual disease–driven, time-limited approach [ASH abstract 395]. Blood. 2021;138(suppl 1).
New Acalabrutinib Formulation Enables Co-Administration With Proton Pump Inhibitors and Dosing in Patients Unable to Swallow Capsules (ELEVATE-PLUS)
Acalabrutinib is approved for the treatment of CLL and mantle cell lymphoma.1 The solubility of acalabrutinib decreases with increasing pH, and therefore concomitant use of proton pump inhibitors is not recommended.2 Additionally, cancer patients who have difficulty swallowing capsules may require an alternative method of delivery. To address these issues, acalabrutinib was developed in a tablet form with an immediate-release film.3 The film coating eases swallowing of the tablet, and the tablet’s volume is reduced by 50% compared with the capsule formulation. The acalabrutinib maleate tablet is quickly and completely released in vitro at all physiologic pH levels.
Three open-label, single-dose, crossover phase 1 studies were conducted to assess the pharmacologic and clinical properties of the acalabrutinib maleate tablet or acalabrutinib suspension formulation as compared with the capsules. The investigators also evaluated the effects of a high-fat diet vs fasting on the properties of the tablet. These studies included 66 subjects to establish pharmacokinetic similarity between the acalabrutinib maleate tablet (100 mg) and the acalabrutinib capsule (100 mg); 14 patients who received the acalabrutinib maleate tablet (100 mg) plus rabeprazole; 16 patients who received the acalabrutinib maleate tablet (100 mg) while following a high-fat diet or in a fasting state; and 20 patients who received the acalabrutinib maleate (100 mg) suspension delivered by a nasogastric tube for the assessment of pharmacokinetics. Pharmacodynamics were evaluated by measuring the BTK target occupancy in peripheral blood mononuclear cells.
Systemic exposure of acalabrutinib and ACP-5862—its most prevalent pharmacologically active metabolite—were bioequivalent between acalabrutinib and the acalabrutinib maleate tablet, showing a difference in the geometric mean exposures of less than 5% (Figure 4). The addition of a proton pump inhibitor to the acalabrutinib maleate tablet did not confer any clinically relevant differences in exposure to acalabrutinib or ACP-5862. The BTK target occupancy was at least 95% across all treatment arms. A high-fat diet did not affect exposure to acalabrutinib or ACP-5862, with a BTK target occupancy of 95% or higher observed across all treatment arms. Exposure to acalabrutinib and ACP-5862 was equivalent, with a difference of no more than 10% across the acalabrutinib maleate suspension (100 mg), delivery via nasogastric tube, and the acalabrutinib capsules (100 mg). Exposure to acalabrutinib and its major active metabolite was also equivalent between the capsules and the nasogastric suspension among the patients who did or did not receive a proton pump inhibitor. The novel acalabrutinib tablet formulation was associated with a favorable safety profile. The majority of AEs were mild, with no serious cases reported.
References
1. Calquence [package insert]. Wilmington, DE; AstraZeneca, Inc; 2019.
2. Pepin XJH, Moir AJ, Mann JC, et al. Bridging in vitro dissolution and in vivo exposure for acalabrutinib. Part II. A mechanistic PBPK model for IR formulation comparison, proton pump inhibitor drug interactions, and administration with acidic juices. Eur J Pharm Biopharm. 2019;142:435-448.
3. Sharma S, Pepin X, Burri H, et al. New acalabrutinib formulation enables co-administration with proton pump inhibitors and dosing in patients unable to swallow capsules (ELEVATE-PLUS) [ASH abstract 4365]. Blood. 2021;138(suppl 1).
Characterization of Bruton Tyrosine Kinase Inhibitor–Related Adverse Events in a Head-to-Head Trial of Acalabrutinib vs Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia
The ongoing phase 3 ELEVATE-RR trial is comparing acalabrutinib vs ibrutinib in previously treated patients with CLL.1,2 The study enrolled 533 patients with centrally confirmed del(17p13.1) or del(11q22.3). Patients were randomly assigned to receive acalabrutinib (100 mg, twice daily) or ibrutinib (420 mg, daily) until disease progression or unacceptable toxicity. The patients were a median age of 66 years. Del(17p) was noted in 45% of patients and del(11q) was reported in 64%. After a median follow-up of 40.9 months, the median PFS in both arms was 38.4 months, thus demonstrating noninferiority of acalabrutinib compared with ibrutinib (HR, 1.00; 95% CI, 0.79-1.27). Safety results suggested a reduction in cardiovascular AEs in the acalabrutinib arm.
A post hoc analysis was conducted to provide a more detailed comparison of the rates of AEs with acalabrutinib vs ibrutinib.2 The median treatment exposure was 38.3 months with acalabrutinib vs 35.5 months with ibrutinib. Ibrutinib was associated with an exposure-adjusted higher incidence rate of any-grade atrial fibrillation/flutter (2-fold; Figure 5), hypertension (2.8-fold; Figure 6), and bleeding (1.6-fold). The exposure-adjusted time with event was also greater with ibrutinib by 2.0-, 3.7-, and 1.8-fold, respectively. Ventricular arrhythmias occurred in 3 patients in the ibrutinib arm vs none in the acalabrutinib arm. Sudden cardiac death occurred in 1 additional patient in the ibrutinib arm vs none in the comparator arm. The exposure-adjusted incidence was higher with ibrutinib compared with acalabrutinib in terms of any-grade diarrhea (2.8 vs 1.9), arthralgia (1.3 vs 0.6), back pain (0.5 vs 0.3), muscle spasms (0.7 vs 0.2), and dyspepsia (0.5 vs 0.1). Acalabrutinib was associated with a higher exposure-adjusted incidence of cough (1.1 vs 1.3) and headache (1.1 vs 1.8).
Further characterization showed a prolonged median time to onset of atrial fibrillation/flutter of any grade with acalabrutinib (28.8 months [range, 0.4-52.0 months]) vs ibrutinib (16.0 months [range, 0.5-48.3 months]). The cumulative incidence of atrial fibrillation/flutter was lower with acalabrutinib compared with ibrutinib at all time points examined. The median time to hypertension was similar for acalabrutinib (8.1 months [range, 0.0-44.0 months]) and ibrutinib (7.0 months [range, 0.0-39.8 months]). However, the cumulative incidence of hypertension was lower with acalabrutinib for each time point examined. Based on Cox proportional hazard modeling, acalabrutinib was favored over ibrutinib with rate reductions of 63% for new-onset atrial fibrillation/flutter and 77% for new-onset hypertension. The lower incidences of atrial fibrillation/flutter and hypertension reported with acalabrutinib were maintained in all subgroups. The median time to onset of bleeding was 1.2 months for both treatments. However, the cumulative incidence of any-grade bleeding events was lower with acalabrutinib compared with ibrutinib at every time point examined.
References
1. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452.
2. Seymour JF, Byrd JC, Hillmen P, et al. Characterization of Bruton tyrosine kinase inhibitor–related adverse events in a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia [ASH abstract 3721]. Blood. 2021;138(suppl 1).
A Quality-Adjusted Survival (Q-TWiST) Analysis to Assess Benefit-Risk of Acalabrutinib vs Idelalisib/Bendamustine Plus Rituximab or Ibrutinib Among Relapsed/Refractory Chronic Lymphocytic Leukemia Patients
The ELEVATE-RR trial and the ASCEND study investigated acalabrutinib among patients with previously treated CLL, with overall study populations of 533 and 310, respectively.1,2 The comparator arm received treatment with ibrutinib monotherapy in the ELEVATE-RR study and rituximab plus idelalisib or bendamustine in the ASCEND study. A post hoc analysis was conducted to estimate the relative risk and benefit of therapies in the 2 studies. Treatment risk was evaluated based on toxicity, and benefit was evaluated based on the length of survival in the absence of disease progression or AEs, by calculating the quality-adjusted time without symptoms or toxicity (Q-TWiST), the mean duration of toxicity prior to disease progression (TOX), and the time from disease progression until death or the last follow-up (REL).3 TWiST was calculated as the difference in the mean durations of PFS and TOX.
An analysis of data from the ASCEND trial that used fixed utility values of 0.5 for TOX, 0.5 for REL, and 1 for TWiST showed that patients treated with acalabrutinib spent significantly less time in the TOX state and the REL state, and more time in the TWiST state, compared with patients treated with the rituximab combinations (Table 1). Q-TWiST was significantly prolonged with acalabrutinib monotherapy vs rituximab plus idelalisib or bendamustine (17.48 vs 15.52 months; difference, 1.96 months; P<.001).
In an analysis of the ELEVATE-RR trial—which calculated TOX based only on grade 3/4 AEs—the TOX, REL, TWiST, and Q-TWiST values were not significantly different between acalabrutinib vs ibrutinib (P>.05 for each). However, significant differences emerged between the 2 treatments when data sets for toxicity were narrowed to focus on particular events. For example, when grade 2 to 4 AEs were included in the TOX calculation, acalabrutinib was favored over ibrutinib in terms of Q-TWiST (Table 2; Q-TWiST difference, 2.58; P=.031). Similarly, when calculated based on the AEs that occurred in at least 10% of patients, Q-TWiST was again significantly better among patients treated with acalabrutinib compared with ibrutinib (Q-TWiST difference, 2.56 months; P=.031).
References
1. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452.
2. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861.
3. Seymour JF, Gaitonde P, Emeribe U, Cai L, Mato A. A quality-adjusted survival (Q-TWiST) analysis to assess benefit-risk of acalabrutinib versus idelalisib/bendamustine plus rituximab or ibrutinib among relapsed/refractory (R/R) chronic lymphocytic leukemia patients [ASH abstract 3722]. Blood. 2021;138(suppl 1).
SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib vs Bendamustine + Rituximab in Patients With Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Zanubrutinib is a second-generation BTK inhibitor that has improved target selectivity compared with ibrutinib.1 Cohort 1 of the global, open-label phase 3 SEQUOIA trial evaluated zanubrutinib vs bendamustine plus rituximab in patients with treatment-naive CLL or small lymphocytic lymphoma (SLL).2,3 Eligible patients met the iwCLL criteria for treatment. They were ages 65 years or older or were unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Patients in arm A received zanubrutinib (160 mg, twice daily) until disease progression or unacceptable toxicity, and patients in arm B received 6 cycles of bendamustine (90 mg/m2, days 1 and 2) plus rituximab (375 mg/m2, day 1 of cycle 1, then 500 mg/m2, cycles 2-6). Patients with del(17p) at screening were assigned to cohort 2/arm C, for treatment with zanubrutinib monotherapy, or to cohort 3/arm D, for treatment with zanubrutinib plus venetoclax. The primary endpoint was PFS by independent assessment.
The study randomly assigned 479 patients without del(17p) to arms A and B.2 The patients’ median age was 70 years (range, 66-75 years). Twenty-nine percent of patients in each arm had Binet stage C disease, and 29% to 31% had bulky disease (≥5 cm). In each arm, more than half of patients (52%-53%) had unmutated IGHV. Del(11q) was reported in 18% of patients in arm A and 19% of patients in arm B. After a median follow-up duration of approximately 26 months, the 24-month PFS was 85.5% with zanubrutinib vs 69.5% with bendamustine plus rituximab (HR, 0.42; 95% CI, 0.27-0.63; P<.0001; Figure 7). The median PFS was superior with zanubrutinib vs bendamustine plus rituximab in nearly all subgroups examined, including patients with bulky disease (HR, 0.52; 95% CI, 0.27-0.97), patients with unmutated IGHV (HR, 0.24; 95% CI, 0.24-0.43), and patients with del(11q) at baseline (HR, 0.21; 95% CI, 0.09-0.50). Zanubrutinib had a more favorable safety profile vs bendamustine plus rituximab, with fewer AEs of grade 3 or higher (53% vs 80%), fewer serious AEs (37% vs 50%), fewer AEs leading to dose reduction (8% vs 37%), and fewer AEs leading to discontinuation of study treatment (8% vs 14%).
Arm D of the SEQUOIA trial is evaluating zanubrutinib plus venetoclax in patients with treatment-naive CLL/SLL with del(17p), with a planned enrollment of 80 patients. Preliminary results were available from 35 enrolled patients. After a median follow-up of 9.7 months, 32 patients remained on study treatment. AEs of any grade were reported in 83% of patients, and serious AEs occurred in 11%. Among 13 patients (37%) with AEs of grade 3 or higher, the most common were neutropenia (n=4) and diarrhea (n=2). One patient with ongoing grade 2 atrial fibrillation at baseline experienced grade 3 atrial fibrillation while receiving the study medication. No tumor lysis syndrome was observed. Among 31 patients available for efficacy analysis, the ORR was 96.8%.
References
1. Gaballa S, Pinilla-Ibarz J. BTK inhibitors in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2021;16(5):422-432.
2. Tam CS, Giannopoulos K, Jurczak W, et al. SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma [ASH abstract 396]. Blood. 2021;138(suppl 1).
3. Tedeschi A, Ferrant E, Flinn IW, et al. Zanubrutinib in combination with venetoclax for patients with treatment-naïve chronic lymphocytic leukemia or small lymphocytic lymphoma with del(17p): early results from arm D of the SEQUOIA (BGB-3111-304) trial [ASH abstract 67]. Blood. 2021;138(suppl 1).
Pirtobrutinib, A Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Updated Results From the Phase 1/2 BRUIN Study
Pirtobrutinib is a highly selective, reversible inhibitor of BTK.1 Its pharmacokinetic properties allow for sustained inhibition of BTK throughout the dosing interval. Pirtobrutinib was designed to bind to BTK reversibly, and therefore inhibition of BTK is sustained even in the presence of high rates of BTK turnover. The phase 1/2 BRUIN study consisted of a dose-escalation phase, using a 3-plus-3 design, followed by expansion.2 Intrapatient dose escalation was allowed, and cohort expansion was permitted based on acceptable safety. Eligible patients had relapsed or refractory CLL/SLL or another B-cell non-Hodgkin lymphoma, with active disease in need of treatment. The escalation and expansion doses of pirtobrutinib ranged from 25 mg to 300 mg, administered daily. The investigators selected 200 mg daily as the recommended phase 2 dose.
The efficacy population included 261 patients, whose median age was 69 years (range, 36-88 years). The median number of prior lines of therapy was 3 (range, 1-11). All of the patients had received prior therapy with a BTK inhibitor, and 88% had received an anti-CD20 antibody. Reasons for discontinuation of prior BTK inhibitor therapy included progressive disease (75%) and toxicity or other (25%). The most common cytogenetic feature was unmutated IGHV (84%). The median follow-up was 9.4 months (range, 0.3-27.4 months), and 74% of patients remained on pirtobrutinib.
Among 252 evaluable patients, the ORR was 68% (95% CI, 62%-74%), including complete responses in 1% (Figure 8). Despite prior treatment with a BTK inhibitor, nearly all patients had some reduction in tumor volume in response to pirtobrutinib. Moreover, reduction in tumor volume was observed in patients who had discontinued prior BTK inhibitor therapy, whether because of disease progression or poor tolerance, and in patients who had been previously treated with venetoclax. The median PFS was not estimable (95% CI, 17.0 months to not estimable). Among patients with prior exposure to a BTK inhibitor and venetoclax, the median PFS was 18 months (95% CI, 10.7 months to not estimable). Subgroup analysis showed favorable response rates, regardless of the prior therapy, the reason for prior discontinuation of BTK-inhibitor therapy, or the presence of unfavorable genetics. BTK C481 mutation status did not predict benefit from pirtobrutinib.
Pirtobrutinib was generally well tolerated. No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. The daily dose of pirtobrutinib was 200 mg or higher in 96% of patients. Only 1% of patients permanently discontinued pirtobrutinib therapy owing to treatment-related AEs. The most common grade 3/4 treatment-related AEs were neutropenia (8%) and fatigue (1%). Other grade 3/4 treatment-related AEs, each observed in less than 1% of patients, included diarrhea, rash, hemorrhage, and hypertension. Treatment-emergent atrial fibrillation/flutter of any grade was noted in 2% of patients.
References
1. De Novellis D, Cacace F, Caprioli V, Wierda WG, Mahadeo KM, Tambaro FP. The TKI era in chronic leukemias. Pharmaceutics. 2021;13(12):2201.
2. Mato AR, Pagel JM, Coombs CC, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: updated results from the phase 1/2 BRUIN study [ASH abstract 391]. Blood. 2021;138(suppl 1).
Matching-Adjusted Indirect Treatment Comparison of Acalabrutinib Alone or in Combination With Obinutuzumab vs Ibrutinib or Venetoclax Plus Obinutuzumab in Patients With Treatment-Naive Chronic Lymphocytic Leukemia
The ELEVATE-RR study compared acalabrutinib vs ibrutinib in previously treated CLL patients.1 To estimate the efficacy and safety of acalabrutinib with or without obinutuzumab vs other therapies in treatment-naive patients with CLL, an unanchored, matching-adjusted, indirect treatment comparison (MAIC) analysis was performed based on patient data from the ELEVATE-TN, Alliance, and CLL-14 trials.2-6
Among patients treated with first-line acalabrutinib vs ibrutinib monotherapy, the PFS was similar (HR, 0.83; 95% CI, 0.50-1.37; P=.454), as was the median OS (HR, 0.69; 95% CI, 0.37-1.29; P=.247). In contrast, the MAIC analysis yielded a significant improvement with acalabrutinib plus obinutuzumab compared with ibrutinib monotherapy for the median PFS (HR, 0.48; 95% CI, 0.27-0.88; P=.017) and OS (HR, 0.41; 95% CI, 0.18-0.91; P=.029). Based on MAIC analysis, there was no significant difference with acalabrutinib monotherapy compared with venetoclax plus obinutuzumab for PFS (HR, 0.96; 95% CI, 0.56-1.65; P=.883) or OS (HR, 0.99; 95% CI, 0.51-1.91; P=.974). However, patients treated with acalabrutinib plus obinutuzumab had a significantly prolonged PFS (HR, 0.38; 95% CI, 0.20-0.73; P=.004; Figure 9) and an improved OS (HR, 0.43; 95% CI, 0.19-0.99; P=.047).
MAIC analysis also showed a favorable safety profile for acalabrutinib monotherapy vs ibrutinib monotherapy and for acalabrutinib plus obinutuzumab vs ibrutinib monotherapy. Acalabrutinib monotherapy was associated with a significantly lower rate of grade 3 or higher AEs, including decreased neutrophil count (P<.001), decreased platelet count (P=.006), atrial fibrillation (P=.001), and hypertension (P<.001). The rates of these same AEs of grade 3 or higher were also lower in patients treated with acalabrutinib plus obinutuzumab compared with ibrutinib monotherapy (P<.05 for decreased neutrophil count, decreased platelet count, atrial fibrillation, and hypertension). Compared with venetoclax plus obinutuzumab, acalabrutinib with or without obinutuzumab yielded significantly lower rates of grade 3 or higher infusion-related reaction, leukopenia, neutropenia, and nonmelanoma skin cancer (P<.05 for each). In addition, acalabrutinib monotherapy was associated with lower rates of febrile neutropenia, secondary primary malignancy, and thrombocytopenia compared with venetoclax plus obinutuzumab (P<.05 for each).
References
1. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452.
2. Davids MS, Emeribe U, Cai L, Gaitonde P. Matching-adjusted indirect treatment comparison of acalabrutinib alone or in combination with obinutuzumab versus ibrutinib or venetoclax plus obinutuzumab in patients with treatment-naïve chronic lymphocytic leukemia [ASH abstract 2633]. Blood. 2021;138(suppl 1).
3. Davids MS, Telford C, Abhyankar S, Waweru C, Ringshausen I. Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. Leuk Lymphoma. 2021;62(10):2342-2351.
4. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.
5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
6. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
A Randomized Phase 3 Study of Venetoclax-Based Time-Limited Combination Treatments vs Standard Chemoimmunotherapy in Frontline Chronic Lymphocytic Leukemia of Fit Patients: First Co–Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial
The phase 3 CLL13 trial compared 3 time-limited venetoclax combination regimens vs chemoimmunotherapy as first-line treatment in fit patients with CLL.1 Enrolled patients had a Cumulative Illness Rating Scale (CIRS) score of at least 6 and a normal creatinine clearance rate. The trial excluded patients with a TP53 mutation or del(17p) according to central screening. Stratification factors included age, disease stage, and geographic region. The chemoimmunotherapy regimen consisted of fludarabine, cyclophosphamide, and rituximab or bendamustine plus rituximab (arm 1; n=229). Venetoclax was combined with rituximab (arm 2; n=237), obinutuzumab (arm 3; n=229), or obinutuzumab and ibrutinib (arm 4; n=231). Undetectable MRD was defined as less than 10-4 based on 4-color flow cytometry.
The 926 patients were a median age of 61 years (range, 27-84 years) and had a median CIRS score of 2 (range, 0-7). More than half of patients (56%) had unmutated IGHV and 18% had del(11q). The median follow-up was 27.9 months. The rate of undetectable MRD at month 15 was 52.0% in arm 1, 57.0% in arm 2, 86.5% in arm 3, and 92.2% in arm 4 (Figure 10). The rate of undetectable MRD was significantly different in arm 3 vs arm 1 (P<.001), meeting the co–primary endpoint of undetectable MRD with obinutuzumab plus venetoclax vs chemoimmunotherapy. Rates of undetectable MRD in the peripheral blood were 37.1% in arm 1, 43.0% in arm 2, 72.5% in arm 3, and 77.9% in arm 4. The ORRs were similar across the 4 arms. However, the CR rate ranged from a low of 31% in arm 1 to a high of 61.9% in arm 4. Interim analysis of PFS was postponed owing to a low number of events.
In arms 1 to 4, AEs of grade 3 or higher of particular interest included febrile neutropenia, infections, and tumor lysis syndrome (Table 3). Grade 5 AEs occurred in 27 patients: 12 during treatment or through day 84 of the study, and 15 during the follow-up period. The most common grade 5 AEs occurring prior to day 84 were non–COVID-19 infection (n=4), secondary neoplasia other than Richter transformation (n=4), and COVID-19 infection (n=2). The most common grade 5 AEs occurring after day 84 were secondary neoplasia other than Richter transformation (n=8), Richter transformation (n=3), and pneumonia (n=2). The rate of treatment discontinuation was less than 15% in all 3 venetoclax combination arms.
Reference
1. Eichhorst B, Niemann CU, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments vs standard chemoimmunotherapy in frontline chronic lymphocytic leukemia of fit patients: first co-primary endpoint analysis of the International Intergroup GAIA (CLL13) trial [ASH abstract 71]. Blood. 2021;138(suppl 1).
Highlights in Chronic Lymphocytic Leukemia From the 63rd American Society of Hematology Annual Meeting and Exposition: Commentary
Presentations in chronic lymphocytic leukemia (CLL) at the 63rd American Society of Hematology (ASH) annual meeting provided important insights into the management of patients with treatment-naive and relapsed/refractory disease. New data were presented for treatments such as the Bruton’s tyrosine kinase (BTK) inhibitors acalabrutinib, zanubrutinib, and pirtobrutinib; ublituximab/umbralisib; and venetoclax combinations.
BTK Inhibitors
Acalabrutinib
Dr Wojciech Jurczak presented 3-year follow-up data for the randomized phase 3 ASCEND study, which evaluated acalabrutinib in relapsed/refractory CLL.1,2 The trial compared acalabrutinib vs 1 of 2 options as a control: either rituximab plus idelalisib or bendamustine plus rituximab (BR). The initial results of this important trial led the US Food and Drug Administration (FDA) to approve acalabrutinib for the treatment of relapsed/refractory CLL.1 Additionally, ASCEND was the first head-to-head randomized comparison of novel agents in this setting. The primary endpoint of the trial demonstrated superior progression-free survival for acalabrutinib over both of the controls.1 Importantly, the updated analysis provided information about safety, showing that BTK inhibitors had superior safety vs phosphatidylinositol 3-kinase (PI3K) inhibitors.2 The discontinuation rate for acalabrutinib owing to adverse events was low, at 20%. In contrast, adverse events led 60% of patients to discontinue idelalisib. This rate of discontinuation exceeded 70% when adding patients who stopped idelalisib owing to progressive disease. Importantly, these data can help clinicians make prospective sequencing decisions about whether BTK inhibitors should proceed a PI3K inhibitor. The 3-year follow-up analysis confirmed the initial findings. The progression-free survival advantage for acalabrutinib over the controls continues to widen with time.
The randomized phase 3 ELEVATE-RR trial was a head-to-head comparison of acalabrutinib vs ibrutinib in the relapsed/refractory setting in patients with high-risk features, including deletion 11q or deletion 17p.3 The primary endpoint in the trial was noninferiority of acalabrutinib vs ibrutinib. Many of the key secondary endpoints focused on safety. At the ASH meeting, Dr John Seymour presented results from an expanded safety analysis.4 The primary endpoint of the trial was met, in that acalabrutinib was noninferior to ibrutinib. Interestingly, there was an important safety signal for fewer cardiovascular events with acalabrutinib. Acalabrutinib was associated with lower rates of atrial fibrillation, hypertension, all-grade bleeding events, and arthralgias. Overall, data from the original report and the expanded safety data analysis showed that acalabrutinib appeared to be equally effective to ibrutinib, but with a far more favorable safety profile.3,4 Based on these data and results of the ELEVATE-TN trial,5 acalabrutinib is being increasingly used as a standard of care, in both the frontline and relapsed/refractory settings.
The multicenter, prospective, randomized phase 3 MAJIC trial is comparing acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab in the frontline setting. Dr Matthew Davids presented this study as a trial-in-progress.6 I am a co-leader of the trial, along with Dr Davids and Dr Jeff Sherman. The trial will compare 2 doublet regimens, using a minimal residual disease (MRD)-driven approach with 1 vs 2 years of therapy in both arms. The trial will perform noninferiority hypothesis testing to evaluate if both regimens are equally effective. This trial is important because it is addressing the question of which is the best doublet in the frontline setting. The trial will allow investigators to use MRD to make decisions about the duration of therapy, which is a new concept for the design of large, randomized clinical trials in CLL.
Zanubrutinib
The randomized phase 3 SEQUOIA trial compared zanubrutinib vs BR in the frontline setting.7 This study is similar in design to the ALLIANCE trial, which compared ibrutinib with or without rituximab vs BR.8 Several novel agent–based regimens have now been compared against chemoimmunotherapy in randomized trials.8-10 The SEQUOIA study was designed to allow possible regulatory approval of zanubrutinib in the frontline setting. This BTK inhibitor demonstrated a favorable adverse event profile, as well as superior progression-free survival vs BR in all subgroups. The results are similar to those reported with ibrutinib (vs BR) in the ALLIANCE trial,8 and they may lead to the FDA approval of zanubrutinib in the frontline setting. The study provided further confirmatory evidence supporting zanubrutinib as a next-generation BTK inhibitor that is active and safe in both the frontline and relapsed/refractory settings.
Dr Alessandra Tedeschi presented early results from one of many arms of the phase 3 SEQUOIA trial, which is evaluating zanubrutinib (BGB-3111) in patients with treatment-naive CLL or small lymphocytic leukemia.11 These data are for a relatively small group of patients (<100) with deletion 17p who received zanubrutinib plus venetoclax. Treatment led to a high overall response rate and durable remissions. The safety profile appeared favorable as compared with safety data for ibrutinib plus venetoclax from the CAPTIVATE and GLOW trials.12,13 This preliminary report did not provide data for survival or MRD.
In another report of data from the SEQUOIA trial, zanubrutinib monotherapy in patients with deletion 17p was effective.14 It is likely that monotherapy will have fewer side effects than a combination regimen. The question now is whether patients with poor-risk features should receive a combination of 2 novel agents in a fixed-duration or MRD-driven strategy, or if monotherapy with a BTK inhibitor should be considered the standard of care.
Pirtobrutinib
Pirtobrutinib is a next-generation, highly selective, noncovalent BTK inhibitor under investigation in CLL. Pirtobrutinib was designed to be highly selective for BTK, but also to bind in a different location on that target in order to overcome resistance.15 The overall design was meant to be highly effective in both wild-type and cysteine 481–mutated disease, while also being well tolerated based on the high specificity for BTK. The phase 1/2 BRUIN trial examined doses of pirtobrutinib between 25 mg and 300 mg once daily in patients with CLL and B-cell lymphomas.16 The trial followed a standard 3-plus-3 design. I presented updated results for 252 patients with CLL who had received previous treatment with a covalent BTK inhibitor (100%). Other common previous therapies included venetoclax in 41% and PI3K inhibitors in 20%. Most patients had also received chemoimmunotherapy.
Pirtobrutinib was extremely well tolerated. Only 1% of patients discontinued treatment owing to adverse events. The drug was active, with an overall response rate of 68%. For the entire study cohort in this analysis, the median progression-free survival was not reached. Among patients previously exposed to a BTK inhibitor and venetoclax, the median progression-free survival was 18 months (median of 5 prior therapies). Importantly, the BRUIN study demonstrated that cysteine 481 mutational status had no impact on progression-free survival in patients who discontinue a covalent BTK inhibitor owing to disease progression.16 Pirtobrutinib is an important addition to therapy in terms of activity and safety profile. The drug addresses an unmet need for patients who develop progressive disease during treatment with covalent BTK inhibitors and for patients who are double-exposed to a BTK inhibitor and venetoclax.
Ublituximab/Umbralisib
Dr Lindsey Roeker presented results from a phase 2 study evaluating the addition of ublituximab/umbralisib (U2) to ibrutinib in patients with CLL.17 The study followed an MRD-driven, time-limited approach. Patients with CLL are now being offered combination therapies consisting of doublets and triplets. Combination therapies are likely important for certain patients with high-risk disease and those with an inadequate response to targeted agents administered as monotherapies. However, this strategy can also lead to overtreatment of many patients. The study evaluated an “add-on” approach, in which the combination of umbralisib plus ublituximab was added to ibrutinib. This regimen was administered in the frontline or relapsed/refractory settings to patients who had received ibrutinib for at least 6 months, with the goal of inducing a deeper remission to allow discontinuation of the drug. The primary endpoint was the rate of undetectable MRD. Key secondary endpoints included safety, time to undetectable MRD, and progression-free survival.
There were several take-home messages from the trial. The results showed that the U2 combination could be successfully added to ibrutinib from a safety perspective.17 In more than 70% of patients, the treatment induced undetectable MRD in the peripheral blood with a sensitivity of 10-4. When patients discontinued treatment, they were able to maintain durable remissions for prolonged periods. Among the 27 patients evaluable for efficacy, only 1 had developed progressive disease at the time of the report. Overall, this study demonstrated proof of concept that an “add-on” approach for a PI3K inhibitor plus a BTK inhibitor can induce undetectable MRD and durable remissions. The study also provided additional evidence for the use of a venetoclax-free triple combination regimen, which could be viewed as a time-limited, MRD-driven approach.
Venetoclax Combinations
Dr Barbara Eichhorst provided results of the phase 3 CLL13 trial, a 4-arm comparison of venetoclax plus ibrutinib vs venetoclax vs rituximab vs venetoclax plus obinutuzumab vs chemoimmunotherapy in the frontline setting.18 It should be noted that the report provided extremely preliminary data. This trial found that the venetoclax-based arms were superior to chemoimmunotherapy in terms of depth of remission. Another important finding was that rates of undetectable MRD appeared higher with obinutuzumab than rituximab. The take-away message from this trial is that when venetoclax is combined with an anti-CD20 monoclonal antibody, the latter should be obinutuzumab based on the depth of remission. It was interesting to see this comparison of multiple venetoclax-based arms in the frontline setting. Data are still lacking for safety and progression-free survival.
Dr Paolo Ghia presented 2-year post-randomization data from the CAPTIVATE study.19 This important study was the first attempt at an MRD-driven approach for treatment with ibrutinib plus venetoclax. Patients received 3 months of ibrutinib followed by 12 months of combination therapy with ibrutinib plus venetoclax. Patients were then randomly assigned to treatment based on their MRD status. Patients with undetectable MRD were randomly assigned to either continue treatment with ibrutinib or receive placebo. Patients with detectable MRD were randomly assigned to receive ibrutinib or continued therapy with ibrutinib plus venetoclax. The primary endpoint was comparison of 12-month disease-free survival in the undetectable MRD cohort. The presentation by Dr Ghia provided results for 24-month disease-free survival in patients with confirmed undetectable MRD.19 A previous report showed that there was no statistically significant difference in 12-month disease-free survival between the ibrutinib vs placebo arms.12 There were no new cases of disease progression in either arm. This analysis again supports the earlier data showing that if a patient achieves undetectable MRD after 12 months of combination therapy with ibrutinib plus venetoclax, there is likely no benefit for continuing ibrutinib alone as maintenance therapy.
An analysis of patients with detectable MRD showed that continued treatment with ibrutinib plus venetoclax, but not ibrutinib alone, deepened response.19 There might be a subset of patients with detectable MRD in whom continued venetoclax-based therapy might deepen responses and possibly improve progression-free survival.
Disclosure
Dr Mato has provided services to AbbVie, Adaptive Biotechnologies Corp, AstraZeneca, Bio Ascend, Bristol Myers Squibb, Curio Science LLC, Genentech, Janssen Biotech, Inc, Loxo Oncology, Merck & Co Inc, Octapharma, OncLive, Pfizer, Pharmacyclics, TG Therapeutics, and prIME Oncology.
References
1. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861.
2. Jurczak W, Pluta A, Wach M, et al. Three-year follow-up of the ASCEND trial: acalabrutinib vs rituximab plus idelalisib or bendamustine in relapsed/refractory chronic lymphocytic leukemia [ASH abstract 393]. Blood. 2021;138(suppl 1).
3. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452.
4. Seymour JF, Byrd JC, Hillmen P, et al. Characterization of Bruton tyrosine kinase inhibitor–related adverse events in a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia [ASH abstract 3721]. Blood. 2021;138(suppl 1).
5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291.
6. Davids MS, Mato AR, Hum J, et al. MAJIC: a phase 3 prospective, multicenter, randomized, open-label trial of acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma [ASH abstract 1553]. Blood. 2021;138(suppl 1)
7. Tam CS, Giannopoulos K, Jurczak W, et al. SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma [ASH abstract 396]. Blood. 2021;138(suppl 1).
8. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
9. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.
10. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.
11. Tedeschi A, Ferrant E, Flinn IW, et al. Zanubrutinib in combination with venetoclax for patients with treatment-naïve chronic lymphocytic leukemia or small lymphocytic lymphoma with del(17p): early results from arm D of the SEQUOIA (BGB-3111-304) trial [ASH abstract 67]. Blood. 2021;138(suppl 1).
12. Ghia P, Allan JN, Siddiqi T, et al. Fixed-duration (FD) first-line treatment (tx) with ibrutinib (I) plus venetoclax (V) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): primary analysis of the FD cohort of the phase 2 CAPTIVATE study [ASCO abstract 1135]. J Clin Oncol. 2021;35(15 suppl).
13. Munir T, Moreno C, Owen C, et al. First prospective data on minimal residual disease (MRD) outcomes after fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O) for first-line treatment of CLL in elderly or unfit patients: the GLOW study [ASH abstract 70]. Blood. 2021;138(suppl 1).
14. Tam CS, Giannopoulos K, Jurczak W, et al. SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma [ASH abstract 396]. Blood. 2021;138(suppl 1).
15. De Novellis D, Cacace F, Caprioli V, Wierda WG, Mahadeo KM, Tambaro FP. The TKI era in chronic leukemias. Pharmaceutics. 2021;13(12):2201.
16. Mato AR, Pagel JM, Coombs CC, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: updated results from the phase 1/2 BRUIN study [ASH abstract 391]. Blood. 2021;138(suppl 1).
17. Roeker LE, Leslie L, Soumerai J, et al. A phase 2 study evaluating the addition of ublituximab and umbralisib to ibrutinib in patients with chronic lymphocytic leukemia: a minimal residual disease–driven, time-limited approach. Blood. 2021;138(suppl 1).
18. Eichhorst B, Niemann CU, Kater AP, et al. A randomized phase III study of venetoclax-based time-limited combination treatments vs standard chemoimmunotherapy in frontline chronic lymphocytic leukemia of fit patients: first co-primary endpoint analysis of the International Intergroup GAIA (CLL13) trial [ASH abstract 71]. Blood. 2021;138(suppl 1).
19. Ghia P, Allan JN, Siddiqi T, et al. First-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia: 2-year post-randomization disease-free survival results from the minimal residual disease cohort of the phase 2 CAPTIVATE study [ASH abstract 68]. Blood. 2021;138(suppl 1).