Ahn, Inhye E.

Introduction: Bruton tyrosine kinase (BTK) inhibitors are effective therapies for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Their use can be limited by intolerance and/or acquired resistance, due to BTK mutations. BGB-16673 is a bivalent small molecule that induces BTK degradation by binding specifically to BTK and the E3 ligase. The E3 ligase catalyzes the transfer of ubiquitin molecules to BTK which marks BTK for destruction by the proteasome. In preclinical models, BGB-16673 degraded wild-type and mutant forms of BTK associated with resistance to covalent and noncovalent BTK inhibitors, leading to tumor suppression. CaDAnCe-101 (BGB-16673-101, NCT05006716) is an ongoing, open-label, first-in-human, phase 1/2 study designed to evaluate BGB-16673 monotherapy in patients with B-cell malignancies. Here, updated results in patients with relapsed or refractory (R/R) CLL/SLL enrolled in the phase 1 portion are presented. Methods: Eligiblepatients must have confirmed R/R CLL/SLL (≥2 prior therapies), an ECOG performance status of 0-2, and adequate organ function. In the US, EU, and Australia, patients must have previously received a covalent BTK inhibitor (cBTKi). BGB-16673 was dosed once daily orally in 28-day cycles. Dose escalation used a Bayesian optimal interval design (6 planned dose levels, 50-600 mg once daily). Primary objectives were to assess safety/tolerability (CTCAE v5.0 and iwCLL hematologic toxicity criteria), and to establish the maximum tolerated dose (MTD) and the recommended phase 2 dose. Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks (cycle 1). A secondary objective was to evaluate the overall response rate (ORR, iwCLL 2018 criteria or 2014 Lugano criteria for SLL), with the first assessment occurring after 12 weeks of treatment. Results: As of May 24, 2024, 49 patients with CLL were enrolled and treated (50 mg, n=1; 100 mg, n=5; 200 mg, n=16; 350 mg, n=15; 500 mg, n=12). The median age was 70 years (range, 50-91 years), and the median number of prior therapies was 4 (range, 2-10), including prior cBTKis (n=45 [92%]), BCL2 inhibitors (n=42 [86%]), and noncovalent BTK inhibitors (ncBTKis; n=12 [24%]). Of tested patients, 63% (31/49) had del(17p) and/or TP53 mutation and 82% (32/39) had unmutated IGHV. The median follow-up was 7.9 months (range, 0.3-23.1 months). Ninety-six percent of patients reported any-grade treatment-emergent adverse events (TEAEs; grade ≥3, 57%), of which the most common (≥25%) were fatigue (35%; grade ≥3, 2%), contusion (29%; no grade ≥3), and diarrhea (27%; grade ≥3, 2%). The most common grade ≥3 TEAEs (≥10%) were neutropenia/neutrophil count decreased (20%) and pneumonia (10%). One patient (2%) each experienced hypertension (grade 1), febrile neutropenia (in the context of COVID-19 pneumonia and norovirus diarrhea), and major hemorrhage. No atrial fibrillation was observed. Three patients (6%) experienced a TEAE that led to dose reduction. One DLT occurred in 1 patient at 200 mg (grade 3 maculopapular rash on day 27; decreased to grade 1 after 5-day hold; patient continues on treatment). The MTD was not reached. Three patients had TEAEs that led to death (septic shock, bronchopulmonary aspergillosis/cerebral aspergillosis, and pneumonia in the context of disease progression; n=1 each); none of the deaths were considered related to treatment. In 49 response-evaluable patients, the ORR (partial response with lymphocytosis or better) was 78% (38/49), and the CR/CR with incomplete hematologic recovery rate was 4% (n=2). At 200 mg, the ORR was 94% (15/16) including the 2 CRs. Median time to first response was 2.8 months (range, 2.6-8.3 months). Seventeen patients remained on treatment for ≥9 months and all 17 have ongoing responses. Responses were seen at the lowest dose, as well as in patients previously treated with a cBTKi, ncBTKi, double- (cBTKi and BCL2i) and triple- (cBTKi, BCL2i, ncBTKi) exposed patients, and in patients with and without BTK mutations. Conclusions: Emerging data from this ongoing, first-in-human study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows promising and deep overall responses in heavily pretreated patients with R/R CLL/SLL, including those with prior BTK inhibitor treatment and BTK resistance mutations.

Abstract Background CLL International Prognostic Index (CLL-IPI) is a weighted scoring system combining five prognostic factors that was developed for risk stratification of TN CLL in the era of chemoimmunotherapy [CLL-IPI Working Group. Lancet Oncol 2016]. Recently, the four-factor model (CLL4) was validated in patients (pts) receiving ibrutinib, primarily for the treatment of relapsed or refractory CLL [Ahn et al. J Clin Oncol 2021]. Data on model performance are limited when ibrutinib is used as first-line therapy. Here we evaluated CLL4 and CLL-IPI in TN CLL pts aged 65 years or older in the Alliance A041202 trial (NCT01886872) [Woyach et al. N Engl J Med 2018]. Methods Pts were randomized to bendamustine plus rituximab (BR group) or ibrutinib-based therapy with or without rituximab (I/IR group). The CLL4 score was determined for individual pts by assigning 1 point each to the presence of TP53 aberration, β-2 microglobulin (B2M) ≥5 mg/L, elevated lactate dehydrogenase (LDH), and prior treatment, and summing over points; risk categories were low (0-1), intermediate (2), and high (3-4). We utilized the first three factors of CLL4 since all pts were previously untreated. The CLL-IPI score was determined based on the presence of TP53 aberration (4 points), B2M >3.5 mg/L (2 points), unmutated IGHV (2 points), age >65 years (1 point), and Rai stage I-IV (1 point), and summing over points; risk categories were low (0-1), intermediate (2-3), high (4-6), and very high (7-10). Two of five CLL-IPI risk factors contributed little information since all pts had Rai stage I-IV and nearly all had age >65 years. The primary endpoint for risk stratification was progression-free survival (PFS). We used Kaplan-Meier estimates and Cox proportional hazards models for analyses. Results Of 547 pts randomized, 472 pts had a complete set of data required for the calculation of CLL4 scores. The median age was 71 years, and 92% were older than 65 years. 12% had TP53 aberration including deletion 17p and TP53 mutation. Of 334 pts with known IGHV status, 61% had unmutated IGHV. The median follow-up for PFS was 4.5 years. In these 472 pts, 359 (76%) were low risk, 99 (21%) intermediate risk, and 14 (3%) high risk. In the BR group, PFS was significantly shorter for intermediate/high risk CLL4 than low risk (HR 2.43, 95% CI 1.55-3.79, p=0.0001). However, differences in PFS were less apparent for the I/IR group (HR 1.60, 95% CI 1.00-2.56, p=0.05). In 334 pts in whom CLL-IPI scores could be calculated, 6 (2%) were low risk, 38 (11%) intermediate risk, 262 (78%) high risk, and 28 (8%) very high risk. In the BR group, PFS was significantly shorter for high risk CLL-IPI than intermediate risk (HR 3.73, 95% CI 1.16-12.04, p=0.03) and for very high risk CLL-IPI than high risk (HR 6.05, 95% CI 2.80-13.08, p<0.0001). However, there were no significant PFS differences for the I/IR group (high risk CLL-IPI vs intermediate risk: HR 1.33, 95% CI 0.53-3.33, p=0.54; very high risk CLL-IPI vs high risk: HR 1.21, 95% CI 0.48-3.02, p=0.69). We next assessed individual components of the prognostic models in the 334 pt subset including both BR and I/IR groups (Table). Variables significantly associated with PFS were B2M, elevated LDH, and unmutated IGHV when controlling for the treatment group. In contrast, TP53 aberration conferred a poor prognosis in the BR group, but not in the I/IR group (interaction test, p=0.008), indicating first-line therapy with ibrutinib can improve the outcome of TP53 aberrant CLL to levels seen in pts without the aberration. In a multivariable model, the interaction between TP53 aberration and the treatment group remained significant. All adverse risk factors except elevated LDH maintained their independent prognostic value. Conclusions Neither CLL4 nor CLL-IPI effectively discriminated PFS of older adults receiving ibrutinib-based therapy for TN CLL. When given as a first-line treatment, ibrutinib can overcome the poor prognostic impact of TP53 aberration. IGHV mutation status and B2M had independent prognostic value in our dataset. Support: U10CA180821, U10CA180882, U24CA196171; Pharmacyclics, An AbbVie Company Clinicaltrials.gov identifier: NCT01886872 Figure 1 Figure 1. Disclosures Ruppert: Telios Pharma: Consultancy. Wiestner: Merck: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding; Nurix: Research Funding; Genmab: Research Funding. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Byrd: Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria. Stone: AbbVie: Consultancy; Jazz: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Janssen: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; Novartis: Consultancy, Research Funding; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; GlaxoSmithKline: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Boston Pharmaceuticals: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding.

Background : The presence of TP53 aberrations (defined as del(17p) or TP53 gene mutation) is a strong negative predictor of survival in patients (pts) with CLL. First-line chemoimmunotherapy is suboptimal in pts with CLL bearing TP53 aberrations, with 3-year progression-free survival (PFS) and overall survival (OS) rates of only 18% and 38%, respectively, with fludarabine, cyclophosphamide, and rituximab (Hallek, Lancet 2010). Ibrutinib is the only once-daily Bruton's tyrosine kinase (BTK) inhibitor with significant PFS and OS benefit demonstrated in multiple randomized phase 3 studies (eg, RESONATE-2, ECOG1912) in the first-line treatment of CLL/small lymphocytic lymphoma (SLL). Previous reports of single-agent ibrutinib or ibrutinib-based combination treatments have further demonstrated favorable PFS benefit in pts with TP53 aberrations in both the first-line and relapsed/refractory settings. Despite these study-specific subgroup analyses, there are limited data on long-term outcomes in pts with TP53 aberrations treated with first-line BTK inhibitors. We performed a pooled analysis of data across 4 studies to evaluate the long-term efficacy and safety of first-line ibrutinib-based therapy in pts with CLL bearing TP53 aberrations. Methods : Data for first-line ibrutinib treatment in pts with TP53 aberrations were pooled across 4 clinical trials in CLL/SLL: PCYC-1122e (NCT01500733; single-agent ibrutinib; n=34), PCYC-1130 (NCT02264574; ibrutinib + obinutuzumab; n=18), ECOG1912 (NCT02048813; ibrutinib + rituximab; n=26), and RESONATE-2 (NCT01722487; single-agent ibrutinib; n=11). ECOG1912 and RESONATE-2 excluded pts with del(17p) but did not exclude pts with TP53 mutations. Long-term PFS (assessed by investigator), OS, and safety are reported. Results : Eighty-nine pts with TP53 aberrations receiving first-line ibrutinib treatment were included in this pooled analysis. Median age was 65 years (range 33-87), and 69% of pts were male. At baseline, 53% had Rai stage III/IV, 38% had bulky disease (lymph nodes ≥5 cm), and 69% (of 87 evaluable) had unmutated IGHV. All patients had either del(17p) or TP53 mutation; 53% (of 89 evaluable) had del(17p) and 91% (of 58 evaluable) had TP53 mutation. Among 16 pts with del(17p) who had TP53 sequencing results available, 11 (69%) had both del(17p) and TP53 mutation. Forty-five pts received ibrutinib as a single agent and 44 received ibrutinib in combination with an anti-CD20 agent. With a median follow-up of 50 months (range 0.1 to 95.9 months), median PFS was not reached (95% CI: 67 months to not estimable; Figure 1A). At 48 months, the PFS rate was 79% and the OS rate was 88% (Figure 1B). Median duration of ibrutinib treatment was 46 months (range 0.1 to 95.5 months). Reasons for treatment discontinuation were progressive disease (20%), study closure (12%), adverse event (10%), withdrawal by pt (7%), death (3%), and other (physician decision due to scheduled pt surgery; 1%). Grade ≥3 adverse events of clinical interest with up to 8 years of treatment with ibrutinib were infection (22%; most commonly pneumonia in 7%), hypertension (13%), atrial fibrillation (12%), and major hemorrhage (7%). With the current follow-up, 46% of pts with TP53 aberrations remained on ibrutinib treatment. Conclusions : With a median follow-up of 4 years, first-line ibrutinib-based treatment resulted in sustained efficacy with high PFS and OS rates in CLL pts with TP53 aberrations, a population with historically poor outcomes. Although pts with TP53 aberrations remain at risk for progression, first-line treatment with ibrutinib has partially overcome the poor prognosis in this high-risk population with 4-year PFS and OS rates of 79% and 88%, respectively. No new safety signals were identified in this analysis. These results from a large, pooled, multi-study dataset demonstrated the long-term benefit of first-line ibrutinib-based treatment in pts with TP53 aberrations. Disclosures Allan: Janssen, AbbVie, and AstraZeneca: Other: Travel/accommodations/expenses; Celgene, Genentech, AstraZeneca, TG Therapeutics, and Janssen: Research Funding; AstraZeneca, Pharmacyclics LLC, an AbbVie Company, Genentech, AbbVie, Ascentage, and Cellectar: Consultancy; Janssen, AstraZeneca, and AbbVie: Honoraria. Shanafelt:Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding; Mayo Clinic: Patents & Royalties: and other intellectual property. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Moreno:Janssen, AbbVie, Sunesis, and AstraZeneca: Consultancy; AbbVie and Janssen: Research Funding; Janssen: Speakers Bureau. O'Brien:Eisai: Consultancy; Juno Therapeutics: Consultancy; Aptose Biosciences: Consultancy; GlaxoSmithKline: Consultancy; Sunesis: Research Funding; Acerta: Research Funding; Amgen: Consultancy; Celgene: Consultancy; Pfizer: Research Funding; Pharmacyclics: Research Funding; Astellas: Consultancy; Gilead: Consultancy; TG Therapeutics: Research Funding; Vida Ventures: Consultancy; KITE: Research Funding; Vaniam Group LL: Consultancy; Alexion: Consultancy; Regeneron: Research Funding; AbbVie: Consultancy; Verastem: Consultancy; Janssen Oncology: Consultancy. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Liu:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Dean:AbbVie: Current equity holder in publicly-traded company; Pharmacyclics LLC, an AbbVie Company: Current Employment. Lai:Pharmacyclics LLC, an AbbVie Company: Current Employment; AbbVie and Bristol-Myers Squibb: Current equity holder in publicly-traded company; AbbVie: Other: Travel/accommodations/expenses.

Key Points Early progression of disease within 2 years of initial therapy independently predicts inferior survival in CLL. Early progression of disease is a robust clinical end point and a useful posttreatment risk stratification tool.

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.