The study of primary and acquired resistance to first-line osimertinib to improve the outcome of EGFR-mutated advanced Non-small cell lung cancer patients: the challenge is open for new therapeutic strategies.

The development of targeted therapy in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients has radically changed their clinical perspectives. Current first-line standard treatment for advanced disease is commonly considered third-generation tyrosine kinase inhibitors (TKI), osimertinib. The study of primary and acquired resistance to front-line osimertinib is one of the main burning issues to further improve patients' outcome. Great heterogeneity has been depicted in terms of duration of clinical benefit and pattern of progression and this might be related to molecular factors including subtypes of EGFR mutations and concomitant genetic alterations. Acquired resistance can be categorized into two main classes: EGFR-dependent and EGFR-independent mechanisms and specific pattern of progression to first-line osimertinib have been demonstrated. The purpose of the manuscript is to provide a comprehensive overview of literature about molecular resistance mechanisms to first-line osimertinib, from a clinical perspective and therefore in relationship to emerging therapeutic approaches.

Efficacy of Pyrotinib With/Without Trastuzumab in Treatment-Refractory, HER2-Positive Metastatic Colorectal Cancer: Result From a Prospective Observational Study.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a promising therapeutic target in metastatic colorectal cancer (mCRC). This study was to evaluate the efficacy and safety of pyrotinib alone or pyrotinib with trastuzumab in patients with HER2-positive mCRC. PATIENTS AND METHODS: In this prospective observational study, patients with HER2 positive, Ras Sarcoma Viral Oncogene Homolog (RAS) wild type mCRC who received at least one standard treatment of palliative chemotherapy were enrolled. Patients were treated with oral pyrotinib alone or pyrotinib with trastuzumab. The primary endpoint was progression free survival (PFS), and the secondary endpoints were overall survival (OS), confirmed objective response rate (ORR), and safety. This trial is registered with chitcr.org, number ChiCTR2100046381. RESULTS: From February 15, 2021, to January 10, 2023, 32 patients were enrolled in this study. Twenty (62.5%) patients were treated with pyrotinib, while 12 (37.5%) received pyrotinib and trastuzumab. As of June 24, 2023, with a median follow-up of 11.0 months, the median PFS was 5.7 months (95%CI 4.5-10.2), while OS was not evaluable (NE), ORR and disease control rate (DCR were 34.4% and 87.5%. Patients' PFS in the pyrotinib plus trastuzumab subgroup and pyrotinib monotherapy group were 8.6 and 5.5 months, OS was not evaluable (NE) and 10.9 months, ORR was 50.0% and 25.0%, respectively. Most treatment-related adverse events (TRAEs) were grade 1-2, diarrhea was the most frequent TRAE (81.3%, 26/32). Grade 3 TRAEs occurred in 11 patients: 9 for diarrhea, 1 for nausea, and 1 for oral mucositis. CONCLUSION: Pyrotinib with or without trastuzumab showed promising anti-tumor activity and acceptable toxicities in treatment-refractory, HER2-positive mCRC.

HER2-positive advanced biliary tract cancer responds to second-line pyrotinib therapy: a case report.

Biliary tract cancers are solid tumors with poor prognosis and over 70% of patients present in advanced stages. The efficacy of second-line treatment for patients who progressed on GC chemotherapy is limited. Median OS of these patients is less than 1 year with palliative treatment. Despite the success of anti-HER2 therapy in HER2-positive breast cancer, the targeted therapy of HER2 mutations in BTCs is still being explored. This case report is the first report suggesting a 15-month PFS and partial response of pyrotinib in HER2-positive BTC. We report a 64-year-old female with HER2-positive biliary tract cancer. She was diagnosed with AJCC clinical stage IV (cT3N1M1) intrahepatic biliary tract cancer and got PD after 3 cycles of systemic chemotherapy of gemcitabine plus cisplatin. Due to the HER2-positive signature, pyrotinib (400 mg daily in 21-day cycles), an oral irreversible pan-ErbB TKI was prescribed in September 2021, with her informed consent. The tumor shrank significantly after this treatment and imaging assessments conducted on 24 September 2022 showed PR. Until the writing of the case draft, the patient had achieved 15 months of PFS. The present case suggests that Pyrotinib might be a potential effective treatment for HER2-positive advanced BTC.

Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Pyrotinib-based therapeutic approaches for HER2-positive breast cancer: the time is now.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a highly aggressive subtype associated with poor prognosis. The advent of HER2-targeted drugs, including monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) and antibody-drug conjugates, has yielded improved prognosis for patients. Compared with widely used monoclonal antibodies, small-molecule TKIs have unique advantages including oral administration and favorable penetration of blood-brain barrier for brain metastatic BC, and reduced cardiotoxicity. Pyrotinib is an irreversible TKI of the pan-ErbB receptor, and has recently been shown to be clinically effective for the treatment of HER2-positive BC in metastatic and neoadjuvant settings. This review highlights the development on the application of pyrotinib-based therapeutic approaches in the clinical settings of HER2-positive BC.

Overall Survival for Osimertinib Wows.

The final overall survival (OS) results for the ADAURA trial show that osimertinib reduces the risk of death by 51% in patients with EGFR-mutated non-small cell lung cancer. For stage II or IIIA disease, the 5-year OS was 85% in patients who received osimertinib and 73% in the control group. The findings were nearly identical when patients with stage IB tumors were included in the analysis.

Construction of IMMS Containing Multi-site Liposomes for Dynamic Monitoring of Blood CTC in Patients with Osimertinib-resistant Non-small-cell Lung Cancer and its Mechanism.

OBJECTIVE: This article aims to establish a liquid biopsy system for gene detection of circulating tumor cells (CTC) in lung cancer, systematically analyze the significance of osimertinib resistance, and formulate an individualized diagnosis and treatment plan. METHODS: Liposome-contained magnetic microspheres coated with Fe3O4 nanoparticles were synthesized by microemulsion, and the surface was modified with EGFR antibody to form EGFR/EpCAM multi-site liposome-contained immunomagnetic microspheres (IMMSs). The CTCs were isolated and identified from peripheral blood samples and the cell lines of lung cancer patients collected by the multi-site liposome-contained IMMSs. To investigate the effects of the order of use of IMMSs sequence at different sites on the sorting and trapping efficiency of non-small-cell lung cancer (NSCLC) cells . The preliminary verification of drug-resistant gene function and dynamic monitoring of CTCs in 20 patients with EGFR-positive NSCLC were screened and statistically analyzed before and after osimertinib treatment. Sensitivity analysis and drug resistance evaluation of oxitidine were detected in vitro. RESULTS: Results showed the prepared multi-site liposome-contained IMMSs had high stability and specificity. The number of CTCs in blood samples of the patients with NSCLC was detected, revealing high sorting efficiency, and positive sorting rate reaching more than 90%. We investigated the effect of osimertinib on the HER-2 expression on the EGFR-mutated NSCLC cells and found that osimertinib increased the expression of HER-2 on the cell surface of NSCLC cell lines., And further explored the therapeutic potential of osimertinib combined with T-DM1 at different dosing times. CONCLUSION: Our results demonstrate that the prepared multi-site liposome-contained IMMSs can efficiently isolate CTCs from the peripheral blood in lung cancer. Combined with the experimental data about osimertinib can be effectively identified, the resistant genes of NSCLC including EGFR, which will provide a new scientific basis for guiding clinical medication and formulating individualized treatment plans.

Efficacy and Risk Factors of Pyrrotinib in Second- and Third-Line Treatments for HER2-Positive Advanced Breast Cancer.

A study to examine the efficacy and risk factors associated with pyrrotinib in the second- and third-line treatment of advanced breast cancer with Human epidermal growth factor receptor 2- (HER2-) positive cells was conducted. Progression-free survival (PFS) was assessed as the primary endpoint, and the objective response rate (ORR), overall survival (OS), and safety were secondary endpoints. Across all the patients, the ORR was 48.57%, and the disease control rate (DCR) was 94.29%. In the follow-up period, the median PFS was 15 months, and second-line treatment had significantly longer PFS than third-line treatment (P = 0.027). The OS among all the patients was up to 28 months, but the median OS has not yet been reached. Diarrhea (69.57%) was the most important AE, mainly in grades 1 and 2. According to the COX regression analysis, brain metastasis was a risk factor for PFS, while second-line treatment and capecitabine chemotherapy were relevant to a longer PFS correlation among patients. In the second- and third-line treatment, pyrrotinib is still highly effective and safe. Pyrrotinib is a potential ideal salvage treatment plan for patients who failed in first-line treatments.

Efficacy and Safety of Befotertinib (D-0316) in Patients With EGFR T790M-Mutated NSCLC That Had Progressed After Prior EGFR Tyrosine Kinase Inhibitor Therapy: A Phase 2, Multicenter, Single-Arm, Open-Label Study.

INTRODUCTION: Befotertinib (D-0316) is a novel, third-generation EGFR tyrosine kinase inhibitor (TKI). This study evaluated befotertinib in patients with locally advanced or metastatic NSCLC who developed an EGFR T790M mutation after progression on first- or second-generation EGFR TKI therapy. METHODS: This was a single-arm, open-label, phase 2 study at 49 hospitals across mainland China. Patients with locally advanced or metastatic NSCLC harboring EGFR T790M mutations with disease progression after prior first- or second-generation EGFR TKI therapy received oral befotertinib of 50 mg (cohort A) or 75 to 100 mg (cohort B) once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee in intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT03861156. RESULTS: A total of 176 patients and 290 patients were included in cohorts A (50 mg) and B (75-100 mg), respectively. At data cutoff (August 15, 2021), independent review committee-assessed ORR was 67.6% (95% confidence interval [CI]: 61.9%-72.9%) in cohort B. The investigator-assessed ORR was 54.0% (95% CI: 46.3%-61.5%) in cohort A and 65.9% (95% CI: 60.1%-71.3%) in cohort B. The median investigator-assessed progression-free survival was 11.0 (95% CI: 9.6-12.5) months in cohort A and 12.5 (95% CI: 11.1-13.8) months in cohort B. The median independent review committee-assessed progression-free survival in cohort B was 16.6 (95% CI: 15.0-not evaluable [NE]) months. The intracranial ORR was 26.7% (95% CI: 7.8%-55.1%) in cohort A by investigator assessment, while 57.1% (95% CI: 34.0%-78.2%) and 55.9% (95% CI: 37.9%-72.8%) in cohort B by investigator and independent review committee assessment, respectively. The median investigator-assessed intracranial progression-free survival was 16.5 (95% CI: 8.6-NE) months in cohort A, while the median intracranial progression-free survival was not evaluable in cohort B due to immature data regardless of investigator or independent review committee assessment. and NE (95% CI: 13.8-NE) in cohort B. The overall survival was immature. Grade 3 or higher treatment-related adverse events and treatment-related serious adverse events occurred in 20.5% and 11.4% of patients in cohort A and in 29.3% and 10.0% of patients in cohort B, respectively. CONCLUSIONS: Befotertinib of 75 to 100 mg has satisfying efficacy and manageable toxicity in patients with locally advanced or metastatic NSCLC harboring T790M mutation with resistance to first- or second-generation EGFR TKIs. A phase 3 randomized trial is underway (NCT04206072).

Sequence-dependent synergistic effect of aumolertinib-pemetrexed combined therapy on EGFR-mutant non-small-cell lung carcinoma with pre-clinical and clinical evidence.

BACKGROUND: Inevitably developed resistance of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) limited its clinical benefit on non-small cell lung cancer (NSCLC). Upfront combination therapy is promising to prevent this resistance. Compelling clinical evidence indicated the failure of third-generation EGFR TKIs combined with either immunotherapy or antiangiogenic agents. In comparison, combined treatment of third-generation EGFR TKIs and chemotherapy might be a favorable choice. Herein, we systematically analyzed and compared the effects of pemetrexed and a novel third-generation EGFR TKI aumolertinib combined in different sequences, subsequently revealed the potential mechanisms and proved the optimal combination schedule with clinical retrospective study. METHODS: Three combination schedules involving pemetrexed and aumolertinib in different sequences were developed. Their inhibition effects on cell proliferation and metastasis were firstly compared upon three human NSCLC cell lines in vitro, by cell counting kit-8, colony formation, wound healing and transwell assays respectively. Further evaluation in vivo was proceeded upon H1975 and HCC827 xenograft model. Gene and protein expression were detected by Q-PCR and western blot. Drug concentration was determined by LC-MS/MS. VEGF secretion was determined by ELISA. Tumor vessel was visualized by immunofluorescence. Lastly, a clinical retrospective study was raised with 65 patients' data. RESULTS: The combination of pemetrexed and aumolertinib exhibited a sequence-dependent and EGFR mutant-dependent synergistic effect in vitro and in vivo. Only treatment with aumolertinib following pemetrexed (P-A) exhibited synergistic effect with stronger anti-tumor growth and anti-metastasis ability than monotherapy and also other combination sequences. This synergism could exclusively be observed in H1975 and HCC827 but not A549. Pathway analysis showed that P-A significantly enhanced the suppression of EGFR pathway. In addition, our results intriguingly found an obvious reduction of VEGF secretion and the accompanying normalization of the intratumor vessel, consequently increasing intratumoral accumulation of pemetrexed in P-A group. Finally, the clinical retrospective study verified the synergistic effect of P-A combination by significantly superior tumor response than aumolertinib monotherapy. CONCLUSION: Aumolertinib-pemetrexed combined therapy is promising for EGFR mutant NSCLC but only in right administration sequence. P-A could become an advantageous combination strategy in clinical with synergistic inhibition of tumor growth and metastasis.