Implications of the PLANET Trial at ESMO 2025 for Cancer Treatment
The PLANET trial presented at ESMO 2025 significantly advances precision medicine in cancer treatment by expanding next-generation sequencing (NGS) recommendations across multiple cancer types, with several genomic alterations being upgraded to higher clinical actionability levels. 1
Key Genomic Alterations with New Clinical Significance
Non-Small Cell Lung Cancer (NSCLC)
- NRG1 fusions are now classified as level IIB based on zenocutuzumab's demonstrated antitumor activity (ORR 35%) in NRG1-positive NSCLC, with breakthrough therapy designation from FDA 1
- RET fusions upgraded from level IC to IA based on the LIBRETTO-431 trial showing selpercatinib significantly improved PFS compared to chemotherapy (HR 0.46) 1
- NGS testing remains standard of care for advanced non-squamous NSCLC 1
Breast Cancer
- ESR1 mutations upgraded to level IA based on the EMERALD trial showing elacestrant improved PFS in hormone receptor-positive/HER2-negative ABC (HR 0.70), with greater benefit in patients with ESR1 mutations (HR 0.55) 1
- PIK3CA/AKT1/PTEN alterations now have FDA-approved targeted therapy with capivasertib plus fulvestrant showing improved PFS (HR 0.60) 1
- Somatic BRCA1/2 mutations (ORR 50%) and germline PALB2 variants (ORR 82%) reclassified as level IIB for PARP inhibitor therapy 1
Colorectal Cancer (CRC)
- KRASG12C mutations upgraded to level IA based on the CodeBreak 300 trial showing sotorasib plus anti-EGFR therapy improved PFS (HR 0.49) 1
- POLE mutations in MMR-proficient tumors classified as level IIB for PD-1 inhibitor therapy 1
- ERBB2 amplifications (level IIB) now actionable with anti-HER2 therapies showing 30-40% response rates 1
- NGS recommended for all advanced CRC patients if not adding extra cost compared to standard testing 1
Prostate Cancer
- BRCA1/2 alterations maintained at level IA with PARPi showing OS benefits 1
- ATM alterations downgraded from IIA to IIB based on limited benefit in subgroup analyses 1
- PALB2 alterations remain at level IIB due to low prevalence but demonstrated activity 1
Implementation Recommendations
Testing Strategy
- Tumor NGS recommended as standard of care for:
Clinical Considerations
- For breast cancer patients, NGS testing should be done after resistance to endocrine therapy to optimize detection of ESR1 mutations 1
- Patients with high likelihood of germline BRCA1/2 mutations should undergo dedicated germline testing even with negative tumor NGS (7% false negative rate) 1
- Ensure NGS panels include fusion detection capability for actionable fusions like NRG1, RET, and NTRK 1
Mortality and Quality of Life Impact
- The continued expansion of precision medicine approaches is contributing to declining cancer mortality rates, with nearly 4.5 million deaths averted since 1991 2
- Targeted therapies based on molecular profiling generally offer improved quality of life compared to conventional chemotherapy due to better tolerability profiles 3
- Despite advances, significant racial disparities persist in cancer outcomes that must be addressed alongside molecular testing improvements 2
Caveats and Pitfalls
- NGS implementation should be carefully considered regarding cost-effectiveness at the local level 1
- Not all genomic alterations have the same level of evidence; prioritize level I alterations for treatment decisions 1
- Tumor NGS may miss approximately 7% of germline BRCA1/2 mutations, necessitating dedicated germline testing in high-risk patients 1
- Ensure NGS panels include comprehensive fusion detection capability, as these are increasingly actionable targets 1
The PLANET trial findings reinforce the critical role of comprehensive molecular profiling in modern cancer care, with implications for improved survival and quality of life across multiple tumor types through more precise treatment selection 1, 2.