Efficacy of gefitinib in patients with advanced non-small cell carcinoma of the lung harboring common, uncommon and complex EGFR mutations

Background: As the commonest EGFR-TKI being used in Hong Kong, gefitinib has shown to be efficacious and safe as first line treatment for L858R mutation and exon 19 deletion with less gastrointestinal and cutaneous adverse events than erlotinib and afatinib. However, the evidence for therapeutic efficacy for uncommon and complex EGFR mutations is lacking. Whether gefitinib is efficacious for uncommon and complex EGFR mutations worth studying. Objectives: To assess the therapeutic efficacy of gefitinib, as measured by progression-free survival and overall survival, among advanced stage lung cancer patients with common, uncommon and complex EGFR mutations. Methods: This is a retrospective cohort study that included 241 Chinese patients with advanced non-small cell carcinoma of lung harboring EGFR mutations and received gefitinib 250 mg daily as first-line treatment. The progression-free survival [PFS] and overall survival [OS] for patients with different EGFR mutations, namely exon 19 deletion, L858R mutation in exon 21, uncommon EGFR mutations and complex EGFR mutations were analyzed. Results: Among the 241 patients, 118 [49%] had exon 19 deletion, 104 [43%] had L858R mutation in exon 21, 6 [2.5%] had uncommon EGFR mutations, 13 [5.4%] had complex EGFR mutations. The mean age was 69. 72% of the patients were female and with 81% being non-smoker. For patients with complex EGFR mutations, regardless of the presence of exon 19 deletion and L858R mutation as the component, have better PFS and OS than patients with single common EGFR mutations [Exon 19 deletion or L858R mutation]. Patients with uncommon EGFR mutations have inferior PFS and OS than those with common EGFR mutations. Conclusion: Gefitinib is a possible option for patients with complex EGFR mutations while it may not be the preferred treatment option in patients with single uncommon EGFR mutations.

Conversion from Positive to Negative EGFR Mutation due to Clonal Selection during Long-Term Treatment with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors: A Case Report

A 77-year-old woman with postoperative recurrent non-small cell lung adenocarcinoma, which exhibited an <i>epidermal growth factor receptor (EGFR)</i> L858R mutation, was treated with gefitinib and erlotinib. Seven years after the start of treatment, the patient experienced a recurrence of malignant pleural effusion. However, 3 different genetic tests revealed that the lung adenocarcinoma cells in the pleural effusion had lost <i>EGFR</i> L858R mutation, suggesting that long-term treatment with EGFR-tyrosine kinase inhibitors (TKIs) converted <i>EGFR</i> mutation from positive to negative. The negative conversion of <i>EGFR</i> mutation as a mechanism of acquired resistance to EGFR-TKIs is considered rare and needs to be further investigated.

Case Report: Long Progression-Free Survival of Immunotherapy for Lung Adenocarcinoma With Epidermal Growth Factor Receptor Mutation

BackgroundImmune checkpoint inhibitors (ICIs) have been clinically proven to be efficient in non-small cell lung cancer (NSCLC). However, it has also been found that immunotherapy is not effective for all patients. For instance, some patients with epidermal growth factor receptor (EGFR) mutation tumors have a low overall response rate to ICIs. As a result, we retrospectively analyzed the efficacy of anti-programmed death-ligand 1 (anti-PD-L1) blockade (atezolizumab) treatment for a patient with EGFR mutation, and we explored the interaction between immunotherapy and EGFR mutations in NSCLC.Case PresentationA patient, 62-year-old non-smoking female, with lung adenocarcinoma was initially misdiagnosed as EGFR wild type and received a third-line treatment with atezolizumab, experiencing partial response (PR) and progression-free survival (PFS) for 23 months. She had later been confirmed with EGFR L858R mutation prior to taking atezolizumab. On top of that, the patient developed T790M mutation after being administered with atezolizumab instead of EGFR tyrosine kinase inhibitors (TKIs). She started with osimertinib, although the lesion continued to progress. Tumor mutational burden (TMB), PD-L1 expression, and tumor-infiltrating lymphocytes (TILs) had been tested for further analysis.ConclusionThe case report and literature review indicate that ICIs might be more effective for L858R mutation than for other EGFR mutant subtypes, which correlates with certain potential predictors such as TMB and concurrent PD-L1 plus CD8+ TIL expression. However, there is no report on progression from non-primary EGFR T790M mutation to T790M mutation of patients who neither previously suffered from EGFR-TKIs nor responded to osimertinib. This case report will offer some information to guide the investigation on how to identify those who can benefit from immunotherapy and those who do not respond to EGFR-TKIs among the patients with EGFR mutations.

PD-L1 expression as a predictor of postoperative recurrence and the association between the PD-L1 expression and EGFR mutations in NSCLC

Although information on the PD-L1 expression and EGFR mutations in non-small cell lung cancer (NSCLC) is important for therapeutic strategies, the effect of these factors on postoperative recurrence and the association between each factor have remained unclear. We retrospectively assessed the PD-L1 expression and EGFR mutations in 280 NSCLC patients, and analyzed the associations by multivariate analyses. The hazard ratio (HR) of postoperative recurrence in cases with high (≥ 50%) PD-L1 expression regarding negative expression was 4.83 (95% confidence interval [CI] 1.51–15.5). The HR for the PD-L1 expression, considered a continuous variable, was 1.016 (95% CI 1.01–1.03). The HRs in cases with EGFR major and minor mutations were 0.42 (95% CI 0.14–1.25) and 0.63 (95% CI 0.18–2.15), respectively. The high PD-L1 (≥ 50%) expression was significantly associated with exon 21 L858R mutation (Ex21) of EGFR (odds ratio, 0.10; 95% CI 0.01–0.87). The risk of postoperative recurrence increased 1.016-fold for every 1% increase in the PD-L1 expression, and a marked increase in risk was observed for expression levels of ≥ 50%. Whereas EGFR mutations were not an independent risk factor. The high PD-L1 (≥ 50%) expression was negatively associated with Ex21. These findings may help identify NSCLC patients with an increased risk of postoperative recurrence.

Comparative assessment of NOIR-SS and ddPCR for ctDNA detection of EGFR L858R mutations in advanced L858R-positive lung adenocarcinomas

Genotyping epidermal growth factor receptor (EGFR) is an essential process to indicate lung adenocarcinoma patients for the most appropriate treatment. Liquid biopsy using circulating tumor DNA (ctDNA) potentially complements the use of tumor tissue biopsy for identifying genotype-specific mutations in cancer cells. We assessed the performance of a high-fidelity sequencing method that uses molecular barcodes called the nonoverlapping integrated read sequencing system (NOIR-SS) for detecting EGFR L858R-mutated alleles in 33 advanced or recurrent patients with L858R mutation-positive lung adenocarcinoma revealed by matched tissue biopsy. We compared NOIR-SS with site-specific droplet digital PCR (ddPCR), which was taken as the reference, in terms of sensitivity and ability to quantify L858R variant allele fractions (VAFs). NOIR-SS and ddPCR had sensitivities of 87.9% (29/33) and 78.8% (26/33) for detecting L858R alleles, respectively. The VAFs measured by each assay were strongly correlated. Notably, one specimen was positive with a VAF of 30.12% for NOIR-SS but marginally positive with that of 0.05% for ddPCR because of a previously poorly recognized mechanism: two-base substitution-induced L858R (c.2573_2574delinsGA). These results indicate that NOIR-SS is a useful method for detecting ctDNA, potentially overcoming a limitation of ddPCR which highly depends on the binding ability of primers to specific targeting sequences.

Causal Relationship between Postoperative Recurrence and PD-L1 and EGFR Mutations in NSCLC: A Retrospective Cohort Study

Although information on the PD-L1 expression and EGFR mutations in non-small cell lung cancer (NSCLC) is important for determining therapeutic strategies, the causality between these two factors and postoperative recurrence and the association between each factor have remained unclear. We retrospectively assessed the PD-L1 expression and EGFR mutations in tumors of 280 NSCLC patients. The causality between the PD-L1 expression, EGFR mutations and postoperative recurrence were evaluated by a multivariate Cox proportional hazard analysis. The association between the PD-L1 expression and EGFR mutations was evaluated by a multinomial logistic regression analysis. The adjusted hazard ratio (HR) in cases with high (≥ 50%) PD-L1 expression was 4.83 (95% confidence interval [CI]: 1.51–15.5). The adjusted HRs in cases with EGFR major and minor mutations were 0.42 (95% CI: 0.14–1.25) and 0.63 (95% CI: 0.18–2.15), respectively. The high expression of PD-L1 (≥ 50%) was significantly associated with exon 21 L858R mutation (Ex21) of EGFR (adjusted odds ratio, 0.10; 95% CI, 0.01–0.87). The high expression of PD-L1 was an independent risk factor for postoperative recurrence in NSCLC, whereas EGFR mutations were not. The high expression of PD-L1 was negatively associated with Ex21. These findings may help identify NSCLC patients with an increased risk of postoperative recurrence.

A Lung Adenocarcinoma Patient With a Rare EGFR E709_T710delinsD Mutation Showed a Good Response to Afatinib Treatment: A Case Report and Literature Review

For advanced lung adenocarcinoma patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), tyrosine kinase inhibitors (TKIs) are the standard therapies, and achieve favorable responses. However, for the rare EGFR deletion-insertion mutation of exon 18, there is no evidence of the efficacy of EGFR TKIs. Herein, we report a lung adenocarcinoma patient harboring a rare EGFR E709_T710delinsD mutation who was treated with afatinib as the first-line therapy and achieved a progression-free survival of 23 months. After the disease progressed, the patient received almonertinib treatment and exhibited a stable disease. This case indicated that non-small cell lung cancer patients harboring the EGFR E709_T710delinsD mutation could benefit from afatinib treatment, followed with almonertinib treatment, as a potential therapeutic strategy.

Efficacy and pattern failures of early SBRT to primary tumor in advanced EGFR mutation lung cancer (Target-SBRT): A single-arm phase 2 study.

e21130 Background: It is evitable for advanced NSCLC harboring EGFR mutation with 1st TKI to develop resistance with 9-13 months of PFS and 19-27 months of OS. Initial progression of TKI treatment in NSCLC was 47.2% from the primary sites, 20.4% from the new sites and 32.6% from the primary and new sites. We hypothesized that early stereotactic body radiation therapy (SBRT) to primary tumor in advanced EGFR mutation NSCLC combined with EFGR-TKI treatment could prolong targeted resistance and explored its pattern failures. Methods: Eligible patients pathologically confirmed advanced NSCLC with Exon19 deletion or Exon21 L858R mutation were enrolled (ChiCTR-OIN-17013920). Each patient received EGFR TKI (Icotinib 125mg tid or gefitinib 250mg qd) and early SBRT (40-60 Gy/5-8F/5-10d) for primary tumor about 1 months from the beginning of EGFR TKI until disease progressed. Initial progression in sites of original disease (primary/metastatic) was defined as original site failure (OF) and appearance of new lesions as distant site failure (DF). Simultaneous OF/DF was labeled as ODF. The primary endpoint was PFS and the second endpoints were pattern failures, OS as well as adverse effects (AEs). Study was designed to enroll 50 patients to detect 6 months’ extension of PFS. Results: The study was closed after 41 patients enrolled due to the use of more effective 3rd EGFR-TKI.There were 37 PR and 4 SD after one month of TKI treatment and the average tumor shrinkage rate was 42.5%. The average interval from TKI to SBRT was 1.43 months (0.87-2.77 months). Median PFS and OS were 15.2 months (95% CI 13.1-17.4) and 27.6 months (95% CI 23.1-32.1), respectively. Of 37 patients who progressed, 6 (16.2%) had OF, 21 (56.8%) had DF, and 10 (27.0%) had ODF. The lung was the most common site of initial progression. As for toxicity, there was no ≥Grade 3 AEs and Grade 1-2 radiation Pneumonitis was the most frequent AEs. Conclusions: Early SBRT for primary tumor generated prolonged PFS without serious radiation pneumonitis in advanced EGFR mutation NSCLC patients with TKI treatment. This combined therapy obtained remarkably lower primary tumor progression rate and favorable OS. Clinical trial information: ChiCTR-OIN-17013920.