Epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations represent approximately 4-12% of EGFR mutations and are generally refractory to the 1st and 2nd generation EGFR tyrosine kinase inhibitors (TKIs). Development of effective therapies for patients with EGFRex20ins mutant non-small-cell lung carcinoma (NSCLC) represents a great unmet need. Preclinical models have shown that osimertinib is active in NSCLC harboring EGFRex20ins, while the antitumor activity of osimertinib remains to be evaluated in patients with EGFRex20ins mutations.Tumor genotyping was performed in 2316 Chinese NSCLC cases with targeted next generation sequencing (NGS) covering the whole exons of EGFR gene. The frequency and genetic characteristics of EGFRexon20ins mutations were analyzed. Furthermore, six patients with specific EGFRexon20ins mutations and receiving osimertinib 80 mg once daily were retrospectively included to assess the antitumor activity and safety of monotherapy osimertinib.EGFRex20ins mutations were identified in 4.8% (53/1095) of EGFR mutant NSCLC and 2.3% (53/2316) of all NSCLC cases. The most frequently identified EGFRexon20ins is A767_V769dup (17/53,32.1%). We found that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Four patients with osimertinib therapy achieved partial response and the rest stable disease. Median progression free survival (PFS) was 6.2 months (95% confidence interval 5.0-12.9 months; range 4.9-14.6 months). The most common adverse events (AEs) were diarrhea (2/6), pruritis (2/6), stomatitis (1/6) and nausea (1/6). No grade 3 or more AEs were documented.This study revealed that the genetic characteristics of EGFRex20ins mutations in Chinese patients with NSCLC were comparable to those reported in Caucasian patients. Furthermore, our study firstly demonstrated promising antitumor activity of osimertinib in certain EGFRex20ins mutant advanced NSCLC patients, indicating that osimertinib treatment for EGFRex20ins positive patients deserves further study.
Osimertinib has exhibited promising central nervous system (CNS) efficacy in Epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) patients. In real-world clinical practice, patients would turn to plasma genotyping or take osimertinib blindly after CNS progression on previous tyrosine kinase inhibitors (TKIs). However, the efficacy of osimertinib in those patients according to their T790M mutational status has not been explored.Twenty-five patients who received osimertinib due to intracranial progressions with stable extracranial diseases after early-generation EGFR-TKI treatment were collected from 1032 EGFR-mutated NSCLC. Plasma samples were analyzed for EGFR mutations using next-generation sequencing (NGS) or polymerase chain reaction (PCR).Among the 25 patients, 17 patients took plasma genotyping before osimertinib treatment with 8 patients EGFR T790M mutation-positive and the rest started osimertinib blindly. The median progression-free survival (PFS) was 8.0 months (95% confidence interval [CI]: 6.12-9.94) and median intracranial PFS (iPFS) was 14.4 months (95% CI: 7.27-21.59) for the total population. No statistical difference was found in PFS and iPFS among patients with different EGFR T790M mutational statuses. Intracranial disease control rate (DCR) was 100.0% for 14 patients with evaluable intracranial lesions despite different T790M mutational statuses. DCR for extracranial lesions and overall lesions were 100.0%, 66.7%, and 87.5% for patients with T790M, no T790M, and unknown T790M mutational status, respectively.For EGFR-mutated NSCLC patients with only intracranial progressions after previous TKI treatments, osimertinib is a promising treatment option regardless of T790M mutational status from plasma genotyping.
Background: Nintedanib has been approved for patients with interstitial lung disease (ILD). ILD associated with cancer therapies has been reported in several clinical studies and even causes deaths. To date, there are limited therapies for patients with ILD induced by cancer therapies. Herein, we reported the effect of nintedanib in ten cancer patients with ILD.Methods: Ten cancer patients were diagnosed with ILD, including eight non-small cell lung cancer (NSCLC) patients, one hard palate carcinoma and one nasopharyngeal carcinoma. Six ILDs were induced by targeted therapies and three by immunotherapies and one of unknown cause. All of them received nintedanib 150mg twice daily and underwent routine lung computed tomography (CT).Results: Obvious improvement was observed through radiological images after nintedanib treatment. Tumors were still under control during nintedanib treatment. One patient experienced a decrease in platelet count and recovered through symptomatic treatment. No adverse events were reported in the other patients.Conclusions: Nintedanib might benefit cancer patients with ILD, providing a novel and promising strategy to treat ILD induced by targeted therapies and immunotherapies. Further clinical studies are needed to confirm this strategy.
Several mechanisms including abnormal activation of PI3K-AKT-mTOR pathway have been proved to generate acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). In this study, we investigated the genomic characteristics of PI3K pathway activated in NSCLC patients after progression on EGFR-TKIs and whether both targeting EGFR and PI3K pathway could overcome resistance.A total of 605 NSCLC cases with a history of EGFR TKI treatment were reviewed, in which 324 patients harboring EGFR mutations were confirmed progression on at least one EGFR TKI and finally enrolled. Tumor tissues or blood samples were collected at the onset of TKI progression for next generation sequencing (NGS). Six EGFR mutant patients with co-occurring mutations in PI3K pathway were retrospectively collected to assess the effect of EGFR TKI plus everolimus, a mTOR inhibitor.Forty-nine (14.9%) patients resistant to EGFR TKIs have at least one genetic variation in PI3K pathway. PIK3CA, PTEN and AKT1 variations were detected in 31 (9.5%), 18 (5.5%) and 3 (0.9%) of patients, respectively. No significant differences were observed in distribution of PI3K pathway alterations among patients with different EGFR mutations (EGFR exon19 deletion mutations/EGFR L858R/uncommon EGFR mutations) and among patients resistant to different EGFR TKIs. For patients treated with everolimus and EGFR-TKI, five (5/6, 83.3%) achieved stable disease (SD) and one (1/6, 16.7%) didn't receive disease control. The median progression-free survival (PFS) was 2.1 months (95% confidence interval, 1.35-4.3 months, range, 0.9-4.4 months). The most common adverse events were dental ulcer (6/6), rash (1/6).Our study revealed that PI3K pathway was activated in at least 14.9% in EGFR-TKI resistant patients. EGFR-TKIs plus everolimus showed limited antitumor activity in EGFR mutant NSCLC patients with PI3K pathway aberrations.
e20588 Background: MET exon 14 ( METex14) skipping caused by certain mutations in splice sites of METex14 has been regarded as a promising target for non-small cell lung cancer (NSCLC) treatment with crizotinib, and was observed with lower responsiveness to immunotherapy (Joshua K. et al ASCO 2017). The molecular and immune characteristics, antitumor activity of crizotinib for Chinese NSCLC patients harboring METex14 skipping alterations remain to be elucidated. Methods: Tumor genomic profiling was performed by next-generation sequencing (NGS) assay (GeneCast Biotechnology Co., Beijing) on 9722 samples (FFPE and/or peripheral blood derived from 9289 Chinese NSCLC patients). PD-L1 expression was determined by qualitative immunohistochemical assay. Multiplex immunohistochemistry (mIHC) analysis was adopted to evaluate the immune microenvironment of selected samples. Retrospective analysis was performed to explore antitumor activity of crizotinib monotherapy in 10 patients harboring METex14 skipping alterations. Results: A total of 62 (0.67%) patients with somatic mutations occurred in METex14 splice sites (± 3bp) were identified. Median age of these patients is 64.5 years and 39% patients are female. Main histologic types are adenocarcinoma (81%, 50/62) and squamous carcinoma (13%, 8/62). 30 patients harbored high frequency METex14 mutations ranged from 1.34% to 79.49% nearly without co-existed known driver variants. Other 32 patients had low frequency mutations (below 1%) with some crucial oncogenic mutations such as EGFR 19del/L858R. In addition, very few CD8 + T cells were observed in tumor region and significantly less infiltrated than in stroma region ( P< 0.01). The overall response rate of crizotinib monotherapy on the ten patients with METex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. Conclusions: The occurrence rate of METex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( < 1%) METex14 mutations usually co-exist with other driver mutations while high frequency METex14 mutations do not. That little infiltration of CD8 + T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying METex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring METex14 skipping alterations.
Currently, women with metastatic or recurrent cervical cancer still have very limited treatment options. Despite the rapid advancements in targeted therapies, no targeted therapy was approved for cervical cancer, except for bevacizumab. In the present study, we reported a 52-year-old heavily pre-treated EGFR amplified patient with metastatic cervical squamous cancer who benefited from afatinib with a progression-free survival (PFS) of 5.5 months. The patient was administered with a first-line treatment of chemotherapy and bevacizumab with a PFS of 4.3 months. Subsequently the patient was treated with a second-line regimen of angiogenesis inhibitor apatinib plus chemotherapy and a third-line treatment of pembrolizumab. Genomic profiling revealed significant EGFR amplification in both primary (copy number [CN] =15.9) and metastatic lesions (CN =18). Afatinib monotherapy was then administered as the fourth-line regimen. She achieved partial response (PR) with a PFS of 5.5 months. At disease progression, the CN of EGFR was elevated to 39.9 accompanied by the emergence of PIK3CA amplification (CN =4.2). The patient was treated with everolimus and afatinib and achieved stable disease (SD) after 3 months. To the best of our knowledge, this is the first clinical evidence of an EGFR-amplified metastatic cervical cancer patient benefiting from afatinib as a single agent.
Objective This study aimed to compare the efficacy and safety of different platinum adjuvant chemotherapy regimens for early-stage resected non-small-cell lung cancer (NSCLC). Design Systematic review with network meta-analysis of randomised trials. Data sources PubMed, EMBASE, The Cochrane Library, Web of Science and Scopus Google Scholar were searched through 12 March 2021. Eligibility criteria Eligible randomised controlled trials (RCTs) comparing the postoperative platinum chemotherapy regimen with the observation-controlled group or comparing two platinum chemotherapy regimens head-to-head were included. Data extraction and synthesis The primary outcome was the efficacy of adjuvant chemotherapy regimens including relapse-free survival (RFS), overall survival (OS), 2-year, 3-year, 5-year RFS rate and OS rate. The secondary outcome was the rate of grade 3–4 toxicity assessments. Cochrane Handbook (V.5) was used for the risk of bias assessment. Analyses were performed using R software V.4.3.1. Results 20 RCTs with a sample size of 5483 were enrolled in meta-analysis. The chemotherapy group had a significant RFS and OS advantage compared with the observation group (HR 0.67; 95% CI 0.56 to 0.81, p<0.0001; HR 0.80; 95% CI, 0.73 to 0.88, p<0.0001, respectively). Compared with the observation arm, only the ‘cisplatin_vinorelbine’ regimen had a significant RFS and OS advantage (HR 0.63; 95% CI 0.43 to 0.87; HR 0.74; 95% CI 0.63 to 0.87, respectively) while the remaining chemotherapy regimens had no significant difference of efficacy compared with the observation group. In terms of the safety of adjuvant chemotherapy, the incidence of haematological toxicities and nausea/vomiting was not significantly higher in the ‘cisplatin_vinorelbine’ arm than in other chemotherapy group. Conclusion This study summarised the adjuvant cytotoxicity chemotherapy regimens for patients with early-stage resected NSCLC. Our analysis may provide some guiding significance for the clinicians when determining the optimal chemotherapy regimen.
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