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BTK Inhibitors: In-Focus

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Sergio A. Giralt MD, is a medical oncologist focusing on on bone marrow transplant, multiple myeloma, leukemia, and lymphoma at  Memorial Sloan Kettering Cancer Center.

Sergio A. Giralt, MD, discusses how to determine which patient is a candidate for transplant and the optimal time to perform a transplant in patients with myelodysplastic syndrome.

Giralt on MDS Transplant Timing and Candidacy

Sergio A. Giralt, MD, discusses the current indications for considering stem cell transplants in patients with myelodysplastic syndrome.

Risk Factors and Indications for Stem Cell Transplants in MDS

The biologics license application (BLA) of the subcutaneous formulation of nivolumab (Opdivo) coformulated with human hyaluronidase (rHuPH20) has been accepted by the FDA.

Findings from the CheckMate -67T (NCT04810078) support this BLA of subcutaneous nivolumab as the trial met its coprimary pharmacokinetic end points and key secondary end point of overall response rate (ORR) vs intravenous (IV) nivolumab in clear cell renal cell carcinoma.

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date for December 29, 2024.

The FDA has accepted the BLA of the subcutaneous formulation of nivolumab coformulated with rHuPH20, also known as subcutaneous nivolumab, for all previously approved adult solid tumor indications of nivolumab as a monotherapy, monotherapy maintenance following completion of the combination therapy with nivolumab plus ipilimumab (Yervoy), or in combination with chemotherapy or cabozantinib (Cabometyx).

Results from the phase 3 CheckMate -67T trial of subcutaneous nivolumab support this application. In the trial, experts sought to evaluate subcutaneous nivolumab vs its intravenous (IV) formulation.

 Here, the subcutaneous form demonstrated noninferior pharmacokinetics and efficacy, as well as consistent safety compared with the IV formulation of nivolumab among patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have received prior systemic therapy.

A PDUFA goal date has been set for December 29, 2024. With this, subcutaneous nivolumab shows promise to become the first and only subcutaneously administered PD-1 inhibitor.

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” said Gina Fusaro, PhD, vice president, global program lead, Bristol Myers Squibb, in a press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as IV [nivolumab] but with the improved convenience of an injection administered in 3 to 5 minutes rather than a 30- to 60-minute infusion,” Fusaro continued.

The phase 3, randomized, open-label CheckMate -67T trial is exploring subcutaneous administration of nivolumab coformulated with rHuPH20 vs IV nivolumab for the treatment of patients with advanced or metastatic ccRCC who were previously treated with systemic therapy.

In the study, 495 patients were randomly assigned to receive either subcutaneous nivolumab or IV nivolumab. Enrollment was open to patients with a histological confirmation of ccRCC, advanced RCC not amenable to curative or radiation therapy, metastatic RCC, those who received no more than 2 prior systemic therapies, those with intolerance or progression after last treatment regimen within 6 months of randomization, and those with a Karnofsky performance score ≥ 70 at screening.

Experts assessed the coprimary end points of time-averaged serum concentration over 28 days and trough serum concentration at steady-state of subcutaneous nivolumab vs IV nivolumab. A key secondary end point of the trial was ORR.

The study met its coprimary pharmacokinetic end points and key secondary end point of ORR with subcutaneous nivolumab in this patient population.

 Subcutaneous nivolumab was noninferior in regard to time-averaged nivolumab serum concentration over 28 days and steady-state trough serum concentration vs treatment with IV nivolumab. Additionally, subcutaneous nivolumab also demonstrated a noninferior ORR compared with IV nivolumab.

1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. 

2. Phase 3 Check-Mate -67T trial of subcutaneous nivolumab (nivolumab and hyaluranisade) meets co-primary end points in advanced or metastatic clear cell renal cell carcinoma. News release. Bristol Myers Squibb. October 19, 2024. Accessed May 6, 2024. 

3. A study of subcutaneous nivolumab versus intravenous nivolumab in participants with previously treated clear cell renal cell carcinoma that is advanced or has spread (CheckMate-67T). ClinicalTrials.gov. Updated October 12, 2023. Accessed May 6, 2024. 

https://www.clinicaltrials.gov/study/NCT04810078

The FDA is considering a subcutaneous nivolumab formulation for various solid tumors based on promising data from the phase 3 CheckMate -67T trial. A target action date has been set for December 29, 2024.

News

Clinical

FDA Accepts BLA for Subcutaneous Nivolumab Across Various Solid Tumors

A real-world study showed that treatment with zanubrutinib (Brukinsa) correlated with lower rates of switching agents and subsequent therapy vs other Bruton tyrosine kinase (BTK) inhibitors like acalabrutinib (Calquence) and ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

 showed that irrespective of whether patients were treated with a BTK inhibitor in the first or second line, the switching rate at 60 days or less and 61 to 89 days was lower for patients receiving zanubrutinib compared with those receiving acalabrutinib and ibrutinib (for both first and second line, 

In the first-line setting, the rate of patients switching therapies before 90 days was 10.2% for zanubrutinib (n = 157) compared with 20.5% for acalabrutinib (n = 1238) and 15.9% for ibrutinib (n = 1421). In the second-line setting, the switch rate before 90 days was 7.5% for zanubrutinib (n = 107), 13.2% for acalabrutinib (n = 672), and 21.1% for ibrutinib (n = 474).

“This study highlighted the real-world advantages of zanubrutinib compared [with] other BTK inhibitors in patients with CLL/SLL,” lead study author Javier Pinilla-Ibarz, MD, PhD, and colleagues, wrote in a poster presentation of the data. “Future studies with extended follow-up are necessary to facilitate evaluation of emerging therapies and to assess long-term real-world outcomes.”

Pinilla-Ibarz is a senior member and head of Lymphoma Section in the Department of Malignant Hematology at Moffitt Cancer Center in Tampa, Florida.

The retrospective study utilized the Integra Connect database, which includes electronic medical records from community-based oncology practices, to evaluate real-world switching and sequencing to next-line therapies among patients with CLL or SLL initiating BTK inhibitors in the first-line or second-line setting.

The study period spanned from December 1, 2019, to March 31, 2023, with an index period between January 1, 2020, and February 28, 2023. Investigators gathered data for patients at least 18 years of age with CLL or SLL who initiated treatment with acalabrutinib, ibrutinib, or zanubrutinib during the index period.

On the study, a total of 2816 patients initiated first-line BTK inhibitor therapy; 1253 patients began second-line treatment. In the first-line setting, ibrutinib was the most frequently used BTK inhibitor (50.5%), followed by acalabrutinib (44.0%) and zanubrutinib (5.6%). In the second-line setting, acalabrutinib was most commonly used (53.6%), followed by ibrutinib (37.8%) and zanubrutinib (8.54%).

Demographic and clinical characteristics were assessed at baseline, and study authors noted that there were no significant differences in age, sex, payer type, or Rai stage among the 3 cohorts. The median follow-up duration in the first-line setting was 123 days (interquartile range [IQR], 63-335) for zanubrutinib, 406 days (IQR, 196-659) for acalabrutinib, and 637 days (IQR, 326-921) for ibrutinib (

 <.0001). In the second-line setting, median follow-up durations were 133 days (IQR, 62-385) for zanubrutinib, 503 days (IQR, 265-799) for acalabrutinib, and 524 days (IQR, 259-856) for ibrutinib (

Treatment switching was measured by identifying patients who initiated another treatment within the same line or advanced to the next line of therapy within 90 days. Sequencing to the next line of therapy was calculated using Kaplan-Meier analysis, and the proportion of patients receiving the next line of therapy at 180 days was reported.

Additional data showed the switching rates before 60 days in the first-line setting were 10.2% for zanubrutinib, 17.1% for acalabrutinib, and 13.1% for ibrutinib. The respective switching rates from 61 to 89 days were 0%, 3.4%, and 2.5%. In the second-line setting, the switching rates before 60 days were 7.5% for zanubrutinib, 10.7% for acalabrutinib, and 17.1% for ibrutinib. The switching rates from days 61 to 89 were 0%, 2.5%, and 4.0%, respectively.

The proportion of patients who received their next line of therapy at 180 days was lowest for those treated with zanubrutinib. In the first-line setting, 13.9% of patients treated with zanubrutinib received next-line therapy by day 180 compared with 24.5% of patients treated with acalabrutinib and 21.1% of patients treated with ibrutinib. In the second-line setting, these rates were 9.1% for zanubrutinib, 18.6% for acalabrutinib, and 29.2% for ibrutinib.

Authors noted that the study was limited by a United States–based population, which may not be applicable to all patient populations. They also explained data may be limited by the real-world nature of the study.

Pinilla-Ibarz J, Xue M, Wu E, et al. Real-world treatment switching and sequencing to next line of therapy of zanubrutinib, acalabrutinib, and ibrutinib in CLL/SLL. Presented at: 2024 SOHO Annual Meeting; September 4-7, 2024; Houston, TX. Abstract CLL-354.

Findings from a real-world study showed that zanubrutinib was associated with lower rates of treatment switching and patients receiving subsequent therapy compared with acalabrutinib and ibrutinib in patients with CLL or SLL. 

Canonical

Conference News

In CLL/SLL, Zanubrutinib Linked to Lower Switch Rates vs Other BTK Inhibitors

Ferrajoli’s Highlights From SOHO 2024 on CLL Therapy

Alessandra Ferrajoli, MD, hematologist/oncologist, associate professor of medicine, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the session she was a part of at the 2024 Society of Hematologic Oncology Annual Meeting.

Here, she highlights some of the key takeaways for oncologists treating patients with chronic lymphocytic leukemia based on the presentation.

 We had the pleasure of reviewing how to manage toxicities with targeted therapy in patients with chronic lymphocytic leukemia, and we went and reviewed how we manage toxicity and the relevant toxicity and components that we look at when we treat patients with BCL2 inhibitors. That was the first presentation by Barbara F. Eichhorst, MD. And then we moved to the [Bruton’s tyrosine kinase (BTK) inhibitors, and that was from Lydia Scarfò, MD. And then, because now things are really moving in the combination field, where we use both targeted therapy, BCL2 targeted and BTK targeted therapy together, we then had Catherine C. Coombs, MD, gave us a review regarding combinations.

 There were some important points that were presented. There was very interesting data that compared all the different [adverse] effects with all the targeted therapy that were presented by Dr. Eichhorst, and showed how maybe some BTK may be a little bit better tolerated than others. Definitely the second-generation seems to have less toxicity than the first-generation. But also, she gave some tips on how to handle patients that present with a very high white [blood cell] count. She presented that experience with bendamustine to reduce the white count, and I think that was particularly important.

Then when we moved to the combos, there was also very nice data showing how most of the combination trials that use both BTK inhibitors and BCL2 inhibitors, and sometimes even with the third element of an anti-CD20 monoclonal antibodies, as long as you monitor for neutropenia, that seems to be the most common toxicity, are actually very well-tolerated too.

Alessandra Ferrajoli, MD, discusses the session she was a part of at the 2024 Society of Hematologic Oncology Annual Meeting. 


A higher early overall response rate (ORR) was observed with first-line abemaciclib (Verzenio) with endocrine therapy (ET) vs paclitaxel in patients with hormone receptor (HR)-positive/HER2-negative advanced breast cancer with aggressive disease characteristics, according to findings from the phase 2, randomized ABIGAIL study (NCT04603183) presented at the 2024 ESMO Congress.

The study included 162 patients from 29 sites between June 2021 and January 2024. Patients were randomly assigned 1:1 to arm A to receive abemaciclib plus letrozole or fulvestrant (n = 80; 72.5% letrozole) or arm B (n = 82) to receive paclitaxel. The primary end point of the study was met in the intent-to-treat population as the 12-week ORR in arm A was 58.8% and 40.2% in arm B (odds ratio, 2.11; 95% CI, 1.13-3.96; 

For safety at 12 weeks, the toxicity profile was as expected with each treatment strategy. Patients had better or similar tolerance with the combination of abemaciclib plus ET, except for diarrhea of any grade at 68% with abemaciclib plus ET vs 23% with paclitaxel.

“The ABIGAIL trial demonstrated abemaciclib combined with ET showed superior efficacy after 12 weeks compared [with] the standard chemotherapy as a frontline treatment strategy for [patients with] HR-positive, HER2-negative advanced breast cancer with aggressive disease characteristics,” explained Juan De la Haba Rodriguez, MD, Maimónides Institute of Biomedical Research, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain, during an oral presentation of the data.

Looking at safety, any-grade treatment-emergent adverse events (TEAEs) seen in 10% of patients or more in the abemaciclib plus ET vs paclitaxel arms included neutropenia (27% vs 29%), anemia (16% vs 26%), leukopenia (3% vs 11%), asthenia (37% vs 48%), alopecia (5% vs 39%), nausea (25% vs 18%), neurotoxicity (0% vs 28%), constipation (8% vs 14%), decreased appetite (13% vs 9%), and neuropathy peripheral (0% vs 11%). Grade 3 or greater TEAEs seen in both arms consisted of neutropenia (9% vs 13%), diarrhea (3% vs 1%), and asthenia (3% vs 1%).

While one standard first-line treatment for patients with HR-positive/HER2-negative advanced breast cancer remains a CDK4/6 inhibitor given with ET, chemotherapy given as induction treatment is often used for patients who are at risk of rapid progression. The ABIGAIL trial sought to challenge chemotherapy induction prior to starting an ET-based therapy approach in this patient population.

The open-label, multicenter, non-inferiority study enrolled adult patients with HR-positive/HER2-negative advanced breast cancer. Inclusion in the study was open to patients who had received no prior systemic therapy for their advanced breast cancer, those who had measurable disease, an ECOG performance status of 0 or 1, and 1 or more aggressive disease criteria.

Patient characteristics were balanced between arms and the median age of patients included was 58 years (range, 26-85). In the abemaciclib plus ET arm, 65% of patients had an ECOG performance status of 0 compared with 63.4% in the paclitaxel arm. Further, 64% of patients had visceral disease present, 36% had 3 or more metastatic sites, and 36.2% in the abemaciclib plus ET arm and 28.1% in the paclitaxel arm had de novo advanced breast cancer.

In arm A, patients received oral abemaciclib at a dose of 150 mg twice a day in 28-day cycles plus letrozole given orally at a dose of 2.5 mg a day or fulvestrant via intramuscular injection at a dose of 500 mg on days 1, 15, 29, and once monthly thereafter, at investigator criteria. In arm B, intravenous paclitaxel at a dose of 90 mg/m2 was given to patients on days 1, 8, and 15 every 28 days for 12 weeks. This was followed by abemaciclib with ET. The stratification factor was the presence of visceral disease.

In addition to the primary end point of 12-week ORR as per blinded independent central review using RECIST 1.1, a key secondary end point evaluated was safety.

The study is ongoing with investigators continuing to assess the long-term efficacy, as well as other secondary end points like progression-free survival.

de la Haba-Rodriguez J, Cortés J, Di Cosimo S, et al. ABIGAIL: Randomized phase II study of abemaciclib plus endocrine therapy (ET) with or without a short course of induction paclitaxel in patients (pts) with previously untreated HR-positive/HER2-negative advanced breast cancer (HR+/HER2- ABC) with aggressive disease criteria. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA23.

Superior efficacy at 12 weeks was seen with the frontline combination of abemaciclib and endocrine therapy vs standard chemotherapy in patients with advanced breast cancer.

Abemaciclib With ET Outperforms Chemotherapy in Advanced Breast Cancer

Ribociclib (Kisqali) plus nonsteroidal aromatase inhibitor (NSAI) therapy led to sustained improvements in invasive disease-free survival (iDFS) and distant disease-free survival (DDFS) vs NSAI alone in patients with hormone receptor (HR)-positive, HER2-negative early breast cancer, according to 4-year landmark analysis results from the phase 3 NATALEE trial (NCT03701334) presented at the 

2024 European Society for Medical Oncology (ESMO) Congress.

With a median follow-up of 44.2 months across the intent-to-treat (ITT) population, the 3-year iDFS rates were 90.8% with ribociclib plus NSAI vs 88.1% with NSAI alone, representing a difference of 2.7%. At 4 years, the respective iDFS rates were 88.5% vs 83.6%; a difference of 4.9% (HR, 0.715; 95% CI, 0.609-0.840; 

Of note, most iDFS events in each arm were associated with distant recurrence (6.9% vs 9.6%). The iDFS benefit with the ribociclib-based combination also extended across all key prespecified subgroups based on characteristics such as menopausal status, prior chemotherapy, region, and prior endocrine therapy.

In terms of specific subgroup data, the iDFS rates among patients with stage II disease were 94.4% vs 92.7% at 3 years with a change of 1.7% and 93.9% vs 89.6% at 4 years with ribociclib/NSAI vs NSAI alone with a change of 4.3%, respectively (HR, 0.644; 95% CI, 0.468-0.887). Among those with stage III disease, the respective 3-year iDFS rates were 88.3% vs 84.8% with a change of 3.5%, and the 4-year rates were 84.3% vs 78.4% with a change of 5.9% (HR, 0.737; 95% CI, 0.611-0.888).

Regarding nodal status, the 3-year iDFS rates among patients with N0 disease were 93.4% vs 90.8% with a change of 2.6% with ribociclib/NSAI vs NSAI alone, respectively; the 4-year rates were 92.1% vs 87.0% with a change of 5.1% (HR, 0.666; 95% CI, 0.397-1.118). For those with N1 to N3 disease, the 3-year iDFS rates were 90.4% vs 87.7% with a change of 2.7%, and the 4-year rates were 88.0% vs 83.0% with a change of 5.0% (HR, 0.731; 95% CI, 0.617-0.866).

“The results continue to support the benefit of adding 3 years of ribociclib to adjuvant [NSAI] in this broad population of 

HR-positive, HER2-negative early breast cancer

 at risk of recurrence,” study author Peter A. Fasching, MD, an associate professor of Gynecology and Obstetrics Translational Medicine at the University Hospital Erlangen and Comprehensive Cancer Center Erlangen-EMN in Germany, said in a presentation on these data.

In the NATALEE trial, 5101 patients were randomly assigned to receive ribociclib at 400 mg daily as part of a 3-weeks-on, 1-week-off schedule for 3 years plus NSAI (n = 2549) or NSAI alone (n = 2552). Treatment with NSAI consisted of letrozole (Femara) or anastrozole (Arimidex) for at least 5 years plus goserelin (Zoladex) for male patients and female patients who are premenopausal.

The trial’s primary end point was iDFS based on Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials criteria. Secondary end points included DDFS, recurrence-free survival, overall survival (OS), and safety and tolerability.

Adult patients with HR-positive, HER2-negative early breast cancer were eligible for enrollment on the trial. Those with prior endocrine therapy at 12 months or earlier prior to randomization were able to enroll. Investigators stratified patients based on anatomical stage, menopausal status, receipt of previous chemotherapy, and geographic location.

As of the data cutoff, 62.8% of patients in the experimental arm completed 3 years of treatment with ribociclib. Of note, 36.2% of patients discontinued treatment with ribociclib early, with 20.0% discontinuing due to adverse effects (AEs). The median duration of exposure to study therapy was 45.1 months in the ribociclib/NSAI arm compared with 45.0 months in the NSAI alone arm.

Data showed that treatment with ribociclib/NSAI produced enduring DDFS improvements compared with NSAI alone (HR, 0.715; 95% CI, 0.604-0.847; 

 <.0001) as well as a positive trend associated with OS (HR, 0.827; 95% CI, 0.636-1.074; 

 = .0766). Fasching noted that follow-up for OS is still ongoing.

Any-grade AEs of special interest (AESIs) in the ribociclib/NSAI arm and NSAI alone arm included neutropenia (62.8% vs 4.5%), arthralgia (38.8% vs 44.4%), liver-related toxicity (26.7% vs 11.4%), and nausea (23.5% vs 7.9%). The most common grade 3 or higher AESI in the ribociclib arm was neutropenia (44.4%). AEs associated with the liver generally consisted elevated alanine aminotransferase or aspartate aminotransferase without accompanying increases in bilirubin.

Fasching PA, Stroyakovskiy D, Yardley DA, et al. Adjuvant ribociclib plus nonsteroidal aromatase inhibitor in patients with HR+/HER2– early breast cancer: 4-year outcomes from the NATALEE trial. Presented at the 2024 European Society for Medical Oncology Congress (ESMO); September 13-17, 2024; Barcelona, Spain. LBA13.

Sergio A. Giralt, MD

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