Background and Purpose Gut microbes play an important role in the occurrence of lung cancer, immunotherapy, and chemotherapy. In this study, we analyzed the characteristics of gut microbes in patients with lung cancer and investigated the effect of gut microbes on anti‐PD‐1 therapy combined with chemotherapy. Methods Fecal samples from 21 non‐small cell lung cancer (NSCLC) patients and 22 healthy volunteers who were treated in the Fourth Hospital of Hebei Medical University from 2019 to 2021 were collected. DNA was extracted from all samples, and the V3‐V4 region of the bacterial 16S rRNA gene was PCR‐amplified using the Illumina sequencing platform, and R language was used for data analysis. Results There were significant differences in the Beta diversity and metabolic pathways of gut microbes between NSCLC patients and healthy individuals (p < 0.05). Bifidobacterium, Escherichia, and Sarterella were significantly enriched in patients with clinical benefit response (p < 0.05), and these three bacteria had certain predictive value for clinical benefit. Patients with Bifidobacterium breve had significantly longer median progression‐free survival (mPFS) compared with patients with no detectable Bifidobacterium breve feces at baseline (106 days vs. NR, p < 0.001). Multivariate COX analysis showed that the presence of B.breve was an independent good prognostic factor affecting the PFS of patients receiving combination therapy (p < 0.05). Conclusion The clinical efficacy of anti‐PD‐1 therapy combined with chemotherapy in Chinese advanced NSCLC patients is closely related to the gut microbiota, and Bifidobacterium breve may be a potential biomarker to predict the efficacy of immune‐combined chemotherapy.
e21005 Background: The gut microbiome has been demonstrated to be closely related to not only the occurrence of lung cancer but also its anti-PD-1 based immunotherapy and chemotherapy. There is little characteristic analysis of gut microbiota in Chinese lung cancer patients, and the impact of gut microbiota on combined anti-PD-1 treatment and chemotherapy remains unclear. Methods: Fecal samples from 22 healthy volunteers and advanced-NSCLC 21 patients who were treated in the Fourth Hospital of Hebei Medical University from 2019 to 2021 before and after anti-PD-1 treatment combined with chemotherapy were collected. DNA was extracted from all samples, and the V3-V4 region of the bacterial 16S rRNA gene was PCR-amplified using the Illumina sequencing platform. The study results were analyzed using bioinformatic data. Results: The composition of gut microbes in NSCLC patients and healthy people at the phylum level was roughly similar, with Firmicutes as the main phylum. However, there were significant differences in Beta diversity (P<0.05). The bray_curtis principal coordinate analysis revealed a significant difference in the microbiota between patients before and after combined treatment (P<0.05). According to the RECIST 1.1 criteria, the efficacy of the combination therapy was evaluated. The patients with complete remission, partial remission, or stable efficacy after 6 cycles were the clinical benefit response group (CBR, n=10), and the patients with disease progression in the efficacy evaluation were the non-clinical benefit group (NCB, n=8). The results suggested that the CBR group was enriched in Bifidobacterium_longum, Bifidobacterium_adolescentis, Bifidobacterium_bifidum, and Bifidobacterium_breve at the species level (P<0.05) compared with the NCB group. Compared with the median progression-free survival (mPFS) of patients without Bifidobacterium_breve at baseline, the mPFS of patients with the kind of gut bacteria was significantly prolonged (P<0.001).Specifically, mPFS without Bifidobacterium_breve group was 106 days (95% CI: 37-175), mPFS of the Bifidobacterium_breve group was Not Reached (95% CI: NC-NC). Conclusions: The clinical response of combined anti-PD-1 treatment and chemotherapy in advanced NSCLC patients was closely associated with the gut microbiome,and Bifidobacterium_breve may be effective biomarkers to predict the survival benefit of NSCLC combined therapy, which provided new therapeutic targets for modulating the response to cancer therapy.
e21075 Background: Advanced-stage anaplastic lymphoma kinase fusion-positive (ALK[+]) NSCLC has significantly benefited from ALK-TKI. It is still uncertain which second-generation(2G) ALK-TKI will benefit patients more after crizotinib resistance. Methods: We retrospectively analyzed the treatment history of 104 patients with ALK[+] NSCLC. Grouping was determined according to the type of 2G TKI patients selected after failure of crizotinib, including systemic and intracranial. Results: Overall, the median follow-up time was 24.2 (95%CI: 21.3-27.1) months, and 45(43.2%) eligible patients were alive at the end of follow-up. After Crizotinib treatment failure, 91(87.5%) patients received subsequent therapy (including targeted therapy and chemotherapy), and 90.1% (82/91) of patients received sequential 2G TKI treatment, with overall ORR of 68.3%, mPFS of 13.4 (95%CI:10.0-16.7) months, and mOS of 26.3 (95%CI:11.6-41.1) months. The mOS for Alectinib, Ceritinib, and Brigatinib were 34.5 (95%CI: 14.8-54.3), 19.4 (95%CI: 11.8-27.0) and 43.8 (95%CI: 10.0-77.6) months, respectively. The mPFS of Alectinib, Ceritinib, Brigatinib and Ensartinib were 17.3 (95%CI: 12.9-21.8) months, 13.4 (95%CI: 9.5-17.8) months, 10.7 (95%CI: 6.6-14.9) months and 8.4 (95%CI: 1.3-14.8) months, ORR were 68.6%, 70.8%, 69.2% and 60.0%, respectively (Table.1). For crizotinib resistant patient, 2G TKI showed no significant difference in prolonging PFS (P = 0.599) and OS (P = 0.681). Brain metastases were found in 67.1% (55/82) of crizotinib resistant patients, and mPFS of Alectinib, Ceritinib, Brigatinib and Ensartinib were 22.1 (95%CI:9.6-30.6) months, 12.6 (95%CI:8.3-16.9) months, 21.0 (95%CI:0.5-45.7) months and 14.7 (95%CI:3.8-25.5) months; ORR were 72.4%, 50.0%, 66.7% and 40.0%, respectively (Table.1). In particular, the ORR of Alectinib and Brigatinib was significantly higher than that of Ceritinib and Ensartinib (P < 0.000), while the mPFS of Alectinib was significantly better than Ensartinib (P = 0.029). Conclusions: After crizotinib resistance, nearly 90% of patients choose sequential 2G TKI. There was no significant difference in mPFS and mOS among patients treated with different 2G ALK-TKI. For patients with CNS metastases, treatment with Alectinib and Brigatinib results in higher ORR and PFS.[Table: see text]
e21008 Background: Anaplastic lymphoma kinase (ALK) is one of the major oncogenic driver genes in lung cancer, and fusion as the main mutation type, of which EML4 is the most common fusion ligand. With the development of next-generation sequencing (NGS), some other rare fusion ligands and complex fusions have been discovered. The prognosis of patients with EML4-ALK fusion, non EML4-ALK fusion and multiple ALK fusion was different. Methods: We retrospectively analyzed NGS (including tissue, blood, or other body fluid samples) in 61 patients with ALK[+] lung cancer, including 59 patients with NSCLC and 2 patients with SCLC. Grouping was determined according to whether it was EML4-ALK fusion and multiple fusion. Results: In our data, the partner fused to the ALK gene are diverse, including EML4, KIF5B, TSN and others. Among them, EML4 was the most common ligand in ALK[+] NSCLC, accounting for 93.2% (55/59). Among the different fusion sites of EML4-ALK, V1 (E13:A20) and V3 (E6:A20) mutations were the most common, accounting for 45.5% (25/55) and 41.8% (23/55), respectively. Several novel ALK fusion partners were discovered in this study, including MCFD2, LINC01251, MVP17, CREG2, LINCO1498 and so on. In addition, the incidence of intergenic sequence-ALK fusions was 16.4% (10/61), such as ANXA4-ALK(A[intergenic]:A20), CREG2-ALK (C[intergenic]:A20), HCN1-ALK(H[intergenic]:A20), TSN-ALK(T[intergenic]:A20), RSAD2-ALK(R [intergenic]:A20) and so on. 19.0% (12/61) of the patient had multiple fusion, of which only one patient had multiple fusion of EML4-ALK (V2+V5'+V3a/b), and the remaining patients had co-fusion of EML4-ALK and non EML4-ALK (Table). V3 were more likely to coexist with non EML4-ALK fusions than V1 or other variants (P = 0.047). Multiple fusions were more likely to occur with non EML4-ALK fusions (P < 0.000). Compared with EML4-ALK fusion, mPFS treated with crizotinib in non EML4-ALK fusion were significantly shorter (18.2 vs. 8.5 months, P = 0.035). In the context of crizotinib treatment, multiple fusions were associated with worse mPFS compared with single fusions (13.8 vs. 8.4 months, P = 0.008). In addition, For SCLC patients with ALK fusion (n = 2), the PFS of crizotinib treatment were 8.0 and 30.6 months, respectively. Conclusions: Due to the heterogeneity of tumor development resulting in the diversity of ALK fusions, non EML4-ALK fusions and multiple fusions imply a poorer response to crizotinib. ALK gene status prior to ALK-TKI therapy helps predict drug efficacy and patient prognosis.[Table: see text]
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