EGFR-TKI Therapy Research Articles

Osimertinib showed efficacy on contralateral multiple ground-glass nodules after segmentectomy for lung adenocarcinoma harboring primary EGFR-T790M mutation: a case report and review of the literature

BackgroundMultiple ground-glass nodules (mGGNs) in the lung has been defined as synchronous multiple primary lung cancer (SMPLC), it is has been very difficult challenging to differentiate SMPLC from intrapulmonary metastases, and its treatment remains controversial.Case presentationWe report a case simultaneously involving mGGNs and lung adenocarcinoma harboring primary EGFR-T790M mutation, in which the patient underwent the radical resection of lesions in the left upper lung, and continued the osimertinib treatment for the residual mGGNs in all lobes of the right lung. These mGGNs displayed different responses to osimertinib.ConclusionsWe reported a successful strategy on the postoperative treatment for mGGNs. For those that cannot be completely resected, the chemotherapy, radiotherapy, stereotactic body radiation therapy, immunotherapy and targeted therapy have been performed instead. The EGFR-TKI therapy strategy showed significant advantages, but how to achieve even better therapeutic effect needs more researches.

81P Is PD-1 inhibitor based treatment better than chemotherapy for metastatic NSCLC patients with PD-L1≥50% who develop EGFR-TKI resistance? A real-world investigation

Platinum-based chemotherapy is still the standard of care for Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients after developing EGFR-TKI resistance. However, no study focusing on the role of PD-1 inhibitor based treatments for EGFR mutated NSCLC patients who carried PD-L1 TPS ≥ 50% progressed after EGFR-TKI therapy. Thus, we aimed to investigate the outcomes of PD-1 inhibitor based treatments for these patients and to explore the population that may benefited from PD-1 inhibitor based therapies.

A fluorogenic probe for predicting treatment response in non-small cell lung cancer with EGFR-activating mutations

Therapeutic responses of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) are known to be associated with EGFR mutations. However, a proportion of NSCLCs carrying EGFR mutations still progress on EGFR-TKI underlining the imperfect correlation. Structure-function-based approaches have recently been reported to perform better in retrospectively predicting patient outcomes following EGFR-TKI treatment than exon-based method. Here, we develop a multicolor fluorescence-activated cell sorting (FACS) with an EGFR-TKI-based fluorogenic probe (HX103) to profile active-EGFR in tumors. HX103-based FACS shows an overall agreement with gene mutations of 82.6%, sensitivity of 81.8% and specificity of 83.3% for discriminating EGFR-activating mutations from wild-type in surgical specimens from NSCLC patients. We then translate HX103 to the clinical studies for prediction of EGFR-TKI sensitivity. When integrating computed tomography imaging with HX103-based FACS, we find a high correlation between EGFR-TKI therapy response and probe labeling. These studies demonstrate HX103-based FACS provides a high predictive performance for response to EGFR-TKI, suggesting the potential utility of an EGFR-TKI-based probe in precision medicine trials to stratify NSCLC patients for EGFR-TKI treatment.

CNSC-01. THE GENE LANDSCAPE OF LUNG ADENOCARCINOMA PATIENTS WITH PROGRESSIVE DISEASE OF LEPTOMENINGE

Abstract BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide a better prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the outcome of leptomeningeal metastasis (LM) remains poor. In addition, due to limited access to intracranial tumour tissue, gene alterations associated with leptomeningeal metastasis from lung adenocarcinoma (LM-LUAD) are unclear. METHODS Forty-five patients with LM-LUAD from May 2019 to June 2021 in Guangdong Sanjiu Brain Hospital were enrolled in this study. Seventy-five percent (34/45) of patients with LM harbored EGFR mutations, and patients with progressive disease (PD) of LM had 3rd-generation EGFR-TKI therapy and were defined as Cohort 1; those without 3rd-generation EGFR-TKI therapy were defined as Cohort 2. Next-generation targeted panel sequencing (NGS) was performed in each cerebrospinal fluid (CSF) sample of the two cohorts, and 9/45 LM-LUAD patients had matched plasma (PLA). RESULTS The common gene alterations discovered in the CSF of LM-LUAD were EGFR mutation (34/45, 75%), TP53 (25/45, 56%), CDKN2A (9/45, 20%), ALK (7/45, 16%), CTNNB1 (6/45, 13%), MET (5/45, 11%), APC (4/45, 9%), FGF4 (4/45, 9%), FGF3 (4/45, 9%), ERBB2 (4/45, 9%), and PIK3CG (4/45, 9%). Cooccurring mutations of TP53 and EGFR were found in 49% (22/45) of patients and correlated with poor prognosis. CDKN2A was identified in 20% (9/45) of patients and presented slightly shorter overall survival (OS) than those without (7.1 versus 8.8 months, p=0.2). Cohort 1 had more genes associated with poor prognosis, consisting of CDK4, CDKN2A, PIK3CG, or PIK3CA, and YES1 and MET were more likely to be detected in cohort 2. The alteration of EGFR was comparable between CSF and matched PLA. Incidences of gene alterations such as CDK4, CDKN2A, MET, SOX2, JAK2, BRAF, and PIK3CG were more likely to be identified in CSF. All mutant allele frequencies (MAF) were much higher in CSF than in matched PLA.

ODP359 Thyrotropin secreting pituitary microadenoma and lung adenocarcinoma treated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) Erlotinib and Osimertinib: a case report

Abstract Background Thyrotropin secreting pituitary adenoma (TSHoma) of the pituitary specific transcription factor-1 (PIT-1) lineage, is the rarest subtype of pituitary neuroendocrine tumours (pitNETs). TSHomas must be discriminated from primary hyperthyroidism and can cause morbidity through thyrotoxicosis or local mass effect. Serum alpha-subunit level may be used as a marker of tumour activity, as 50-85% of TSHoma patients have high serum alpha-subunit levels. First line treatment is surgical resection of the tumour. Medical therapy with somatostatin analogues or radiotherapy may be used for tumour control. Epidermal growth factor receptor (EGFR) expression has been demonstrated in pitNETs including corticotrophs, gonadotrophs, lactotrophs and somatotrophs. EGFR inhibiting agent, Lapatinib, has been investigated for treatment of prolactinomas and EGFR expression is implicated in tumorigenesis of corticotrophs. EGFR targeting tyrosine kinase inhibitors (TKIs) can be used first line to treat metastatic adenocarcinoma of the lung harbouring activating EGFR mutations. Case Report A non-smoking 53-year-old male of Middle Eastern heritage was seen in clinic with secondary hyperthyroidism on a background of metastatic adenocarcinoma of the lung and hypertension. The patient had no symptoms of hyperthyroidism and had no personal or family history of thyroid dysfunction. No new headaches or visual disturbance were reported. Physical exam showed brisk reflexes, no specific signs of hyperthyroidism or thyromegaly were seen. Thyroid function tests demonstrated a persistently elevated TSH 5.1mIU/L (0.4-4. 0), T4 21.8pmol/L (9-19) and T3 6.4pmol/L (2.6-6. 0) with negative anti- thyroid receptor, thyroperoxidase and thyroglobulin antibodies. Ultrasound of the thyroid was unremarkable. MRI revealed a well-circumscribed left anterior pituitary lesion of 5.4×6.8mm in size. Surgery was deferred as 3 months prior, he was diagnosed with stage 4 intrapulmonary adenocarcinoma of the lung with an exon-19 deletion mutation in the EGFR gene. He received stereotactic radiotherapy and EGFR targeted therapy using 100mg of Erlotinib daily, which increased to 200mg 6 months later. After 1 year of therapy, his adenocarcinoma progressed and he was transitioned to the 3 rd generation EGFR-TKI Osimertinib. Instead of undergoing the risk of pituitary surgery, a trial of EGFR therapy for its pleiotropic pituitary adenoma effects was decided. During the EGFR-TKI treatment period, alpha subunit levels have remained stable and serial MRI imaging at 1 year showed no interval pituitary adenoma growth. Conclusion This is a rare case of TSHoma identified during treatment of lung cancer with EGFR-TKIs. EGFR signalling is implicated in prolactinomas and corticotrophs though there is a paucity of data regarding TSHomas. To date, our patient has achieved radiological and biochemical stability in his TSHoma, with hyperthyroidism control on EGFR-TKI therapy, suggestive of a therapeutic benefit from EGFR signal blockade. Further studies are needed in larger cohorts to quantify EGFR expression in TSHomas and evaluate its possible role in pathogenesis. Presentation: No date and time listed

Radiation Necrosis Risk in NSCLC Patients Receiving EGFR TKIs or ALK Inhibitors

<h3>Purpose/Objective(s)</h3> Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) and anaplastic lymphoma kinase (ALK) inhibitors have become commonplace in the treatment of locally advanced and metastatic NSCLC with activating mutations. The toxicity of stereotactic radiation therapy (SRT) when given concurrently with these drugs remains unclear. The purpose of this study was to determine the incidence of radiation necrosis (RN) in patients receiving these targeted therapies (TGT). <h3>Materials/Methods</h3> We retrospectively reviewed metastatic NSCLC patients who received EGFR TKI or ALK inhibitor at our institution. Patients with brain metastases treated with SRT with a minimum of 6 months post-SRT follow up were included for analysis, and demographic, oncologic, radiation and imaging records were reviewed. RN diagnosis was based upon the radiologist interpretation, radiation oncologist progress notes, or pathology reports after resection. Local recurrence was defined radiographically or histologically. Biologically effective dose was calculated using the linear quadratic equation using an α/β of 3 (BED3) and 10 (BED10). <h3>Results</h3> Thirty-nine patients with 161 treated brain lesions fit our inclusion criteria. Most patients were female (76.9%), with a median age of 60 (range 27-73), and were treated to a median of 3 (1-27) lesions per patient. EGFR TKI or ALK inhibitor was administered in the 2-week interval surrounding SRT (TGT+) for 116 of 161 lesions, and 28 of 116 (24.1%) developed evidence of RN (21 symptomatic, 18.1%). Among the 45 lesions where TKI or ALK inhibitor was not given in the 2-week interval surrounding SRT (TGT-), one case of RN (2.2%) was identified. Most symptomatic RN lesions (67%) resolved with therapy. Local control among TGT+ and TGT- lesions was 93.1% and 97.7% respectively (p=0.08). The odds for developing RN were higher for TGT+ than TGT- treatments (OR=14; 95%CI 1.8-106). In 19 out of 116 TGT+ lesions, TGT was either held during SRT or initiated within 2 weeks following SRT, and the RN rate was not lower than for SRT where TGT was administered concurrently (26.3% vs 23.7%, p=0.4). Among TGT+ lesions, there was no difference in number of TKIs received prior to, during, or after SRT for those with or without RN. There was no association of prescribed BED3 or BED10 with the development of RN. Lesions that developed RN were more likely to be treated with osimertinib than those without RN (46% vs 23%, p=0.02). <h3>Conclusion</h3> Patients receiving SRT with EGFR TKI or ALK therapy 2 weeks before or after SRT are at higher risk of RN. This risk does not appear to diminish when holding TGT during SRT or delaying TGT initiation until after SRT. Special attention should be given to patients receiving SRT with osimertinib therapy as our data suggest that they are at higher risk of developing RN. Future work will focus on identification of unique dosimetric and temporal factors that may be predictive of RN in patients taking these targeted agents.

Real-world clinical treatment outcomes in Chinese non-small cell lung cancer with EGFR exon 20 insertion mutations.

Background EGFR exon 20 insertions (EGFR ex20ins) constitute a heterogeneous subset of EGFR-activating alterations. However, the effectiveness of standard therapy in patients with EGFR ex20ins remains poor.MethodsIn our study, we retrospectively collected next-generation sequencing (NGS) data from 7,831 Chinese NSCLC patients and analyzed the relationship between EGFR ex20ins variations and medical records.ResultsOur data showed that EGFR ex20ins account for up to 3.5% of all EGFR mutation non-small-cell lung cancer (NSCLC) patients and 1.6% of all NSCLC patients in China. Thirty-eight different variants of EGFR ex20ins were identified in 129 NSCLC patients. We observed that the patients with EGFR ex20ins may benefit from the anti-angiogenesis agents significantly (P = 0.027). In the EGFR ex20ins near-loop group, patients who received second-/third-generation EGFR-TKI therapy treatment as first-line treatment had a longer median progression-free survival (PFS) than those who initiated treatment with first-generation EGFR-TKI or chemotherapy. Patients with co-mutations of EGFR ex20ins near-loop and TP53 tended to have a shorter OS in second-/third-generation EGFR-TKI therapy (P = 0.039). Additionally, median PFS was significantly longer in patients harboring EGFR ex20ins far-loop variants who received chemotherapy as a first-line setting (P = 0.037).ConclusionsOverall survival was significantly longer in EGFR ex20ins patients with anti-angiogenesis agents. For the choice of first-line strategy, NSCLC with EGFR ex20ins near-loop variants may benefit from second-/third-generation EGFR-TKI, while patients harboring EGFR ex20ins far-loop variants might have better outcomes from chemotherapy. TP53 could serve as a potential predictive marker in poor prognosis for EGFR ex20ins near-loop patients.

LBA58 Sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated non-squamous non-small cell lung cancer (EGFRm nsqNSCLC) who progressed on EGFR tyrosine-kinase inhibitors (TKIs) therapy: Second interim analysis of phase III ORIENT-31 study

The randomized, double-blind, phase 3 ORIENT-31 study was to evaluate sintilimab (sin, anti-PD-1 antibody) with or without IBI305 (bevacizumab biosimilar) plus chemotherapy (chemo), vs chemo, in patients (pts) with EGFRm nsqNSCLC who progressed on EGFR TKIs therapy. The first interim analysis (IA) showed sin + IBI305 + chemo significantly improved progression-free survival (PFS) vs chemo alone (Lu, et al. Lancet Oncol 2022). Eligible pts were randomized (1:1:1 at the first stage and 2:2:1 at the second stage) into Arm A (sin + IBI305 + chemo), Arm B (sin + placebo [pb] 2 + chemo) and Arm C (pb1 + pb2 + chemo). Sin/pb1 (200 mg), IBI305/pb2 (15 mg/kg), pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) were administered IV Q3W for 4 cycles, followed by maintenance treatment of sin/pb1, IBI305/pb2 and pemetrexed. The primary endpoint was PFS assessed by IRRC per RECIST v1.1. Per prespecified statistical analysis plan, the second IA (reported here) aimed to evaluate the PFS between Arm B and Arm C, and the superiority conclusion of Arm A over Arm C has been achieved at the first IA. By data cutoff (Mar 31, 2022), 476 pts were randomized (Arm A/B/C: 158/158/160). Median age was 57.0 years. 37.0% pts had brain metastasis. Previously, 63.0% pts received 1st or 2nd generation (G) TKI with T790M-, 26.3% pts received 1st or 2nd and then 3rd G TKI with T790M+, and 10.5% pts received first-line 3rd G TKI. With a median follow-up of 13.1 months, median PFS (95% CI) by IRRC was 7.2 months (6.6, 9.3) in Arm A, 5.5 months (4.5, 6.1) in Arm B, and 4.3 months (4.1, 5.3) in Arm C. PFS was significantly improved in Arm B vs Arm C (HR 0.723, 95% CI: 0.552, 0.948; P=0.0181). Confirmed ORR by IRRC was 48.1%, 34.8% and 29.4% in Arm A, B and C respectively; DCR was 86.1%, 81.6% vs 75.6%; median DOR was 8.5 months, 7.4 months vs 5.7 months. Grade ≥3 treatment-emergent adverse events occurred in 59.5%, 46.2%, and 56.9% pts respectively. Sin combined with or without IBI305 and chemo significantly improved PFS in pts with advanced EGFRm nsqNSCLC who progressed on EGFR-TKI therapy, vs chemo alone.

MA07.09 BBT-176, a 4th generation EGFR TKI, for Progressed NSCLC after EGFR TKI Therapy: PK, Safety and Efficacy from Phase 1 Study

EGFR TKIs are the standard of care for EGFR mutated, advanced-stage NSCLC. Various mechanisms contribute to their resistance, among which a tertiary point mutation in the C797 residue of EGFR is the most well-known. Currently, there is no approved drug for NSCLC in patients harboring the EGFR C797S resistance mutation. BBT-176, a reversible, ATP-competitive inhibitor was developed to target such complex EGFR mutations and was shown to exhibit low nanomolar IC50 values in cell and animal efficacy models.

1077P An updated network meta-analysis of EGFR-TKIs and combination therapy in the first-line treatment of the advanced EGFR mutation positive non-small cell lung cancer

TKIs are standard care option in patients of NSCLC with EGFR mutation. TKIs-based combination treatment modes have shown encouraging outcomes. However, it remains unknown which is the optimal treatment as the first-line regimen for these patients on OS.

EP08.02-072 The Predictive Value of Longitudinal Monitoring of Mutated EGFR in Plasma of Advanced NSCLC Patients on First-Line EGFR-TKIs

The analysis of cell-free DNA in plasma, so called liquid biopsy, significantly improved the detectability of activating and resistance EGFR mutations in advanced non-small cell lung cancer (NSCLC) patients prior EGFR-TKI therapy and upon clinical progression, in particular when sufficient tumor tissue material is not available. Since the acquired resistance to EGFR-TKIs develops gradually under the inhibitor-specific selective pressure, the longitudinal analysis of mutated EGFR in both qualitative and quantitative manner may be more beneficial in term of the real-time treatment monitoring and early detection of resistance mutations.

Impact of TP53 Mutations on EGFR-Tyrosine Kinase Inhibitor Efficacy and Potential Treatment Strategy

BackgroundWe investigated the impact of factors that influence TP53 mutations on the efficacy of EGFR-tyrosine kinase inhibitors and potential treatment strategies. Materials and MethodsTumor samples were collected to screen gene mutations by next-generation sequencing, as well as the patients’ baseline characteristics. The overall response to treatment with TKIs was evaluated based on interval computed tomography scans at each follow-up time point. A Fisher's exact test and log-rank test were used to determine the statistical differences in this study. ResultsA total of 1134 clinical samples were collected from NSCLC patients, and TP53mut was identified in 644 cases and EGFRmut in 622 cases. A low frequency of TP53mut or more than 50% EGFR co-mutation rate were related to the prognosis of TKI-treated patients. In addition, TP53mut in the region outside of the DB domain had the strongest correlation with TKI resistance, whereas various types of mutations in the DB domain only had an impact on PFS. A grouping study of EGFR-TKI-based treatment revealed that EGFR-TKIs with chemotherapy were associated with more significant survival benefits for patients with prognostic TP53mut, whereas EGFR-TKI therapy was favorable for TP53wt patients. Furthermore, TP53mut could shorten the time to the relapse of postoperative patients, who will also likely respond well to EGFR-TKIs with chemotherapy. ConclusionVarious characteristics of TP53mut affect the prognosis of TKI-treated patients to varying degrees. EGFR-TKIs with chemotherapy were benefit for patients’ survival with prognostic TP53mut, which provides an important reference for treatment management of EGFRmut patients.

An updated network meta-analysis of EGFR-TKIs and combination therapy in the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer

ObjectivesTyrosine kinase inhibitors (TKIs) are a standard care option in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI-based combination treatment modes show encouraging outcomes. However, it remains unknown which is the optimal treatment as the first-line regimen for these patients on overall survival (OS).Materials and methodsRandomized controlled trials and meeting abstracts that investigated EGFR-TKIs alone or in combination as front-line care for patients with NSCLC were systematically searched in relevant databases and reviewed. Fixed and random effects network meta-analysis models were used to estimate progression-free survival (PFS), OS, overall response rate, and grade three and higher adverse events (AEs). Surface under the cumulative ranking curves (SUCRAs) were used to rank treatment effects.ResultsEighteen studies covering six treatments and involving a total of 4389 patients were included in this network meta-analysis. On OS, the top three treatment were first-generation EGFR-TKIs (1G EGFR-TKIs) plus chemotherapy (SUCRA, 88.1%), osimertinib (SUCRA, 65.8%) and second-generation EGFR-TKIs (2GEGFR-TKIs) (SUCRA, 63.3%). On PFS, the top three treatments were osimertinib (SUCRA, 96.0%), 1G EGFR-TKIs plus chemotherapy (SUCRA, 67.1%), and 1G EGFR-TKIs plus antiangiogenesis (SUCRA, 48.2%). Two types of TKI-based combination therapy have significantly higher risk of grade three and higher AEs than TKI alone.Conclusion1G EGFR-TKIs plus chemotherapy and osimertinib seem to be the two better options as first-line care in advanced NSCLC patients with EGFR-mutation. Osimertinib caused the lowest incidence of AEs. However, TKIs-based combination therapy significantly increased AEs.

A deep learning-based system for survival benefit prediction of tyrosine kinase inhibitors and immune checkpoint inhibitors in stage IV non-small cell lung cancer patients: A multicenter, prognostic study.

SummaryBackgroundFor clinical decision making, it is crucial to identify patients with stage IV non-small cell lung cancer (NSCLC) who may benefit from tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). In this study, a deep learning-based system was designed and validated using pre-therapy computed tomography (CT) images to predict the survival benefits of EGFR-TKIs and ICIs in stage IV NSCLC patients.MethodsThis retrospective study collected data from 570 patients with stage IV EGFR-mutant NSCLC treated with EGFR-TKIs at five institutions between 2010 and 2021 (data of 314 patients were from a previously registered study), and 129 patients with stage IV NSCLC treated with ICIs at three institutions between 2017 and 2021 to build the ICI test dataset. Five-fold cross-validation was applied to divide the EGFR-TKI-treated patients from four institutions into training and internal validation datasets randomly in a ratio of 80%:20%, and the data from another institution was used as an external test dataset. An EfficientNetV2-based survival benefit prognosis (ESBP) system was developed with pre-therapy CT images as the input and the probability score as the output to identify which patients would receive additional survival benefit longer than the median PFS. Its prognostic performance was validated on the ICI test dataset. For diagnosing which patient would receive additional survival benefit, the accuracy of ESBP was compared with the estimations of three radiologists and three oncologists with varying degrees of expertise (two, five, and ten years). Improvements in the clinicians’ diagnostic accuracy with ESBP assistance were then quantified.FindingsESBP achieved positive predictive values of 80·40%, 75·40%, and 77·43% for additional EGFR-TKI survival benefit prediction using the probability score of 0·2 as the threshold on the training, internal validation, and external test datasets, respectively. The higher ESBP score (>0·2) indicated a better prognosis for progression-free survival (hazard ratio: 0·36, 95% CI: 0·19–0·68, p<0·0001) in patients on the external test dataset. Patients with scores >0·2 in the ICI test dataset also showed better survival benefit (hazard ratio: 0·33, 95% CI: 0·18–0·55, p<0·0001). This suggests the potential of ESBP to identify the two subgroups of benefiting patients by decoding the commonalities from pre-therapy CT images (stage IV EGFR-mutant NSCLC patients receiving additional survival benefit from EGFR-TKIs and stage IV NSCLC patients receiving additional survival benefit from ICIs). ESBP assistance improved the diagnostic accuracy of the clinicians with two years of experience from 47·91% to 66·32%, and the clinicians with five years of experience from 53·12% to 61·41%.InterpretationThis study developed and externally validated a preoperative CT image-based deep learning model to predict the survival benefits of EGFR-TKI and ICI therapies in stage IV NSCLC patients, which will facilitate optimized and individualized treatment strategies.FundingThis study received funding from the National Natural Science Foundation of China (82001904, 81930053, and 62027901), and Key-Area Research and Development Program of Guangdong Province (2021B0101420005).

Radiotherapy with continued EGFR-TKIs for oligoprogressive disease in EGFR-mutated non-small cell lung cancer: A real-world study.

Epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) develops resistance to tyrosine kinase inhibitors (TKIs). Here, we evaluated the efficacy of radiotherapy and continuation of TKIs in patients with advanced NSCLC with oligoprogression after EGFR-TKIs. From January 2011 to January 2019, 33 patients with EGFR-mutated NSCLC on TKIs were treated by radiotherapy and continuation of TKIs for oligoprogressive disease. The primary endpoints were median progression-free survival 1 (mPFS1), mPFS2, and median overall survival (mOS). PFS1 was measured from the start of EGFR-TKIs therapy to the oligoprogression of the disease. PFS2 was measured from the date of oligoprogression to the further progression of the disease, while OS was calculated from oligoprogression to death from any cause or was censored at the last follow-up date. The mPFS1, mPFS2, and mOS were 11.0 (95% CI, 4.4-17.6), 6.5 (95% CI, 1.4-11.6) and 21.8 (95% CI, 14.8-28.8) months, respectively. Univariate analysis showed that EGFR mutation type (p=0.024), radiotherapy method (p=0.001), and performance status (p=0.017) were significantly correlated with PFS2. Univariate analysis showed that sex (p=0.038), smoking history (p=0.031), EGFR mutation type (p=0.012), and radiotherapy method (p=0.009) were significantly correlated with OS. Multivariate analysis suggested that radiotherapy method (p=0.001) and performance status (p=0.048) were prognostic factors for PFS2, and radiotherapy method (p=0.040) was a prognostic factor for OS. Radiotherapy with continued TKIs is effective for EGFR-mutated NSCLC with oligoprogression, and it should be conducted as soon as possible. T790M+ patients have higher sensitivity to radiotherapy, and patients with good performance status and stereotactic body radiation therapy have better PFS2 andOS.

Transcriptional analysis of small cell lung cancer transformation in epidermal growth factor receptor mutated lung adenocarcinomas.

e21100 Background: Epidermal growth factor receptor ( EGFR)-mutated lung adenocarcinoma (LUAD) could benefit from EGFR-TKIs (tyrosine kinase inhibitors) treatment, but drug resistance seems to be inevitable. Small cell lung cancer (SCLC) transformation counts for 3-15% of the resistance mechanism, and was amply studied at genomics level but rarely at transcriptional level. Methods: The expression of 730 mRNAs were investigated by Nanostring nCounter Pancancer Pathway Panel on 72 formalin-fixed and paraffin-embedded (FFPE) samples from 27 EGFR-mutated LUAD patients with SCLC transformation after EGFR-TKIs therapy (19 LUAD samples before transformation, LUAD-BT; 21 SCLC samples after transformation, SCLC-AT), 12 EGFR-mutated LUAD patients never SCLC transformed after EGFR-TKIs therapy (12 samples, LUAD-NT) and 20 stage IIĨIV primary SCLC patients (20 samples, SCLC-P). For patients enrolled in LUAD-NT group, tissue biopsies were performed at least twice, which were all diagnosed as pure LUAD, and the overall survival (OS) since first line therapy was longer than the median transformation time (mTt) of SCLC-transformed patients in our study. mRNA expression patterns and biological pathway scores were compared among four groups. The candidate predictive biomarkers from mRNA expression pattern analysis were validated by area under curve (AUC) of receiver operating characteristic curve (ROC) and the logarithm of fold change to the base 2 (log2FC). Results: On the last day of follow up (1st February 2022), the shortest OS of LUAD-NT patients was 28.4 months, whereas the mTt was 27.5 months. Among four groups, LUAD-NT and LUAD-BT showed the most similar mRNA expression patterns, and SCLC-P were significantly different from the others. 8.6% (63/730) mRNA showed significant downregulation after SCLC transformation, while 3.6% (26/730) showed significant upregulation ( p value adjusted by Benjamin &amp; Hochberg’s method &lt; 0.05, SCLC-AT vs LUAD-BT). In pathway enrichment analysis, the score of RAS and TGF-β pathways were significantly lower in SCLC-AT than LUAD-BT. Compared with SCLC-P, 6 upregulated mRNAs in SCLC-AT were observed (log2FC &gt; 2, AUC &gt; 0.85 and each raw p value &lt; 0.05), including AR, COL5A1, GHR, HMGA2, IGFBP3 and IL6R, which could be further validated as diagnostic markers in a larger cohort. Moreover, compared with LUAD-NT, 4 mRNAs ( BRIP1, CCNE2, CDKN2A and MCM2) were found to be significantly upregulated (log2FC &gt; 1, AUC &gt; 0.75 and each raw p value &lt; 0.05) in LUAD-BT, indicating the predictive value of SCLC transformation. Conclusions: The transformation of LUAD to SCLC may be promoted by transcriptional events. We also described some significantly different expressed mRNAs that could candidate as predictive or diagnostic markers for SCLC transformation, which should be further validated in a larger cohort.

Efficacy and safety of rezivertinib (BPI-7711) in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC: A phase IIb, multicenter, single-arm, open-label study.

9098 Background: Rezivertinib (BPI-7711) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of Rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M mutated non-small cell lung cancer (NSCLC). Methods: Locally advanced or metastatic/recurrent NSCLC patients with histologic or cytologic or plasmatic confirmation of EGFR T790M mutations who progressed after first/second generation EGFR-TKIs therapy or primary EGFR T790M mutations were enrolled. Patients received Rezivertinib at 180mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review (BICR) per RECIST1.1. The efficacy for patients with central nervous system (CNS) metastases was measured by BICR according to the Response Assessment in Neuro-Oncology Brain Metastases. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Safety was assessed as per CTCAE 4.03. Results: A total of 226 patients were enrolled from Jul 5, 2019, to Jan 22, 2020. 91 (40.3%) patients had brain metastases. The tissue sample and plasma sample were positive for EGFR T790M in 120 (53.1%) and 116 (51.3%) patients, respectively. By the data cutoff date on Dec 23, 2021, the ORR by BICR was 64.6% (95%CI:58.0-70.8) and DCR was 89.8% (95%CI:85.1-93.4). The median DoR was 12.5 (95%CI:10.0-13.9) months and median PFS was 12.2 (95%CI:9.6-13.9) months. The median OS was 23.9 (95%CI:20.0-NC) months. Subgroup ORR: exon 19 deletion 72.4% (95%CI:64.4-79.5), L858R 51.9% (95%CI:40.4-63.3), tissue T790M positive 70% (95%CI:61.0-78.0), plasma T790M positive 56.9% (95%CI:47.4-66.1). Subgroup PFS: exon 19 deletion 12.4 (95%CI:8.8-15.1) months, L858R 10.3 (95%CI:8.3-13.9) months, tissue T790M positive 13.9 (95%CI:11.3-17.9) months, plasma T790M positive 9.6 (95%CI:7.0-11.0) months. Among 91 patients with CNS metastases, 29 patients had at least one brain target lesion whose CNS-ORR and CNS-DCR were 69.0% (95%CI:49.2-84.7) and 100% (95%CI:88.1-100), respectively. Time to progression of CNS was 16.5 (95%CI:9.7-NC) months. 188 of 226 (83.2%) patients had at least one adverse drug reaction, with the most common being white blood cell count decreased (27.9%), platelet count decreased (23.0%), anemia (22.6%). No interstitial lung disease was reported. Conclusions: Rezivertinib demonstrated promising efficacy and favorable safety for locally advanced or metastatic/recurrent NSCLC patients with EGFR T790M mutation. Clinical trial information: NCT003812809.

Serum liquid metabolites reveals the heterogeneity in advanced lung adenocarcinoma patients with EGFR sensitizing mutations.

e21065 Background: There is a differential therapeutic efficacy of advanced lung adenocarcinoma (LUAD) patients with EGFR sensitizing mutations (mEGFR). This study aimed to explore the differences in serum liquid metabolites of EGFR mutation types and to provide further evidence for revealing the mechanism of the difference in efficacy. Methods: In total, 42 LUAD patients with mEGFR (19 deletions or 21 L858R mutations) who received EGFR-TKIs therapy were included. Prospectively collected serum samples before initial treatment were utilized to perform nontargeted liquid metabolomics profiling analyses under the application of Ultrahigh Performance Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (UPLC-MS/MS). Multi-dimensional statistical methods such as partial least squares discrimination analysis (PLS-DA) were used to further screen and identify differential metabolites associated with EGFR mutation type. Results: The metabolic signature molecules in the metabolic profile were extracted, and a total of 1995 positive ion mode (ESI+) and 365 negative ion mode (ESI-) signature molecules were obtained. 29 metabolites displayed significant differences between the two groups, which belong to lipids including phosphatidylcholines (PCs), phosphatidylglycerol (PGs), phosphatidylethanolamine (PEs), ceramides (Cers) and sphingomyelins (SMs). Gene mutation subtypes change the proportion of saturated phospholipids and unsaturated phospholipids, with significantly higher saturated phospholipids in patients with the EGFR 21 L858R mutation. Then, pathway enrichment analysis was performed on the differential metabolites, mainly enriched in glycerophospholipid and sphingolipids metabolism pathway. Conclusions: This study not only demonstrates the heterogeneity of lipid metabolism among gene mutation subtypes, but also provides the possibility to reveal the mechanism of survival differences.

The prognosis of EGFR complex mutation or co-mutation with tyrosine kinase inhibitor treatment in non-small cell lung cancer.

e21086 Background: To compare the prognoses of EGFR complex mutation, co-mutation and single mutation with first-line TKI treatment in NSCLC patients. Methods: A retrospective study of 215 patients with EGFR-mutated NSCLC who were admitted to the Department of Medical Oncology, the Fourth Hospital of Hebei Medical University from January 2015 to January 2021, all received first-line EGFR-TKI therapy. According to the type of mutation, they were divided into 48 cases (22.3%) of EGFR single mutation group, 48 cases (22.3%) of complex mutation group, and 142 cases (66.0%) of co-mutation group, of which 23 cases (10.6%) both had complex mutation and co-mutation. The prognoses of the latter two groups were compared with that of the single mutation group respectively. SPSS 26.0 was used to analyze the data, and P &lt; 0.05 indicated the difference was statistically significant. Results: Progression-free survival (PFS): the co-mutation group was shorter than the single mutation group (11.0m vs 13.5m; HR = 1.492, 95%CI: 1.036-2.149; P= 0.030), especially the co-mutation was occurred in TP53 (10.5 m vs 13.0m; HR = 1.665, 95%CI: 1.234-2.248; P= 0.001) or HER family (9.0m vs 12.0m; HR = 2.435, 95%CI: 1.492-3.974; P&lt; 0.001). Overall survival (OS): compared with the single mutation group, complex mutation group (36.5m vs 52.0m; HR = 1.480, 95%CI: 0.821-2.668; P= 0.193), co-mutation group (41.0m vs 52.0m; HR = 1.418, 95%CI: 0.901-2.231; P= 0.131) were not statistically different, but the co-mutation of PTEN pathway significantly reduced OS (24.0m vs 46.0m; HR = 1.884, 95%CI: 1.137 -3.120; P= 0.014). Objective response rate (ORR) and disease control rate (DCR) of first-line EGFR-TKI: single mutation group separately compared with complex mutation group and co-mutation group (ORR: 64.6% vs 6.2% vs 27.4%, P&lt; 0.001; DCR: 100% vs 70.8% vs 91.5%, P &lt; 0.001 and 0.007 respectively). After the first-generation EGFR-TKI treatment and secondary EGFR E20 T790M mutation, the presence or absence of the original sensitive mutation affects the PFS of the first-generation TKI (12.0m vs 11.0m; HR = 1.109, 95%CI:0.739-1.664 ; P= 0.616), PFS of the third-generation TKI (10.0m vs 8.0m; HR = 1.130, 95%CI: 0.717-1.781; P= 0.599) and OS (34.0m vs 44.5m; HR = 0.834, 95%CI: 0.505-1.377; P= 0.478) were not statistically different. Conclusions: EGFR co-mutation is a predictor of poor prognosis in NSCLC patients treated with EGFR-TKI; after first-generation EGFR-TKI resistance, the disappearance of the original sensitive mutation cannot predict the prognosis.

Bone metastasis reduces responsiveness to EGFR-TKIs in patients with EGFR-mutated advanced lung adenocarcinoma.

e21085 Background: The response of epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) to bone metastasis site in patients with EGFR mutated lung adenocarcinoma remains to be determined. Methods: This is a retrospective analysis of the efficacy of EGFR-TKIs for lung adenocarcinoma patients with EGFR mutations, comparing patients with bone metastases (BM) and those with no bone metastases (NBM). BM patients need extra imaging to assess the efficacy of bone metastasis sites . Overall response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and progression patterns were evaluated. Results: Of the 502 patients, 175 were enrolled (BM 96, NBM 79) from January 2012 to December 2017. 125 patients had disease progression on January 31, 2018. The clinical characteristics of the two groups were not significantly difference. The median PFS was 11.0 months in NBM group and 7.0 months in BM group ( P= 0.013) . The median PFS in patients with multiple BM (≥ 4) was significantly lower than that in patients with oligometastases (1-3) and NBM (7.0 months vs 10.0 months vs 11.0 months, P = 0.003). Multivariate analysis confirmed that bone metastasis was an independently negative predictor of PFS for EGFR-TKIs ( P = 0.017). The ORR and DCR of NBM group were higher than those of BM group (70.9% vs 56.3%, P = 0.046 and 96.2% vs 85.4%, P= 0.017). Bone was one of the frequently progressive sites of EGFR-TKIs therapy, accounting for 52 of 125 (41.6%). The incidence of bone progression in NBM patients was significantly lower than that in BM patients(11.8% vs 62.2%, P &lt; 0.001). Conclusions: Bone metastasis, especially multiple bone metastasis, reduces the response to EGFR-TKIs for lung adenocarcinoma with EGFR mutations. Bone metastasis monitoring should be a routine clinical practice for BM patients.