Response to immune checkpoint inhibitor combination therapy in metastatic RET-mutated lung cancer from real-world retrospective data.

BACKGROUND: The impact of immune checkpoint inhibitors (ICIs) based treatments on non-small cell lung cancers (NSCLCs) with RET fusions remains poorly understood. METHODS: We screened patients with RET fusions at the First Affiliated Hospital of Zhengzhou University and included those who were treated with ICIs based regimens for further analysis. We evaluated clinical indicators including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 232 patients with RET fusions were included in the study. Of these, 129 patients had their programmed death-ligand 1 (PDL1) expression levels tested, with 22 patients (17.8%) having a PDL1 level greater than or equal to 50%. Additionally, tumor mutational burden (TMB) status was evaluated in 35 patients, with the majority (30/35, 85.8%) having a TMB of less than 10 mutations per megabase. Out of the 38 patients treated with ICI based regimens, the median PFS was 5 months (95% confidence interval [CI]: 2.4-7.6 months) and the median OS was 19 months (95% CI: 9.7-28.3 months) at the time of data analysis. Stratification based on treatment lines did not show any significant differences in OS (18 vs. 19 months, p = 0.63) and PFS (6 vs. 5 months, p = 0.86). The ORR for patients treated with ICIs was 26.3%. Furthermore, no significant differences were found for PFS (p = 0.27) and OS (p = 0.75) between patients with positive and negative PDL1 expression. Additionally, there was no significant difference in PD-L1 levels (p = 0.10) between patients who achieved objective response and those who did not. CONCLUSIONS: Patients with RET fusion positive NSCLCs may not benefit from ICI based regimens and therefore should not be treated with ICIs in clinical practice.

Association of PD-L1 expression and clinical outcomes in ROS1 - rearranged advanced non-small cell lung cancer treated with crizotinib.

Background: Programmed cell death ligand 1 (PD-L1) is more readily expressed in ROS proto-oncogene 1 (ROS1) rearranged non-small cell lung cancer (NSCLC) compared to NSCLC cases lacking driver gene mutations. Prior research has established a link between PD-L1 expression and reduced effectiveness of EGFR or ALK inhibitors in EGFR or ALK-positive NSCLC. Nonetheless, the relationship between initial PD-L1 levels and the clinical impact of first-line crizotinib therapy in ROS1-rearranged NSCLC is still uncertain. Methods: From January 2016 to December 2021, a total of 246 patients with ROS1 positive tumors were collected. Out of these, 82 patients with advanced ROS1-rearranged NSCLC, who were treated with crizotinib as their initial therapy, were selected for the study. The study aimed primarily to evaluate the objective response rate (ORR) and progression-free survival (PFS), and secondarily to assess disease control rate (DCR) and overall survival (OS). Results: Of the 82 advanced ROS1-rearranged NSCLC patients, 38 exhibited PD-L1 positivity, subdivided into 11 with high and 27 with low expression levels, while the remaining 44 showed no PD-L1 expression. The ORR for all included patients was 80.5%. No statistically significant variance in ORR was observed among ROS1-rearranged NSCLC patients across differing PD-L1 expression statuses. However, there was a statistically significant difference in DCR between PD-L1 negative group (100%) and high expression group (90.9%) (p=0.04). The median PFS spanned 26.4 months for the PD-L1 negative group, 16.6 for the low expression group, and 13.7 for the high expression group (p=0.001). Additionally, a notable statistical disparity was also observed in median PFS between the PD-L1 negative and positive groups (p=0.02). For the entire study population, the median OS was 53.0 months (95% CI 43.8 - 62.2). In the PD-L1-negative group, the median OS reached 57.2 months, compared to 53.0 months in the PD-L1-positive group, a difference lacking statistical significance (p=0.43). Conclusions: Our results suggest that for ROS1-positive NSCLC patients receiving crizotinib as first-line therapy, PD-L1 expression may serve as a negative prognostic marker for PFS rather than OS.

The efficacy of furmonertinib in untreated advanced NSCLC patients with sensitive EGFR mutations in a real-world setting: a single institutional experience.

Background: Furmonertinib is the standard treatment option in the first-line setting for advanced non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations in China. However, there are limited real-world data available. Methods: We conducted a retrospective study at a single center, analyzing a cohort of 73 NSCLC patients who tested positive for EGFR mutations and were treated with furmonertinib as their initial therapy between August 2022 and December 2023. The primary endpoint was progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), overall survival (OS), and safety profile. Results: The median observation period was 9 months (95% confidence interval [CI], 8.0-20.0). The median PFS was 19.5 months (95% CI, 14.6-24.4). OS data were not yet mature. Univariate analysis showed no significant correlation between PFS and factors such as Eastern Cooperative Oncology Group performance status (ECOG PS) score, presence of brain or liver metastases, sex, age, EGFR mutation status, or number of metastatic sites. However, multivariate analysis indicated a potential trend toward extended PFS in patients younger than 65 years (p = 0.053, 95% CI, 0.10-1.02), although the p-value was only marginally significant. The most common adverse events were diarrhea (24%), anemia (36%), and liver injury (32%); however, only four cases experienced severe adverse events. Conclusion: In a real-world setting, furmonertinib appears to be a favorable treatment option for EGFR-mutated patients. The manageable nature of adverse events further supports its use in clinical practice.

Corrigendum: The efficacy of furmonertinib in untreated advanced NSCLC patients with sensitive EGFR mutations in a real-world setting: a single institutional experience.

[This corrects the article DOI: 10.3389/fonc.2024.1331128.].

Efficacy of immune checkpoint inhibitors in advanced large cell neuroendocrine carcinoma of the lung: A single­institution experience.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and highly invasive lung cancer subtype with an overall poor prognosis. Due to its low incidence rate and unusual pathological features, the clinical management of LCNEC remains controversial. The present study aimed to assess the effect of immune checkpoint inhibitors (ICIs) on treatment response and survival outcomes in patients with advanced LCNEC. The clinical data from 148 patients with LCNEC treated with ICIs at The First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between January 2019 and September 2021 were retrospectively analyzed. Kaplan-Meier and multivariable Cox regression analyses were used to evaluate associations between clinicopathological variables and patient outcomes. Patients treated with ICIs demonstrated extended median overall survival (mOS) times [23.5 months; 95% confidence interval (CI), 18.524-28.476] compared with patients who did not receive ICIs (11.2 months; 95% CI, 4.530-18.930) (P<0.001). Univariate analysis revealed that histological subtype (P=0.043), lymph node metastases (P=0.032) and number of metastatic organs (P=0.009) were associated with a poor prognosis. The heterogeneity of pathological components was associated with prognosis, and the mOS time was shorter for mixed LCNEC than that for pure LCNEC (P=0.043). The median progression-free survival (mPFS) (9.78 vs. 9.37 months; P=0.82) and mOS (20.70 vs. 25.79 months; P=0.181) times showed no significant association with regard to different regimens of immuno-based combination therapy (chemotherapy combined with ICIs vs. anti-angiogenic agents combined with ICIs). Poor Eastern Cooperative Oncology Group performance status score (P=0.04), multiple organ metastases (P=0.02) and high cancer antigen 125 levels (P=0.01) were independent risk factors of a poor prognosis. The present findings offer valuable insights into potential prognostic markers and highlight the favorable impact of ICIs on OS in advanced LCNEC. Prospective clinical studies are required to validate the therapeutic value of ICIs in LCNEC.

Camrelizumab combined with anlotinib as second-line therapy for metastatic or recurrent small cell lung cancer: a retrospective cohort study.

Introduction: This retrospective study evaluates the efficacy of camrelizumab combined with anlotinib versus chemotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC) undergoing second-line treatment. Methods: Data were sourced from medical records at a Chinese medical facility, involving 34 patients diagnosed with ES-SCLC after failing first-line treatment. Patients were divided into two groups: one received camrelizumab (200 mg every 3 weeks) with anlotinib (12 mg daily for 14 days followed by a 7-day rest), while the other group received physician-chosen chemotherapy administered every 3 weeks. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: The combination therapy group showed a significant improvement in PFS compared to the chemotherapy group (median PFS: 7 months vs. 3 months; hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.15-0.77; p<0.001). However, there was no statistically significant difference in OS between the groups (16.3 months vs. 17.3 months; p=0.82). The ORR was 52.9% in the combination therapy group versus 23.5% in the chemotherapy group (p=0.08), and the DCR was 82.4% compared to 58.8% (p=0.26). Grade 3 or higher adverse events were observed in 17.6% of the combination therapy group and 29.4% of the chemotherapy group. Conclusions: The findings suggest that the combination of camrelizumab and anlotinib offers a superior anti-tumor response with a manageable safety profile in a second-line setting for ES-SCLC patients. This combination regimen may be a viable option for second-line ES-SCLC treatment.

Efficacy of chemo-immunotherapy in metastatic BRAF-mutated lung cancer: a single-center retrospective data.

Background: The effectiveness of combining immune checkpoint inhibitors (ICIs) with chemotherapy in treating non-small cell lung cancers (NSCLCs) with BRAF mutations has not been sufficiently explored. Methods: We compiled data from 306 NSCLC patients with identified BRAF mutations. We looked at efficacy by assessing the objective response rate (ORR) and disease control rate (DCR), as well as survival through measuring progression-free survival (PFS) and overall survival (OS). Results: Out of the patient pool, 44 were treated with a regimen of immune-chemotherapy. Patients undergoing ICI in combination with chemotherapy had a median PFS of 4 months, and the median OS was recorded at 29 months. There was a notable increase in OS in patients receiving first-line treatment versus subsequent lines (29 vs 9.75 months, p=0.01); however, this was not the case with PFS (9 vs 4 months, p=0.46). The ORR for patients on ICIs was 36.3%. PFS and OS rates did not significantly differ between patients with the BRAF-V600E mutation and those with non-V600E mutations (p=0.75 and p=0.97, respectively). Additionally, we found a significant variation in PD-L1 expression between those who responded to treatment and those who didn't (p=0.04). Conclusion: Our findings indicate that chemo-immunotherapy as an initial treatment may lead to improved OS in patients with BRAF-mutated NSCLC when compared to its use in subsequent lines of therapy. Further studies are needed to validate these results and to delve deeper into how specific types of BRAF mutations and PD-L1 expression levels might predict a patient's response to treatments in NSCLC.

Case report: The effect of second-line vebreltinib treatment on a patient with advanced NSCLC harboring the MET exon 14 skipping mutation after tepotinib treatment.

Background: Highly selective type Ib mesenchymal-epithelial transition gene (MET) tyrosine kinase inhibitors (TKIs) are the standard-of-care (SOC) therapy for previously untreated non-small cell lung cancer (NSCLC) harboring MET exon 14 (METex14) skipping mutations. However, there are rare reports describing effective regimens for patients who fail SOC without identifying resistant mutations or tissue transformation. Case report: We report the first case of a 74-year-old woman with lung adenocarcinoma (cT1cNxM0) harboring METex14 splice region mutation, which was identified by a next-generation sequencing (NGS)-based assay. The patient was administered two treatments, including first-line tepotinib and second-line vebreltinib. The patient achieved progression-free survival (PFS) of 7.6 months, and then disease progression of tepotinib was observed. A re-biopsy was performed for NGS, which revealed the same mutations as before, with no new gene mutations detected. The woman received subsequent vebreltinib therapy and experienced durable clinical benefits. In the first 6.8 months, chest computed tomography demonstrated stable disease. Then, she achieved partial response (PR). The durable PR lasted for more than 13 months, and the PFS is currently over 20 months, exceeding the prior treatment. Conclusion: This case highlights the importance of considering re-biopsy and reanalysis of genetic profiles in NSCLC patients harboring METex14 skipping mutations after progressive disease in MET TKI treatment. This raises the possibility that vebreltinib may have long-term survival benefits for patients without mutations conferring resistance (funded by Beijing Pearl Biotechnology Co., Ltd; ClinicalTrials.gov number, NCT04258033).