Long-term outcomes and overall survival (OS) for zanidatamab + chemotherapy in HER2-positive (HER2+) advanced or metastatic gastroesophageal adenocarcinoma (mGEA): 4-year follow-up of a phase 2 trial.
Bibliographic record
Abstract
4013 Background: Zanidatamab (zani), a dual HER2-targeted bispecific antibody, plus chemotherapy (chemo) has previously demonstrated antitumor activity and a manageable safety profile in the first-line (1L) treatment of patients (pts) with HER2+ mGEA. Here, we report a 4-year follow-up and the first report of both median OS and translational data from this phase 2 trial. Methods: The phase 2 trial (NCT03929666) evaluated zani + chemo (mFOLFOX6, CAPOX, or FP) in the 1L treatment of mGEA. In Part 1, pts had HER2-expressing (IHC 3+ or 2+) mGEA. Pts in Part 2 had HER2+ (IHC 3+ or IHC 2+/FISH+) mGEA by central assessment. After 25 pts were treated, antidiarrheal prophylaxis was added for cycle 1. The primary endpoint was confirmed objective response rate (cORR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), OS, and safety outcomes. Plasma ctDNA samples were collected for NGS testing (Guardant360). Results: In total, 46 pts were enrolled (zani + mFOLFOX6 [n = 24], CAPOX [n = 20], or FP [n = 2]). The majority (41 [89%]) of pts had HER2+ mGEA by central confirmation (ccHER2+); 35 (76%) pts had gastric/GEJ cancer. As of July 28, 2024, the median (range) follow-up was 48 (29-59) mo; 8 pts (17%) were on zani treatment and 19 (41%) in survival follow-up. Efficacy results are shown in the Table. The median OS was 36.5 mo; longest survival time was 57.9 mo (censored without death at data cutoff). The concordance between HER2 gene amplification by centrally assessed ISH vs plasma ctDNA was 90% (18/20). Of 14 pts with matched plasma samples at baseline and on-treatment (Cycle 2, day 15), 8 had a > 90% decrease in total ctDNA levels and 2 had a decrease in HER2 copy number. Common (> 5% of pts) grade 3 or 4 treatment-related AEs (TRAEs) were diarrhea (n = 18 [39%]), hypokalemia (n = 10 [22%]), vomiting (n = 4 [9%]), and nausea (n = 3 [7%]). Grade 3 or 4 diarrhea incidence was reduced from 52% to 24% after prophylaxis implementation. No deaths occurred due to TRAEs. Conclusions: After a median 4-year follow-up, zani + chemo demonstrated clinically meaningful efficacy in the 1L treatment of HER2+ mGEA, with durable responses and a median OS > 3 years, and a manageable safety profile. Zani + chemo markedly reduced total plasma ctDNA levels early in treatment of mGEA. Clinical trial information: NCT03929666 . All pts (N = 46) ccHER2+ GEA pts (n = 41) cORR a , n (% [95% CI]) 32 (76.2 [60.5, 87.9]) 31 (83.8 [68.0, 93.8]) Median DoR b (95% CI), mo 24-mo DoR, % (95% CI) 18.7 (10.4, 44.1) 40 (22, 58) 20.4 (8.3, 44.1) 41 (22, 59) Median PFS (95% CI), mo 12.5 (8.2, 21.8) 15.2 (9.5, 33.4) Median OS (95% CI), mo 36.5 (23.6, NE) 36.5 (23.6, NE) 24-mo OS, % (95% CI) 36-mo OS, % (95% CI) 65 (49, 77) 53 (37, 67) 67 (49, 79) 53 (36, 67) TRAEs, n (%) Any 46 (100) 41 (100) Grade 3 or 4 30 (65) 26 (63) a Response evaluable (n = 42 and 37). b Complete or partial response. NE, non-estimable.
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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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".