The Advent of the BTK inhibitor

Thomas J. Kipps, MD, PhD

The Advent of the BTK inhibitor

The Bruton’s tyrosine kinase (BTK) inhibitor class changed the therapeutic landscape for chronic lymphocytic leukemia (CLL) and paved the road for a new way of treating the disease. This was marked by the FDA approval of IMBRUVICA^® (ibrutinib), a once-daily oral treatment of adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in 2014, followed by the approval of monotherapy in treatment-naïve CLL/small lymphocytic lymphoma (SLL) patients in 2016. As the first BTK inhibitor approved in this class, ibrutinib has been used to treat more than 250,000 patients worldwide across 6 indications.^1* In addition to ibrutinib, the class today includes one other BTK inhibitor approved for treatment of adult patients with CLL and SLL, which became available in 2019.² Before ibrutinib, most patients with CLL had to rely on chemotherapy or chemoimmunotherapy combinations for treatment.^3,4 As our understanding of the disease evolves, it is important to be aware of the treatment options available for CLL patients.

* Source: IQVIA projected claims data and Janssen Data on File (internal shipment demand data and clinical trial data) as of Oct 3, 2021

Understanding the Clinical Data

When choosing a treatment for CLL/SLL, providers should consider the clinical trial data and patient preference. Looking at ibrutinib as an option, it is important to note that it has been studied in 40 clinical trials across all indications, including 5 Phase 3 studies in CLL.¹ Studied against a range of comparators — including ofatumumab monotherapy, chlorambucil monotherapy, and fludarabine, cyclophosphamide and rituximab (FCR) — ibrutinib and ibrutinib plus rituximab has shown superior PFS, alone or in combination, in both previously treated and treatment-naïve patients with CLL/SLL.⁵

Ibrutinib has amassed more than 11 years of clinical trial data in CLL/SLL with up to 7 years of long-term follow-up data in 1L CLL and up to 8 years long-term data in 2L+ CLL/SLL.¹ Specifically, in 1L CLL/SLL, ibrutinib has up to 7 years of long-term progression-free survival (PFS) and overall survival (OS) data that supports the RESONATE™-2 clinical trial. The efficacy and safety data across the following clinical trials underscore the use of ibrutinib for appropriate patients with CLL/SLL:

• The Phase 3 RESONATE study, a multicenter, open-label trial, examined previously treated patients with CLL (N=391; 32%, or 127 with del17p).⁵ Patients on ofatumumab were able to cross over to ibrutinib upon disease progression. Progression-free survival was the primary endpoint.⁶ Overall response rate and overall survival were secondary endpoints.⁶
  • The trial showed that in previously treated patients with CLL at a 9.4-month median follow-up, ibrutinib monotherapy achieved statistically greater (IRC-assessed) PFS [HR=0.22 (95% CI: 0.15, 0.32); P<0.0001] and OS [HR=0.43 (95% CI: 0.24, 0.79); P<0.05] compared with ofatumumab monotherapy.⁶ With an overall follow-up at 63 months, the median investigator-assessed PFS per the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria was 44.1 months [95% CI (38.5, 56.9)] in the ibrutinib arm and 8.1 months [95% CI (7.8, 8.3)] in the ofatumumab arm, respectively.⁵ The study also showed at 63 months an overall response rate of 87.2 percent in the ibrutinib arm versus 22.4 percent in the ofatumumab arm.⁶ Overall response rate (ORR) in patients with del17p in the ibrutinib arm was 88.9 percent at an overall follow-up of 63 months, as assessed by investigators in the ibrutinib arm versus 18.8 percent in the ofatumumab arm.⁵
  • After a median duration of exposure of 8.6 months in patients receiving ibrutinib, the most frequent AEs of any grade that occurred in at least 20 percent of patients were decreased platelets, decreased neutrophils, diarrhea, decreased hemoglobin, musculoskeletal pain, nausea, rash, and pyrexia.⁵
• The RESONATE™-2 study was a Phase 3, multicenter, open-label trial of treatment-naive CLL/SLL patients (N=269), 65 years of age or older, who were randomized 1:1 to ibrutinib 420 mg once daily until disease progression or unacceptable toxicity (n=136) or chlorambucil (n=133) for up to 12 cycles.^5,7 Patients with del 17p were excluded.^5,7 The primary endpoint was PFS as assessed by an IRC per iwCLL criteria (primary analysis) and OS was a secondary endpoint.⁷ Patients with IRC-confirmed disease progression were enrolled in an extension study (long-term follow-up) and second-line treatment per investigator’s choice (including ibrutinib for patients progressing on chlorambucil).⁷
  • The primary analysis (median follow-up of 18.4 months) demonstrated an 84 percent reduction in the risk of disease progression or death (Hazard Ratio (HR) 0.16 [95% CI: 0.09-0.28]; P<0.0001). With 41 percent of patients switching from chlorambucil to ibrutinib, the OS analysis after median follow-up of 28.1 months in the intent-to-treat (ITT) patient population showed a statistically significant Hazard Ratio (HR) of 0.44 [95% CI (0.21, 0.92)] and 2-year survival rate estimates of 94.7% [95% CI (89.1, 97.4)] and 84.3% [95% CI (76.7, 89.6)] in the ibrutinib and chlorambucil arms, respectively.⁵
  • The most frequent (≥ 20%) AEs of any grade with ibrutinib were decreased neutrophils, decreased platelets, diarrhea, musculoskeletal pain, decreased hemoglobin, fatigue, nausea, cough and rash.⁵
• The E1912 study was a Phase 3 open-label trial of patients 70 years of age or younger with treatment-naïve CLL, who were randomized 2:1 to ibrutinib plus rituximab for 6 cycles, followed by ibrutinib until disease progression or unacceptable toxicity, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR).⁸ The primary endpoint was PFS, and OS was a secondary endpoint.⁸ The trial was designed and conducted by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) and sponsored by the National Cancer Institute, part of the National Institutes of Health.
  • The study showed ibrutinib plus rituximab may help patients live longer without progression of their cancer compared to FCR. At median 33.6-month follow-up, the estimated PFS rate for ibrutinib plus rituximab was 89.4 percent (95% CI: 85, 92) versus an estimated PFS rate of 72.9 percent for FCR (95% CI: 61, 78) (HR 0.35 [95% CI 0.22-0.52; P<0.0001]).⁸ With median follow-up of 49 months, median overall survival was not reached in either treatment arm.
  • After a median duration of exposure of 34.3 months, the most frequent AEs (≥ 20%) of any grade that occurred in at least 15 percent of patients were fatigue, musculoskeletal pain, diarrhea, decreased neutrophils, rash, decreased platelets, hypertension, arthralgia, headache, nausea, increased creatinine, bruising, cough, hemorrhage, increased bilirubin, upper respiratory tract infection, peripheral edema, pyrexia, decreased hemoglobin, increased AST, stomatitis, pain, dyspnea and dizziness in the ibrutinib arm.⁵

Other Key Considerations

As with any medicine, it is important to review the Prescribing Information for ibrutinib, including its recommended dosing. This allows for further evaluation of its studies, including methodology and the full efficacy and safety findings. It is also important to factor in other considerations, such as special patient characteristics. For example, in CLL, it is common for patients to carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p and trisomy 12.⁹ Between 5 and 9 percent of newly diagnosed patients with CLL have 17p deletion, but among patients with relapsed or refractory disease, this number is much higher at approximately 50 percent.¹⁰ Ibrutinib is approved for use in CLL patients with or without 17p deletion, a mutation that is associated with a poor prognosis.^5,11

I am thankful for the different treatment options for my CLL/SLL patients. Each patient is different, so the more treatment options available, the better. When it comes to prescribing a treatment for my patients with CLL/SLL, I look holistically at ibrutinib– including its available safety and efficacy data and NCCN^® recommendation – as I consider this option for my appropriate patients with CLL/SLL.

Recommended Ibrutinib Dosage and Administration

The recommended dosage of ibrutinib is 420 mg orally once daily until disease progression or unacceptable toxicity.^5,13 Ibrutinib can be administered for CLL/SLL as a single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR).⁵ Agents administered in combination with ibrutinib require infusion.⁵ When administering ibrutinib in combination with rituximab or obinutuzumab, consider administering ibrutinib prior to rituximab or obinutuzumab when given the same day.⁵

Administer ibrutinib at approximately the same time each day with a glass of water. Swallow tablets or capsule whole. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets. If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Do not take extra doses of ibrutinib to make up for the missed dose.

Dose modifications of ibrutinib in patients with B-cell malignancies are recommended when used concomitantly with posaconazole, voriconazole and moderate CYP3A inhibitors.⁵ If coadministered with a moderate CYP3A inhibitor, decrease dosage to 280 mg once daily. If coadministered with posaconazole suspension 100 mg once daily, 100 mg twice daily, 200 mg twice daily, or 200 mg voriconazole twice daily, dosage of ibrutinib should be reduced to 140 mg once daily.⁵ If administered with posaconazole suspension 200 mg three times daily, 400 mg twice daily, or posaconazole intravenously 300 mg once daily or posaconazole delayed-release tablets 300 mg once daily, dosage of ibrutinib should decrease to 70 mg once daily.⁵ Avoid coadministration with strong CYP3A inhibitors.⁵ For Adverse Reactions (ARs) listed in Table 1, interrupt IMBRUVICA^® therapy at each occurrence of the same AR. Once the AR has improved to Grade 1 or baseline (recovery), follow the recommended dose modifications (see Table 1).

Additionally, ibrutinib is to be taken once daily until disease progression or unacceptable toxicity and may be co-administered with proton pump inhibitors (PPIs), which are commonly used to treat gastroesophageal reflux disease (GERD).⁵ This is an important consideration for physicians to discuss with patients as up to 55 percent of patients receiving cancer therapy, including patients with CLL, are taking an acid-reducing agent.^14,15 For further information on use with CYP3A inhibitors and inducers, and in patients with hepatic impairment, please see the full Prescribing Information. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

INDICATIONS

IMBRUVICA^® (ibrutinib) is a kinase inhibitor indicated for the treatment of adult patients with:

• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients who received IMBRUVICA^®. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA^® in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA^®, respectively.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA^® increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA^® without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA^®. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA^® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA^® therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B-cell malignancies who received IMBRUVICA^® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA^®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately.

Cardiac Arrhythmias, Cardiac Failure, and Sudden Death: Fatal and serious cardiac arrhythmias and cardiac failure have occurred with IMBRUVICA^®. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received IMBRUVICA^® in clinical trials, including in patients who received IMBRUVICA^® in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events.

Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received IMBRUVICA^® in clinical trials, including in patients who received IMBRUVICA^® in unapproved monotherapy or combination regimens. These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections.

Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, and consider the risks and benefits of continued IMBRUVICA^® treatment.

Hypertension: Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received IMBRUVICA^® in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from a subset of these patients, (N=1,124), the median time to onset was 5.9 months (range, 0 to 24 months). In a long-term safety analysis over 5 years of 1,284 patients with B-cell malignancies treated for a median of 36 months (range, 0 to 98 months), the cumulative rate of hypertension increased over time. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%. Monitor blood pressure in patients treated with IMBRUVICA^®, initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA^® as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension.

Cytopenias: In 645 patients with B-cell malignancies who received IMBRUVICA^® as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 2.8%, based on laboratory measurements. Monitor complete blood counts monthly.

Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients with B-cell malignancies who received IMBRUVICA^® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA^®. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA^® can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA® and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥30%) in adult patients with B-cell malignancies were thrombocytopenia (55%)*, diarrhea (44%), fatigue (39%), musculoskeletal pain (39%),neutropenia(39%)*, rash (36%), anemia (35%)*, bruising (32%), and nausea (30%).

The most common Grade ≥ 3 adverse reactions (≥5%) in adult patients with B-cell malignancies were neutropenia (21%)*, thrombocytopenia (14%)*, pneumonia (8%), and hypertension (8%).

Approximately 9% (CLL/SLL), and 14% (WM) of adult patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL) and 5% (WM) of adult patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in adult or pediatric patients with cGVHD were fatigue (57%), anemia (49%)*, bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, musculoskeletal pain (30%), pyrexia (30%), muscle spasms (29%), stomatitis (29%), hemorrhage (26%), nausea (26%), abdominal pain (23%), pneumonia (23%), and headache (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in adult or pediatric patients with cGVHD were pneumonia (14%), anemia (13%)*, fatigue (12%), pyrexia (11%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), osteonecrosis (9%), stomatitis (9%), hypokalemia (7%), headache (5%), and musculoskeletal pain (5%).

Discontinuation of IMBRUVICA^® treatment due to an adverse reaction occurred in 24% of adult patients and 23% of pediatric patients. Adverse reactions leading to dose reduction occurred in 26% of adult patients and 19% of pediatric patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA^® with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. Dose modifications of IMBRUVICA^® are recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA^® if strong inhibitors are used short-term (e.g., for ≤ 7 days). Avoid grapefruit and Seville oranges during IMBRUVICA® treatment, as these contain strong or moderate inhibitors of CYP3A. See dose modification guidelines in USPI sections 2.3 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Pediatric Use: The safety and effectiveness of IMBRUVICA^® have not been established for the treatment of cGVHD after failure of one or more lines of therapy in pediatric patients less than 1 year of age. The safety and effectiveness of IMBRUVICA^® in pediatric patients have not been established in CLL/SLL, CLL/SLL with 17p deletion, WM, or in patients with mature B-cell non-Hodgkin lymphoma.

In the randomized population from a study that included 35 patients (26 pediatric patients age 5 to less than 17 years) with previously treated mature B-cell non-Hodgkin lymphoma, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.

Hepatic Impairment:

Adult Patients with B-cell Malignancies: Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA^® in patients with severe hepatic impairment. In patients with mild or moderate impairment, reduce recommended IMBRUVICA^® dose and monitor more frequently for adverse reactions of IMBRUVICA^®.

Patients with cGVHD: Avoid use of IMBRUVICA^® in patients with total bilirubin level > 3x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering IMBRUVICA^® to patients with total bilirubin level > 1.5 to 3x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).

Please click here to see the full Prescribing Information.

PRC-09614 09/22

References

1. IMBRUVICA^® data on file.
2. Calquence^® Prescribing Information. https://www.azpicentral.com/calquence/calquence.pdf
3. Seymour EK. Rapid transitions in the standard of care for chronic lymphocytic leukemia (CLL). Oncotarget. 2019;10(26):2484-2485. Published 2019 Apr 2. doi:10.18632/oncotarget.26826
4. Jain N, OʼBrien S. The shifting paradigm in chronic lymphocytic leukemia: is chemotherapy still relevant?. Cancer J. 2019;25(6):374-377. doi:10.1097/PPO.0000000000000417
5. IMBRUVICA^® Prescribing Information. https://www.imbruvica.com/files/prescribing-information.pdf
6. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi:10.1056/nejmoa1400376
7. Burger J., Barr P., et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. doi: 10.1038/s41375-019-0602-x. Epub 2019 Oct 18. PMID: 31628428; PMCID: PMC7214263.
8. Shanafelt, T., et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. August 1, 2019. https://www.nejm.org/doi/full/10.1056/NEJMoa1817073. Accessed June 2021.
9. Gogia A, Gupta R, Kumar L, Sharma A, Soni L. Chronic lymphocytic leukemia with deletion 17p: an Indian scenario. South Asian J Cancer. 2019;8(1):40. doi:10.4103/sajc.sajc_287_18
10. Gaidano G, Rossi D. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematology Am Soc Hematol Educ Program. 2017;2017(1):329-337. doi:10.1182/asheducation-2017.1.329
11. Campo E, Cymbalista F, Ghia P, et al. TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics. Haematologica. 2018;103(12):1956-1968; https://doi.org/10.3324/haematol.2018.187583.
12. Referenced with permission from the NCCN^® Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V2.2022. ^© National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed October 15, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN^® makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
13. Wierda WG, Byrd JC, Abramson JS, Bilgrami SF, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 4. 2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(2):185-217.
14. Sharma M, Holmes HM, Mehta HB, et al. The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer. Cancer. 2019;125(7):1155-1162. doi:10.1002/cncr.31917
15. Conte C, Bourrel R, Despas F, et al. Is there overuse of proton pump inhibitors in B-cell non-Hodgkin lymphomas? A cohort study based on the French health insurance database in the Midi-Pyrénées region. Fundam Clin Pharmacol. 2019;33(3):327-338.