Science

Amol Akhade: WCLC25 Highlight – HARMONi-A Trial in EGFR-mutant NSCLC

Amol Akhade/hiranandanihospital.org

Sep 8, 2025, 09:46

Amol Akhade: WCLC25 Highlight – HARMONi-A Trial in EGFR-mutant NSCLC

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

“WCLC25 Highlight: HARMONi-A Trial in EGFR-mutant NSCLC.

The HARMONi-A Phase III trial tested this strategy: ivonescimab + pemetrexed/platinum vs placebo + chemo in patients with EGFRm NSCLC after progression on a third-gen EGFR TKI.

Study snapshot

N = 438 randomized (219/arm), ~25% with baseline brain mets, global enrollment (China + Western patients).
Primary endpoint: PFS (by blinded review).
Secondary endpoints: OS, ORR, intracranial PFS, safety.

Results (WCLC25 presentation)

Median PFS: 6.8 vs 4.4 months (HR 0.52; p<0.001) → nearly 50% reduction in risk of progression.

PFS benefit consistent across subgroups, including patients with brain metastases (HR 0.34). ORR: 44.7% vs 34.2%. Intracranial

PFS: improved with ivonescimab combination.

OS (final): 16.8 vs 14.0 months (HR 0.79; p=0.057) → trend positive, but not statistically significant.

Safety: Grade ≥3 TRAEs in 50% vs 42%; expected VEGF-related events (hypertension, proteinuria).

Discontinuation rates modest (7.3% vs 5.0%).

Interpretation:

HARMONi-A delivers a clear PFS and intracranial efficacy win, and an encouraging trend for OS, but technically missed the OS endpoint. This distinction is important: regulators and guideline committees weigh OS heavily for practice-changing adoption, particularly in the West.

Nevertheless, the trial highlights several key insights:

CNS efficacy matters — nearly one-quarter of patients had brain mets, and intracranial control was notably better with ivonescimab. VEGF + PD-1 synergy may overcome resistance where PD-1 alone has failed in EGFRm. OS miss tempers enthusiasm — unlike FLAURA2 (positive OS), here the survival signal is supportive but not definitive. Regional adoption may diverge — approval and uptake may be faster in China, whereas in Western practice, competition from amivantamab-based regimens and emerging bispecifics may limit ivonescimab’s global footprint.

The bigger picture:

HARMONi-A is another step in the post-TKI EGFRm journey. While FLAURA2 redefined the frontline with osimertinib + chemo (HR 0.77 for OS), HARMONi-A suggests that bispecific immunotherapy may carve a role after progression. The lesson: the EGFR story is shifting toward combinatorial strategies across the disease continuum — whether chemo, IO, VEGF, or bispecifics.

Takeaway:

HARMONi-A is PFS-positive, OS-trending. Not practice-changing yet, but clinically relevant for patients with brain metastases and high disease burden after osimertinib. It represents both the promise and the challenge of immunotherapy in EGFRm NSCLC.”

Read Key Highlights from WCLC25 by Amol Akhade.