Chlorambucil

AstraZeneca’s oncology R&D chief, Susan Galbraith, Ph.D., highlighted that Calquence's positive early overall survival trend in first-line mantle cell lymphoma was the first for a BTK inhibitor. As AbbVie and Johnson & Johnson’s Imbruvica retreated, AstraZeneca’s Calquence has become the first BTK inhibitor to claim a unique win in previously untreated mantle cell lymphoma (MCL). Calquence, used in combination with bendamustine and rituximab (BR), significantly staved off cancer progression or death compared with the standard chemoimmunotherapy alone in newly diagnosed MCL, AstraZeneca said Thursday. The result came from an interim analysis of a phase 3 trial called ECHO, for which AZ most recently projected a readout in 2025. Data from ECHO could potentially help Calquence convert its existing accelerated approval in previously treated MCL into a full nod. But a big question remains whether AZ can immediately file with the FDA, especially given the bad precedent of Imbruvica. The ECHO readout clearly arrived earlier than AZ had expected. The trial bears a primary completion date in October 2025. Although the trial met its primary endpoint of progression-free survival, the FDA has in the past asked other drugs for more mature overall survival data before an application can be submitted. For now, AZ has reported a positive life extension trend in favor of the Calquence combo, but the patient survival data were still not mature at the time of the analysis. The study will continue to assess that key secondary endpoint. In a Thursday statement, AZ’s oncology R&D chief, Susan Galbraith, Ph.D., highlighted the early overall survival signal was the first for a BTK inhibitor. She also touted Calquence’s “differentiated safety profile,” alongside the tumor progression win. In response to a Fierce Pharma inquiry, an AZ spokesperson said the data will be shared with health authorities and that the trial remains ongoing. AZ’s success came a year after AbbVie and J&J decided to pull Imbruvica’s accelerated approval in previously treated MCL and marginal zone lymphoma. It was exactly overall survival data that tripped up Imbruvica’s MCL indication. In the phase 3 SHINE study in first-line MCL, Imburvica’s combination with BR significantly slashed the risk of disease progression or death by 25% compared with BR alone. However, overall survival was similar in the two arms, as the Imbruvica regimen was linked to a marginal 7% increased risk of death. Even though Imbruvica is out of the picture, Calquence might still face competition in the form of BeiGene’s Brukinsa in first-line MCL in the future. Brukinsa, which also has an FDA accelerated approval in previously treated MCL, is being evaluated alongside rituximab alone versus the BR combo in untreated MCL in the phase 3 BGB-3111-306 trial. The BeiGene trial finished recruitment at the beginning of 2024 and bears a primary completion date in March 2027, according to ClinicalTrials.gov. Brukinsa and Calquence are locked in a new round of rivalry, as first-to-market Imbruvica lost the favor of increasingly more doctors in part because of its safety profile. In 2023, BeiGene recorded $1.3 billion in global Brukinsa sales, which marked a 129% jump year over year. During the same period, Calquence brought AZ $2.5 billion sales after a 22% increase. In the all-important first-line chronic lymphocytic leukemia (CLL) setting, Calquence remained the leading BTK inhibitor across the U.S. and Europe, according to AZ. A few days ago, the company read out the phase 3 ChangE trial in Asia showing Calquence monotherapy beat the combination of chlorambucil and rituximab on PFS in untreated CLL. Meanwhile, the phase 3 AMPLIFY trial is pairing Calquence with AbbVie and Roche’s BCL2 inhibitor Venclexta with or without Roche’s anti-CD20 antibody Gazyva in first-line CLL. Similarly, BeiGene is combining Brukinsa with its own second-generation BCL2 inhibitor sonrotoclax in CLL. Editor's Note: The story has been updated to reflect that the phase 3 ChangE trial for Calquence has already read out.

None By: Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene The steady increase in treatment advancements for chronic lymphocytic leukemia (CLL) has provided new hope for patients whose options were previously limited. Now, currently available treatments, such as Bruton’s tyrosine kinase (BTK) inhibitors, have become established standard of care in the first-line and refractory settings and have vastly improved patient treatment outcomes. Promising investigational therapies in development could further change the treatment landscape in these settings as well. But with more options available, the burden is on the scientific community to provide the most robust and clinically relevant data to support treatment decisions made by physicians and patients. The “gold standard” of making clinical treatment decisions is head-to-head randomized clinical trials, often comparing combinations of agents and even within a drug class. There have been recent head-to-head clinical trials of BTK inhibitors in R/R CLL, including BeiGene’s global Phase 3 ALPINE trial of BRUKINSA® (zanubrutinib) versus ibrutinib, in which BRUKINSA demonstrated sustained superiority in progression-free survival (PFS).[i] Acalabrutinib, another BTK inhibitor, has demonstrated improvement in PFS versus rituximab plus idelalisib/bendamustine in R/R CLL in the ASCEND trial and has also demonstrated PFS noninferiority versus ibrutinib in R/R CLL patients with chromosome 17p or 11q deletions in the ELEVATE-RR trial.[ii],[iii] However, there are currently no head-to-head clinical trials that compare this next generation of BTK inhibitors. In the absence of these trials, there are a variety of statistical methodologies available to researchers, aiming to derive “apples-to-apples” comparisons between existing data sets, such as matching adjusted indirect comparisons or “MAICs” and network meta-analyses. Healthcare providers, as well as broader audiences, should be aware of the limitations of MAIC analyses when comparing treatment options. It is important to remember they are meant to be hypothesis-generating and do not establish superior efficacy or safety of one drug over another. The end goal is to allow physicians and patients to make informed decisions, and that requires a commitment to transparency and rigor in the comparative analyses of data sets. A recently conducted MAIC presented at the 28th Annual International Congress on Hematologic Malignancies® (Shadman et al) evaluated the relative efficacy of BRUKINSA versus acalabrutinib in R/R CLL based on data from the Phase 3 ALPINE and Phase 3 ASCEND trials.[iv] The analysis was conducted to address significant limitations of a MAIC previously published in The American Journal of Hematology (Kittai et al), some of which were acknowledged by the study authors.[v] The Shadman et al MAIC suggested a progression-free survival (PFS) and complete response (CR) advantage for BRUKINSA versus acalabrutinib, as well as potentially improved overall survival. The results differ from the previous MAIC, likely because it addressed certain important limitations that precluded a robust efficacy comparison in the previous MAIC. Limitations of the prior MAIC included: Disparate Data Cut-offs: The Kittai et al MAIC had a ~17 month difference in the median efficacy data cut-offs used for each trial. The Shadman et al MAIC analysis used closely matched data cut-offs using most recent data from ALPINE, which was presented at the American Society of Hematology (ASH) Annual Meeting and Exposition 2023 and showed durable PFS response after a median study follow-up of 36.3 months, with only a 3-month difference.[vi]   Limited Matching Criteria: Variables with significant differences across trials, such as number of prior therapies, were not included in the Kittai et al MAIC. The Shadman et al MAIC used a comprehensive matching criteria.   No Adjustment for COVID-19: In the Kittai et al MAIC, the data cutoff used for ALPINE was August 2022 (post-pandemic), while the data cutoff for ASCEND was February 2020 (pre-pandemic). The Shadman et al MAIC adjusted for the disproportionate effects of COVID-19 on ALPINE patients, an important factor for patients with CLL.   Imbalanced Effective Sample Size: In the Kittai et al MAIC, 327 patients from ALPINE were compared with only 99 patients from ASCEND.  The Shadman et al MAIC balanced the populations being compared (185 from ALPINE and 155 from ASCEND). Patients and physicians deserve the most comprehensive and rigorous data sets when it comes to evaluating potential treatments. This is why BeiGene’s research and development team focuses on best-in-class science and research, such as our BRUKINSA clinical development program, and we strive to fulfill this mission each and every day. U.S. Indications and Important Safety Information for BRUKINSA (zanubrutinib) INDICATIONS BRUKINSA is a kinase inhibitor indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). IMPORTANT SAFETY INFORMATION  Warnings and Precautions  Hemorrhage  Fatal and serious hemorrhage has occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher hemorrhage including intracranial and gastrointestinal hemorrhage, hematuria, and hemothorax was reported in 3.8% of patients treated with BRUKINSA in clinical trials, with fatalities occurring in 0.2% of patients. Bleeding of any grade, excluding purpura and petechiae, occurred in 32% of patients. Bleeding has occurred in patients with and without concomitant antiplatelet or anticoagulation therapy. Coadministration of BRUKINSA with antiplatelet or anticoagulant medications may further increase the risk of hemorrhage.  Monitor for signs and symptoms of bleeding. Discontinue BRUKINSA if intracranial hemorrhage of any grade occurs. Consider the benefit-risk of withholding BRUKINSA for 3-7 days before and after surgery depending upon the type of surgery and the risk of bleeding.  Infections  Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA. Grade 3 or higher infections occurred in 26% of patients, most commonly pneumonia (7.9%), with fatal infections occurring in 3.2% of patients. Infections due to hepatitis B virus (HBV) reactivation have occurred. Consider prophylaxis for herpes simplex virus, pneumocystis jirovecii pneumonia, and other infections according to standard of care in patients who are at increased risk for infections. Monitor and evaluate patients for fever or other signs and symptoms of infection and treat appropriately. Cytopenias Grade 3 or 4 cytopenias, including neutropenia (21%), thrombocytopenia (8%) and anemia (8%) based on laboratory measurements, developed in patients treated with BRUKINSA. Grade 4 neutropenia occurred in 10% of patients, and Grade 4 thrombocytopenia occurred in 2.5% of patients. Monitor complete blood counts regularly during treatment and interrupt treatment, reduce the dose, or discontinue treatment as warranted. Treat using growth factor or transfusions, as needed.  Second Primary Malignancies  Second primary malignancies, including non-skin carcinoma, have occurred in 14% of patients treated with BRUKINSA. The most frequent second primary malignancy was non-melanoma skin cancers (8%), followed by other solid tumors in 7% of the patients (including melanoma in 1% of patients) and hematologic malignancies (0.7%). Advise patients to use sun protection and monitor patients for the development of second primary malignancies. Cardiac Arrhythmias   Serious cardiac arrhythmias have occurred in patients treated with BRUKINSA. Atrial fibrillation and atrial flutter were reported in 4.4% patients treated with BRUKINSA, including Grade 3 or higher cases in 1.9% of patients.  Patients with cardiac risk factors, hypertension, and acute infections may be at increased risk. Grade 3 or higher ventricular arrhythmias were reported in 0.3% of patients.   Monitor for signs and symptoms of cardiac arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea, chest discomfort), manage appropriately, and consider the risks and benefits of continued BRUKINSA treatment. Embryo-Fetal Toxicity  Based on findings in animals, BRUKINSA can cause fetal harm when administered to a pregnant woman. Administration of zanubrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity, including malformations at exposures that were 5 times higher than those reported in patients at the recommended dose of 160 mg twice daily. Advise women to avoid becoming pregnant while taking BRUKINSA and for 1 week after the last dose. Advise men to avoid fathering a child during treatment and for 1 week after the last dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.  Adverse Reactions  The most common adverse reactions (≥30%), including laboratory abnormalities, in patients who received BRUKINSA (N=1729) are decreased neutrophil count (51%), decreased platelet count (41%), upper respiratory tract infection (38%), hemorrhage (32%), and musculoskeletal pain (31%).   Drug Interactions  CYP3A Inhibitors: When BRUKINSA is co-administered with a strong CYP3A inhibitor, reduce BRUKINSA dose to 80 mg once daily.  For coadministration with a moderate CYP3A inhibitor, reduce BRUKINSA dose to 80 mg twice daily.  CYP3A Inducers: Avoid coadministration with strong or moderate CYP3A inducers. Dose adjustment may be recommended with moderate CYP3A inducers.  Specific Populations  Hepatic Impairment: The recommended dose of BRUKINSA for patients with severe hepatic impairment is 80 mg orally twice daily. Please see full U.S. Prescribing Information including U.S. Patient Information at BRUKINSA.com.   [i] Brown JR, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. doi: 10.1056/NEJMoa2211582. Epub 2022 Dec 13. PMID: 36511784. [ii] Ghia P, 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 Sep 1;38(25):2849-2861. doi: 10.1200/JCO.19.03355. Epub 2020 May 27. PMID: 32459600. [iii] Sharman JP, 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 Apr 18;395(10232):1278-1291. doi: 10.1016/S0140-6736(20)30262-2. Erratum in: Lancet. 2020 May 30;395(10238):1694. PMID: 32305093; PMCID: PMC8151619. [iv] Shadman M, Brown JR, Williams R, et al. Efficacy of zanubrutinib versus acalabrutinib in the treatment of relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC). Presented at: 28th International Congress on Hematologic Malignancies; February 29 to March 3, 2024. Miami, Florida. [v] Kittai AS, et al. A matching-adjusted indirect comparison of acalabrutinib versus zanubrutinib in relapsed or refractory chronic lymphocytic leukemia. Am J Hematol. 2023 Dec;98(12):E387-E390. doi: 10.1002/ajh.27110. Epub 2023 Oct 9. PMID: 37811799. [vi] Brown JR, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Presented at: 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, California; Paper No. 0202. https://doi.org/10.1182/blood-2023-174289