The edition · Oncology
Adding venetoclax to DA-EPOCH-R in double-hit lymphoma killed more patients than it saved
ALLIANCE A051701 closed its double-hit cohort early after six of 37 patients died on treatment with venetoclax added, against one of 36 without. Progression-free survival did not improve, and 24-month overall survival was 52% against 72%. Elsewhere, ivonescimab extended progression-free survival in EGFR-mutant lung cancer after TKI failure.
The edition in brief
The most important result today is a harm. ALLIANCE A051701 randomised 73 patients with newly diagnosed double-hit lymphoma to DA-EPOCH-R with or without venetoclax. Median progression-free survival was 7.7 months with venetoclax and 28.4 months without, a hazard ratio of 1.13 whose wide interval means the efficacy question was never answered. What closed the cohort was mortality: six of 37 patients died on treatment in the venetoclax arm, four from sepsis, against one of 36 in the control arm. Twenty-four-month overall survival was 52% against 72%, hazard ratio 2.49. A rational combination, on paper, that killed people. HARMONi randomised 438 patients with EGFR-mutated non-small-cell lung cancer progressing after TKI therapy to ivonescimab plus chemotherapy or chemotherapy alone. Median progression-free survival was 6.8 against 4.4 months, hazard ratio 0.52. Overall survival was 16.8 against 14.0 months, hazard ratio 0.79 with an interval reaching 1.01 — so not yet significant. Serious treatment-related adverse events nearly doubled, 28% against 15%. GETUG AFU 18 gives a rare long-term answer: dose-escalated radiotherapy at 80 Gy raised 10-year progression-free survival to 83.6% from 72.2% in high-risk prostate cancer, with no increase in late grade 3 toxicity over 9.5 years of follow-up.
Venetoclax added to DA-EPOCH-R closed a cohort early for excess deaths
Adding venetoclax to DA-EPOCH-R for double-hit lymphoma produced no progression-free survival benefit and a 17% on-treatment mortality against 3%, closing the cohort early.
Ivonescimab extended progression-free survival after EGFR TKI failure, at a cost in serious toxicity
Ivonescimab plus chemotherapy extended median progression-free survival from 4.4 to 6.8 months after EGFR TKI failure, with a not-yet-significant overall survival trend and nearly double the serious adverse events.
Dose-escalated radiotherapy held its advantage in high-risk prostate cancer at ten years
Dose-escalated radiotherapy to 80 Gy raised ten-year progression-free survival to 83.6% from 72.2% in high-risk prostate cancer on long-term androgen deprivation, without increasing grade 3 toxicity.
No new regulatory action; EMERALD-3 adds progression-free survival in HCC without survival benefit yet
Nothing new from the regulators; EMERALD-3 improved progression-free survival in hepatocellular carcinoma by 3.2 months with no significant survival gain and serious adverse events rising from 23% to 64%.
A sound mechanism is not a safety argument
A sound mechanistic rationale predicts where efficacy might come from and tells you almost nothing about what a combination will do to patients — toxicity emerges from interactions no model captures.
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