Neoadjuvant aumolertinib monotherapy for EGFR-mutant lung squamous cell carcinoma: a case report.

Background: Lung cancer is the malignant tumor with high incidence and mortality in China, and more than 30% of non-small cell lung cancer (NSCLC) patients are in the locally advanced stage at the first-time diagnosis. Currently, neoadjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combined with radical surgery is effective in the treatment of unresectable stage III EGFR-mutated NSCLC (NSCLCm), and related studies are gradually increasing. But the feasibility of neoadjuvant EGFR-TKI combined with radical surgery for unresectable stage III EGFR-mutant lung squamous cell carcinoma (LUSQm) remains controversial. Case Description: This report presented a successful case of neoadjuvant target-therapy with aumolertinib, the third-generation EGFR-TKI, combined with radical surgery for a stage IIIA LUSQm female patient. After four cycles (28 days/cycle) of neoadjuvant target-therapy, the tumor had a partial response on imaging evaluation and pathological evaluation after surgery showed complete tumor response. The neoadjuvant target-therapy was well tolerated. All adverse events (AEs) that occurred during the treatment were grade I, including decreased platelets, impaired liver function, and diarrhea. The patient was instructed to continue taking Aumolertinib for 3 years after surgery. At the cut-off date of April 1, 2024, the patient had no recurrence after 20 months of treatment. Conclusions: The result of patient treatment demonstrated the potential feasibility of neoadjuvant Aumolertinib monotherapy for locally advanced LUSQm. The report provides some support for neoadjuvant target-therapy for LUSQm.

A heterogeneous tumor immune microenvironment of uncommon epidermal growth factor receptor mutant non-small cell lung cancer.

Common epidermal growth factor receptor (EGFR) mutations are usually not considered for immunotherapy in non-small cell lung cancer (NSCLC) due to poor efficacy. However, whether uncommon EGFR mutations are suitable for immunotherapy has not been thoroughly studied. Thus, we explored the tumor immune microenvironment (TME) features in uncommon EGFR mutant NSCLC. In this study, a total of 41 patients with EGFR mutations were included, the majority (85.4%) of whom were stage I. Among them, 22 patients harbored common mutations, while 19 patients presented with uncommon mutations. Compared with common mutations, uncommon mutations exhibited more infiltrating T cells and fewer M2 macrophages, upregulated expression of antigen processing and a presentation pathway. Unsupervised clustering based on the mIF profile identified two classes with heterogeneous TME in uncommon mutations. Class 1 featured the absence of PD-1+ cytotoxic T cell infiltration, and class 2 displayed a hotter TME because of the downregulated expression of hypoxia (p < 0.001), oxidative phosphorylation (p = 0.009), and transforming growth factor beta signaling (p = 0.01) pathways as well as increased expression of CTLA4 (p = 0.001) and PDCD1 (p = 0.004). The association of CTLA4 and PDCD1 with TME profiles was validated in a TCGA lung adenocarcinoma cohort with uncommon EGFR mutations. Our study reveals the distinct and heterogeneous TME features in uncommon EGFR mutant NSCLC.

The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC.

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.

ATTLAS, IMpower151 and ORIENT-31: Dusting off IMpower150 for Post-Osimertinib in EGFR-Mutated NSCLC?

Treatment strategies for post-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in EGFR-mutant non-small cell lung cancer (NSCLC) is an ongoing challenge. Previously, the IMPRESS trial comparing platinum doublet chemotherapy with or without EGFR-TKI did not demonstrate any progression-free survival (PFS) benefit. The retrospective subgroup analysis of IMpower150 indicated that the quad regimen (carboplatin, paclitaxel, bevacizumab, atezolizumab) improved PFS and overall survival (OS) in patients with EGFR-mutant NSCLC who progressed on first-generation EGFR-TKIs. Given the retrospective nature of the analysis, the IMpower150 regimen is not approved in the US for post-EGFR-TKI treatment. Currently, osimertinib or other third-generation (3G) EGFR-TKIs is the first-line standard of care for advanced EGFR-mutant NSCLC. MARIPOSA-2 provided the first randomized trial post-osimertinib in EGFR-mutant NSCLC patients with another quad regimen (platinum, pemetrexed, lazertinib, amivantamab). The IMpower150 and MARIPOSA-2 quad regimens differ in the principle of whether to continue or even "double-down" on EGFR inhibition. Recently, three prospective randomized trials conducted in Asia offered promising results, showing that a quad regimen of doublet platinum chemotherapy plus anti-angiogenesis agent and ICI may be as efficacious as MARIPOSA-2 with a lower rate of toxicities and accounting for the PFS difference if 1L chemotherapy plus osimertinib instead of osimertinib monotherapy. In particular, the median PFS achieved by the quad regimens of ATTLAS and IMpower151 is 8.5 months. However, only 8.2% and 17.9% of the EGFR-mutant NSCLC patients who received the quad regimens progressed on 3G EGFR-TKI, respectively. Here, we discuss how the results of IMpower151 and ATTLAS may rejuvenate interest in a non-EGFR containing quad regimen as a potential post-osimertinib monotherapy treatment. Randomized trials comparing the results of these studies, including the quad regimen of MARIPOSA-2 versus the quad regimen of IMpower151/Impower150/ATTLAS in post-osimertinib (or other 3G EGFR-TKI) progression, are urgently needed.

Long-term survival of a patient with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and untreated multiple brain metastases treated with zorifertinib: A case report.

Brain metastases (BM) are common in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and confer poor prognoses. Zorifertinib (AZD3759), an EGFR-tyrosine kinase inhibitor (TKI) with high blood-brain barrier penetration, has previously demonstrated promising systemic and intracranial antitumor activity in phase 1-3 studies. This is the first report of a patient with EGFR-mutant (exon 21 L858R) NSCLC and symptomatic untreated multiple BM who achieved a long overall survival (OS) of more than 65 months after sequential treatment with zorifertinib and a third-generation EGFR-TKI. This new treatment paradigm offers a new treatment option and deserves further clinical exploration to prolong OS of patients with EGFR-mutant NSCLC and untreated multiple BM.

Neoadjuvant EGFR-TKI therapy in Non-Small cell lung cancer.

Non-small cell lung cancer (NSCLC) stages I-III are predominantly treated with surgery and combination immunotherapy and chemotherapy. A majority of these studies excluded patients with EGFR and ALK alterations. There are several completed and ongoing trials evaluating neoadjuvant treatment with EGFR-TKI monotherapy, combination therapy with chemotherapy, and combination therapy with immunotherapy. Here, we review completed clinical trials and discuss current ongoing trials' potential benefits, challenges, and future directions in the field.

Outcomes of patients with advanced epithelial growth factor receptor mutant lung cancer treated with first-line osimertinib who would not have met the eligibility criteria for the FLAURA clinical trial.

OBJECTIVES: Osimertinib is largely used as first-line therapy for metastatic epithelial growth factor receptor (EGFR) mutant lung cancers based on the FLAURA clinical trial. Real-world patient outcomes often differ from clinical trial outcomes. This study evaluated the efficacy of first-line osimertinib in patients treated in British Columbia (BC), Canada. Furthermore, we compared the outcomes of patients who would and would not have been eligible for the original FLAURA trial. METHODS: Consecutive patients receiving first-line osimertinib for metastatic EGFR exon19 or L858R lung cancer were identified using the BC Cancer Pharmacy Database. Patient eligibility for the FLAURA clinical trial were retrospectively reviewed based on the following criteria: ECOG ≥ 2, symptomatic brain metastases or on steroids, hemoglobin < 90 g/L, platelets < 100x109/L, or a creatinine clearance < 50 mL/min. mOS was assessed for the entire population and compared between patients who would have been eligible and ineligible for FLAURA. RESULTS: From January 2020 to October 2021, 311 patients received first-line osimertinib; 44 % (137/311) were deemed FLAURA ineligible, predominantly due to low ECOG (n = 120). After a median follow-up of 26.5 months, the mOS for the entire cohort was 27.4 months (95 %CI 23.8-30.1). The mOS for ineligible patients was 18 months shorter than eligible patients (15.8 vs 34.2, p < 0.001). Ineligible patients had higher rates of de novo stage IV disease, higher rates of stage IVB disease, and more sites of disease than eligible patients. CONCLUSION: In this real-world population, nearly half of patients would have been ineligible for FLAURA. The mOS was one year shorter than reported in FLAURA. However, patients who would have been eligible for the FLAURA clinical trial had similar OS to patients enrolled in FLAURA. Trial ineligible patients had a higher burden of disease at baseline which may have led to inferior outcomes. Further research is needed to improve outcomes in these patients.

ALDOA coordinates PDE3A through the ß-catenin/ID3 axis to stimulate cancer metastasis and M2 polarization in lung cancer with EGFR mutations.

Lung cancer has a high incidence rate and requires more effective treatment strategies and drug options for clinical patients. EGFR is a common genetic alteration event in lung cancer that affects patient survival and drug strategy. Our study discovered aberrant aldolase A (ALDOA) expression and dysfunction in lung cancer patients with EGFR mutations. In addition to investigating relevant metabolic processes like glucose uptake, lactate production, and ATPase activity, we examined multi-omics profiles (transcriptomics, proteomics, and pull-down assays). It was observed that phosphodiesterase 3A (PDE3A) enzyme and ALDOA exhibit correlation, and furthermore, they impact M2 macrophage polarization through ß-catenin and downstream ID3. In addition to demonstrating the aforementioned mechanism of action, our experiments discovered that the PDE3 inhibitor trequinsin has a substantial impact on lung cancer cell lines with EGFR mutants. The trequinsin medication was found to decrease the M2 macrophage polarization status and several cancer phenotypes, in addition to transduction. These findings have potential prognostic and therapeutic applications for clinical patients with EGFR mutation and lung cancer.

Perioperative Treatment Strategies in EGFR-Mutant Early-Stage NSCLC: Current Evidence and Future Challenges.

Treatment with 3 years of adjuvant osimertinib is considered a new standard in patients with completely resected stage I to IIIA NSCLC harboring a common sensitizing EGFR mutation. This therapeutic approach significantly prolonged the disease-free survival and the overall survival versus placebo and revealed a significant role in preventing the occurrence of brain metastases. However, many unanswered questions remain, including the optimal duration of this therapy, whether all patients benefit from adjuvant osimertinib, and the role of adjuvant chemotherapy in this population. Indeed, there is a renewed interest in neoadjuvant strategies with targeted therapies in resectable NSCLC harboring oncogenic drivers. In light of these considerations, we discuss the past and current treatment options, and the clinical challenges that should be addressed to optimize the treatment outcomes in this patient population.

Intracranial Outcomes of De Novo Brain Metastases Treated With Osimertinib Alone in Patients With Newly Diagnosed EGFR-Mutant NSCLC.

Introduction: Patients with EGFR-mutant NSCLC have a high incidence of brain metastases. The EGFR-directed tyrosine kinase inhibitor osimertinib has intracranial activity, making the role of local central nervous system (CNS)-directed therapies, such as radiation and surgery, less clear. Methods: Patients with EGFR-mutant NSCLC and brain metastases who received osimertinib as initial therapy after brain metastasis diagnosis were included. Individual lesion responses were assessed using adapted RANO-BM criteria. CNS progression and local progression of brain metastasis from osimertinib start were analyzed using cumulative incidence treating death as a competing risk. Overall survival was estimated using Kaplan-Meier methodology. Results: There were 36 patients who had a median interval from brain metastasis diagnosis to first-line osimertinib initiation of 25 days. In total, 136 previously untreated brain metastases were tracked from baseline. Overall, 105 lesions (77.2%) had complete response and 31 had partial response reflecting best objective response of 100%. Best response occurred at a median of 96 days (range: 28-1113 d) from baseline magnetic resonance imaging. This reflects a best objective response rate of 100%. Two-year overall survival was 80%. CNS progression rates at 1-, 2-, and 3-years post-osimertinib were 21%, 32%, and 41%, respectively. Lesion-level local failure was estimated to be 0.7% and 4.7% at 1- and 2-years post-osimertinib, respectively. No clinicodemographic factors including brain metastasis number were associated with post-osimertinib progression. Conclusions: Intracranial response to osimertinib is excellent for patients with EGFR-mutant NSCLC with de novo, previously untreated brain metastases. Very low local failure rates support a strategy of upfront osimertinib alone in selected patients.

Treatment outcomes of non-small cell lung cancers treated with EGFR tyrosine kinase inhibitors: a real-world cohort study.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are a standard of care treatment options in non-small cell lung cancer (NSCLC). The present study investigated real-world EGFR TKI use and patient outcomes in NSCLC. MATERIAL AND METHODS: We collected all the patients who had reimbursement for EGFR TKIs in Finland 2011-2020 and had data available at Finnish Cancer Registry. Survival and time-on-treatment (ToT) were analyzed from the first EGFR TKI purchase and patients were stratified according to the TKIs. RESULTS: Whole patient cohort consisted of 1498 individuals who were treated with erlotinib (n = 998), afatinib (n = 258), or gefitinib (n = 238). In the EGFR mutant cohort (all gefitinib users and afatinib users with non-squamous histology; n = 466), survival was comparable to registrational trials while patients treated with afatinib had improved survival (HR 0.67 CI 95% 0.53-0.85) and longer ToT (13.9 vs 11.9 months, NS) compared to those treated with gefitinib. Females treated with afatinib had improved survival (HR 0.61 CI 95% 0.44-0.83) and longer ToT (15.1 vs 12.5 months, NS) compared to gefitinib while similar was not observed in males. Later line osimertinib treatment was applied for 78 patients. Approximately 20% of the individuals treated with previous gefitinib or afatinib had later line osimertinib treatment. Efficacy analysis of osimertinib treated showed similar ToT and survival regardless of the first line EGFR TKI. CONCLUSIONS: EGFR mutants treated with afatinib have improved outcomes compared to gefitinib while later-line osimertinib was applied only for around 20% of the individuals. The study further highlights the good real-world performance of EGFR TKIs and sheds light on therapy sequencing.

Expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed small cell lung cancer.

Background: The transformation of epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) into small cell lung cancer (SCLC) accounts for 3-14% of the resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). At present, there is no relevant research to explore the dynamic expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed SCLC/neuroendocrine carcinoma (NEC). Methods: Genetic analysis and protein level analysis by next-generation sequencing (NGS), Whole-exome sequencing (WES) and immunohistochemistry were performed to explore expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed SCLC. The research used three patient-derived organoids (PDOs) to explore the efficacy of combo [chemotherapy (chemo) plus TKI or bevacizumab] treatment. According to the subsequent treatment regimens after SCLC/NEC transformation, 35 patients were divided into chemo (n=21) and combo (n=14) groups. Results: EGFR L858R and EGFR E746-750 del protein expression by immunohistochemistry was 80.0% (4/5) and 100% (6/6), respectively (P=0.455) in initially-transformed tissues. Meanwhile, EGFR-mutant proteins were expressed in 85.7% (6/7) of dynamic rebiopsy tissues or effusion samples after the first transformation. Then, by the pathway enrichment analysis of tissue and plasma NGS, the EGFR-related pathways were still activated after SCLC/NEC transformation. Moreover, WES analysis revealed that transformed SCLC shared a common clonal origin from the baseline LUAD. The drug sensitivity of three PDOs demonstrated potent anti-cancer activity of EGFR-TKIs plus chemo, compared with chemo or TKI alone. There were significant differences in objective response rate (ORR) between the combo and chemo groups [42.9 % vs. 4.8%, P=0.010, 95% confidence interval (CI): 1.5-145.2]. Furthermore, the median post-transformation progression-free survival (pPFS) was significantly prolonged in the combo group, with 5.4 (95% CI: 3.4-7.4) versus 3.5 (95% CI: 2.7-4.3, P=0.012) months. Conclusions: EGFR 19del or L858R-mutant proteins could be constantly expressed, and EGFR pathway still existed in EGFR-mutant transformed SCLC/NEC with a common clonal origin from the baseline LUAD. Taking together, these molecular characteristics potentially favored clinical efficacy in transformed SCLC/NEC treated with the combo regimen.

Management and outcome of EGFR mutant lung cancer with SARS-CoV-2 infection.

The world and India, in particular, have been grappling with the coronavirus disease (COVID-19) pandemic for more than a year now. The simultaneous presence of active COVID-19 infection with lung cancer poses both a diagnostic and therapeutic dilemma, because of similar clinical, radiological features along with increased susceptibility to ICU admissions and death. We present the case of a metastatic EGFR mutant lung cancer patient who was started on Gefitinib during active COVID-19 infection. He had made a complete recovery from COVID-19 infection while achieving a partial response to therapy in terms of primary lung cancer. The case highlights the importance of active involvement of a medical oncologist in the care of all cancer patients with COVID-19 infection instead of the traditional holding of all therapy for cancer until COVID-19 recovery as suggested by the majority of guidelines.

SLC12A8 mediates TKI resistance in EGFR-mutant lung cancer via PDK1/AKT axis.

PURPOSE: Epidermal growth factor receptor (EGFR) mutation is a prominent driver of lung cancer. Tyrosine kinase inhibitors (TKIs) have shown efficacy in treating EGFR-mutant lung cancer, but the emergence of drug resistance poses a significant challenge. Recent research has highlighted solute carrier family 12 member 8 (SLC12A8) as one of the highly upregulated genes in various cancer types. However, its oncogenic function remains largely unexplored. METHODS: 343 consecutive lung cancer patients were prospectively recruited and were followed for over 10 years. SLC12A8 expression in lung cancer tissues was measured by qPCR and was associated with patient survival. The association of SLC12A8 with TKI resistance was studied in in vitro EGFR-mutant lung cancer cell line as well as in in vivo xenograft tumor model. High-throughput kinome screening was employed to investigate SLC12A8-mediated oncogenic signaling pathway in lung cancer. RESULTS: SLC12A8 is a predictive biomarker of poor prognosis in lung cancer, particularly in patients with EGFR mutations. SLC12A8 overexpression diminishes the effectiveness of TKIs in EGFR-mutant lung cancer, resulting in treatment failure and disease progression. More importantly, SLC12A8-induced TKI resistance is mediated by the PDK1/AKT signaling axis, while silencing SLC12A8 expression inhibits oncogenic PDK1/AKT signaling, restoring TKI sensitivity in lung cancer cells. CONCLUSION: SLC12A8 mediates TKI resistance in EGFR-mutant lung cancer via PDK1/AKT axis. These findings not only advance our understanding of the molecular mechanisms driving TKI resistance, but also offer novel alternative strategies for the treatment of lung cancer.

Improved survival and intracranial tumor control of EGFR-mutated NSCLC patients with newly developed brain metastases following stereotactic radiosurgery and EGFR-TKI: a large retrospective cohort study and meta-analyses.

PURPOSE: To examine the differential effects of SRS and TKI on EGFR-mutated NSCLC patients with brain metastases (BMs) and outcomes following continuation of the same TKI agent in case of new BMs. METHODS: This study included 608 NSCLC patients (2,274 BMs) while meta-analyses included 1,651 NSCLC patients (> 3,944 BMs). Overall survival (OS) and intracranial progression free survival (iPFS) were estimated using Kaplan-Meier methods. Hazard ratios (95% CI) of prognostic factors were estimated using Cox regression models. RESULTS: The median OS/iPFS (95% CI) (months) for patients with wildtype EGFR/ALK, EGFR mutations, and ALK rearrangements were 17.7 (12.9-23.6)/12.1 (9.8-15.6), 28.9 (23.8-33.3)/17.7 (14.8-21.2), and 118.0 (not reached)/71.7 (15.1-not reached), respectively. In EGFR-mutated patients, meta-analyses combining our data showed significantly improved OS and iPFS of patients who received SRS and TKI (OS:35.1 months, iPFS:20.0 months) when compared to those who have SRS alone (OS:20.8 months, iPFS:11.8 months) or TKI alone (OS:24.3 months, iPFS:13.8 months). Having SRS for newly diagnosed BMs while keeping the existing TKI agent yielded OS (30.0 vs. 32.1 months, p = 0.200) non-inferior to patients who started combined SRS and TKI therapy for their newly diagnosed NSCLC with BMs. Multivariable analyses showed that good performance score and TKI therapy were associated with improved outcomes. CONCLUSIONS: Combined SRS and TKI resulted in favorable outcomes in EGFR-mutated NSCLC patients with newly diagnosed BMs. Continuation of the same TKI agent plus SRS in case of new brain metastases yielded good clinical outcomes and may be considered a standard-of-care treatment.

Impact of thoracic tumor radiotherapy on survival in non-small-cell lung cancer with malignant pleural effusion treated with targeted therapy: Propensity score matching study.

BACKGROUND: EGFR-mutant (EGFR-M) and ALK-positive (ALK-P)are common in malignant pleural effusion (MPE) with metastatic non-small-cell lung cancer (NSCLC) (MPE-NSCLC). The impact of thoracic tumor radiotherapy on survival in such patients remains unclear. We aimed to investigate whether thoracic tumor radiotherapy could improve overall survival (OS) in such patients. METHODS: According to whether or not patients accepted thoracic tumor radiotherapy, 148 patients with EGFR-M or ALK-P MPE-NSCLC treated with targeted therapy were classified into two groups: DT group without thoracic tumor radiotherapy and DRT group with thoracic tumor radiotherapy. Propensity score matching (PSM) was performed to balance clinical baseline characteristics. Overall survival was analyzed by Kaplan-Meier, compared by log-rank test, and evaluated using Cox proportional hazards model. RESULTS: Median survival time (MST) was 25 months versus 17 months in the DRT group and DT group. The OS rates at 1, 2, 3, 5 years in the DRT group and DT group were 75.0%, 52.8%, 26.8%, 11.1% and 64.5%, 28.4%, 9.2%, 1.8%, respectively (χ2 = 12.028, p = 0.001). Compared with DT group, the DRT group still had better survival after PSM (p = 0.007). Before and after PSM, factors associated with better OS through multivariable analysis were that thoracic tumor radiotherapy, radiotherapy, N0-2 , and ALK-TKIs. Grades 4-5 radiation toxicities were not observed in patients; 8 (11.6%) and 7 (10.1%) out of the DRT group suffered from Grade 3 radiation esophagitis and radiation pneumonitis, respectively. CONCLUSION: Our results for EGFR-M or ALK-P MPE-NSCLC showed that thoracic tumor radiotherapy may be crucial factor in improving OS with acceptable toxicities. Potential biases should not be neglected: Further randomized controlled trials are necessary to confirm this result.

Real world efficacy of osimertinib in second line/beyond in patients with metastatic EGFR+ non-small cell lung cancer and role of paired tumour-plasma T790M testing at tyrosine kinase inhibitor resistance.

Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) approved for use in EGFR-mutant lung cancer. We examined its performance in the second/subsequent line after resistance to first- and second-generation (1/2G) EGFR-TKI. Methods: We reviewed electronic records of 202 patients who received osimertinib from July 2015 to January 2019 in the second/subsequent line after progression on prior EGFR-TKI. Of these, complete data from 193 patients were available. Clinical data including patient characteristics, primary EGFR mutation, T790M mutation status, presence of baseline brain metastases (BM), first-line EGFR-TKI use, and survival outcomes were extracted, and results retrospectively analyzed. Results: Of 193 evaluable patients, 151 (78.2%) were T790M+ (T790M positive) with 96 (49.2%) tissue confirmed; 52% of patients received osimertinib in the second line setting. After median follow up of 37 months, median progression-free survival (PFS) of the entire cohort was 10.3 [95% confidence interval (CI): 8.64-11.50] months and median overall survival (OS) was 20 (95% CI: 15.61-23.13) months. Overall response rate (ORR) to osimertinib was 43% (95% CI: 35.9-50.3%); 48.3% in T790M+ vs. 20% in T790M- (T790M negative) patients. OS in T790M+ patients was 22.6 vs. 7.9 months in T790M- patients (HR 0.43, P=0.001), and PFS was 11.2 vs. 3.1 months respectively (HR 0.52, P=0.01). Tumour T790M+ was significantly associated with longer PFS (P=0.007) and OS (P=0.01) compared to tumour T790M- patients, however this association was not seen with plasma T790M+. Of the 22 patients with paired tumor/plasma T790M testing, response rate (RR) to osimertinib was 30% for those plasma T790M+/tumour T790M-, compared to 63% and 67% for those who were plasma T790M+/tumour T790M+ and plasma T790M-/tumour T790M+, respectively. By multivariable analysis (MVA), Eastern Cooperative Oncology Group (ECOG) performance status ≥2 was associated with shorter OS (HR 2.53, P<0.001) and PFS (HR 2.10, P<0.001), whereas presence of T790M+ was associated with longer OS (HR 0.50, P=0.008) and PFS (HR 0.57, P=0.027). Conclusions: This cohort demonstrated the efficacy of osimertinib in second line/beyond for EGFR+ (EGFR mutation-positive) non-small cell lung cancer (NSCLC). Tissue T790M result appeared more predictive of osimertinib efficacy compared to plasma, highlighting potential T790M heterogeneity and the advantage with paired tumor-plasma T790M testing at TKI resistance. T790M- disease at resistance remains an unmet treatment need.

Multiomics analysis revealed the mechanisms related to the enhancement of proliferation, metastasis and EGFR-TKI resistance in EGFR-mutant LUAD with ARID1A deficiency.

INTRODUCTION: Dysregulated ARID1A expression is frequently detected in lung adenocarcinoma (LUAD) and mediates significant changes in cancer behaviors and a poor prognosis. ARID1A deficiency in LUAD enhances proliferation and metastasis, which could be induced by activation of the Akt signaling pathway. However, no further exploration of the mechanisms has been performed. METHODS: Lentivirus was used for the establishment of the ARID1A knockdown (ARID1A-KD) cell line. MTS and migration/invasion assays were used to examine changes in cell behaviors. RNA-seq and proteomics methods were applied. ARID1A expression in tissue samples was determined by IHC. R software was used to construct a nomogram. RESULTS: ARID1A KD significantly promoted the cell cycle and accelerated cell division. In addition, ARID1A KD increased the phosphorylation level of a series of oncogenic proteins, such as EGFR, ErbB2 and RAF1, activated the corresponding pathways and resulted in disease progression. In addition, the bypass activation of the ErbB pathway, the activation of the VEGF pathway and the expression level changes in epithelial-mesenchymal transformation biomarkers induced by ARID1A KD contributed to the insensitivity to EGFR-TKIs. The relationship between ARID1A and the sensitivity to EGFR-TKIs was also determined using tissue samples from LUAD patients. CONCLUSION: Loss of ARID1A expression influences the cell cycle, accelerates cell division, and promotes metastasis. EGFR-mutant LUAD patients with low ARID1A expression had poor overall survival. In addition, low ARID1A expression was associated with a poor prognosis in EGFR-mutant LUAD patients who received first-generation EGFR-TKI treatment. Video abstract.

Integrated CRISPR screening and drug profiling identifies combination opportunities for EGFR, ALK, and BRAF/MEK inhibitors.

Anti-tumor efficacy of targeted therapies is variable across patients and cancer types. Even in patients with initial deep response, tumors are typically not eradicated and eventually relapse. To address these challenges, we present a systematic screen for targets that limit the anti-tumor efficacy of EGFR and ALK inhibitors in non-small cell lung cancer and BRAF/MEK inhibitors in colorectal cancer. Our approach includes genome-wide CRISPR screens with or without drugs targeting the oncogenic driver ("anchor therapy"), and large-scale pairwise combination screens of anchor therapies with 351 other drugs. Interestingly, targeting of a small number of genes, including MCL1, BCL2L1, and YAP1, sensitizes multiple cell lines to the respective anchor therapy. Data from drug combination screens with EGF816 and ceritinib indicate that dasatinib and agents disrupting microtubules act synergistically across many cell lines. Finally, we show that a higher-order-combination screen with 26 selected drugs in two resistant EGFR-mutant lung cancer cell lines identified active triplet combinations.