Treatment Of Non-small Cell Lung Cancer Patients Research Articles

Clinical efficacy of Apatinib combined with Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) in nonsmall cell lung cancer after EGFR-TKI resistance.

To evaluate the efficacy and safety of Apatinib combined with epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) in the treatment of patients with non-small cell lung cancer (NSCLC) and acquired EGFR-TKI resistance. Clinical records of 106 patients with NSCLC at Shanxi Tumor Hospital of the Chinese Academy of Medical Sciences Cancer Hospital from January 2017 to October 2020, with acquired drug resistance after EGFR-TKI treatment were retrospectively analyzed. Among them, 52 patients received Apatinib combined with EGFR-TKI (Apatinib group), and 54 patients received a standard chemotherapy (pemetrexed combined with platinum) (chemotherapy group). Clinical efficacy indicators, follow-up results, and adverse reactions in both groups were compared. There was no significant difference in the objective response rate and disease control rate between the two groups (P>0.05). The progression free survival (PFS) of the Apatinib group was significantly longer than that of the chemotherapy group (10.5 months vs. 5.7 months; P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). Compared with standard chemotherapy, Apatinib combined with EGFR-TKI has the same efficacy in treating NSCLC patients with EGFR-TKI resistance, and was associated with longer PFS with no significant increase in adverse reactions.

Chest wall resections for non-small cell lung cancer: a literature review.

The development of early screening for lung cancer has led to improved overall survival in patients with non-small cell lung cancer (NSCLC). However, the management of NSCLC patients with resectable and potentially resectable chest wall invasion (CWI) requires attention. The purpose of this review is to summarize the role of surgery (chest wall resections) in NSCLC patients with CWI. A literature search and review from three databases (PubMed, Embase, and ScienceDirect) comprised the last 39 years. This review was focused on the treatment of NSCLC patients with CWI, mainly including the preoperative evaluation, principles of treatment and strategic decision-making, surgical complications, and prognostic factors. Through the collection of relevant literature on NSCLC that invades the chest wall, this narrative review describes the actual role in clinical practice and future developments of chest wall resections. Preoperative treatment requires the multidisciplinary team (MDT) team to conduct accurate clinical staging of the patient and pay attention to the patient's lymph node status and rib invasion status. The successful implementation of chest wall resection and possible chest wall reconstruction requires refined individualized treatment based on the patient's clinical characteristics, supplemented by possible postoperative systemic treatment. Surgery plays an important role in treating NSCLC patients with CWI, and a collaborative, experienced MDT is an essential component of the successful treatment of CWI with lung cancer. In the future, more high-quality clinical research is needed to focus on CWI patients so that patients can receive more effective treatment options and better clinical prognosis.

Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC.

Kristen Rat Sarcoma viral oncogene (KRAS) mutations are one of the most common oncogenic drivers found in 12-14% of non-small cell lung cancer (NSCLC) and 4% of colorectal cancer tumors. Although previously difficult to target, sotorasib and adagrasib are now approved for previously treated NSCLC patients with KRAS G12C mutations. In preclinical studies, divarasib was 5 to 20 times as potent and up to 50 times as selective as sotorasib and adagrasib. While sotorasib met its primary endpointin the phase III second line study against docetaxel, the progression-free survival (PFS) benefit was small and no overall survival (OS) benefit was observed. Adagrasib has demonstrated clinical benefitin the phase I/II KRYSTAL-1 study setting, however, 44.8% of patients reported grade 3 or higher toxicities. Divarasib has been studied in a phase I dose expansion cohort with promising efficacy [objective response (ORR) 53.4% and PFS 13.1 months]. Although most patients reported toxicities, the majority were low-grade and manageable with supportive care. Here we discuss these results in the context of the evolving KRAS G12C landscape.

The EGFR inhibitor exerts a suppressive influence on the response of CD8+ T cells in Non-Small Cell Lung Cancer

Abstract Lung cancer is the leading cause of death worldwide, predominantly characterized by non-small cell lung cancer (NSCLC). The foremost treatment for NSCLC patients with EGFR mutations involves EGFR-tyrosine kinase inhibitors (EGFR-TKIs), demonstrating notable enhancements in patient survival and the preservation of quality of life. Immune checkpoint blockade (ICB) that reinvigorates T cell response is a promising immunotherapeutic approach to treat NSCLC patients with an efficacy of approximately 20%. Thus, comprehending the intricate interplay between EGFR-TKIs and immune regulation is pivotal, laying the groundwork for strategic combination therapies. Despite its critical importance, the relationship between EGFR-TKIs and immune regulation remains elusive, necessitating further investigation into the immunomodulatory role of EGFR-TKIs. This study unveils that EGFR-TKIs contribute to the reduced proliferation and effector cytokine production of CD8+ T cells. Treatment with EGFR-TKIs suppresses the response of tumor-infiltrating T cells in two syngeneic tumor mouse models. Furthermore, employing EGFR-TKI-specific antibodies and mass spectrum analysis, we identified the target profile of EGFR-TKIs. Remarkably, NSCLC patients undergoing EGFR-TKI therapy exhibited a diminished frequency of IFNγ-producing CD8+ T cells. These findings significantly inform the future development of therapeutic strategies and the optimization of drug administration timing for NSCLC patients.

Abstract CT055: Efficacy of YK-029A, a novel EGFR TKI, in advanced NSCLC patients with acquired T790M mutation

Abstract In the multicenter, dose-escalation and dose-expansion phase 1 clinical trial (NCT05767866), we evaluated safety and tolerability of YK-029A in various EGFR mutated non-small-cell lung cancer (NSCLC). We have reported efficacy of YK-029A in untreated NSCLC with EGFR ex20ins mutation[1]. This time we report efficacy of YK-029A in patients with acquired EGFR T790M mutation after failure of first or second generation EGFR tyrosine kinase inhibitors (TKIs). Method: This dose-escalation and dose-expansion phase 1 trial recruited previously treated NSCLC patients with EGFR T790M mutation or patients with EGFR ex20ins or EGFR rare mutations. In dose-escalation phase, patients with EGFR T790M mutation were enrolled. YK-029A was given at doses of 50, 100, 150, 200 to 250 mg/day (3+3 design). In dose-expansion phase, patients with EGFR T790M, EGFR ex20ins, or EGFR rare mutations were enrolled. The primary objective was safety. Dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) were explored. Efficacy of YK-029A in EGFR T790M mutated NSCLC was assessed by the investigators. Results: A total of 114 patients were recruited into the study. Safety profile of the first 108 patients was reported previously[1]. By the cut-off date on Sep 12, 2023, 38 patients harbored EGFR T790M mutation were included in efficacy analysis. All these patients were previously treated with first or second generation EGFR-TKIs. The objective response rate (ORR; RECIST 1.1) was 65.8% (95%CI: 48.6%-80.4%) and disease control rate (DCR) was 84.2% (95%CI: 68.7%-94.0%). With a median follow-up time of 8.2 months,the median progression free survival (PFS) was 11.0 months (95%CI: 7.75-NR). The median overall survival (OS) was not reached. Among the 8 patients with measurable brain metastases, intracranial ORR was 75% (95%CI: 35.6%-95.6%) . Conclusions: YK-029A has promising activity in previously treated NSCLC patients harboring EGFR T790M mutation. Reference[1] DUAN J, WU L, YANG K, et al. Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial [J]. J Thorac Oncol, 2023. Citation Format: Rui Wan, Yi Fung Chau, Jun Zhao, Zhe Liu, Mingfang Zhao, Yanqiu Zhao, Xiumei Dai, Yueyin Pan, Zhihong Zhang, Yu Yao, Kunyu Yang, Lin Wu, Yanyan Xie, Bi Chen, Yixuan Yang, Yongqi Guo, Jie Wang, Jianchun Duan. Efficacy of YK-029A, a novel EGFR TKI, in advanced NSCLC patients with acquired T790M mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT055.

Abstract 1947: Studies on pMEK inhibitors for the treatment of RAS-mutant cancers as a single agent or combinations

Abstract RAS mutations are the most common oncogene in human cancers and KRAS has the highest frequency in non-small cell lung cancer (NSCLC) and pancreatic cancer (PDAC). KRAS G12C inhibitors have been approved to treat NSCLC patients. However, drug-resistance is eventually developed for these treatments. Preclinical studies suggested MAPK pathway reactivation is one possible mechanism. Among many MEK inhibitors in clinical development, CH5126766 binds to MEK1 inactive conformation and blocks its phosphorylation and activation. We believe this compound should prevent MAPK “paradoxical activation” commonly observed in most RAF and MEK inhibitors such as vemurafenib and cobimetinib. We studied this compound in various in vitro assays and found its potential in combating the paradoxical activation, which might be the cause of drug-resistance for MAPK signal pathway inhibitors, including RAS-, RAF- MEK- and ERK-inhibitors, as a single agent or in combination with above-mentioned inhibitors. In addition, we are developing a series of compounds based on CH5126766, by improving the inhibition of MEK1/2 kinase activity in addition to its activation. In summary, studies on the pMEK inhibitor demonstrated that this class of compounds might mitigate the MAPK pathway reactivation and prolong drug efficacies in clinical. Detailed research results will be discussed. Citation Format: Xiaobing Lv, Min Xu, Yong Hu, Lanjiao Zhao, Xiuquan Chen, Youqin Chen, Chen Yang, Jizhi Li, Chen Chen. Studies on pMEK inhibitors for the treatment of RAS-mutant cancers as a single agent or combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1947.

Tet methylcytosine dioxygenase 2 (TET2) deficiency elicits EGFR-TKI (tyrosine kinase inhibitors) resistance in non-small cell lung cancer

Despite epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC), acquired resistance inevitably develops, limiting clinical efficacy. We found that TET2 was poly-ubiquitinated by E3 ligase CUL7FBXW11 and degraded in EGFR-TKI resistant NSCLC cells. Genetic perturbation of TET2 rendered parental cells more tolerant to TKI treatment. TET2 was stabilized by MEK1 phosphorylation at Ser 1107, while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7FBXW11. Loss of TET2 resulted in the upregulation of TNF/NF-κB signaling that confers the EGFR-TKI resistance. Genetic or pharmacological inhibition of NF-κB attenuate the TKI resistance both in vitro and in vivo. Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2, and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency. Therefore, combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.

Durvalumab and taxane family combination therapy enhances the antitumoral effects for NSCLC: An in vitro study.

Immunotherapy has lately become the most preferred cancer treatment method, and for non-small cell lung cancer (NSCLC) first-line treatment, there are many immunotherapy options. This study aimed to assess the effectiveness and toxicity of paclitaxel (PTX), docetaxel (DTX) chemotherapy, immune checkpoint inhibitor treatment (durvalumab; DVL), and their combination in NSCLC. A-549 cells were treated with DVL in combination with PTX and DTX (a quarter of the IC50 ) to investigate their anticancer effects on these cells. The MTT assay, wound healing tests, and double-staining with Annexin V/PI were used to assess the cell viability, apoptosis, and migration. The results showed that a combination of 0.35 mg/mL DVL with 6.5 μg/mL PTX and 1.75 μg/mL DTX produced a synergistic effect with CI values of 0.88, 0.37, and 0.81, respectively. Moreover, the PTX + DTX + DVL combination led to a significantly increased apoptotic rate up to 88.70 ± 3.39% in the A549 cell line compared to monotherapy (p < .001). In addition, we found that the combination therapy with these agents increased the expression level of Bax, Cas-3, p53, and Bax/Bcl-2 ratio in all experimental groups. In conclusion, the results suggest that combining anti-PD-L1 antibody therapy with chemotherapy may provide a promising approach to enhance treatment outcomes and be a potentially efficacious strategy for treating NSCLC patients. Further research and clinical investigations are needed to elucidate the underlying molecular mechanisms and validate the therapeutic potential of these compounds in vivo.

Design, synthesis and antitumor activity of 4-arylamine substituted pyrimidine derivatives as noncovalent EGFR inhibitors overcoming C797S mutation

Clinical researches have shown that epidermal growth factor receptor (EGFR) is a key target for treatment of non-small cell lung cancer (NSCLC). Many EGFR inhibitors were successfully developed as ani-tumor drugs to treat NSCLC patients. Unfortunately, drug resistances were found in clinic. To overcome C797S mutation in EGFR, a novel series of 4-arylamine substituted pyrimidine derivatives were designed and synthesized under the principle of structure-based drug design. Interestingly, compounds 6e and 9i demonstrated the best anti-proliferative activity against A549, NCI–H1975, and HCC827 cells. In particular, the IC50 values against HCC827 cells reached to 24.6 nM and 31.6 nM, which were much lower than human normal cells 2BS and LO2. Furthermore, compounds 6e and 9i showed extraordinary activity against EGFR19del/T790M/C797S (IC50 = 16.06 nM and 37.95 nM) and EGFRL858R/T790M/C797S (IC50 = 11.81 nM and 26.68 nM), which were potent than Osimertinib (IC50 = 52.28 nM and 157.60 nM). Further studies have shown that compounds 6e and 9i could pertain inhibition of HCC827 colony formation, and arrest HCC827 cells at G2/M phase. Moreover, the most promising compound 6e could inhibit the migration of HCC827 cells, induce HCC827 cells apoptosis, and significantly inhibit the phosphorylation of EGFR, AKT and Erk1/2. In vivo xenograft mouse model with HCC827 cells, compound 6e resulted in remarkable tumor regression without obvious toxicity. In addition, molecular docking studies suggested that compound 6e could firmly combine with T790M-mutant, T790 M/C797S-mutant, and L858R/T790 M/C797S-mutant EGFR kinases as ATP-competitive inhibitor.

Binding Thermodynamics of Fourth-Generation EGFR Inhibitors Revealed by Absolute Binding Free Energy Calculations.

The overexpression or mutation of the kinase domain of the epidermal growth factor receptor (EGFR) is strongly associated with non-small-cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) have proven to be effective in treating NSCLC patients. However, EGFR mutations can result in drug resistance. To elucidate the mechanisms underlying this resistance and inform future drug development, we examined the binding affinities of BLU-945, a recently reported fourth-generation TKI, to wild-type EGFR (EGFRWT) and its double-mutant (L858R/T790M; EGFRDM) and triple-mutant (L858R/T790M/C797S; EGFRTM) forms. We compared the binding affinities of BLU-945, BLU-945 analogues, CH7233163 (another fourth-generation TKI), and erlotinib (a first-generation TKI) using absolute binding free energy calculations. Our findings reveal that BLU-945 and CH7233163 exhibit binding affinities to both EGFRDM and EGFRTM stronger than those of erlotinib, corroborating experimental data. We identified K745 and T854 as the key residues in the binding of fourth-generation EGFR TKIs. Electrostatic forces were the predominant driving force for the binding of fourth-generation TKIs to EGFR mutants. Furthermore, we discovered that the incorporation of piperidinol and sulfone groups in BLU-945 substantially enhanced its binding capacity to EGFR mutants. Our study offers valuable theoretical insights for optimizing fourth-generation EGFR TKIs.

Inhibition of PKA/CREB1 pathway confers sensitivity to ferroptosis in non-small cell lung cancer

Ferroptosis is a type of regulated cell death characterized by iron accumulation and lipid peroxidation. The molecular mechanisms underlying ferroptosis regulation in non-small cell lung cancer (NSCLC) are poorly understood. In this study, we found that protein kinase A (PKA) inhibition enhanced ferroptosis susceptibility in NSCLC cells, as evidenced by reduced cell viability and increased lipid peroxidation. We further identified cAMP-responsive element protein 1 (CREB1), a transcription factor and a substrate of PKA, as a key regulator of ferroptosis. Knockdown of CREB1 sensitized NSCLC cells to ferroptosis inducers (FINs) and abolished the effects of PKA inhibitor and agonist, revealing the pivotal role of CREB1 in ferroptosis regulation. Using a high-throughput screening approach and subsequent validation by chromatin immunoprecipitation (ChIP) and dual-luciferase assays, we discovered that CREB1 transcriptionally activated stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids. SCD conferred ferroptosis resistance by decreasing the availability of polyunsaturated fatty acids for lipid peroxidation, and its overexpression rescued the effect of CREB1 knockdown on ferroptosis in vitro. Besides, CREB1 knockdown suppressed xenograft tumor growth in the presence of Imidazole Ketone Erastin (IKE), a potent FIN, and this effect was reversed by SCD. Finally, we showed that high expression of CREB1 was associated with poor prognosis in NSCLC patients from public datasets and our institution. Collectively, this study illustrates the effect of PKA/CREB1/SCD axis in regulating ferroptosis of NSCLC, targeting this pathway may provide new strategies for treating NSCLC patients.

Epidermal Growth Factor Receptor-Targeted Neoantigen Peptide Vaccination for the Treatment of Non-Small Cell Lung Cancer and Glioblastoma.

The epidermal growth factor receptor (EGFR) plays crucial roles in several important biological functions such as embryogenesis, epithelial tissue development, and cellular regeneration. However, in multiple solid tumor types overexpression and/or activating mutations of the EGFR gene frequently occur, thus hijacking the EGFR signaling pathway to promote tumorigenesis. Non-small cell lung cancer (NSCLC) tumors in particular often contain prevalent and shared EGFR mutations that provide an ideal source for public neoantigens (NeoAg). Studies in both humans and animal models have confirmed the immunogenicity of some of these NeoAg peptides, suggesting that they may constitute viable targets for cancer immunotherapies. Peptide vaccines targeting mutated EGFR have been tested in multiple clinical trials, demonstrating an excellent safety profile and encouraging clinical efficacy. For example, the CDX-110 (rindopepimut) NeoAg peptide vaccine derived from the EGFRvIII deletion mutant in combination with temozolomide and radiotherapy has shown efficacy in treating EGFRvIII-harboring glioblastoma multiforme (GBM) patients undergone surgery in multiple Phase I and II clinical trials. Furthermore, pilot clinical trials that have administered personalized NeoAg peptides for treating advanced-stage NSCLC patients have shown this approach to be a feasible and safe method to increase antitumor immune responses. Amongst the vaccine peptides administered, EGFR mutation-targeting NeoAgs induced the strongest T cell-mediated immune responses in patients and were also associated with objective clinical responses, implying a promising future for NeoAg peptide vaccines for treating NSCLC patients with selected EGFR mutations. The efficacy of NeoAg-targeting peptide vaccines may be further improved by combining with other modalities such as tyrosine kinase or immune checkpoint inhibitor (ICI) therapy, which are currently being tested in animal models and clinical trials. Herein, we review the most current basic and clinical research progress on EGFR-targeted peptide vaccination for the treatment of NSCLC and other solid tumor types.

A randomized phase III study of docetaxel alone versus docetaxel plus S-1 in patients with previously treated non-small cell lung cancer: JMTO LC09-01.

This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone. Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients.

Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells

Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necroptosis-related regulator MLKL in human NSCLC tissues and cell lines. Knockdown of Skp2 inhibited viability, anchorage-independent growth, and in vivo tumor development of NSCLC cells. We also found that the Skp2 protein is negatively correlated with MLKL in NSCLC tissues. Moreover, Skp2 is increased and accompanied by an upregulation of MLKL ubiquitination and degradation in cisplatin-resistant NSCLC cells. Accordingly, inhibition of Skp2 partially restores MLKL and sensitizes NSCLC cells to cisplatin in vitro and in vivo. Mechanistically, Skp2 interacts and promotes ubiquitination-mediated degradation of MLKL in cisplatin-resistant NSCLC cells. Our results provide evidence of an Skp2-dependent mechanism regulating MLKL degradation and cisplatin resistance, suggesting that targeting Skp2-ubiquitinated MLKL degradation may overcome NSCLC chemoresistance.

Short-term outcomes of robot-assisted versus video-assisted thoracoscopic surgery for non-small cell lung cancer patients with neoadjuvant immunochemotherapy: a single-center retrospective study.

Neoadjuvant immunochemotherapy has been increasingly applied to treat non-small cell lung cancer (NSCLC). However, the comparison between robotic-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) in the feasibility and oncological efficacy following neoadjuvant immunochemotherapy is scarce. This study aims to assess the superiorities of RATS over (VATS) concerning short-term outcomes in treating NSCLC patients with neoadjuvant immunochemotherapy. NSCLC patients receiving RATS or VATS lobectomy following neoadjuvant immunochemotherapy at Shanghai Chest Hospital from 2019 to 2022 were retrospectively identified. Baseline clinical characteristics, perioperative outcomes, and survival profiles were analyzed. Forty-six NSCLC patients with neoadjuvant immunochemotherapy were included and divided into the RATS (n=15) and VATS (n=31) groups. The baseline clinical characteristics and induction-related adverse events were comparable between the two groups (all p>0.050). The 30-day mortality in the RATS and VATS groups were 0% and 3.23%, respectively (p=1.000). Patients undergoing RATS were associated with reduced surgical-related intensive unit care (ICU) stay than those receiving VATS (0.0 [0.0-0.0] vs. 0.0 [0.0-1.0] days, p=0.026). Moreover, RATS assessed more N1 LNs (6.27 ± 1.94 vs 4.90 ± 1.92, p=0.042) and LN stations (3.07 ± 1.03 vs 2.52 ± 0.57, p=0.038) compared with VATS. By comparison, no difference was found in surgical outcomes, pathological results, and postoperative complications between the RATS and VATS groups (all p>0.050). Finally, RATS and VATS achieved comparable one-year recurrence-free survival (82.96% vs. 85.23%, p=0.821) and the timing of central nervous system, LN, and bone recurrences (all p>0.050). RATS is safe and feasible for NSCLC patients with neoadjuvant immunochemotherapy, reducing surgical-related ICU stay, assessing increased N1 LNs and stations, and achieving similar survival profiles to VATS.

Comparison of efficacy and safety of second- and third-generation TKIs for non-small-cell lung cancer with uncommon EGFR mutations.

The efficacy of definite for non-small-cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations has been preliminarily demonstrated. However, there is a paucity of data with which to compare the efficacy and safety of second- and third-generation TKIs in patients with NSCLC carrying uncommon EGFR mutations. We compared the efficacy and safety of second- and third-generation TKIs in all NSCLC patients in whom next-generation sequencing confirmed uncommon EGFR mutations, including G719X, S768I, and L861Q. The parameters analyzed included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The rate of treatment-related adverse events (AEs) reflected the safety of these TKIs. Eighty-four NSCLC patients with uncommon EGFR mutations were enrolled between April 2016 and May 2022 at Zhejiang Cancer Hospital, including 63 treated with second-generation TKIs and 21 treated with third-generation TKIs. The ORR for all patients receiving TKIs was 47.6%, and the DCR was 86.9%. The median PFS for NSCLC patients with uncommon EGFR mutations receiving TKIs was 11.9 months and OS was 30.6 months. There was no significant difference in PFS after treatment with second- or third-generation TKIs (13.3 vs. 11.0 months, respectively, P = 0.910) or in OS (30.6 vs. 24.6 months, respectively P = 0.623). The third-generation TKIs showed no severe toxicity. The efficacy of second- and third-generation TKIs for NSCLC with uncommon EGFR mutations does not differ, and so can be used to treat NSCLC patients with these mutations.

Abstract 5056: ABN401 demonstrates robust anti-tumor efficacy in orthotopic PDX models of MET-driven NSCLC brain metastases in a pre-clinical study

Abstract Background Brain metastases (BM) are manifested in approximately 30-50% of patients with non-small cell lung cancer (NSCLC) and are associated with catastrophic implications on prognosis and survival. The development of blood-brain barrier-penetrant therapies for brain metastases of NSCLC is imperative and is a major clinical hurdle. ABN401, a highly potent and selective c-MET inhibitor, shows promising anti-tumor activity without significant safety concerns in patients with advanced NSCLC. Here, we report that ABN401 exhibits potent anti-tumor efficacy in pre-clinical orthotopic patient-derived xenografts (PDXs) derived from MET-driven NSCLC brain metastases. Methods Anti-tumor efficacy of ABN401 was assessed in two lung cancer PDXs (LU5349 and LU5406) from BM models harboring high-level MET amplification grown in NOD/SCID mice. Subcutaneous PDXs (n=14/group) were treated with ABN401 (60 mg/kg QD, 125 mg/kg QD, and 165 mg/kg QD) or control groups. Established PDXs were orthotopically implanted into the brain (n=14/group) and were treated with ABN401 (125mg/kg QD), or control groups. The tumor volume of orthotopic model was monitored using magnetic resonance imaging (MRI). Brain, plasma, and tumor samples were collected for pharmacokinetics (PK) and pharmacodynamics (PD) correlation analysis. Results The efficacy of ABN401(125 mg/kg QD) was confirmed in the subcutaneous PDX models (LU5349 and LU5406). Treatment with ABN401 showed up to 95% and 99% tumor growth inhibition in the LU5349 and LU5406 models, respectively. ABN401 (125 mg/kg QD) treatment induced complete or near-complete tumor growth regressions in the orthotopic tumor model. ABN401 also showed a desirable PK and safety profile with no significant changes in body weight. Conclusions ABN401 treatment showed robust anti-tumor efficacy in PDX models of MET-driven NSCLC brain metastases. Our findings suggest that ABN401 has excellent potential for treating NSCLC patients with BM and supports its ongoing clinical development. Citation Format: Nirmal Rajasekaran, Kyung Eui Park, Saehyung Lee, Na Young Kim, Suk-Jae Chung, Young Kee Shin, Jun Young Choi. ABN401 demonstrates robust anti-tumor efficacy in orthotopic PDX models of MET-driven NSCLC brain metastases in a pre-clinical study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5056.

Challenges and knowledge gaps with immune checkpoint inhibitors monotherapy in the management of patients with non-small-cell lung cancer: a survey of oncologist perceptions

Immune checkpoint-inhibitors (ICIs) are changing outcomes in different cancer settings, notably for patients with non-small-cell lung cancer (NSCLC). There are, however, still important gaps of evidence for clinical practice when using these novel treatments. In this study, we assessed physicians' opinion and experience on challenges for clinical practice with ICIs monotherapy in NSCLC. A survey was conducted on experienced physicians treating patients with NSCLC with ICIs. Two rounds of pilot tests were carried out for validation among a group of experts. Topics under analysis were in relation to treatment of elderly populations, performance status, brain metastases, use of steroids or antibiotics, the effects of gut microbiome, autoimmune diseases, human immunodeficiency virus infection, solid organ transplants, use of anti-programmed cell death protein 1 versus anti-programmed death-ligand 1 drugs, atypical tumour responses, predictors of response, duration of treatment and a final open question on additional relevant challenges. Two hundred and twenty-one answers were collected, including 106 (48%) valid answers from experts for final analysis (physicians who have treated at least 20 patients with NSCLC with ICIs). The vast majority agreed that the selected topics in this study are important challenges ahead and more evidence is needed. Moreover, predictors of response, treating brain metastasis, shorter duration of treatment, the effects of gut microbiome and concomitant use of steroids were voted the most important topics to be further addressed in prospective clinical research. This survey contributed to understanding which are the main challenges for clinical practice with ICIs monotherapy in NSCLC. It can also contribute to guide further clinical research, considering the opinions and experience of those who regularly treat NSCLC patients with ICIs.

What is the yield of EBUS-TBNA for re-evaluation of previously treated non-small-cell lung cancer?

Locoregional recurrence in lung cancer still remains an important problem. We aimed to indicate the effectiveness of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for reevaluation in previously treated nonsmall cell lung cancer (NSCLC). : NSCLC patients who underwent EBUS for rebiopsy of suspicious recurrent or progressive lesions between January 2010 and June 2017 were reviewed. Patients were categorized into two groups based on the previous treatment modalities: Group 1 (G1) consisted of patients who had been treated with chemoradiotherapy, and Group 2 (G2) consisted of patients who had undergone radical surgery. Of 115 patients, 100 patients enrolled in the study. Of 26 patients with 35 lymph nodes in G1, malignant cells were identified in thirteen patients (50%). Anthracosis was detected in the remaining. Malignancy was detected in 28 patients (37.8%) in G2. Thirty-threepatients were diagnosed as benign (24 anthracosis; 8 lymphocytes, and 1 granulomatous); 8 were not sampled, and inadequate material was obtained in five. The sensitivity, specificity, negative and positive predictive value, and overall diagnostic accuracy of EBUS-TBNA for rebiopsy in G1 were 84.8%, 100%, 89.1%, 100%, and 93.2%, respectively. These values were all perfect in G2. EBUS-TBNA could be preferred as a feasible and efficient procedure for rebiopsy in previously treated NSCLC patients.

HTA142 Potential Impact of Biomarker Guided-Decisions on Overtreatment in Immunotherapy for Non-Small Cell Lung Cancer Patients

With only 30% of non-small cell lung cancer (NSCLC) patients showing a durable disease control to immune-oncology drugs, biomarkers are expected to enable more personalized treatment. We have applied statistical and machine learning methods to sequential serum protein measurements to predict early disease progression in immunotherapy treated NSCLC patients. This study evaluates the potential impact of introducing such a prediction model in clinical practice on cancer management and subsequent costs.