Frequent driver gene mutations
Quite a few scientific research and focused therapies regarding EGFR mutations, probably the most prevalent driver mutations in NSCLC in China, have emerged in recent times. Third-generation EGFR inhibitors similar to osimertinib, furmonertinib, and almonertinib have been efficiently launched. On the idea of the outcomes from the IBIO-103 and IBIO-102 research, the fourth third-generation EGFR-targeted remedy befotertinib has develop into accessible. In contrast with icotinib, befotertinib considerably prolongs progression-free survival (PFS) as a first-line therapy [22.1 months vs. 13.8 months, Hazard Ratio (HR) = 0.49, P 1. For patients with T790M mutations, befotertinib has also demonstrated a promising objective response rate (ORR) of 66.2%, with a median overall survival (OS) of 31.5 months2. On the basis of these data, the National Medical Products Administration (NMPA) approved befotertinib for both first- and second-line treatment of patients with EGFR mutations, and has included this grade I recommendation in the 2024 CSCO, thus further solidifying the role of third-generation EGFR inhibitors in the treatment of advanced NSCLC.
To address the limited efficacy of monotherapy, researchers have explored combinations of targeted therapies and other treatments. In the phase III FLAURA2 trial, osimertinib combined with chemotherapy significantly prolonged PFS (25.5 months vs. 16.7 months, HR = 0.62, P 3. FLAURA2 established osimertinib-chemotherapy as a new first-line treatment for EGFR NSCLC; this treatment has been approved by both the NMPA and Food and Drug Administration (FDA). Additionally, in the MARIPOSA study a combination of lazertinib and amivantamab (EGFR-MET bispecific antibody), compared with osimertinib, significantly extended the PFS (23.7 months vs. 16.6 months, HR = 0.70, P 4. However, because neither drug has been introduced in China, this combination is included only in the descriptive section of the updated guidelines. In the MARIPOSA-2 trial, PFS was significantly longer for amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy vs. chemotherapy (6.3 and 8.3 vs. 4.2 months, respectively), and showed a higher ORR (64% and 63% vs. 36%, respectively).
EGFR exon 20 insertion (exon20ins) mutations present a major challenge in the targeted treatment of NSCLC. Historically, platinum-based doublet chemotherapy or anti-angiogenesis therapies were the primary treatments for patients with this mutation. Mobocertinib, an exon20ins-targeting tyrosine kinase inhibitor (TKI), initially demonstrated moderate efficacy in the phase II EXCLAIM trial. However, because it did not show superiority as a front-line treatment in a phase III trial, the FDA withdrew its approval for this indication5. Sunvozertinib, a new target for exon20ins, has emerged as a promising option, demonstrating an ORR of 61% as a second-line treatment in the WONKONG-6 study6. Sunvozertinib addresses a major gap in the treatment of exon20ins; this treatment was granted “breakthrough therapy” designation by both the FDA and NMPA, and subsequently gained approval in China as a later-line treatment. Given sunvozertinib’s exceptional performance, the 2024 CSCO guidelines list this drug as a grade I recommendation for second-line treatment of EGFR exon20ins. This update highlights the substantial progress in the treatment of exon20ins, particularly in targeted therapy. In the PAPILLON study, amivantamab combined with chemotherapy, compared with chemotherapy alone, significantly prolonged PFS in patients with advanced NSCLC with EGFR ex20ins mutation (16.7 months vs. 11.4 months, HR = 0.40, P EGFR ex20ins mutation. With the introduction of novel drugs and further accumulation of clinical data, treatment options for patients with exon20ins are expected to become increasingly diverse and personalized.
ALK fusions have been described as “diamond” mutations because of their low morbidity and favorable prognosis. With advancements in ALK inhibitors, advanced NSCLC with ALK fusion has gradually become a chronic disease. In first-line treatment, alectinib, brigatinib, and lorlatinib are preferred in the recommendations, because they have been found to achieve significantly longer PFS than crizotinib. Additionally, after the INSPIRE study, the NMPA approved iruplinalkib as a first-line treatment for ALK-fusion advanced NSCLC on January 16, 2024, on the basis of clinical data showing a median PFS of 27.7 months, compared with 14.6 months with crizotinib (HR = 0.34, P 7. Furthermore, iruplinalkib demonstrated high efficacy as a second-line treatment, with an ORR of 69.9% in the INTELLECT study, thus further confirming its clinical value8. Another promising medicine targeting c-Met/ALK/ROS1 is envonalkib. Compared with crizotinib, envonalkib significantly extends the median PFS in patients with ALK fusion (24.9 months vs. 11.6 months, HR = 0.47, P 9. With the approval of these therapies, the options for ALK-targeted medicine have become increasingly robust. Currently, 8 drugs have been approved in China for ALK-fusion NSCLC, including 6 international drugs and 2 domestic drugs.
Rare driver gene mutations
ROS1 fusion occurs primarily in lung adenocarcinoma without smoking. The current CSCO guidelines include updates for 2 TKIs targeting ROS1: repotrectinib and unecritinib. As the first approved second-generation NTRK/ROS1 inhibitor, repotrectinib demonstrated high response rates and durability in patients with ROS1-fusion NSCLC, as shown in the TRIDENT-1 study, with an ORR of 79% and median PFS of 35.7 months as a first-line treatment. As a second-line treatment, repotrectinib achieved an ORR of 38%, a median PFS of 9.0 months, and median OS of 25.1 months10. On the basis of these results, repotrectinib has been granted a breakthrough therapy designation by the FDA and NMPA for both first- and second-line treatment of ROS1-fusion NSCLC. Additionally, unecritinib was approved by the NMPA in October, 2024, and has shown an ORR of 80.2% in second-line treatment and a median PFS of 16.5 months11.
NSCLC with BRAF V600 mutation has historically derived limited clinical benefits from conventional chemotherapy, and the main standard treatment involved a combination of dabrafenib and trametinib. However, the PHAROS study in 2023 has provided a new treatment option. The combination of encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) as a first-line treatment for BRAF V600 NSCLC achieved an ORR of 75%, with a good safety profile12. Only 15% of patients discontinued treatment because of intolerable adverse events. On the basis of these results, encorafenib combined with binimetinib has been approved by the FDA for the treatment of BRAF V600 advanced NSCLC. Therefore, the 2024 CSCO guidelines include encorafenib and binimetinib as a first-line treatment for BRAF V600 advanced NSCLC as a grade III recommendation.
MET exon 14 skipping (METex14) mutations are rare but aggressive in advanced NSCLC. Traditional chemotherapy and immunotherapy have demonstrated limited efficacy in this population, with a median OS of only 6.7 months for chemotherapy and a median PFS of 1.9 months for immunotherapy. These data highlight the urgent need for more effective strategies. In the past year, rapid advancements in targeted therapies for METex14 have provided new hope for these patients. Tepotinib, gumarontinib, and vebreltinib have all demonstrated ORR exceeding 50% as a first-line treatment, and achieve significantly longer PFS and OS than chemotherapy13–15. Second-line treatments have also yielded positive results. All these drugs have been approved by the NMPA and are grade I recommendations in the 2024 CSCO guidelines, thus marking a notable change in the treatment landscape for METex14 NSCLC. Additionally, the 2023 WCLC presented data on savolitinib, showing an ORR of 59.5% and a median PFS of 12.6 months in first-line treatment16. Because it has not yet received NMPA approval, savolitinib is currently listed as a grade II recommendation in the guidelines. These targeted therapies offer significantly improved outcomes for patients with METex14 and enable precision medicine for this subset of NSCLC.
RET fusions occur in approximately 2% of patients with NSCLC, and traditional platinum-based chemotherapy treatments have provided limited benefits. In recent years, the introduction of the new RET inhibitors pralsetinib and selpercatinib has markedly advanced the treatment of RET fusion NSCLC. In the LIBRETTO-001 study, selpercatinib achieved an ORR of 84% as a first-line treatment and 61% as a second-line treatment17. The LIBRETTO-431 study, presented at the 2023 European Society for Medical Oncology (ESMO) Congress, demonstrated remarkable enhancements in PFS (24.8 months vs. 11.2 months, HR = 0.46, P vs. 11.5 months), and intracranial disease control (response rate: 82% vs. 58%; progression rate: 6% vs. 20%). On the basis of these results, the 2024 CSCO guidelines have elevated the recommendation for selpercatinib from grade III to grade I, reflecting its potential as a superior therapeutic option. Additionally, updated data from the ARROW study in Chinese patients with RET fusion-positive NSCLC indicated an ORR of 83% and a median PFS of 12.7 months. Consequently, pralsetinib was approved by the NMPA for first-line treatment of RET fusion NSCLC, and its recommendation has been upgraded to grade I.
In advanced NSCLC with KRAS G12C mutations, multiple small molecule inhibitor treatment has progressed. Garsorasib has achieved in an ORR and disease control rate of 40.5% and 91.9%, respectively, with a median PFS of 8.2 months and a median duration of response of 7.1 months. The ORR for JDQ443 was 45% in the all of doses and 57.1% in the 200 mg group. In postline treatment of advanced NSCLC with KRAS G12C mutation, fosfomycin achieved an ORR of 61.2% and a disease control rate of 92.5%. HER2, EGFR exon 20ins, and TROP2-targeting ADCs have all shown promising results. HER2 mutations are identified in approximately 2% to 4% of patients with NSCLC in China, and these mutations or amplifications are a major mechanism underlying acquired resistance to EGFR-TKIs in NSCLC. The DESTINY-Lung02 study has revealed the outstanding efficacy of trastuzumab deruxtecan (T-DXd) in previously treated patients with HER2-positive NSCLC, achieving ORRs of 50.8% and 73.3% at doses of 5.4 mg/kg and 6.4 mg/kg, respectively. Furthermore, the median PFS was 10.8 months for the 5.4 mg/kg dose and an impressive 15.4 months for the 6.4 mg/kg dose.18. On the basis of these results, T-DXd received accelerated approval from the FDA for HER2 NSCLC and was designated a “breakthrough therapy” by the CDE in January 2024. The drug is already available for clinical use in China and has recently been approved by NMPA for second-line treatment of HER2 NSCLC. The phase III PAPILLON study has shown that amivantamab combined with platinum-based chemotherapy significantly prolongs PFS (11.4 months vs. 6.7 months, HR = 0.395, P vs. 47%) in patients with EGFR exon 20ins, thus leading to FDA approval as a first-line treatment19. However, because of the current unavailability and lack of approval of this ADC in China, it has been categorized as a grade III recommendation in the guidelines.
