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Cancers Oct 2022(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene ()...
Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon Mutations: A Comparative Cohort Study in China (AFANDA Study).
(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene () mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 ( = 0.006), but fewer G3 ( = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon mutations.
PubMed: 36358728
DOI: 10.3390/cancers14215307 -
Translational Lung Cancer Research Jun 2023Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and...
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC) and contributed to the development of precision medicine. Osimertinib is a standard first-line (1L) treatment for -mutated NSCLC and has demonstrated superior survival benefits over previous-generation TKIs. However, resistance to osimertinib is nearly inevitable, and subsequent treatment strategies remain unmet medical needs in this setting. Afatinib, a second-generation EGFR-TKI, exhibits activity against certain uncommon mutation types in the 1L setting. There are a few case reports on the efficacy of afatinib against -dependent resistance after osimertinib treatment, although these have not been prospectively investigated.
METHODS
The present phase II, single-arm multicenter trial aims to verify the efficacy and safety of afatinib rechallenge after 1L osimertinib resistance. Patients (aged ≥20 years) with advanced or recurrent non-squamous NSCLC harboring drug-sensitive mutations (deletion of exon 19 or L858R) who were previously treated with 1L osimertinib and second-line chemotherapy other than TKIs are considered eligible. Undergoing next-generation sequence-based comprehensive genomic profiling is one of the key inclusion criteria. The primary endpoint is the objective response rate; the secondary endpoints are progression-free survival, overall survival, and tolerability. Thirty patients will be recruited in December 2023.
DISCUSSION
The results of this study may promote incorporating afatinib rechallenge into the treatment sequence after 1L osimertinib resistance, a setting in which concrete evidence has not been yet established.
REGISTRATION
UMIN Clinical Trial Registry: UMIN000049225.
PubMed: 37425417
DOI: 10.21037/tlcr-23-12 -
Integrative Cancer Therapies 2022In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR tyrosine kinase inhibitors (TKI) leads to disease...
In epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC), acquired resistance to EGFR tyrosine kinase inhibitors (TKI) leads to disease progression. Strategies to overcome the resistance are required in treatment for advanced lung cancer. In this study, we investigated the therapeutic effect of afatinib and HangAmDan-B1 (HAD-B1) co-administration in gefitinib-resistant NSCLC using HCC827-GR, NSCLC cell line with gefitinib resistance, and the HCC827-GR cell implanted mouse model. HAD-B1 consists of 4 herbs, Radix, , C. A. Mey, and Birdwood, and has been reported to be effective in patients with advanced lung cancer in clinical practice. Our findings demonstrated that HAD-B1 combined with afatinib markedly inhibited cell proliferation and induced apoptosis compared to afatinib monotherapy and HAD-B1 monotherapy. Inhibition of HCC827-GR cell proliferation by HAD-B1 occurred through MET amplification and reduced phosphorylation, and the synergistic effect of afatinib and HAD-B1 induced cell cycle arrest and apoptosis in HCC827-GR cells via the downregulation of ERK and mTOR signaling pathways. In hematology and biochemistry tests, HAD-B1 alleviated the toxicity of tumor. In conclusion, HAD-B1 combined with afatinib would be a promising therapeutic strategy for NSCLC with EGFR-TKI resistance.
Topics: Animals; Mice; Carcinoma, Non-Small-Cell Lung; Afatinib; Gefitinib; Lung Neoplasms; Quinazolines; ErbB Receptors; Cell Line, Tumor; Drug Resistance, Neoplasm; Mutation
PubMed: 36565160
DOI: 10.1177/15347354221144311 -
Cancer Treatment and Research... 2022After the development of acquired resistance to osimertinib, the standard-of-care treatment for advanced EGFR-mutated NSCLC is chemotherapy. Whether afatinib, a pan-ErbB...
INTRODUCTION
After the development of acquired resistance to osimertinib, the standard-of-care treatment for advanced EGFR-mutated NSCLC is chemotherapy. Whether afatinib, a pan-ErbB family tyrosine kinase inhibitor, is active after progression on osimertinib is unknown.
METHODS
We conducted a single-institution retrospective analysis of patients with advanced EGFR-mutated NSCLC who received afatinib-containing therapy after progression on osimertinib. Kaplan-Meier analyses evaluated progression-free survival (PFS) and overall survival (OS) from initiation of afatinib.
RESULTS
After progression on first (N=3) or second-line plus (N=12) osimertinib, 15 patients received afatinib monotherapy (N=3), afatinib and cetuximab (N=10), or afatinib and bevacizumab (N=2). The objective response rate was 6.7% and disease control rate was 53.3%. Median PFS was 2.5 months and median OS was 7.7 months. Median PFS of ≥ 6 months versus < 6 months on osimertinib was associated with a significantly greater median PFS on afatinib (4.0 versus 1.4 months; P=0.003), although there was no significant difference in median OS (9.3 versus 6.6 months; P=0.123). Best response of stable disease/partial response versus progressive disease on osimertinib was associated with a significantly greater median PFS on afatinib (3.4 versus 1.6 months; P=0.036) and a significantly greater median OS (8.7 versus 4.6 months; P=0.017).
CONCLUSION
Afatinib-containing therapy had limited activity in patients with EGFR-mutated NSCLC after progression on osimertinib in this cohort of mostly second-line plus osimertinib. Response and longer PFS to prior osimertinib may be predictive of response to afatinib. Strategies based on osimertinib resistance mechanisms may further define the role of subsequent afatinib.
PubMed: 34920242
DOI: 10.1016/j.ctarc.2021.100497 -
Pharmaceuticals (Basel, Switzerland) Apr 2023The epidermal growth factor receptor (EGFR) plays a critical role in the tumorigenesis of various forms of cancer. Targeting the mutant forms of EGFR has been identified... (Review)
Review
The epidermal growth factor receptor (EGFR) plays a critical role in the tumorigenesis of various forms of cancer. Targeting the mutant forms of EGFR has been identified as an attractive therapeutic approach and led to the approval of three generations of inhibitors. The quinazoline core has emerged as a favorable scaffold for the development of novel EGFR inhibitors due to increased affinity for the active site of EGFR kinase. Currently, there are five first-generation (gefitinib, erlotinib, lapatinib, vandetanib, and icotinib) and two second-generation (afatinib and dacomitinib) quinazoline-based EGFR inhibitors approved for the treatment of various types of cancers. The aim of this review is to outline the structural modulations favorable for the inhibitory activity toward both common mutant (del19 and L858R) and resistance-conferring mutant (T790M and C797S) EGFR forms, and provide an overview of the newly synthesized quinazoline derivatives as potentially competitive, covalent or allosteric inhibitors of EGFR.
PubMed: 37111291
DOI: 10.3390/ph16040534 -
Scientific Reports Nov 2023Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along...
Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation is brain metastasis (BM)-prone. We determined the impact of this hallmark, along with EGFR subtype and generation of tyrosine kinase inhibitor (TKI) treatment, on patients' outcome. 553 metastatic EGFR-mutant NSCLC patients received front-line EGFR-TKI treatment. Progression-free survival (PFS), overall survival (OS) and secondary T790M rate were analysed. BM was observed in 211 (38.2%) patients. BM (HR 1.20 [95% CI 0.99-1.48]; p = 0.053), ECOG PS 0-1 (HR 0.71 [95% CI 0.54-0.93]; p = 0.014) and afatinib treatment (HR 0.81 [95% CI 0.66-0.99]; p = 0.045) were associated with PFS. Afatinib-treated patients without BM demonstrated a significantly longer PFS (16.3 months) compared to afatinib-treated patients with BM (13.7 months) and to gefitinib/erlotinib-treated patients with (11.1 months) or without BM (14.2 months; p < 0.001). CNS-only progression trended higher in afatinib-treated patients. ECOG PS 0-1 (HR 0.41 [95% CI 0.31-0.56]; p < 0.001) and EGFR L858R mutation (HR 1.46 [95% CI 1.13-1.88]; p = 0.003), but not BM, were the predictors for OS. BM (OR 2.02 [95% CI 1.02-4.08]; p = 0.040), afatinib treatment (OR 0.26 [95% CI 0.12-0.50]; p < 0.001) and EGFR L858R mutation (OR 0.55 [95% CI 0.28-1.05]; p = 0.070) were associated with secondary T790M rate. In BM patients, gefitinib/erlotinib-treated ones with 19 deletion mutation and afatinib-treated ones with L858R mutation had the highest and the lowest T790M rate (94.4% vs. 27.3%, p < 0.001), respectively. BM and generation of EGFR-TKI jointly impact PFS and secondary T790M rate in patients with EGFR-mutant NSCLC, whereas OS was mainly associated with EGFR subtype.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Erlotinib Hydrochloride; Gefitinib; ErbB Receptors; Lung Neoplasms; Protein Kinase Inhibitors; Mutation; Treatment Outcome; Brain Neoplasms
PubMed: 37989860
DOI: 10.1038/s41598-023-45815-8 -
Frontiers in Oncology 2023Afatinib is mainly used to treat advanced non-small cell lung cancer, but its therapeutic effect on hepatocellular carcinoma is still unclear.
BACKGROUND
Afatinib is mainly used to treat advanced non-small cell lung cancer, but its therapeutic effect on hepatocellular carcinoma is still unclear.
METHODS
Over 800 drugs were screened by CCK8 technology and afatinib was found to have a significant inhibitory effect on liver cancer cells. The expression of PDL1 in tumor cells treated with drugs were detected by qRT-PCR and Weston Blot experiments. The effects of afatinib on the growth, migration and invasion of HCC cells were evaluated using wound healing, Transwell, and cell cloning assays. The in vivo effects of afatinib in combination with anti-PD1 were evaluated in C57/BL6J mice with subcutaneous tumorigenesis. Bioinformatics analysis was performed to explore the specific mechanism of afatinib's inhibition of ERBB2 in improving the expression level of PD-L1, which was subsequently verified through experiments.
RESULTS
Afatinib was found to have a significant inhibitory effect on liver cancer cells, as confirmed by in vitro experiments, which demonstrated that it could significantly suppress the growth, invasion and migration of HCC cells. qRT PCR and Weston Blot experiments also showed that Afatinib can enhance the expression of PD-L1 in tumor cells. In addition, in vitro experiments confirmed that afatinib can significantly enhance the immunotherapeutic effect of hepatocellular carcinoma. Afatinib's ability to increase PD-L1 expression is mediated by STAT3 activation following its action on HCC cells.
CONCLUSION
Afatinib enhances PD-L1 expression in tumor cells through the STAT3/PD-L1 pathway. The combination of afatinib and anti-PD1 treatment significantly increases the immunotherapeutic effect of HCC.
PubMed: 37324014
DOI: 10.3389/fonc.2023.1198118 -
Scientific Reports Dec 2023There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and... (Randomized Controlled Trial)
Randomized Controlled Trial
There is no strong and reliable predictive biomarker in head and neck squamous cell carcinoma (HNSCC) for EGFR inhibitors. We aimed to identify predictive and pharmacodynamic biomarkers of efficacy of afatinib, a pan-HER tyrosine kinase inhibitor, in a window-of-opportunity trial (NCT01415674). Multi-omics analyses were carried out on pre-treatment biopsy and surgical specimen for biological assessment of afatinib activity. Sixty-one treatment-naïve and operable HNSCC patients were randomised to afatinib 40 mg/day for 21-28 days versus no treatment. Afatinib produced a high rate of metabolic response. Responders had a higher expression of pERK1/2 (P = 0.02) and lower expressions of pHER4 (P = 0.03) and pRB1 (P = 0.002) in pre-treatment biopsy compared to non-responders. At the cellular level, responders displayed an enrichment of tumor-infiltrating B cells under afatinib (P = 0.02). At the molecular level, NF-kappa B signaling was over-represented among upregulated genes in non-responders (P < 0.001; FDR = 0.01). Although exploratory, phosphoproteomics-based biomarkers deserve further investigations as predictors of afatinib efficacy.
Topics: Humans; Afatinib; Squamous Cell Carcinoma of Head and Neck; Quinazolines; Head and Neck Neoplasms; Biomarkers; Protein Kinase Inhibitors
PubMed: 38110561
DOI: 10.1038/s41598-023-49887-4 -
Clinical Cancer Research : An Official... Jun 2020Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC)....
PURPOSE
Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia.
EXPERIMENTAL DESIGN
We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied and for efficacy and safety.
RESULTS
Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non-small cell lung cancer (NSCLC), displayed nontumor/tumor IC ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patient-derived HNSCCs. Finally, toxicity studies in -deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters.
CONCLUSIONS
Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia.
Topics: Afatinib; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Fanconi Anemia; Female; Gefitinib; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 32005748
DOI: 10.1158/1078-0432.CCR-19-1625 -
The Oncologist May 2024The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how...
BACKGROUND
The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC.
PATIENTS AND METHODS
Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population.
RESULTS
Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths.
CONCLUSION
We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.
PubMed: 38761385
DOI: 10.1093/oncolo/oyae107