Interim and end-of-treatment FDG-PET demonstrate limited ability to predict 3-year progression-free survival with nivolumab-AVD in first-line treatment of advanced stage Hodgkin lymphoma: Imaging sub-analysis of Phase 3 S1826 study
Bibliographic record
Abstract
Abstract Introduction: The primary analysis of the randomized Phase 3 S1826 study in patients (pts) with previously untreated, advanced stage Hodgkin lymphoma (HL) showed a marked improvement in 1- and 2-year progression-free survival (PFS) with nivolumab, doxorubicin, vinblastine, dacarbazine (Nivo-AVD) compared to brentuximab vedotin (BV)-AVD (Herrera, NEJM, 2024). Multiple previous trials have explored the utility of interim (i) and end-of-treatment (EoT) PET scans in both early and advanced stage HL using the visual 5-point scale (5PS) score to predict outcomes and to escalate or de-escalate therapy. The Phase 3 ECHELON-1 study comparing BV-AVD to ABVD in advanced stage HL showed 5-yr PFS in the BV-AVD arm of 60.6% in pts with a positive iPET (5PS 4-5) compared to 84.9% in pts with a negative iPET (5PS 1-3) (Straus, Lancet Haematol 2021). In patients with relapsed HL receiving single agent PD-1 inhibitors, determining response using conventional PET response criteria has proved challenging due to persistent or new FDG-avid foci that may represent inflammation rather than active disease. The prognostic value of interim and EoT PET with the Nivo-AVD regimen has not been previously reported. Methods: Eligible pts ≥ age12 yrs with stage 3-4 HL were randomized to 6 cycles (C) of Nivo-AVD or BV-AVD. Response and disease progression were assessed by investigators for the primary endpoints using Lugano 2014 criteria. iPET following C2 was required for all participants enrolled through the Children's Oncology Group and was optional for all other participants. EoT PET was required for all pts within 4-8 weeks after C6D15. All scans were submitted for retrospective central imaging review performed by the NCI Imaging and Radiation Oncology Core. Both at interim and EoT, 5PS 1-3 was considered complete remission and 5PS 4-5 was partial remission or progressive disease based on comparison with baseline PET scan. Results: 994 pts were enrolled from 07/09/2019 to 10/05/2022 and randomized to N-AVD (n=496) or BV-AVD (n=498). 970 patients were eligible and comprised the intention to treat cohort. 742 (76%) pts had a centrally read iPET (368 N-AVD, 374 BV-AVD), 863 (89%) had a centrally read EoT PET (440 Nivo-AVD, 423 BV-AVD), and 693 (71%) had both. Landmark analyses from C3D1 and C6D28 comparing the entire study population to the subset with a centrally read PET showed a 3-yr PFS of 86% (C3D1all pts) and 87% (iPET subset) and 3-yr PFS 87% (C6D28 all pts) and 88% (EoT PET subset) confirming pts with centrally read PETs were representative of the entire study population. 3-yr landmark PFS was 89% (93% N-AVD, 85% BV-AVD) for iPET-neg, 77% (84% N-AVD, 73% BV-AVD) for iPET-pos (HR 2.31, P< 0.0001), 93% (94% N-AVD, 93% BV-AVD) for EoT PET-neg and 52% (68% N-AVD, 41% BV-AVD) for EoT PET-pos (HR 10.4, P <0.0001). Exploratory analyses showed no difference in 3-yr PFS for iPET 4 vs 5 but a difference in 3-yr PFS for EoT PET 4 (64%) vs 5 (29%), HR 2.93, P< 0.0001. There was no difference in 3-yr PFS for EOT PET 1-2 vs 3. Landmark 3-yr PFS, based on combined interim and EoT PET results, was 94% (iPET-neg, EoT PET-neg, n=527), 93% (iPET-pos, EoT PET-neg, n=75), 28% (iPET-neg, EoT PET-pos, n=35), and 60% (iPET-pos, EoT PET-pos, N=56). Landmark 3-yr PFS based on investigator-assessed PET response was 89% iPET-neg, 81% iPET-pos, 93% EoT PET-neg, 64% EoT PET-pos, all closely aligned with central read PFS analyses. 2% and 6% of iPETs and EoT PETs were read as indeterminate by local investigators. When comparing patient-level investigator and central 5PS scores among the overall population, discrepancies occurred in 20% of iPET reads and 12% of EoT reads; differences were similar in the Nivo and BV arms. Conclusions: Like prior studies in advanced stage HL, both iPET and EoT PET showed statistically significant differences in 3-year PFS for PET-neg vs. PET-pos, however EoT PET results were more clinically significant. Importantly, 84% of iPET-pos pts and 68% of EOT PET-pos pts treated with N-AVD remain progression-free at 3 yrs, suggesting significant limitations of PET Lugano criteria when applied to current therapies in HL and emphasizing the need to continue exploring new response assessment tools such as ctDNA. In pts treated with N-AVD, these results do not support altering therapy based on interim PET and suggest biopsy or close follow-up for most pts with an EoT positive PET.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".