Targeted therapy and immunotherapy play an important role in the treatment of non-small cell lung cancer (NSCLC). Molecular typing is the prerequisite for the implementation of NSCLC treatment. The standardization of tests can improve the accuracy of test results and benefit patients to a greater extent. With the development of molecular detection technology and in-depth study of tumor-related pathways, more and more genes and loci related to the treatment of NSCLC have been found.

The 2025 first edition of the national comprehensive cancer network (NCCN) guidelines for non-small cell lung cancer has been updated with new recommendations for markers of lung cancer detection.

In this NCCN guideline, it is recommended to add two new targets for detection: NRG1 gene fusion and FGFR mutation, and the corresponding targeted drugs are Zenocutuzumab-zbco and Erdafitinib respectively. At the same time, in addition to HER2 gene mutation detection for lung cancer, recommendations for HER2 protein overexpression detection have been added to the 25th edition of the Guidelines to guide ADC drugs.

HER2 IHC

Molecular biomarker therapy recommendations for advanced or metastatic patients ^[1]

This recommendation is based primarily on the primary analysis results in patients with HER2 overexpression, non-resectable, or metastatic non-squamous NSCLC in the Phase 2 trial DESTINY-Lung01. HER2 overexpression was defined as an immunohistochemical score of 3+ or 2+ and no known HER2 mutations. These patients had poor efficacy or relapsed after standard treatment, or no standard treatment option was available. The study primary endpoint was the objective response rate confirmed by an independent central review board, 26.5%(13 /49, partial response) in Cohort 1 (6.4 mg/kg) and 34.1%(14 /41, 2 complete response and 12 partial response) in Cohort 1A (5.4 mg/kg). At both doses, trastuzumab deruxtecan has consistent and encouraging remission data for HER2 overexpressed NSCLC in patients who have been treated extensively in the past, and overall efficacy is consistent regardless of the patient's stable central nervous system metastasis at baseline, PD-1 or PD-L1 targeted therapy in the past, or whether the patient carries an EGFR mutation or a KRAS mutation or HER2 amplification.

Waterfall diagram and past situation of two queues ^[2]

Additional efficacy measures also support the anti-tumor activity of trastuzumab deruxtecan. The disease control rates were 69.4% and 78.0% in Cohort 1 and Cohort 1A, respectively, the median duration of response was 5.8 months and 6.2 months, the median progression-free survival was 5.7 months and 6.7 months, respectively, and the median overall survival was 12.4 months and 11.2 months, respectively ^[2].

Destination-lung 01 studied OS and PFS in 2 cohorts ^[2]

Although the guidelines add a test recommendation for HER2 IHC, questions related to immunohistochemical testing are expressed in the test description, there are no specific IHC antibodies, and there is no treatment scoring criterion for lung cancer.

NCCN guidelines describe HER2 testing ^[1]

FGFR Detection:

The 25 edition of the guidelines adds the variation of FGFR to the new biomarker panel and the corresponding drug is Erdafitinib, with the corresponding addition of footnote c: "For FGFR mutations that are carcinogenic or may be carcinogenic, see the definition on the oncokb.org." FGFR is a popular target for "unlimited cancer species". FGFR signaling pathway plays an important role in the process of cell proliferation, differentiation and survival. Its gene mutation may lead to abnormal cell growth and tumor development. Erdeneb, a targeted drug targeting the FGFR gene mutation, has shown efficacy in some patients with lung cancer in clinical studies, providing a new therapeutic approach for these patients.

Novel biomarker panel for identifying novel therapies for patients with metastatic NSCLC ^[1]

The reasons for the increase in NCCN guidelines are based primarily on results from the RAGNAR study. The researchers treated 217 patients with 16 different tumor types with erlotinib, of which 14 patients with squamous cell carcinoma of the lung and 9 patients with NSCLC that were not squamous cell carcinoma were included. In patients with squamous cell carcinoma of the lung, the ORR is 21% and the DCR is 86%. The ORR of patients with NSCLC who are not squamous cell carcinomas is 33%, and the DCR is 56%^[3].

The Independent Evaluation Commission (IRC) assessed a reduction in the maximum percentage of target lesions compared to baseline based on tumor tissue type and FGFR genetic changes ^[3]

Effect-confirming reactions in different tumor types ^[3]

NGR1 fusion detection:

On December 4, 2024, the US Food and Drug Administration (FDA) accelerated the approval of Merus's Zenocutuzumab (also known as ZDV) for the systemic treatment of advanced non-small cell lung cancer (NSCLC) and advanced pancreatic ductal adenocarcinoma (PDAC) adult patients who had failed previous treatments but harbored NRG1 gene fusion.

The NCCN guidelines upgraded it to a Category 1 recommendation and increased the detection of NRG1 in adenocarcinomas, large cell carcinomas, non-small cell lung carcinomas with uncertain pathological types, and squamous cell carcinomas. NRG1 fusion is rare, with a prevalence of less than 1% in various tumor types, and it has been reported in the literature as about 0.232% in lung cancer ^[4].

Treatment recommendations for NRG1 in the guidelines ^[1]

Summary

With the accumulation of clinical practice experience and clinical research data of targeted therapy and immunotherapy in the treatment of NSCLC, more and more targeted therapy drugs and immunotherapy drugs will be applied in clinical practice. At the same time, with the continuous improvement of molecular pathology detection technology, more and more treatment-related target genes and loci will be found. The improvement of detection technology, the popularity of Qualcomm assay detection platform, and the continuous approval of detection kits will promote the wide application of molecular pathology detection in NSCLC.

The newly added genetic detection markers in the NCCN guidelines for lung cancer have brought new opportunities and challenges to the diagnosis and treatment of lung cancer. We believe that under the guidance of the guidelines, through multi-disciplinary collaboration and continuous research and innovation, new breakthroughs will be made in the precision medical treatment of lung cancer, bringing more hope for survival and a better quality of life to the vast majority of patients with lung cancer.

References:

[1] NCCN Guidelines for Non-Small Cell Lung Cancer 2025.V1

[2] Lancet Oncol. 2024 Apr; 25(4):439-454.

[3] Lancet Oncol. 2023 Aug; 24(8):925-935.

[4] 2023 ASCO Poster：3132