Introduction: Time-limited ibrutinib plus venetoclax (Ibr+Ven) demonstrated superior PFS, overall survival (OS), and time to next treatment (TTNT) vs chlorambucil plus obinutuzumab (Clb+O) in elderly or comorbid pts with untreated CLL in the GLOW study (Niemann et al. Lancet Oncol 2023). Longer FU provides insight into the sustained benefit of Ibr+Ven and the predictive clinical impact of IGHV status and minimal residual disease (MRD) at end of treatment (EOT). With various effective treatment (tx) options available in CLL, balancing overall benefit with AEs is important. As such, a tx-emergent AE (TEAE)-free PFS analysis provides a clinically meaningful assessment of tx benefit by capturing the time pts spend without significant toxicity or disease progression, offering a more comprehensive view of tx impact. Here we report clinical outcomes from the 64-mo FU of the GLOW study, including subgroup analysis by IGHV and MRD status, and an evaluation of grade 3/4 (G3/4) TEAE-free PFS benefit.

Methods: Elderly or comorbid pts with untreated CLL/small lymphocytic leukemia were randomized 1:1 to Ibr+Ven (3 cycles Ibr lead-in then 12 cycles Ibr+Ven, n = 106) or 6 cycles Clb+O (n = 105). MRD in peripheral blood was measured by next-generation sequencing 3 months post-EOT (EOT+3), with undetectable MRD (uMRD) defined as < 10-4. TEAEs were collected until 30 days after EOT; therefore, AE collection was longer for Ibr+Ven vs Clb+O (median exposure: Ibr+Ven, 13.8 mo vs Clb+O, 5.1 mo). AEs after this were not considered tx emergent unless specifically considered tx related by investigator. Outcomes reported include investigator-assessed PFS, TTNT, and OS. Additionally, TEAE-free PFS was assessed (using restricted mean survival time, based on G3/4 TEAEs only), including quantification of time spent in different health states (time with G3/4 TEAEs and G3/4 TEAE-free PFS).

Results: At a median FU of 64 mo, Ibr+Ven prolonged PFS, reducing the risk of progression or death by 73% vs Clb+O (HR 0.27 [95% CI, 0.18-0.39]; p < 0.0001); 60-mo PFS rates were 59.9% and 17.8% for Ibr+Ven and Clb+O, respectively. Ibr+Ven prolonged PFS independent of IGHV status (unmutated IGHV [uIGHV], HR 0.26 [95% CI, 0.17-0.42]; p < 0.0001; mutated IGHV [mIGHV], HR 0.24 [95% CI, 0.10-0.62]; p = 0.0014). Estimated 60-mo PFS rates in the Ibr+Ven arm were 52.2% and 82.5% for pts with uIGHV (n = 67) and mIGHV (n = 32), respectively. In the Ibr+Ven arm, PFS rates at 48 mo post tx were 69% in pts who achieved uMRD at EOT+3 (n = 58) and 61% in pts with detectable MRD (dMRD; n = 31). Among Ibr+Ven-treated pts with uIGHV, PFS rates at 48 mo post tx were 67% for those achieving uMRD at EOT+3 (n = 40) and 40% for those with dMRD (n = 16). For Ibr+Ven-treated pts with mIGHV, PFS rates at 48 mo post-tx were ≥ 84% regardless of MRD status (uMRD, n = 13; dMRD, n = 14).

Ibr+Ven prolonged TTNT and reduced risk of need for second-line (2L) therapy vs Clb+O in pts with uIGHV (HR 0.18 [95% CI, 0.09-0.36]; p < 0.0001); there was no difference in TTNT in pts with mIGHV (HR 1.20 [95% CI, 0.31-4.60], p = 0.7878). Ibr+Ven prolonged OS vs Clb+O, reducing relative risk of death by 54% (HR 0.46 [95% CI, 0.27-0.79]; p = 0.004); 60-mo OS rates were 81.6% and 60.8% for Ibr+Ven and Clb+O, respectively. OS rates were prolonged in pts with mIGHV (HR 0.22 [95% CI, 0.06-0.77]; p = 0.010), while a trend was seen in pts with uIGHV (HR 0.51 [95% CI, 0.26-1.02]; p = 0.052).

At 64-mo FU, the time pts spent without significant toxicity or progression (TEAE-free PFS) was significantly longer for Ibr+Ven vs Clb+O (52 vs 31 mo, respectively). TEAE-free PFS analysis showed that while pts receiving 15 mo of Ibr+Ven spent slightly more time in the G3/4 toxicity state vs pts receiving 6 mo of Clb+O (2 vs 1 mo), pts in the Ibr+Ven arm spent substantially more time in TEAE-free PFS (50 vs 30 mo). These results show a 20-mo improvement in TEAE-free PFS with Ibr+Ven vs Clb+Ob, indicating longer disease control without significant toxicity.

Conclusion: With 64-mo FU, Ibr+Ven continues to show superior PFS, reduced risk of requiring 2L tx, and sustained OS advantage vs Clb+O. Moreover, analysis integrating clinical benefits and risks shows improved survival time free from G3/4 toxicity or relapse for Ibr+Ven. This long-term FU of time-limited Ibr+Ven provides valuable insights into the combination's durable efficacy and tolerability profile, offering a robust foundation for informed clinical decision-making in pts with previously untreated CLL.

Disclosures

Niemann:AbbVie, Janssen, AstraZeneca, Novo Nordisk Foundation, Octapharma: Consultancy, Research Funding; Novo Nordisk: Research Funding; CSL Behring, Genmab, Takeda, Beigene, MSD, Lilly: Consultancy. Munir:Janssen, AbbVie, AstraZeneca, Alexion, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Owen:AbbVie, AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; Janssen, Roche, Merck, Gilead, Servier, Seattle Genetics, Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Follows:Roche, AbbVie, Janssen, Takeda, Eli-Lilly, AstraZeneca: Consultancy, Other: Lecturing. Hernandez Rivas:BMS-Celgene: Research Funding; Janssen, Roche, Abbvie, AstraZeneca, Beigene, Lilly, Gilead, BMS-Celgene, Amgen, Takeda, Jazz Pharmaceuticals, Rovi, Incyte, MSD: Membership on an entity's Board of Directors or advisory committees; Janssen, Roche, Abbvie, AstraZeneca, Gilead, BMS-Celgene, Amgen, Takeda, Astra Zeneca, Lilly, Beigene: Other: Scientific Talks. Janssens:AbbVie, AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie, AstraZeneca: Other: Travel; MSD: Consultancy; Amgen, Beigene, Janssen, Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; Eli lilly, Sobi: Other: Speaker; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Speaker; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levin:Janssen, AbbVie: Other: Travel. Robak:Lilly: Research Funding; Cilag: Consultancy, Research Funding; GSK: Honoraria; Regeneron: Honoraria; OctoPharma: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel funding, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Takeda: Research Funding; Johnson & Johnson: Consultancy, Other: Travel funding. Simkovic:Janssen-Cilag, AstraZeneca, AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel. Voloshin:Abbvie: Honoraria, Other: non-financial clinical trial support; Janssen: Honoraria, Other: non-financial clinical trial support; Novartis: Honoraria, Other: non-financial clinical trial support; Astra Zeneca: Honoraria; Sanofi: Honoraria; BieGene: Other: non-financial clinical trial support; BIOCAD: Other: non-financial clinical trial support. Ysebaert:AbbVie, AstraZeneca, Janssen, Roche, Beigene, BMS/Celgene, Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schuier:Janssen: Current Employment. Baeten:Janssen: Current Employment. Xu:Janssen: Current Employment. Tran:Janssen, Amgen: Current equity holder in publicly-traded company; Janssen: Current Employment. Levitan:Janssen: Current Employment, Current equity holder in publicly-traded company. Kavanagh:Janssen: Current Employment. Kater:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Patents planned, issued or pending; Steering Committee, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Research Funding; LAVA: Membership on an entity's Board of Directors or advisory committees, Other: Patents planned, issued or pending; Steering Committee; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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2024
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