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The progress made with novel combination regimens coupled with their game-changing data in both frontline and relapsed/refractory chronic lymphocytic leukemia is unprecedented.
The progress made with novel combination regimens coupled with their game-changing data in both frontline and relapsed/refractory chronic lymphocytic leukemia (CLL) is unprecedented, according to Anthony Mato, MD, MSCE, in a presentation during the 25th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma, a program hosted by Physician’s Education Resource (PER®), LLC.1
“Now we’re entering into a time where there are even more agents in development and we’re learning how to put these agents together in order to induce deep remissions,” said Mato, director of the CLL Program at Memorial Sloan Kettering Cancer Center. “Certainly, there are several areas where there has been tremendous progress, including targeting the microenvironment, B-cell receptor signaling, and novel cell-surface targets.”
In his presentation, Mato recounted the recent pivotal data across the frontline and relapsed/refractory CLL settings that are slated to transform the paradigm.
Ramping Up Treatment-Naïve CLL
The phase 3 CLL14 trial combined the BCL-2 inhibitor venetoclax (Venclexta) and obinutuzumab (Gazyva) in patients with previously untreated patients with CLL and co-existing medical conditions. Patients were randomized 1:1 to 6 cycles of venetoclax/obinutuzumab followed by 6 cycles of single-agent venetoclax or 6 cycles of chlorambucil/obinutuzumab followed by 6 cycles of chlorambucil alone. The primary end point was progression-free survival (PFS); secondary end points included response, minimal residual disease (MRD), and overall survival (OS).
Updated data from the trial, which were presented at the 2020 ASH Annual Meeting and Exposition, showed that individual clonal growth rates can be used to estimate MRD doubling after fixed-duration therapy, and clonal growth was lower following venetoclax/obinutuzumab vs chlorambucil/obinutuzumab; however, in a subgroup of patients on the venetoclax arm, clonal growth was not measurable during observation.2 Additionally, one-third of patients on venetoclax/obinutuzumab were found to have deepened MRD response during the 6 cycles of venetoclax alone.
“This really speaks to the fact that what we should be doing in the future is designing therapies based on depth of remission rather than a fixed duration for all patients,” said Mato. “There may be a subset of patients who don’t necessarily need a year’s worth of therapy in order to get to their deepest possible response.”
At a median follow-up of 52.4 months, the updated findings also highlighted a median PFS that was not reached with venetoclax/obinutuzumab vs 36.4 months with chlorambucil/obinutuzumab (HR, 0.33; 95% CI, 0.25-0.45; P <.0001). The 4-year PFS rates were 74.0% and 35.4%, respectively. The median OS was not reached in either arm (HR, 0.85; 95% CI, 0.54-1.35; P = .4929), and the 4-year OS rates were 85.3% and 83.1%, respectively. Additionally, the median time to next treatment (TTNT) was not reached in either arm but favored venetoclax/obinutuzumab (HR, 0.46; 95% CI, 0.32-0.65; P < .0001), and the 4-year TTNT rates were 81.08% and 59.9%, respectively.
Another trial that had the “flavor” of MRD-driven decision making was the multicenter, phase 2 CAPTIVATE trial, which also had findings presented at the 2020 ASH Annual Meeting and Exposition.
Venetoclax was combined with ibrutinib in this study, which enrolled treatment-naïve patients with CLL/small lymphocytic lymphoma (SLL) who were aged younger than 70 years and had an ECOG performance status of 0 or 1. Ibrutinib was given as a lead-in treatment at 420 mg daily for 3 cycles, followed by the addition of venetoclax at a ramp-up dose up to 400 mg daily for 12 cycles.
Based on MRD status, patients were randomized 1:1 to their next treatment: those with confirmed undetectable MRD (uMRD) received placebo or ibrutinib, while those with unconfirmed uMRD received ibrutinib monotherapy or ibrutinib/venetoclax. The primary end point was 1-year disease-free survival (DFS) rate.
Following randomization in patients to ibrutinib or placebo in the uMRD-confirmed cohort, results showed that the 1-year DFS rate was 100% with ibrutinib and 95.3% with placebo (P = .1475).3 In the uMRD-unconfirmed group, increases in uMRD were higher with ibrutinib/venetoclax vs ibrutinib alone after 12 cycles of the combination. All patients, regardless of cohort, achieved a 30-month PFS rate above 95.2%.
“The take-home [message] here is that results were excellent across the board in terms of PFS,” Mato said. “[Adverse effects] were [seen] relatively early [on] and the combination was generally well tolerated.”
Additional studies are also evaluating 3-drug regimens in CLL. For example, in the investigator-initiated, phase 2 AVO trial (NCT03580928), investigators looked to improve bone marrow uMRD rates in patients with CLL with the frontline triplet combination of acalabrutinib (Calquence), venetoclax, and obinutuzumab. The study added a cohort to include patients strictly with TP53-mutant disease.
Results showed that the regimen was found to be safe and led to a 100% response rate in all patients by cycle 16 (n = 34) via International Workshop on Chronic Lymphocytic Leukemia response, including those with TP53 aberrations (n = 10).4 Eleven patients in bone marrow–uMRD CR were able to discontinue treatment after 15 cycles.
To date, no patients had progressed on the triplet or had recurrent MRD, Mato explained.
An ongoing phase 3 trial (NCT03836261) is investigating acalabrutinib, venetoclax, plus or minus obinutuzumab vs chemoimmunotherapy in patients with treatment-naïve CLL, he added.
Zanubrutinib (Brukinsa) is the newest BTK inhibitor on the market for patients with mantle cell lymphoma, and the drug is also being in the phase 3 SEQUOIA trial (NCT03336333) in patients 65 years and older with treatment-naïve CLL with 17p deletions [del(17p); n = 109]. In a nonrandomized cohort of the study, investigators administered zanubrutinib at 160 mg twice daily until disease progression.
“What has been noticeably lacking from the acalabrutinib, and also from the ibrutinib, datasets are large prospective datasets looking at high-risk patients in the frontline [setting],” said Mato. “[With SEQUOIA,] we get a window into this patient population where we haven’t seen that with other BTK inhibitors in the frontline [setting].”
Data showed that the ORR was 94.5% (95% CI, 88.4%-98.0%) via investigator assessment; at a median follow-up of 21.9 months (range, 5.0-30.2), the 18-month PFS and OS rates were 90.6% and 95.4%, respectively.5
Numerous clinical trials have shown impressive outcomes with combination strategies in the relapsed/refractory population as well, including the pivotal phase 3 MURANO trial, which evaluated the combination of venetoclax and rituximab (Rituxan).
In the most recent update of these data presented at the 2020 ASH Annual Meeting and Exposition, investigators sought to evaluate the difference in MRD conversion status based upon patient genetic profiles at the end of treatment, including del(17p), complex karyotype (≥3 variations) and IGVH mutation status.
“The answer is ‘yes’,” said Mato. “Disease biology on some levels trumps depth of remission in terms of durability of uMRD status.”
Long-term follow-up presented at the meeting also showed that, at a median follow-up of 59 months, the OS benefit was sustained among patients treated with venetoclax/rituximab. The 5-year OS rates were 82.1% with the combination compared with 62.2% with bendamustine/rituximab. The median OS was not estimable in either group (HR, 0.40; 95% CI, 0.26-0.62; P < .0001).6
Based on earlier findings from the MURANO study, the FDA granted a standard approval to venetoclax for the treatment of patients with CLL/SLL, with or without del(17p), following at least 1 prior therapy. The BCL-2 inhibitor was also granted approval for use in combination with rituximab (Rituxan) in the same patient population.
Blood Cancer UK TAP CLARITY
In the phase 2 Blood Cancer UK TAP Clarity trial, the combination of ibrutinib and venetoclax was tested in the relapsed/refractory setting of 50 patients with CLL who harbor del(17p) following 1 or more prior line of therapy. What was innovative about this study, Mato noted, was the specific patient population: patients could not have received prior treatment with ibrutinib, venetoclax, or another BTK or BCL-2 inhibitor.
“This patient population doesn’t exist in the United States; hardly a patient exists who hasn’t received ibrutinib or venetoclax already. With that being said, they achieved excellent PFS and overall survival,” Mato said, adding that the regimen had an acceptable safety profile.
Additional long-term follow-up showed that ibrutinib/venetoclax was associated with 36-month PFS and OS rates of 95.9% and 97.7%, respectively.7
The combination of the PI3K inhibitor umbralisib and the anti-CD20 antibody ublituximab, known as U2, was compared with obinutuzumab/chlorambucil in patients with both treatment-naïve and relapsed/refractory CLL in the phase 3 UNITY-CLL trial.
In the frontline cohort, the median PFS via independent review committee was 31.9 months with U2 vs 17.9 months with obinutuzumab/chlorambucil, demonstrating an approximate 45% reduction in the risk of disease progression or death in the ITT population (HR, 0.546).8 The 1-year PFS rates were 60.8% and 40.4%, respectively. Additionally, U2 showed a 93% disease control rate, and 62% of patients on this regimen maintained their response for 2 years.
These data “may ultimately lead to the approval for this combination for patients with CLL,” Mato said. “Although this combination was well tolerated, we still need to be on the lookout for PI3K inhibitor–associated toxicities.”
In December 2020, a rolling submission of a biologics license application to the FDA was initiated for ublituximab plus umbralisib for the treatment of patients with CLL.
The BTK inhibitor “floodgates” have opened in CLL, according to Mato, speaking to the garnered interest surrounding LOXO-305, a next-generation, highly selective, non-covalent BTK inhibitor in previously treated patients with CLL/SLL.
In the phase 1/2 BRUIN study of heavily pretreated patients with B-cell malignancies, LOXO-305 demonstrated an acceptable safety profile, with 5 of 323 patients (1.5%) discontinuing treatment due to treatment-related AEs. The recommended phase 2 dose has been determined as 200 mg daily.
Findings from this study, which also presented during the 2020 ASH Annual Meeting and Exposition, showed that the ORR in 139 patients with CLL/SLL was 63%; in those who received prior treatment with a BTK inhibitor (n = 121), the ORR was 62%.9 Of note, the ORR was found to increase with longer follow-up: at least 6 months (68%), at least 8 months (71%), and at least 10 months (86%). Efficacy was observed regardless of patients’ BTK experience and other prior therapy.
CAR T-cell therapy has also proven to be an exciting area of investigation in CLL as well, Mato concluded.