FDA Actions: April 2022

Axi-cel Approved in Second Line for LBCL, Expands CAR T Pool by 11,000 in US Alone

The FDA on April 1 authorized the use of Kite Pharma’s axicabtagene ciloleucel (axi-cel) for patients who have relapsed just once from large B-cell lymphoma (LBCL), a change that could expand the pool of patients eligible for chimeric antigen receptor (CAR) T-cell therapy by 11,000 just in the United States.^1,2 This change will expand use of a high-cost cancer treatments from the sickest patients to those who are comparatively fit, raising new questions for payers and policy makers.

“[This] approval brings that hope to more patients by enabling the power of CAR T-cell therapy to be used earlier in the treatment journey,” Christi Shaw, CEO of Kite Pharma, said in a statement.¹ This milestone has been years in the making. On behalf of the entire Kite community, we would like to thank the patients and physicians who have been on this journey with us.”

The expanded use of axi-cel, sold as Yescarta, while not unexpected, nonetheless represents uncharted territory in cancer care at a time when clinicians are highlighting problems with utilization management. However, Lori Ann Leslie, MD, director of indolent lymphoma and chronic lymphocytic leukemia research programs at John Theurer Cancer Center, said she looked forward to discussing the treatment with patients as early as the week of April 4.

“I’ve talked to a few of my patients about the pending approval, and how treatment landscapes are evolving,” Leslie said in an interview with Evidence-Based Oncology™. “Once we see the label, we’ll see—it may be very relevant for them.”

The approval is based data from ZUMA-7, which showed that patients treated with axi-cel were 2.5 times more likely to be alive after 2 years without the need for additional treatment than those who received standard of care (40.5% vs 16.3%).²

During his presentation at the 2021 meeting of the American Society of Hematology (ASH), Moffitt Cancer Center’s Frederick Locke, MD, highlighted a key point: Of the patients randomized to axi-cel, 94% successfully received CAR T-cell treatment; in comparison, only 36% of those randomized to standard of care received high-dose therapy and autologous stem-cell therapy (ASCT).

The question will be whether the payer infrastructure can manage a wave of new patients seeking treatment with axi-cel, including some who conceivably could be treated with the existing standard of care, which is high-dose therapy followed by ASCT. Payer delays in approving axi-cel could make this expensive treatment less effective once it reaches patients, and it could force clinicians to order rounds of chemotherapy to stabilize patients during the manufacturing process, adding to costs.

For their part, Kite Pharma officials said they will use the same network of 112 authorized centers to administer the treatments that they’ve been using since axi-cel was first approved for third-line treatment in 2017. Kite officials say the process to secure payer approval for CAR T-cell therapy has greatly improved since that time.

Cost is a major consideration for payers. Axi-cel treatments have been listed at $373,000 and that does not include the cost of hospitalization or treatment of adverse events, which can include cytokine release syndrome (CRS). Over time, management of CRS has vastly improved. 

References
1. Yescarta receives US FDA approval as first CAR T-cell therapy for initial treatment of relapsed or refractory large B-cell lymphoma. News release. Gilead. April 1, 2022. Accessed April 1, 2022. https://bit.ly/3K2ocNd
2. Caffrey M. With approval for axi-cel in second-line on the horizon, CAR T-cell therapy poised to enter a new phase. Am J Manag Care. 2022;28(SP2):SP85-SP87.

Olaparib Approval Expands Breast Cancer Treatment Options

Olaparib (Lynparza; AstraZeneca/Merck) has received FDA approval for the adjuvant treatment of deleterious/suspected deleterious germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer in adult patients who have received adjuvant or neoadjuvant chemotherapy.¹

This latest indication for olaparib adds to excitement about the poly (ADP-ribose) polymerase (PARP) inhibitor, which is also being investigated for use in prostate cancer. The agent has current indications in the United States, European Union,² and Japan for ovarian cancer,³ gBRCAm HER-2 negative metastatic breast cancer following chemotherapy, and gBRCAm HER-2 negative hormone receptor–positive metastatic breast cancer following endocrine therapy. An additional indication in the European Union and Japan is for patients with locally advanced breast cancer.

“This important approval gives early-stage high-risk breast cancer patients in the [United States] with a germline BRCA mutation a new targeted therapy option in the adjuvant setting starting today. Lynparza reduced the risk of disease recurrence in these patients, and now new data confirm it also significantly extended patients’ lives versus placebo,” said David Fredrickson, executive vice president of the oncology business unit at AstraZeneca, in a statement.⁴ “These data underline the importance of germline BRCA testing as soon as possible after diagnosis to help identify patients who may be eligible for Lynparza.”

The FDA based its approval on updated data from the randomized, double-blind, placebo-controlled international OlympiA trial (NCT02032823), which show the PARP inhibitor can reduce risks of invasive breast cancer recurrence, second cancers, and death, and improve overall survival.⁵ Data were first presented at the 2021 American Society of Clinical Oncology Annual Meeting, from among 1836 patients.⁶

With primary and secondary end points of invasive disease-free survival (IDFS) and overall survival, respectively, statistically significant improvements were seen for both compared with placebo:

• 42% reduced risk of IDFS (HR, 0.58; 95% CI, 0.46-0.74; P < .0001)
• 32% reduced risk of death (HR, 0.68; 95% CI, 0.50-0.91; P = .0091)

For this study, the authors defined IDFS as, “time from randomization to the date of the first loco-regional or distant recurrence or new cancer or death from any cause."

The most common adverse events (AEs) overall in OlympiA were nausea (57%), fatigue (42%), and anemia (24%), with the top grade 3 AEs being anemia (9%), neutropenia (5%), and leukopenia (3%). Thirty-one percent of trial participants required dose interruptions and 23% required dose reductions, with anemia being cited as the most common reason in both cases, at 11% and 8%, respectively. An additional 10% discontinued olaparib treatment, mostly because of nausea (2%).

OlympiA’s treatment protocol comprised 1 year of 300-mg twice-daily olaparib administered orally, which is also the recommended olaparib dose, vs placebo. To be included in the trial, patients had to have a history of at least 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes, or both.

Close to twice as many events were seen in the placebo vs olaparib arm (20% vs 12%), with IDFS at 3 years in the treatment arm besting that in the placebo arm by 9 percentage points: 86% vs 77%. In addition, the treatment arm had one-third fewer deaths: 75 (8%) vs 109 (12%).

These results are especially noteworthy because breast cancer is the most diagnosed cancer worldwide; they highlight the importance of genetic testing among women with high-risk breast cancer, to increase their targeted treatment options. Inherited breast cancers are typically more aggressive and deadly, despite their 5% to 10% occurrence as a breast cancer, and women with BRCA mutations have a 72% lifetime risk of breast cancer vs 12% for women overall.

BRCA mutations cause cell instability because they inhibit cell repair by inhibiting protein production or preventing its proper function. The result is a greater likelihood of developing cancer-related genetic alterations. 

References
1. FDA approves olaparib for adjuvant treatment of high-risk early breast cancer. FDA. March 11, 2022. Accessed March 14, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breast-cancer
2. Caffrey M, Shaw ML. AstraZeneca’s Camille Hertzka discusses interim PROpel trial findings. The American Journal of Managed Care®. February 25, 2022. Accessed March 14, 2022. https://www.ajmc.com/view/astrazeneca-s-camille-hertzka-discusses-interim-propel-trial-findings-in-mcrpc
3. McNulty R. Dr Bradley Monk discusses indications for PARP inhibitors in ovarian cancer. The American Journal of Managed Care®. December 30, 2020. Accessed March 14, 2022. https://www.ajmc.com/view/dr-bradley-monk-discusses-indications-for-parp-inhibitors-in-ovarian-cancer
4. FDA approves Lynparza (olparib) as adjuvant treatment for patients with germline BRCA-mutated (gBRCAm), HER2-negative, high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. News release. Merck. March 11, 2022. Accessed March 14, 2022. https://bit.ly/3MN2ePP
5. Olaparib as adjuvant treatment in patients with germline BRCA mutated high risk HER2 negative primary breast cancer (OlympiA). ClinicalTrials.gov. Updated December 8, 2021. Accessed March 14, 2022. https://clinicaltrials.gov/ct2/show/NCT02032823
6. Tutt ANJ, Garber JE, Kaufman B, et al; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215


FDA Approves Third Filgrastim Biosimilar: Releuko

Releuko, a filgrastim biosimilar developed by Kashiv BioSciences LLC and Amneal Pharmaceuticals, Inc, is the third filgrastim biosimilar to be granted approval from the FDA. The product is also the first biosimilar to receive approval in 2022 and the first to receive FDA approval for both the Kashiv and Amneal teams.

Releuko, which references Neupogen, is indicated for the treatment and prevention of febrile neutropenia, a common chemotherapy complication among patients with cancer. The companies said they expect to launch the product during the third quarter of 2022.

“The US approval of our first biosimilar is a very significant milestone for Amneal. Biosimilars represent the next wave of providing access to affordable medicines in the United States,” Chirag and Chintu Patel, co–chief executive officers of Amneal, said in a statement. “We are building a global biosimilars business by leveraging partner assets to start, then leveraging our own key capabilities over time.”¹

The companies are also working together to develop 2 other oncology biosimilars: a pegfilgrastim biosimilar, referencing Neulasta; and a bevacizumab biosimilar, referencing Avastin. Both are under review by FDA, and their launches are anticipated in 2022.

“It is a proud moment for the Kashiv team and our partners at Amneal to have our first biosimilar, Releuko, approved by the FDA,” said Chandramauli Rawal, MBBS, chief operating officer of Kashiv, in a statement. “Kashiv is one of a few domestic companies to manufacture and launch a biosimilar in the United States. Kashiv aims to continue bringing high-quality biosimilars to the global markets over the coming years.”²

Releuko was approved for administration for intravenous and subcutaneous use, either as single-dose vials or prefilled syringes, both of which come in a 300-mcg/mL dose and 480-mcg/1.6 mL dose.

References
1. Amneal enters US biosimilars market with approval of Releuko (filgrastim-ayow). News release. BusinessWire; March 1, 2022. Accessed March 20, 2022. https://bwnews.pr/3imI3KF
2. Kashiv Biosciences receives approval for its first biosimilar Releuko (filgrastim-ayow). News release. BusinessWire; March 2, 2022. Accessed March 20, 2022. https://bwnews.pr/3JsGFlE


FDA Approves Cilta-cel to Treat R/R Multiple Myeloma

The list of approved chimeric antigen receptor T-cell therapies grew on February 28, 2022, as the Janssen Pharmaceutical Companies of Johnson and Johnson and Legend Biotech’s ciltacabtagene autoleucel (cilta-cel; Carvykti) received approval for treatment of relapsed or refractory multiple myeloma.¹

The B-cell maturation antigen–directed immunotherapy will be the second such therapy for multiple myeloma, following the approval of idecabtagene vicleucel (ide-cel; Abecma) nearly a year ago.² However, ide-cel, sold by Bristol Myers Squibb, has been beset by manufacturing problems since its launch, leaving room for competition.³

Multiple myeloma is a cancer that affects white blood cells in the bone marrow. Although many therapies have been developed to treat it, the disease is incurable. The likelihood of disease progression rises once patients have received treatments from the 3 major therapy classes: immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies. Under the FDA approval, patients must receive at least 4 treatments, including 1 in each of these classes, before being considered for cilta-cel.

FDA approval is based on CARTITUDE-1 (NCT03548207), a phase 1b/2 trial in which investigators reported cilta-cel produced an objective response rate of 98% (95% CI, 92.7%-99.7%) and a stringent complete response rate of 78% (95% CI, 68.8%-86.1%). Median duration of response was 21.8 months after a median of 18 months of follow-up.⁴ Data presented at the 2021 American Society of Hematology Annual Meeting and Exposition found that 74% of patients were alive at 2 years, with progression free survival at 61%.

“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” principal study investigator Sundar Jagannath, MBBS, director of the Center of Excellence for Multiple Myeloma and professor of medicine, hematology, and medical oncology at The Tisch Cancer Institute at Mount Sinai in New York, New York, said in a statement.¹

“The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from antimyeloma therapies for a period of time.”

Janssen officials said in their statement that cilta-cel will be offered in a limited network at first to allow for the proper training and certification of oncologists who will administer the personalized therapy. Availability of the treatment will increase throughout 2022 and beyond, the statement said.

“This approval of Janssen’s first cell therapy is a testament to our continuing commitment in oncology to deliver new therapeutic options and drive toward our vision of the elimination of cancer,” said Mathai Mammen, MD, PhD, executive vice president of pharmaceuticals at Janssen Research and Development, LLC, Johnson and Johnson. “Today’s approval underscores our determination to develop therapies that can help patients living with what remains an intractable blood cancer today and, at the same time, offer hope for the future.” 

References
1. US FDA approves CARVYKTI (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen Pharmaceutical Companies of Johnson and Johnson; February 28, 2022. Accessed February 28, 2022. https://www.jnj.com/u-s-fda-approves-carvykti-ciltacabtagene-autoleucel-janssens-first-cell-therapy-a-bcma-directed-car-t-immunotherapy-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma
2. McNulty R. FDA approves idecabtagene vicleucel for multiple myeloma. American Journal of Managed Care®. Published March 27, 2021. Accessed March 1, 2022. https://www.ajmc.com/view/fda-approves-idecabtagene-vicleucel-for-multiple-myeloma
3. Liu A. Bristol Myers hits CAR-T manufacturing bottleneck as Abecma demand outstrips supply. Fierce Pharma. Published July 28, 2021. Accessed March 1, 2022. https://www.fiercepharma.com/manufacturing/bristol-myers-hits-car-t-manufacturing-bottleneck-as-abecma-demand-outstrips-supply
4. Martin T, Usmani SZ, Berdeja JG, et al. Updated results from CARTITUDE-1: phase 1b/2study of ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in patients with relapsed/refractory multiple myeloma. Presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Accessed March 1, 2022. https://ash.confex.com/ash/2021/webprogram/Paper146060.html.

FDA Grants Breakthrough Device Designation to Foundation Medicine’s ctDNA Tracker

On February 15, 2022, the FDA granted a breakthrough device designation for the Foundation Medicine, Inc circulating tumor DNA (ctDNA) detection and molecular monitoring assay, the FoundationOne Tracker. The assay is designed to optimize algorithms for the purpose of identifying patient-specific variants and allow for the detection of ctDNA in plasma cells, according to a company statement.¹

The designation was given to Foundation Medicine for the assay’s ability to detect molecular residual disease (MRD) in patients with early-stage cancer after receiving curative therapy. The detection of MRD can help guide providers in making decisions on therapeutic regimens dependent on the patient’s MRD status and risk of relapse.

The assay was developed in partnership with Natera, Inc and combines Foundation Medicine’s tissue-based comprehensive genomic profiling (CGP) platform with Natera’s personalized ctDNA monitoring experience. The FoundationOne Tracker was launched by the companies in June 2021. Foundation Medicine and Natera will continue to collaborate to support biopharma and their academic partners with clinical trial evaluations and planning for companion diagnostics.

In addition to the breakthrough device designation, the assay’s personalized technology will be used for the detection of ctDNA and molecular monitoring in patients with early- or advanced-stage cancers, as well as the assessment of patient therapeutic responses, MRD detection, MRD surveillance, and detection of molecular residual relapse following curative intent therapy.

“Foundation Medicine continues to shape the future of clinical care and research by helping oncologists and our industry partners find the answers they need to bring precision cancer care to patients,” said Brian Alexander, MD, MPH, CEO of Foundation Medicine. “Personalized molecular disease monitoring enables early detection of ctDNA and can monitor for risk of relapse and track therapy response to help oncologists make personalized treatment plans for their patients. We are enthusiastic about our work to accelerate development of this assay so it can more quickly impact care decisions in the clinic.”

The FDA’s breakthrough device program is a voluntary initiative for medical devices and device-led combination products that enables more effective treatment or diagnosis of diseases or conditions that are considered life-threatening or irreversibly debilitating. The goal of the program is to accelerate the development, assessment, and review of devices while continuing to preserve the statutory standard for premarket approval and regulatory authorization. This ensures more patients and providers have timely access to the medical devices.

Data presented at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium demonstrated the feasibility of MRD in patients with metastatic colorectal cancer who have received curative intent surgical resection.² Foundation Medicine presented additional MRD data on the genomics of resected early-stage bladder cancer at the 2022 ASCO Genitourinary Cancers Symposium, which focused on how data can be used to validate detection of MRD in ctDNA, utilizing CGP assessments.³ 

References
1. Foundation Medicine’s ctDNA monitoring assay, FoundationOne Tracker, granted breakthrough device designation by US Food and Drug Administration. News release. Foundation Medicine; February 15, 2022. Accessed February 15, 2022. foundationmedicine.com/press-releases/af7bb7df-2dcf-411f-bc7d-ebb8ab90d788
2. Nimeiri H, Young A, Madison R, et al. Comprehensive genomic profiling (CGP)-informed personalized molecular residual disease (MRD) detection: an exploratory analysis from the PREDATOR study of metastatic colorectal cancer (mCRC) patients undergoing surgical resection. J Clin Oncol. 2022;40(suppl 4):187. doi:10.1200/JCO.2022.40.4_suppl.187
3. Young A, Nimeiri H, Madison R, et al. Molecular residual disease (MRD) detection with a tissue comprehensive genomic profiling (CGP)-informed personalized monitoring assay: an exploratory analysis of the IMvigor-010 observation arm. J Clin Oncol. 2022;40(suppl 6):448. doi:10.1200/JCO.2022.40.6_suppl.448

FDA Accepts sNDA for Zanubrutinib to Treat CLL/SLL

The FDA has accepted a supplemental new drug application for zanubrutinib (Brukinsa; BeiGene) for the treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. The target action date is October 22, 2022.¹

The filing includes data from 2 pivotal randomized phase 3 studies: ALPINE (NCT03734016), comparing zanubrutinib to ibrutinib in patients with relapsed or refractory (R/R) disease; and SEQUOIA (NCT03336333), comparing zanubrutinib to bendamustine and rituximab (BR) in treatment-naïve patients. The filing also included data from 8 supportive studies in B-cell malignancies.

Zanubrutinib is already approved by the FDA for the treatment of adults with R/R marginal zone lymphoma (MZL)² who have received at least 1 anti-CD20–based regimen, for adults with Waldenström macroglobulinemia (WM), and for adults with mantle cell lymphoma who have received at least 1 prior therapy.³

ALPINE and SEQUOIA were global studies, with patients from 17 countries. The results of ALPINE were reported at the 26th European Hematology Association (EHA21) Congress, and results from SEQUOIA were reported at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition.

“With superiority in investigator-assessed [objective response rate] over ibrutinib in ALPINE for relapsed or refractory patients and in PFS [progression-free survival] over chemoimmunotherapy in the SEQUOIA study for treatment-naïve patients, Brukinsa has demonstrated its potential to improve treatment outcomes for CLL patients,” Jane Huang, MD, chief medical officer of hematology at BeiGene, said in a statement.¹

Zanubrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor that minimizes the off-target inhibition of TEC- and EGFR-family kinases seen with ibrutinib, which has been the standard of care in CLL. This more targeted treatment improves outcomes and reduces toxicity, Peter Hillmen, PhD, MB, ChB, professor at the University of Leeds and honorary consultant hematologist at Leeds Teaching Hospitals NHS Trust in the United Kingdom, explained while presenting interim results of ALPINE at EHA21.⁴

SEQUOIA found zanubrutinib produced prolonged PFS compared with BR. The estimated 24-month PFS was 85.5% for zanubrutinib vs 69.5% for BR. The estimated overall survival was 94.3% vs 94.6%.⁵

Constantine S. Tam, MD, MBBS, a consulting hematologist and professor at Peter MacCallum Cancer Centre in Melbourne, Australia, and lead author on a SEQUOIA abstract, presented at ASH 2021, noting that zanubrutinib had better tolerance with reduced adverse events compared with the BR arm. “This confirms the highly tolerable nature of BTK inhibitors in general,” he said in an interview with The American Journal of Managed Care®.

In addition, although BTK inhibitors are associated with atrial fibrillation, in SEQUOIA, the rates of atrial fibrillation were the same as the comparator arm. “This confirms earlier data that [demonstrated] zanubrutinib is less cardiotoxic than other BTK inhibitors, and in particular, less cardiotoxic than ibrutinib,” Tam said.⁶

Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute in Boston, Massachusetts, and principal investigator of ALPINE and SEQUOIA, echoed in a statement the safety and efficacy benefits of zanubrutinib. “[Although] previously approved BTK inhibitors have been transformational for some patients with CLL, there continues to be unmet need, as not all patients achieve a favorable clinical response, [whereas] others are unable to tolerate currently approved BTK [inhibitor] therapies,” she said. “As demonstrated in both the ALPINE and SEQUOIA studies, Brukinsa was generally well tolerated in CLL patients, with low rates of atrial fibrillation, and showed strong efficacy compared [with] ibrutinib and chemoimmunotherapy, respectively.”

The European Medicines Agency also accepted applications for zanubrutinib in CLL and MZL. The therapy is currently approved for patients with WM who have received at least 1 prior therapy or for first-line treatment of patients unsuitable for chemoimmunotherapy.⁷

References
1. BeiGene announces US FDA acceptance of supplemental new drug application for BRUKINSA (zanubrutinib) in chronic lymphocytic leukemia. News release. Business Wire; February 22, 2022. Accessed February 23, 2022. https://bwnews.pr/3IEDDKE
2. Caffrey M. Zanubrutinib gains accelerated approval in R/R marginal zone lymphoma. American Journal of Managed Care®. Published September 15, 2021. Accessed March 1, 2022. https://www.ajmc.com/view/zanubrutinib-gains-accelerated-approval-in-r-r-marginal-zone-lymphoma
3. Kaltwasser J. Dual US, China approval process for zanubrutinib shows regulatory differences. American Journal of Managed Care®. Published October 7, 2020. Accessed March 1, 2022. https://www.ajmc.com/view/dual-us-china-approval-process-for-zanubrutinib-shows-regulatory-differences
4. Hillmen P, Eichhorst B, Brown JR, et al. First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 26th European Hematology Association Congress; June 9-17, 2021; Accessed February 23, 2022, virtual. https://bit.ly/3vy1nMP
5. Tam CS, Giannopoulous K, Jurczak W, et al. SEQUOIA: results of a phase 3 randomized study of zanubrutinib versus bendamustine + rituximab (BR) in patients with treatment-naïve (TN) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Atlanta, GA. Accessed February 23, 2022. https://ash.confex.com/ash/2021/webprogram/Paper148457.html
6. Dr Constantine Tam touts outcomes of zanubrutinib vs bendamustine/rituximab therapy in CLL/SLL. American Journal of Managed Care®. Published December 12, 2021. Accessed March 1, 2022. https://bit.ly/3vxwoAG
7. BeiGene announces European Medicines Agency acceptance of applications for BRUKINSA (zanubrutinib) in chronic lymphocytic leukemia and marginal zone lymphoma. News release. BeiGene; February 22, 2022. Accessed March 1, 2022. https://ir.beigene.com/news-details/?id=55b59685-f28d-4059-83db-1363feff0b24