The approval of ibrutinib over a decade ago introduced Bruton tyrosine kinase (BTK) inhibition as a foundational, chemotherapy-free treatment approach for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). A continuous single-agent BTK inhibitor (BTKi) or a time-limited B cell lymphoma 2 inhibitor (BCL2i)-based regimen plus an anti-CD20 monoclonal antibody or BTKi is now standard of care for CLL/SLL. Although ibrutinib offers durable remission for many patients, its use is limited by side effects associated with inhibition of kinases other than BTK (off-target effects). The second-generation BTKi zanubrutinib was developed to provide sustained BTK inhibition with greater selectivity for BTK in order to improve clinical efficacy and tolerability with minimized off-target effects. The head-to-head ALPINE study of patients with relapsed/refractory (R/R) CLL/SLL demonstrated superior efficacy with zanubrutinib versus ibrutinib, with superior overall response rates and prolonged progression-free survival (PFS), while acalabrutinib demonstrated non-inferior PFS outcomes versus ibrutinib in patients with high-risk R/R CLL/SLL. Data also showed improved safety outcomes with zanubrutinib versus ibrutinib with significantly lower rates of atrial fibrillation/flutter, and infection, and a trend toward lower rates of other adverse events associated with ibrutinib, with the exception of neutropenia. This is reflected in treatment guidelines for CLL, where zanubrutinib and the other approved second-generation BTKi, acalabrutinib, are recommended over ibrutinib owing to their superior safety profiles (particularly reduced cardiotoxicity). In this review, we consider the pharmacologic properties of zanubrutinib that differentiate it from ibrutinib and acalabrutinib, and provide a comprehensive overview of the efficacy and safety data that led to zanubrutinib monotherapy becoming a preferred therapy for a significant subgroup of patients with CLL/SLL. We also highlight trials in CLL/SLL and Richter’s transformation with zanubrutinib in targeted therapy combinations that offer the potential for time-limited treatment courses.
PurposeSeveral anticancer drugs can cause chemotherapy-induced peripheral neurotoxicity (CIPN) in approximately 70% of patients; of these, 30% continue to have chronic symptoms hampering quality of life. As more people live with and beyond cancer therapy, it is becoming increasingly important for clinicians to assess those at higher risk of CIPN and provide care for managing CIPN severity. Biomarkers could be appropriate in this regard. However, an initial step towards biomarker-informed care is to advance scientific knowledge regarding the potential of current biomarkers such as neurofilament light chain (NfL). Here, outcomes of a CIPN biomarker workshop and discussions among clinical and scientific experts held during the MASCC 2024 annual conference are reported. The aims of this work are to (1) identify knowledge gaps regarding the potential for serum NfL (sNfL) as a predictive CIPN biomarker, (2) provide guidance for future biomarker research, and (3) explore whether sNfL is ready for use in clinical practice.MethodsConsensus of the experts was gained using a Normative Group Technique. A two-stage iterative approach was used: Stage 1 involved a literature review and an in-person workshop; Stage 2 involved a virtual zoom event to confirm understanding and priorities following the workshop.ResultsEleven studies identified that increases in serum NfL after receiving 2-3 chemotherapy doses are associated with CIPN severity post treatment. Despite preliminary evidence suggesting positive correlations among sNfL and CIPN objective and subjective measures, wide variation in sNfL levels, the prescribed neurotoxic chemotherapy agent, dose and schedule, and symptom assessment time points make it difficult to use sNfL as a predictor of CIPN severity.ConclusionsWhile there is potential for sNfL to be a useful biomarker, larger scale research exploring the predictive value is needed before sNfL can be used to inform clinical decision-making. Identifying links with validated clinical assessments could be utilized to enhance biomarker accuracy and to address the multiple pathological mechanisms of neurotoxicity that occur from the differing chemotherapies. Moreover, workshop participants identified significant barriers to biomarker implementation (e.g. costs, long processing time, and unknown cut off points).
BACKGROUND:The SOUND trial, published in 2023, demonstrated the oncologic safety of sentinel lymph node biopsy (SLNB) for select patients with early-stage breast cancer. We evaluated whether earlier awareness of the results of the SOUND trial was associated with increased intent to implement SLNB omission. METHODS:This multicenter, cross-sectional study surveyed North American physicians on current SLNB use, awareness of the SOUND trial results, and intent to implement trial findings. Intent was measured using the Innovation-Specific Implementation Intentions scale and scenario-based questions (ages 50 vs 60; whole- vs partial-breast irradiation), on a 5-point scale. The primary outcome was high intent to omit SLNB ("moderate" to "very great" extent). Multiple logistic regression identified factors associated with intent. RESULTS:The response rate was 21% (208/1004): 148 (71.5%) surgeons, 32 (13.04%) medical and 27 (15.46%) radiation oncologists. Overall, 47.8% had already omitted SLNB in select patients aged < 70 years, and 63.6% reported high intent to use SOUND results. Among those who had not yet omitted SLNB (n = 108), 59.3% had high intent. Length of awareness of the SOUND trial (odds ratio 1.13) and practicing in Northeast USA vs Western USA (odds ratio 3.45, p = 0.032) were associated with increased intent to omit SLNB. In scenario-based questions, most endorsed omission for a 60-year-old patient receiving whole-breast irradiation (n = 105 [50.5%]); willingness decreased for a 50 year old or when partial-breast irradiation was planned. Across scenarios, intent was not associated with SOUND awareness duration, clinician characteristics, or referral workflows. CONCLUSIONS:Earlier awareness of the SOUND trial and regional differences were associated with greater intent to omit SLNB.
BackgroundThe Lynch syndrome INtegrative Epidemiology And GEnetics (LINEAGE) consortium was established to address gaps in understanding genotype-specific cancer risks and risk-modifiers in contemporary North American Lynch syndrome (LS) populations. LINEAGE is a multi-center, longitudinal cohort to systematically collect data on risk factors, adherence to care, quality of surveillance, and patient-, provider-, and system-level factors associated with incident LS-associated cancers.MethodsLINEAGE recruits individuals with confirmed pathogenic or likely pathogenic variants in LS-associated genes from participating institutions. Data includes retrospective and prospective collection, encompassing clinical abstraction (demographics, surgical history, endoscopic data, treatments), patient-reported surveys (behavioral/lifestyle factors, quality of life, procedures), endoscopist-level data, and biosample metadata. A standardized REDCap database, data harmonization protocols, and a virtual biobank support reproducibility and linkage of clinical data and biosamples. Rigorous quality assurance/quality control processes are embedded for data integrity.ResultsParticipating centers will contribute data to determine gene-specific risks, and gene-environment interactions for Lynch-associated, and other cancers. We will evaluate associations with exposure to, and quality of cancer risk-reduction care, including endoscopic surveillance, risk-reduction surgery, and chemoprevention. The inclusion of provider-level variables, such as endoscopist training and experience, enables unique research into modifiers of post-endoscopy cancer risk. The linked biosample resources will further facilitate mechanistic studies and biomarker discovery.ConclusionsLINEAGE provides a robust platform for advancing LS research by integration of clinical, pathological, epidemiological and genetic data across institutions. Its standardized, collaborative framework enhances the validity and generalizability of risk estimates that will guide decision-making and policy for surveillance to ultimately reduce morbidity and mortality for individuals with Lynch syndrome.
LBA109 Background: Although PD-1/PD-L1 inhibitors plus chemo have expanded treatment options for previously untreated PD-L1–positive advanced TNBC, there still remains a critical unmet need to improve outcomes. SG previously demonstrated significant clinical benefit in pretreated metastatic TNBC (mTNBC). We report results from the ASCENT-04/KEYNOTE-D19 study in patients with previously untreated, PD-L1–positive (CPS ≥ 10; 22C3 assay) locally advanced unresectable or mTNBC. Methods: Patients were randomized 1:1 to SG (10 mg/kg IV, day 1 & 8) + pembro (200 mg, day 1, max 35 cycles) in 21-day cycles or chemo (gemcitabine + carboplatin, paclitaxel, nab-paclitaxel) + pembro until disease progression or unacceptable toxicity. Randomization was stratified by curative treatment-free interval, geography, and prior exposure to anti–PD-(L)1 therapy in the curative setting. Primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Key secondary endpoints include overall survival (OS); objective response rate (ORR) and duration of response (DOR) by BICR; and safety. Results: 443 patients were randomized at a 1:1 ratio: 221 to SG + pembro and 222 to chemo + pembro. The median follow-up was 14 mo. SG + pembro showed a significant improvement in PFS by BICR compared with chemo + pembro (hazard ratio [HR], 0.65; 95% CI, 0.51-0.84; P = .0009; Table). Median DOR was 16.5 mo for SG + pembro vs 9.2 mo for chemo + pembro (Table). Although OS data were immature, a positive early trend in OS improvement was also noted. The most frequent (≥ 10% of patients) grade ≥ 3 treatment-emergent adverse events (TEAEs) with SG + pembro were neutropenia (43%) and diarrhea (10%); and with chemo + pembro were neutropenia (45%), anemia (16%), and thrombocytopenia (14%). Conclusions: SG + pembro led to a statistically significant and clinically meaningful improvement in PFS vs chemo + pembro with durable responses, no new safety concerns for SG or pembro, and a lower rate of treatment discontinuation due to TEAEs in patients with previously untreated, PD-L1–positive advanced TNBC. These data support the use of SG + pembro as a potential new standard of care treatment in this patient population. Clinical trial information: NCT05382286 . Efficacy, BICR, intent-to-treat SG + pembro(n = 221) Chemo + pembro(n = 222) Median PFS (95% CI), mo 11.2 (9.3-16.7) 7.8 (7.3-9.3) HR (95% CI); P -value (adjusted for randomization stratification factors) 0.65 (0.51-0.84); P = .0009 ORR (95% CI), % 59.7 (52.9-66.3) 53.2 (46.4-59.9) Median DOR (95% CI), mo 16.5 (12.7-19.5) 9.2 (7.6-11.3) Safety (TEAEs), all treated, n (%) n = 221 n = 220 Any grade; grade ≥ 3 220 (> 99); 158 (71) 219 (> 99); 154 (70) Led to dose reduction 78 (35) 96 (44) Led to any treatment discontinuation 26 (12) 68 (31)
