On the evening of October 21, Beijing time, the New England Journal of Medicine (NEJM) and the 2023 annual meeting of the European Society of Medical Oncology (ESMO) being held in Madrid, Spain, simultaneously published the results of two international multi-center phase III trials led by Professor Zhou Caicun of the Institute of Oncology of Tongji University School of Medicine and Shanghai Pulmonary Hospital affiliated to Tongji University: the PAPILLON study proved that amivantamab (evantumab) +Chemotherapy significantly prolongs median progression-free survival in advanced non-small cell lung cancer carrying EGFR (epidermal growth factor receptor) exon 20 insertion mutations (11.4 months vs. 6.7 months; HR，0.40；95% CI，0.30~0.53；P<0.001）； In another phase III LIBRETTO-431 trial including RET (transfection rearrangement) fusion-positive non-small cell lung cancer, selpercatinib (selpercatinib) increased median progression-free survival by more than 1-fold compared with platinum-containing chemotherapy ± pembrolizumab (24.8 versus 11.2 months; HR，0.46；95% CI，0.31~0.70；P<0.001）。
These two studies further confirm that timely, comprehensive genomic testing will provide an important basis for initial treatment decisions in all patients with non-small cell lung cancer.
This is the first time that the same Chinese scholar has published two international multi-center clinical research results in NEJM as the first and corresponding author. Other Chinese authors also made key contributions: Professor Tang Kejing from the First Affiliated Hospital of Sun Yat-sen University, Professor Liu Baogang from the Cancer Hospital of Harbin Medical University as the lead author of the PAPILLON study, Professor Han Baohui from the Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and Professor Zhou Jianying from the First Affiliated Hospital of Zhejiang University School of Medicine were the lead authors of the LIBRETTO-431 study.
About 20 years ago, the discovery of EGFR kinase domain mutations (known as "classical" mutations) in non-small cell lung cancer (NSCLC) led to the development of EGFR tyrosine kinase inhibitors (TKIs) and significantly improved patient survival. Classical mutations occur in about 70% of cases, while the remaining 30% of other EGFR kinase domain mutations receive less attention.
EGFR exon 20 insertion mutations are less sensitive to third-generation TKIs, and non-small cell lung cancer carrying EGFR exon 20 insertion mutations urgently needs new therapies. Unlike small molecule inhibitors, amivantamab is a novel targeted therapy. It is an antibody drug that targets both EGFR and MET (interstitial epithelial transformation). The drug has a variety of possible mechanisms of action.
PAPILLON is a global phase III randomized trial that divides untreated patients with advanced EGFR exon 20 insertion mutation lung cancer into a 1:1 ratio to receive amivantamab plus chemotherapy (amivantamab + chemotherapy) or chemotherapy alone. A total of 308 patients were randomized. The primary endpoint of the trial was progression-free survival (PFS) as determined by an independent review committee. The study found that the median PFS of amivantamab+ chemotherapy group was 11.4 months, which significantly exceeded that of 6.7 months in the chemotherapy group (HR, 0.40; 95% CI, 0.30~0.53; P<0.001). The response rate was 73% in the amivantamab+ chemotherapy group, which was also higher than 47% in the chemotherapy group (P<0.001).
Selpercatinib is a highly selective and potent RET inhibitor that penetrates the blood-brain barrier, and it has shown efficacy in patients with advanced RET fusion-positive non-small cell lung cancer in non-randomized phase I-II studies.
LIBRETTO-431 is an open-label, randomized controlled phase III study to evaluate the efficacy of selpercatinib in patients with advanced or metastatic, untreated RET fusion-positive NSCLC. In this trial, the efficacy and safety of first-line selpercatinib was compared with control platinum-based chemotherapy (at the discretion of the investigator to decide whether to use pembrolizumab in combination).
In the intention-to-treat pembrolizumab population, a total of 212 patients were randomized. When the interim efficacy analysis was performed according to the pre-planned, the median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to unestimated) in the selpercatinib group and 11.2 months (95% CI, 8.8~16.8) in the control group (risk ratio of progression or death, 0.46; 95% CI, 0.31~0.70; P<0.001）。 The objective response rate was 84% (95% CI, 76%~90%) in the selpercatinib group and 65% (95% CI, 54%~75%) in the control group. The cause-specific risk ratio for the time of progression of central nervous system disease was 0.28 (95% CI, 0.12~0.68).
Studies have shown that selpercatinib significantly prolongs progression-free survival in patients with advanced RET fusion-positive non-small cell lung cancer compared with platinum-based chemotherapy (with or without pembrolizumab).
"Although advanced non-small cell lung cancer usually requires immediate initiation of treatment after diagnosis, the results of these two findings further demonstrate the importance of incorporating biomarker testing into routine care to guide clinical decision-making and develop the most effective treatment options at an early stage." Professor Zhou Caicun said.