Science

Amol Akhade/hiranandanihospital.org

Sep 1, 2025, 13:26

Amol Akhade: ACROSS-2 vs FLAURA2

Amol Akhade, Senior Consultant at Fortis Hospitals Mumbai, shared a post on LinkedIn:

“Aumolertinib, Osimertinib, and the Face off

ACROSS-2 Vs FLAURA2

One of the most intriguing parallels at WCLC 2025 is between ACROSS-2, the phase III trial of aumolertinib + chemotherapy, and the already practice-shaping FLAURA2, which evaluated osimertinib + chemotherapy in the first-line EGFR-mutant NSCLC setting.

Both studies ask the same fundamental question: can we improve on third-generation EGFR-TKI monotherapy by adding platinum–pemetrexed upfront?

The designs are strikingly similar—randomized, first-line, PFS-driven—with maintenance TKI plus pemetrexed after 4 cycles of platinum.

Where ACROSS-2 steps further is in its explicit attention to concomitant tumor-suppressor co-alterations (e.g., TP53, RB1)—a biologically tougher subset in which TKIs alone often underperform.

PFS Landscape: What We Know and What We Predict

FLAURA2 (osimertinib ± chemo) already established a strong PFS signal: median PFS 25.5 vs 16.7 months; HR ~0.62—an ~9-month absolute gain, with broad subgroup consistency and early, durable curve separation.

ACROSS-2 (aumolertinib ± chemo) results are pending. Single-arm phase II data of aumolertinib + chemo were impressive (mPFS ~28 months; ORR >90%), but the phase III is enriched for co-mutations that typically depress TKI-alone outcomes.

My prediction for ACROSS-2: median PFS ~20–24 months with the combo vs ~12–15 months for aumolertinib alone; HR ~0.58–0.66 (absolute gain ~7–9 months). The absolute medians may look lower than FLAURA2 because the biology is harsher, but the magnitude of benefit (HR and absolute delta) should be comparable.

OS Horizon: Learning from FLAURA2

A recent press release stated that FLAURA2 achieved a statistically significant, clinically meaningful OS improvement with osimertinib + chemo vs osimertinib alone. Until the full dataset is presented, the magnitude remains a prediction.

Based on prior interim curves (HR ~0.75 at ~41% maturity, medians NR vs ~36.7 months), my best estimate for the final readout is OS HR ~0.76 with a median OS gain of ~10 months (≈~49 vs ~39 months). The direction is clear; the exact numbers and subgroup details must await full presentation/publication at WCLC2025

What do you think—will ACROSS-2 mirror FLAURA2’s proportional gains in a tougher, co-mutant population, or surprise us with a different pattern of benefit?”

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