FGFR1 Gain Linked to Shorter PFS in Advanced LUSC
09/01/2026
Key Takeaways
- In advanced LUSC treated with first-line ICI-based therapy, FGFR1 CN gain was present in 24.3% of patients and was associated with shorter PFS.
- Disease control was lower with FGFR1 CN gain at 81.8% versus 94.9%, and early progression was more common.
- ORR was similar between FGFR1 CN-gain and non-gain groups despite the difference in disease control.
- Among patients receiving first-line chemoimmunotherapy, FGFR1 CN gain was also associated with shorter PFS.
- OS did not differ significantly by FGFR1 status.
Investigators conducted a retrospective single-center cohort at Shanghai Chest Hospital that included 181 patients with histologically confirmed stage IIIB-IV advanced LUSC treated from January 2018 to July 2023. Eligibility required pretreatment next-generation sequencing (NGS) and PD-L1 immunohistochemistry, first-line ICI monotherapy or ICI plus chemotherapy, measurable disease, and follow-up imaging assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Pretreatment targeted NGS used the 68-gene Lung Core panel on an Illumina NextSeq500 platform with target depth 1,000×; FGFR1 CN gain was defined as copy number greater than 2, and copy number 6 or greater was explored as a high-level amplification threshold. Progression-free survival (PFS) was the primary endpoint, with overall survival (OS), objective response rate (ORR), and disease control rate (DCR) as secondary endpoints.
FGFR1 CN gain was associated with lower disease control in the overall cohort, and best-response distributions also differed significantly because progressive disease was more common in that group. Median PFS was 7.7 months versus 9.5 months (P=0.025). By contrast, ORR and OS were not significantly different by FGFR1 status. The authors interpreted that pattern as more consistent with shorter durability of disease control than with reduced initial tumor shrinkage.
After adjustment for clinicopathologic variables, FGFR1 CN gain remained independently associated with shorter PFS with HR 1.554 (95% CI 1.077-2.242; P=0.018). The same direction appeared in the chemoimmunotherapy subgroup, where median PFS was 7.8 months versus 9.5 months (P=0.009), while subgroup ORR and OS were not significantly different. In a sensitivity analysis, the CN 6 or greater subgroup trended toward shorter PFS and OS without statistical significance, but it included only 16 patients.
The authors noted that the retrospective single-center design leaves room for selection bias, and sample size was limited overall and especially in the high-level amplification subgroup. Residual treatment heterogeneity, incomplete data on subsequent therapy that may affect OS interpretation, lack of tumor mutational burden and broader tumor immune microenvironment profiling, and platform-dependent FGFR1 CN thresholds also complicate interpretation. Because this was a Shanghai cohort, the findings should not be assumed to generalize directly to U.S. practice, even though the treatment setting overlaps with first-line ICI-based regimens used in North America. Any biologic explanation for relative ICI resistance remained hypothesis-generating, and the observed association does not establish FGFR1 CN gain as a causal mechanism or a stand-alone basis for treatment selection.
According to the authors, FGFR1 CN gain identified patients with advanced LUSC who were at higher risk of earlier progression on first-line ICI-based therapy, with a signal that appeared stronger for durability of disease control than for initial radiographic response. They called for prospective multicenter validation before the marker is used more broadly.
Clinician Questions
How was FGFR1 CN gain defined in advanced LUSC receiving first-line ICI-based therapy?
Investigators used pretreatment targeted NGS with the 68-gene Lung Core panel sequenced on an Illumina NextSeq500 platform at 1,000× target depth, defined FGFR1 CN gain as copy number greater than 2 in the primary analysis, and explored copy number 6 or greater as a high-level amplification threshold in sensitivity analysis.
Did PD-L1 category differences account for the shorter PFS seen with FGFR1 CN gain in advanced LUSC?
The authors reclassified PD-L1 tumor proportion score into categories of less than 1%, 1% to 49%, and 50% or greater, found no significant distribution difference between FGFR1 groups, and reported that FGFR1 CN gain remained independently associated with shorter PFS after incorporating that PD-L1 model.
Was the FGFR1 signal in advanced LUSC more about early progression than lack of initial tumor shrinkage?
According to the authors, the pattern was more consistent with earlier progression than with failure to achieve initial shrinkage, because ORR was similar by FGFR1 status whereas progressive disease was more common at 18.2% versus 5.1% in the FGFR1 CN-gain group.
Did FGFR1 CN gain remain linked to shorter PFS in patients receiving ICI plus chemotherapy?
Yes. In the subgroup treated with first-line ICI plus chemotherapy, FGFR1 CN gain showed the same direction of association with shorter PFS, while subgroup ORR and OS were not significantly different.
Recommended Reading
- For more on first-line chemoimmunotherapy in squamous NSCLC: Evidence-Based Care for PD-L1-Negative Non-Small Cell Lung Cancer
- For more on biomarker-driven first-line decisions in NSCLC: Closing the Gap in First-Line Treatment of KRAS G12C–Mutated Advanced NSCLC: From Biology to Bedside Decisions and Trial-Ready Care