Calquence (acalabrutinib)

Introduction – We previously reported the efficacy and safety results of a combination of ibrutinib with rituximab in patients (pts) with mantle cell lymphoma (MCL) ≥ 65 years. Conclusions – Chemotherapy-free frontline therapy with AR is highly effective, safe, induces deep MRD negative responses and alters immune landscape in older pts with MCL. Randomized studies are needed to confirm whether this regimen can be the new first line standard treatment for older MCL patients.

Two pts were switched to zanubrutinib due to PD on U2, both achieved response. AU2 is a highly effective regimen in pts with previously untreated MCL, including those with high-risk genetics (100% CR rate), and achieves a high molecular uMRD rate. Pts who develop progressive disease can be effectively salvaged with subsequent therapies.

Acalabrutinib in combination with BR provides a significant PFS benefit in pts with previously untreated MCL, including those with high-risk features. Furthermore, the addition of acalabrutinib to BR provided a greater PFS effect among pts in the ABR arm with the longest exposure to acalabrutinib. The PFS improvement may be partially driven by the contribution of acalabrutinib to sustained MRD-negative status and deepened responses after the end of induction.

The combination of the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, the BCL-2 inhibitor venetoclax (V), and the anti-CD20 monoclonal antibody (mAb) obinutuzumab (O) has demonstrated safety and efficacy in R/R and TN MCL (Le Gouill, Blood 2021). AVO is safe and active in pts with R/R and TP53-aberrant/transplant ineligible TN MCL. Preliminary efficacy and feasibility of an MRD-guided treatment approach is encouraging in this high-risk TN cohort B. Our data supports further investigation of a targeted triplet approach, and the phase II TN transplant eligible and TP53 wild type cohort is enrolling based on demonstrated safety and efficacy in cohort B. Updated results will be presented at the meeting.

Responses are durable, with 89%, 87%, and 77% 4-yr PFS in all-comer, uIGHV, and TP53 aberrant pts. Our data support further study of AVO for pts with TN high risk CLL in GCLLSG CLL16 and future trials.

The combination of durvalumab and acalabrutinib showed encouraging preliminary clinical activity in a heavily pre-treated cohort with relapsed/refractory aggressive B-cell lymphoma. The combination was well tolerated and deliverable to a predominantly elderly and frail population and warrants further study in this context.

Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton’s tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439)... High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles.

This study demonstrates that the ALR regimen has high rates of durable complete and molecular responses, and is feasible as a time-limited initial therapy for patients with both TP53 wild type and mutant MCL. The ALO regimen is feasible with encouraging initial safety and efficacy. MRD and cfDNA analyses provide real-time and non-invasive monitoring of molecular response and mutational evolution, which warrants further evaluation in response-adapted strategy.

Introduction: Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts with previously untreated CLL. We observed a very high rate of BM U-MRD6 at 6-months and 12-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents.

P=N/A, N=104, Completed, AstraZeneca | Active, not recruiting --> Completed

P1/2, N=24, Recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P2, N=100, Not yet recruiting, VA Office of Research and Development | Trial completion date: Dec 2029 --> Dec 2030 | Trial primary completion date: Jun 2029 --> Jun 2030

P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Dec 2023 --> Dec 2026

P=N/A, N=67, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | N=50 --> 67

P1/2, N=50, Recruiting, University of Washington | Trial completion date: Mar 2030 --> Mar 2031 | Trial primary completion date: Mar 2025 --> Mar 2026

P=N/A, N=200, Recruiting, AstraZeneca | Trial completion date: Apr 2026 --> Oct 2026 | Trial primary completion date: Apr 2026 --> Oct 2026

The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling...To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation...In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.

P2, N=36, Recruiting, City of Hope Medical Center | Trial completion date: Sep 2024 --> Dec 2024 | Trial primary completion date: Sep 2024 --> Dec 2024

Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).

P4, N=60, Not yet recruiting, AstraZeneca

P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Jan 2025 --> Dec 2023

This study identified significant deficiencies in six functionally distinct DC subsets in blood of untreated CLL (UT-CLL) patients and selective normalization of pDCs in response to acalabrutinib (a Bruton tyrosine kinase inhibitor) therapy...Regarding clinical parameter, cDC subset deficiencies are associated with adverse prognostic indicators of disease progression, including IGHV mutation, CD49d, CD38, and ZAP-70 status. Importantly, UT-CLL patients with shared DC subset deficiencies had shorter time-to-first treatment (TTFT), uncovering a profound alteration in innate immunity with the potential to instruct therapeutic decision-making.

Tailored chemo-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different response spectra.

However, bendamustine + rituximab had a more favorable safety profile for grade ⩾3 AEs when compared with ibrutinib (risk ratio 0.62 (95% credible interval 0.40-0.86)), acalabrutinib (0.69 (0.45-0.94)), zanubrutinib (0.64 (0.42-0.91)), and venetoclax + rituximab (0.87 (0.79-0.96)). Our findings showed that venetoclax + rituximab, acalabrutinib, and zanubrutinib have acceptable safety profiles, which indicates that they may be the preferred therapeutic options in the setting of relapsed/refractory CLL. PROSPERO CRD42022304330.

P2, N=39, Completed, University of Rochester | Active, not recruiting --> Completed

P2, N=52, Recruiting, Ohio State University Comprehensive Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=9, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=30 --> 9

This study demonstrated high ORR in acalabrutinib-treated Chinese patients with R/R CLL with no unexpected safety concerns. This trial is registered on ClinicalTrials.gov (NCT03932331).

P1/2, N=180, Not yet recruiting, AstraZeneca

P2, N=108, Active, not recruiting, AstraZeneca | Trial completion date: Jan 2029 --> Jul 2028 | Trial primary completion date: Jan 2029 --> Jul 2028

However, withthe availability of ibrutinib, acalabrutinib, and zanubrutinib, limited dataexists to guide sequencing of BTKi therapy in the relapsed/refractory setting. Ongoing studies are pushing theenvelope, utilizing targeted drug combinations and minimal residual diseasemarkers as well as receptor tyrosine kinase-like orphan receptor 1 inhibitors, chimericantigen receptor T-cells and novel BTK degraders. However, zanubrutinibrepresents a strong contender in the arsenal of treatment options forrelapsed/refractory CLL.

P=N/A, N=15000, Active, not recruiting, University Hospital, Caen

P1, N=11, Active, not recruiting, Acerta Pharma BV | Trial completion date: Jun 2024 --> Aug 2026

P=N/A, N=120, Not yet recruiting, AstraZeneca

P3, N=120, Recruiting, AbbVie | Not yet recruiting --> Recruiting

P2, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=80, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P2, N=100, Not yet recruiting, VA Office of Research and Development

P1/2, N=63, Terminated, MingSight Pharmaceuticals, Inc | N=117 --> 63 | Trial completion date: Jun 2024 --> Nov 2023 | Recruiting --> Terminated | Trial primary completion date: Apr 2024 --> Nov 2023; The study is terminated due to major protocol revisions. A new study in CLL patients is planned.

P2, N=108, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting

P1, N=21, Recruiting, Washington University School of Medicine | Trial completion date: Oct 2030 --> Dec 2027 | Trial primary completion date: Jul 2025 --> Mar 2026

P2, N=40, Recruiting, City of Hope Medical Center | Initiation date: Jun 2024 --> Sep 2024