BRUKINSA® Superior to IMBRUVICA® in Relapsed/Refractory CLL/SLL

SUMMARY: The American Cancer Society estimates that for 2022, about 20,160 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4410 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® demonstrated survival benefits when compared to chemoimmunotherapy both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to IMBRUVICA® discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.

Zanubrutinib (BRUKINSA®) is an irreversible, potent, next-generation, small molecule inhibitor of Bruton’s Tyrosine Kinase, designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity, while minimizing off-target inhibition of TEC- and EGFR-family kinases. It has been hypothesized that the increased selectivity of BRUKINSA® may minimize toxicities, (such as those often associated with IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

ALPINE study is a randomized, global, Phase III trial in which BRUKINSA® was compared with IMBRUVICA® in previously treated patients with relapsed or refractory CLL or SLL. In this trial, a total of 652 patients were randomly assigned 1:1 to receive either BRUKINSA® 160 mg orally twice daily or IMBRUVICA® 420 mg orally once daily, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior systemic therapy and were required to have measurable lymphadenopathy by CT scan or MRI. Exclusion criteria included current or past Richter’s transformation and prior treatment with BTK inhibitors. Approximately 20% of patients had a del(17p) and/or TP53 mutation and fewer than 15% of patients were on anticoagulants. The Primary end point of the trial was Overall Response Rate (ORR) assessed by investigator and Independent Review Committee (IRC), and Secondary end points included Progression Free Survival (PFS), event rate of Atrial Fibrillation or Flutter, Duration of Response, Time to Treatment Failure, Overall Survival (OS), Patient-Reported Outcomes, and Safety.

BeiGene recently announced that BRUKINSA® achieved superior Progression Free Survival (PFS) when compared to IMBRUVICA® in the final analysis of this Phase III ALPINE trial, as assessed by an Independent Review Committee (IRC) and investigator. This data will be presented at future scientific meetings. The interim analysis conducted at a median follow-up was 15 months showed significantly higher Overall Response Rate with BRUKINSA®, compared with IMBRUVICA® (78.3% versus 62.5%; P =0.0006). The Overall Response Rate was higher in patients with del11q (83.6% versus 69.1%) and del17p (83.3% versus 53.8%) with BRUKINSA®, as well as the overall 12-month Progression Free Survival (94.9% versus 84.0%) and Overall Survival rates (97.0% versus 92.7%). Major bleeding rates as well as adverse events leading to treatment discontinuation, was lower with BRUKINSA®, compared to IMBRUVICA®. The rate of Atrial Fibrillation/Flutter, a pre-specified safety endpoint, was significantly lower with BRUKINSA®, compared to IMBRUVICA® (2.5% versus 10.1%; P=0.0014).

It was concluded from this randomized, Phase III study that, among patients with relapsed/refractory CLL/SLL, BRUKINSA® was superior to IMBRUVICA®, with a lower rate of Atrial Fibrillation/Flutter. The researchers added that BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes.

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. Brown JR, Hillmen P, Eichhorst B, et al. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-115.

Investigator and Health Systems Insights on Real-World Evidence Associated With a First-Generation BTK Inhibitor in Patients With CLL/SLL

Written by: AJMC® Editorial Staff

Content Sponsored by: BeiGene

Adults experience chronic lymphocytic leukemia (CLL) at a greater rate than they do any other type of leukemia.1 In 2014, ibrutinib became the first Bruton tyrosine kinase (BTK) inhibitor approved by the FDA for the treatment of CLL.2,3 In a 3-year safety study of patients with CLL/small lymphocytic lymphoma (SLL) taking a daily dose of this first-generation medication, ibrutinib was shown to have both a high response rate that increased in quality and frequency over time and modest toxicity.4

However, treatment with ibrutinib has been shown to be associated with adverse events (AEs) that can lead to discontinuation and/or down-dosing.5,6 In particular, atrial fibrillation (AF) is a known AE associated with BTK inhibitor treatment that has been reported in clinical trials.7,8

To determine the economic burden of down-dosing and therapy discontinuation due to AEs after initiation of ibrutinib therapy in patients with CLL/SLL, a team from Milliman, Inc, analyzed 2015 to 2019 data from a proprietary Medicare Advantage claims database that contains annual enrollment information and all Parts A, B, and D claims for approximately 2.5 million annual members.9 Investigators identified patients who developed AF within the first 12 months of starting treatment with ibrutinib. The results of this claims-based analysis were presented during a Science & Innovation Theater presented during the Academy of Managed Care Pharmacy Nexus 2021, held from October 18 to 21, 2021, in Denver, Colorado.9

In the group identified for analysis, investigators examined rates of and average time to discontinuation, down-dosing, and AEs as well as total health care costs accumulated during the 12 months following ibrutinib start.9 Using these key metrics, investigators then compared patients who newly experienced AF (new AF) during this 12-month episode period with those who did not experience new AF during this period. The results of the analysis showed that patients with claims for new AF discontinued ibrutinib at more than twice the rate of patients without claims for new AF and had significantly higher health care utilization.9 These results are explored in detail in a review article, “Real-World Evidence Associated with a First-Generation BTK Inhibitor in Patients With CLL/SLL,” published by The American Journal of Managed Care® (AJMC®) on ajmc.com. In an interview following the review, principal investigator and health care consultant from Milliman, Inc, Kathryn Fitch, RN, MEd, discusses the study’s findings regarding treatment patterns among patients who developed new AF after starting ibrutinib, the costs associated with the development of new AF, and her team’s recent research in this field. In a final interview, Michael Kolodziej, MD, FACP, medical oncologist and Senior Advisor at ADVI Health, LLC, discussed the analysis and its potential implications for managed care.

REFERENCES

1. The American Cancer Society Medical and Editorial Content Team. What is chronic lymphocytic leukemia? American Cancer Society. Updated May 10, 2018. January 13, 2022. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html

2. Chronic lymphocytic leukemia/small lymphocytic lymphoma: FDA updates. Lymphoma Research Foundation. Updated April 21, 2020. Accessed January 13, 2022. https://lymphoma.org/aboutlymphoma/cll/cllfdaupdates/

3. Center for Drug Evaluation and Research. Approval package for application number 205552Orig2s000. Trade name: Imbruvica. United States Food and Drug Administration. February 12, 2014. Accessed January 13, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205552Orig2s000Approv.pdf

4. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506. doi:10.1182/blood-2014-10-606038

5. Imbruvica. Prescribing information. Janssen Biotech; 2020. Accessed January 13, 2022. https://www.imbruvica.com/files/prescribing-information.pdf

6. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874-879. doi:10.3324/haematol.2017.182907

7. Brown JR, Moslehi J, O’Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica. 2017;102(10):1796-1805. doi:10.3324/haematol.2017.171041

8. Caldeira D, Alves D, Costa J, Ferreira JJ, Pinto FJ. Ibrutinib increases the risk of hypertension and atrial fibrillation: systematic review and meta-analysis. PLoS One. 2019;14(2):e0211228. doi:10.1371/journal.pone.0211228

9. Fitch KV. Assessing the treatment emergent burden in BTKi therapy: a Medicare analysis in CLL (chronic lymphocytic leukemia). Presented at the Academy of Managed Care Pharmacy Nexus 2021; October 20, 2021; Denver, CO. Accessed January 18, 2022. https://2021.amcpnexus.org/program/science-innovation-theaters

Updated Data on Fixed Duration VENCLEXTA® for Frontline Chronic Lymphocytic Leukemia

SUMMARY: The American Cancer Society estimates that for 2021, about 21,250 new cases of CLL will be diagnosed in the US and 4320 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.BCR-Signal-Pathways-and-MOA-of-New-Agents

CLL14 Trial is a prospective, multicenter, open-label, randomized Phase III study conducted in close collaboration with the German CLL Study Group (DCLLSG). This study was designed to evaluate the efficacy and safety of a fixed duration combination of VENCLEXTA® and GAZYVA® (Obinutuzumab) versus GAZYVA® and Chlorambucil in previously-untreated patients with CLL and coexisting medical conditions. In this trial, 432 treatment-naïve patients with CLL were randomized in a 1:1 ratio to receive fixed duration of 12 months of VENCLEXTA® in combination with six cycles of GAZYVA®, or 6 cycles of GAZYVA® in combination with Chlorambucil. Both treatment groups were well balanced and the median patient age was 72 years. The Primary endpoint was Progression Free Survival (PFS) assessed by an Independent Review Committee. Secondary endpoints included Minimal Residual Disease (MRD) status, Overall Response Rate, Complete Response, Complete Remission with Incomplete Hematologic Recovery (CRi), Overall Survival, duration of response, Time to Next CLL Treatment, and safety.

The median PFS was not reached in either treatment groups after a median follow-up of 28 months. The trial demonstrated a statistically significant improvement in PFS for patients who received VENCLEXTA® plus GAZYVA®, compared with those who received GAZYVA® plus Chlorambucil (HR 0.33; P<0.0001), suggesting a 67% reduction in the risk of progression or death with the VENCLEXTA® plus GAZYVA® combination. The Overall Response Rate was 85% in VENCLEXTA® plus GAZYVA® group compared to 71% in GAZYVA® plus Chlorambucil group (P=0.0007). Based on this data, the FDA in May 2019 approved VENCLEXTA® (Venetoclax) as frontline treatment for adult patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (SLL).

The authors in this presentation provided updated efficacy and safety data from the ongoing follow up of the CLL14 study, with all patients off study treatment for at least 3 years. After a median follow-up of 52.4 months, PFS continued to be superior for VENCLEXTA® plus GAZYVA® group, compared to GAZYVA® plus Chlorambucil (median Not Reached versus 36.4 months; HR=0.33 P<0.0001). At 4 years after randomization, the estimated PFS rate was 74.0% in the VENCLEXTA® plus GAZYVA® arm and 35.4% in the GAZYVA® plus Chlorambucil arm. This benefit was noted across all clinical and biological risk groups, including patients with TP53 mutation/deletion (4-year PFS 53.0% versus 20.8%) and unmutated IGHV status (4-year PFS 68.0% versus 19.8%). Time to Next Treatment was significantly longer in the VENCLEXTA® plus GAZYVA® group, compared to GAZYVA® plus Chlorambucil group (4-year TTNT 81.1% versus 59.9%; HR=0.46, P<0.0001). Further, majority of patients received and responded to BTK inhibitor monotherapy as a second-line treatment after progressive disease in both the treatment groups.

Assessment of MRD in peripheral blood 30 months after the end of treatment showed that 26.9% of patients in the VENCLEXTA® group still had undetectable MRD (less than 10-4), compared with 3.2% in the GAZYVA® plus Chlorambucil group. The median OS has not yet been reached in either treatment groups. No new safety signals were observed.

It was concluded that the fixed duration combination of VENCLEXTA® plus GAZYVA® continued to confer a PFS advantage over GAZYVA® plus Chlorambucil, for patients with previously untreated CLL, and remains an effective treatment for all patients with CLL and with coexisting conditions.

Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Al-Sawaf O, Zhang C, Robrecht S, et al. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021. Abstract S146.

CALQUENCE® May Be Safer Than IMBRUVICA® in CLL Patients

SUMMARY: The American Cancer Society estimates that for 2021, about 21,250 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4320 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Ibrutinib demonstrated survival benefits when compared to chemoimmunotherapy both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to Ibrutinib discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.BCR-Signal-Pathways-and-MOA-of-New-Agents

Acalabrutinib (CALQUENCE®) is a highly selective, next-generation, oral, covalent, irreversible Bruton Tyrosine Kinase (BTK) inhibitor with minimal activity against other kinases. Acalabrutinib has a shorter plasma half-life and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Acalabrutinib demonstrated superior Progression Free Survival (PFS) versus chemoimmunotherapy in patients with previously untreated (ELEVATE-TN), as well as Relapsed or Refractory (ASCEND) CLL. Acalabrutinib was better tolerated with lower rates of treatment discontinuation due to adverse events, and also demonstrated efficacy and tolerability in Ibrutinib-intolerant patients with CLL.

ELEVATE-RR is a prospective, randomized, multicenter, open-label, noninferiority, Phase III study, conducted to compare the efficacy and safety of Acalabrutinib with Ibrutinib, in patients with previously treated CLL, and to test the hypothesis that Acalabrutinib was noninferior to Ibrutinib in PFS, with improved tolerability. This trial included 533 previously treated patients with CLL who were randomly assigned 1:1 to receive Acalabrutinib 100 mg orally twice daily (N=268) or Ibrutinib 420 mg orally once daily (N=265). Treatment was continued until disease progression or unacceptable toxicity, and crossover between treatment groups was not permitted. Enrolled patients had centrally confirmed del(17)(p13.1) or del(11)(q22.3) and patients were stratified based on cytogenetics, ECOG Performance Status and number of prior therapies. Patients with significant cardiovascular disease, concomitant vitamin K antagonist treatment, prior BTK or BCL2 inhibitor treatment, or those requiring treatment with Proton-Pump Inhibitors were excluded. The Primary end point was Independent Review Committee-assessed noninferiority of Progression Free Survival (PFS). Secondary end points included incidences of any grade Atrial Fibrillation, Grade 3 or higher infections, Richter transformation and Overall Survival (OS)

After a median follow-up of 40.9 months, Acalabrutinib was determined to be noninferior to Ibrutinib with a median PFS of 38.4 months in both arms (HR=1.00), thus meeting the noninferiority criterion. Any-grade Atrial Fibrillation/Atrial Flutter incidence was significantly lower with Acalabrutinib compared to Ibrutinib (9.4% versus 16.0%; P=0.02). Bleeding events were less frequent with Acalabrutinib (38%) versus Ibrutinib (51.3%). The median Overall Survival was not reached in either treatment groups. Treatment was discontinued due to adverse events in 14.7% of Acalabrutinib-treated patients and 21.3% of Ibrutinib-treated patients.

The authors concluded that this is the first direct comparison of Ibrutinib with Acalabrutinib in CLL and Acalabrutinib demonstrated noninferior PFS and provides improved safety, with fewer Atrial Fibrillation events and discontinuations because of adverse events, when compared to Ibrutinib.

Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. Byrd JC, Hillmen P, Ghia P, et al. DOI: 10.1200/JCO.21.01210 Journal of Clinical Oncology. Published online July 26, 2021.

Updated Data on Fixed Duration VENCLEXTA® for Frontline Chronic Lymphocytic Leukemia

SUMMARY: The American Cancer Society estimates that for 2021, about 21,250 new cases of CLL will be diagnosed in the US and 4320 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells.MOA-of-VENCLEXTA

CLL14 Trial is a prospective, multicenter, open-label, randomized Phase III study conducted in close collaboration with the German CLL Study Group (DCLLSG). This study was designed to evaluate the efficacy and safety of a fixed duration combination of VENCLEXTA® and GAZYVA® (Obinutuzumab) versus GAZYVA® and Chlorambucil in previously-untreated patients with CLL and coexisting medical conditions. In this trial, 432 treatment-naïve patients with CLL were randomized in a 1:1 ratio to receive fixed duration of 12 months of VENCLEXTA® in combination with six cycles of GAZYVA®, or 6 cycles of GAZYVA® in combination with Chlorambucil. Both treatment groups were well balanced and the median patient age was 72 years. The Primary endpoint was Progression Free Survival (PFS) assessed by an Independent Review Committee. Secondary endpoints included Minimal Residual Disease (MRD) status, Overall Response Rate, Complete Response, Complete Remission with Incomplete Hematologic Recovery (CRi), Overall Survival, duration of response, Time to Next CLL Treatment, and safety.

The median PFS was not reached in either treatment groups after a median follow-up of 28 months. The trial demonstrated a statistically significant improvement in PFS for patients who received VENCLEXTA® plus GAZYVA®, compared with those who received GAZYVA® plus Chlorambucil (HR 0.33; P<0.0001), suggesting a 67% reduction in the risk of progression or death with the VENCLEXTA® plus GAZYVA® combination. The Overall Response Rate was 85% in VENCLEXTA® plus GAZYVA® group compared to 71% in GAZYVA® plus Chlorambucil group (P=0.0007). Based on this data, the FDA in May 2019 approved VENCLEXTA® (Venetoclax) as frontline treatment for adult patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (SLL).

The authors in this presentation provided updated efficacy and safety data from the ongoing follow up of the CLL14 study, with all patients off study treatment for at least 3 years. After a median follow-up of 52.4 months, PFS continued to be superior for VENCLEXTA® plus GAZYVA® group, compared to GAZYVA® plus Chlorambucil (median Not Reached versus 36.4 months; HR=0.33 P<0.0001). At 4 years after randomization, the estimated PFS rate was 74.0% in the VENCLEXTA® plus GAZYVA® arm and 35.4% in the GAZYVA® plus Chlorambucil arm. This benefit was noted across all clinical and biological risk groups, including patients with TP53 mutation/deletion (4-year PFS 53.0% versus 20.8%) and unmutated IGHV status (4-year PFS 68.0% versus 19.8%). Time to Next Treatment was significantly longer in the VENCLEXTA® plus GAZYVA® group, compared to GAZYVA® plus Chlorambucil group (4-year TTNT 81.1% versus 59.9%; HR=0.46, P<0.0001). Further, majority of patients received and responded to BTK inhibitor monotherapy as a second-line treatment after progressive disease in both the treatment groups.

Assessment of MRD in peripheral blood 30 months after the end of treatment showed that 26.9% of patients in the VENCLEXTA® group still had undetectable MRD (less than 10-4), compared with 3.2% in the GAZYVA® plus Chlorambucil group. The median OS has not yet been reached in either treatment groups. No new safety signals were observed.

It was concluded that the fixed duration combination of VENCLEXTA® plus GAZYVA® continued to confer a PFS advantage over GAZYVA® plus Chlorambucil, for patients with previously untreated CLL, and remains an effective treatment for all patients with CLL and with coexisting conditions.

Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Al-Sawaf O, Zhang C, Robrecht S, et al. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021. Abstract S146.

IMBRUVICA® (Ibrutinib)

The FDA on April 21, 2020 expanded the indication of IMBRUVICA® to include its combination with RITUXAN® (Rituximab) for the initial treatment of adult patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). IMBRUVICA® is a product of Pharmacyclics LLC.

FDA Approves CALQUENCE® for Chronic Lymphocytic Leukemia

SUMMARY: The FDA on November 21, 2019, approved CALQUENCE® (Acalabrutinib), for adults with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The American Cancer Society estimates that for 2019, about 20,720 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 3,930 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies.

Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. CALQUENCE® is a highly selective, oral, covalent irreversible Bruton Tyrosine Kinase (BTK) inhibitor with minimal activity against other kinases. CALQUENCE® inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. The present FDA approval was based on two randomized, actively controlled trials, ELEVATE-TN and ASCEND in patients with CLL.

ELEVATE-TN is a randomized, multicentre, open-label Phase III trial which evaluated the safety and efficacy of CALQUENCE® alone or in combination with GAZYVA® (Obinutuzumab) versus Chlorambucil in combination with GAZYVA®, in previously-untreated patients with CLL. GAZYVA® is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody. In this trial, 535 patients were randomized 1:1:1 to receive CALQUENCE® monotherapy 100 mg twice daily orally continuously (N=179) or in combination with GAZYVA® (N=179), or Chlorambucil 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for 6 cycles along with GAZYVA® (N=177). The dose of GAZYVA® was 100 mg on day 1 and 900 mg on day 2 of Cycle 1, 1000 mg on day 8 and 15 of Cycle 1, and 1000 mg on day 1 of Cycles 2–6, of each 28 day cycle. Pts were stratified by del(17p) status, ECOG status (1 or less versus 2), and geographic region. The median patient age was 70 years and 69% had high risk and 12% had very high risk CLL IPI scores. The Primary endpoint was PFS in the CALQUENCE® plus GAZYVA® group compared to the Chlorambucil and GAZYVA® group, assessed by an independent review committee (IRC). A key secondary endpoint was PFS in the CALQUENCE® monotherapy arm, compared to the chlorambucil and GAZYVA® arm. Other secondary endpoints included Objective Response Rate, time to next treatment and Overall Survival.

At a median follow-up of 28 months, the combination of CALQUENCE® plus GAZYVA® significantly prolonged PFS compared to Chlorambucil plus GAZYVA® (median Not Reached versus 22.6 months; HR 0.10, P<0.0001), reducing the risk of progression or death by 90%. CALQUENCE® monotherapy also significantly prolonged PFS compared to Chlorambucil plus GAZYVA® (HR=0.20; P<0.0001). PFS improvement with CALQUENCE® plus GAZYVA® as well as CALQUENCE® monotherapy was consistent across all subgroups examined including del(17p). The median OS was not reached in any treatment group. The ORR was higher with CALQUENCE® plus GAZYVA® versus Chlorambucil plus GAZYVA® (94% versus 79%; P<0.0001). The ORR with CALQUENCE® monotherapy was 85%. Complete Response rates were higher with CALQUENCE® plus GAZYVA® versus Chlorambucil plus GAZYVA® (13% versus 5%).

ASCEND is a global, randomized, multicentre, open-label Phase III trial which evaluated the efficacy and safety of CALQUENCE® versus physician’s choice of Rituximab/ZYDELIG® (Idelalisib) or Rituximab/Bendamustine combination in patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL). This study included 310 eligible patients who were randomly assigned 1:1 to receive CALQUENCE® 100 mg orally twice daily until disease progression versus Rituximab/ ZYDELIG® combination (ZYDELIG® 150 mg orally twice daily in combination with up to eight IV infusions of Rituximab 375 or 500 mg/m2) or Rituximab/Bendamustine combination (Bendamustine 70 mg/m2 IV on day 1 and 2 of each cycle in combination with Rituximab 375 or 500 mg/m2 IV on day 1 of each 28-day cycle for up to six cycles). The median age was 67 years and patients were stratified by del(17p) status, ECOG performance scale and prior lines of therapy. The Primary endpoint was Progression Free Survival as assessed by Independent Review Committee (IRC) and Secondary end points included Overall Response Rate and Duration of Response, as well as Overall Survival. Patients with confirmed disease progression on Rituximab/ ZYDELIG® or Rituximab/Bendamustine, were allowed to cross over to receive CALQUENCE®.

At a median follow-up of 16.1 months, there was a statistically significant and clinically meaningful improvement in PFS with CALQUENCE® monotherapy compared to a combination regimen of Rituximab plus physician’s choice of ZYDELIG® or Bendamustine. The PFS with CALQUENCE® monotherapy was not reached versus 16.5 months with the comparators (HR= 0.31, P<0.0001). This represented a 69% reduction in risk of progression or death. Progression Free Survival was improved with CALQUENCE® monotherapy across subgroups including del(17p), TP53 mutation, and Rai stage. There was however no significant difference in the Overall Response Rates among the treatment groups and 23% of the patients randomly assigned to Rituximab/ ZYDELIG® or Rituximab/Bendamustine combinations crossed over to receive subsequent treatment with CALQUENCE®. The most common side effects of CALQUENCE® were anemia, neutropenia, upper respiratory tract infection, thrombocytopenia, headache, diarrhea, and musculoskeletal pain.

In conclusion, CALQUENCE® monotherapy as well as in combination with GAZYVA®, significantly improved Progression Free Survival in Relapsed/Refractory CLL, as well as treatment naïve patients with CLL, respectively.

ELEVATE TN: Phase 3 Study of Acalabrutinib Combined with Obinutuzumab (O) or Alone Vs O Plus Chlorambucil (Clb) in Patients (Pts) with Treatment-Naive Chronic Lymphocytic Leukemia (CLL). Sharman JP, Banerji V, Fogliatto LM, et al. Blood. 2019 Nov 13;134(Supplement_1):31.

ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelasib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Ghia P, Pluta A, Wach M, et al. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Netherlands. Abstract LB2606.

IMBRUVICA® and RITUXAN® Combination Superior to FCR in Patients with CLL

SUMMARY: The American Cancer Society estimates that for 2019, about 20,720 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 3,930 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies. Chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab (FCR) has long been the gold standard and the most commonly used treatment regimen for younger, fit, treatment naïve patients with CLL.This is based on phase III trial data showing improvement in both Progression Free Survival (PFS) and Overall Survival (OS) compared with chemotherapy alone. FCR regimen however is associated with significant toxicities and cannot be tolerated by all CLL patients. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® in phase III trials showed improved PFS and OS when compared to Chlorambucil in previously untreated, elderly patients with CLL. Nonetheless, the efficacy of IMBRUVICA® as a first-line treatment for younger CLL patients (70 years or younger), compared to the most efficacious regimen such as FCR, is unknown.BCR-Signal-Pathways-and-MOA-of-New-Agents

E1912, led by the ECOG-ACRIN Research Group (ECOG-ACRIN), is a randomized phase III study in which IMBRUVICA® plus RITUXAN® (Rituximab) was compared to Fludarabine, Cyclophosphamide, and RITUXAN® (FCR) chemotherapy regimen, in previously untreated patients aged 70 years or younger with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). In this trial, 529 patients were randomly assigned in a 2:1 ratio to receive IMBRUVICA® 420 mg orally daily until disease progression along with RITUXAN® 50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, 500 mg/m2 on day 1 of cycles 3-7 (N=354) or six courses of Fludarabine 25 mg/m2 IV along with Cyclophosphamide 250 mg/m2 IV days 1-3 and RITUXAN® 50 mg/m2 IV on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, 500 mg/m2 on day 1 of cycles 2-6, given every 28 days (N=175). The median age was 58 years and 40% of the patients were 60 years of age or older. The Primary endpoint was Progression Free Survival (PFS) and the Secondary endpoint was Overall Survival (OS).

With a median follow up of 33.6 months, at the first interim analysis, IMBRUVICA® plus RITUXAN® significantly improved PFS and was 89.4%, compared to 72.9% with FCR, at 3 years (HR=0.35; P<0.0001). This meant a 65% reduction in the risk of progression or death with IMBRUVICA® plus RITUXAN® compared with FCR. The combination of IMBRUVICA® plus RITUXAN® also demonstrated improved OS and was 98.8% at 3 years versus 91.5% with FCR (HR=0.17; P=0.0003). This suggested that IMBRUVICA® plus RITUXAN® combination reduced the risk of death by 83% compared with FCR. In a subgroup analysis, the PFS benefit with IMBRUVICA® plus RITUXAN® was seen independent of age, sex, Performance Status (0-2), disease stage, as well as presence or absence of cytogenetic abnormality, deletion 11q23. At the time of this analysis, IMBRUVICA® plus RITUXAN® was also superior to FCR among IGHV unmutated patients (90.7% versus 62.5% at 3 years,HR=0.26; P<0.0001),suggesting a 74% reduction in the risk of progression or death with IMBRUVICA® plus RITUXAN®, compared to FCR. A statistically significant benefit however was not observed among those with IGHV mutations, although there was a positive trend noted (HR=0.44; P=0.07). Treatment-related Grade 3 or higher toxicities were similar in both treatment groups. FCR however was more frequently associated with Grade 3 or higher infectious complications than IMBRUVICA® plus RITUXAN® combination (20.3% versus 10.5%; P<0.001).

It was concluded that a combination of IMBRUVICA® and RITUXAN® was superior and significantly improved PFS and OS, when compared to FCR among patients 70 years of age or under, with previously untreated CLL. These findings may have immediate practice changing implications and establish IMBRUVICA®-based therapy as the most effective first-line therapy for untreated patients with CLL. Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. Shanafelt TD, Wang XV, Kay NE, et al. N Engl J Med 2019; 381:432-443

FDA Approves Fixed Duration VENCLEXTA® for Frontline Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

SUMMARY: The FDA on May 15, 2019 approved VENCLEXTA® (Venetoclax) for adult patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). The FDA in 2018 had approved VENCLEXTA® for patients with CLL or SLL with or without 17p deletion, who have received at least one prior therapy. The American Cancer Society estimates that for 2019, about 20,720 new cases of CLL will be diagnosed in the US and 3,930 patients will die of the disease. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. BCR-Signal-Pathways-and-MOA-of-New-Agents

CLL14 Trial is a prospective, multicenter, open-label, randomized Phase III study, conducted in close collaboration with the German CLL Study Group (DCLLSG). This study was designed to evaluate the efficacy and safety of a fixed duration combination of VENCLEXTA® and GAZYVA® (Obinutuzumab) versus GAZYVA® and Chlorambucil in previously-untreated patients with CLL and coexisting medical conditions. In this trial, 432 treatment-naïve patients with CLL were randomized in a 1:1 ratio to receive fixed duration of 12 months of VENCLEXTA® in combination with six cycles of GAZYVA®, or 6 cycles of GAZYVA® in combination with Chlorambucil. Both treatment groups were well balanced and the median patient age was 72 years. The Primary endpoint was Progression Free Survival (PFS) assessed by an Independent Review Committee. Secondary endpoints included Minimal Residual Disease (MRD) status, Overall Response Rate, Complete Response, Complete Remission with Incomplete Hematologic Recovery (CRi), Overall Survival, duration of response, time to next CLL treatment, and safety.

The trial demonstrated a statistically significant improvement in PFS for patients who received VENCLEXTA® plus GAZYVA® compared with those who received GAZYVA® plus Chlorambucil (HR 0.33; P<0.0001), suggesting a 67% reduction in the risk of progression or death with the VENCLEXTA® plus GAZYVA® combination. The median PFS was not reached in either treatment groups after a median follow-up of 28 months. The Overall Response Rate was 85% in VENCLEXTA® plus GAZYVA® group compared to 71% in GAZYVA® plus Chlorambucil group (P=0.0007). The trial also demonstrated statistically significant improvements in rates of Minimal Residual Disease (MRD) negativity (less than one CLL cell per 104 leukocytes) in bone marrow and peripheral blood. The rate of MRD-negativity in the bone marrow was 57% in the VENCLEXTA® group compared with 17% in the GAZYVA® plus Chlorambucil group. The MRD-negativity rates in the peripheral blood were 76% versus 35%, respectively. Overall Survival data were not mature at this analysis. The most common adverse events in the VENCLEXTA® plus GAZYVA® group included neutropenia, thrombocytopenia, anemia, diarrhea, nausea, upper respiratory tract infection, cough, musculoskeletal pain, fatigue, and edema.

It was concluded that a combination of VENCLEXTA® and GAZYVA® among patients with previously untreated CLL significantly improved Progression Free Survival, compared to patients treated with standard of care GAZYVA® plus Chlorambucil. The authors added that VENCLEXTA® plus GAZYVA® is the only chemotherapy-free regimen of fixed duration, and is a major step forward in the management of previously untreated CLL patients. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-venetoclax-cll-and-sll