Receptor Tyrosine Kinase Inhibitor Treatment Research Articles

Influence of TP53 mutation on efficacy and survival in advanced EGFR-mutant non-small cell lung cancer patients treated with third-generation EGFR tyrosine kinase inhibitors.

TP53 comutation is related to poor prognosis of non-small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third-generation EGFR-TKIs in two independent cohorts. A total of 117 patients from the Sun Yat-sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress-free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha-helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p=0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha-helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01-4.18), p=0.048] and OS [HR 3.62(1.60-8.17), p=0.002] in the SYSUCC cohort. TP53 mutation in alpha-helix region was related to inferior clinical outcomes in patients treated with third-generation EGFR-TKIs.

Case report: NSCLC with pulmonary embolism after treatment with almonertinib

Rationale: Almonertinib is the first independently developed third generation epidermal growth factor receptor tyrosine kinase inhibitors in China. It can be used not only for epidermal growth factor receptor (EGFR) sensitive mutation patients but also for T790M (+) resistant patients, and has better safety and survivability compared to the first and second generation EGFR-TKIs. The previous literature and case studies have reported significant treatment-related adverse reactions in non-small cell lung cancers patients treated with almonertinib, including elevated blood creatine phosphatase, prolonged cardiac QT interval, altered myocardial contractility, interstitial lung disease, eye disease, and hematological events. But there are few individual reports of pulmonary embolism events. Patient concerns: A 55-year-old female with no history of smoking visited a local hospital with mild cough and lower sacrococcygeal pain without obvious cause. Diagnosis: She was diagnosed with right lung adenocarcinoma with multiple bone metastases (T2bN1M1c, stage IVB) after image and histological examination, with EGFR 21 exon L858R sensitive mutation. Interventions: She initially underwent surgical treatment due to the discovery of a sacral tumor, and the pathology of the surgery indicated metastatic lung adenocarcinoma. Genetic testing results showed EGFR 21 exon L858R sensitive mutation. Combined with positron emission tomography/computed tomography imaging results and sacral tumor surgical pathology results, it was considered that the patient had lung adenocarcinoma with multiple bone metastases. Treatment plan: targeted treatment with almonertinib which is the third-generation EGFR-TKIs. After only 1 month of targeted treatment, chest enhanced computed tomography revealed pulmonary embolism imaging, combined with coagulation indicators, considering pulmonary embolism. As the thromboembolic site is located at the end of the pulmonary artery branch and imaging shows that tumor lesions are stable. Consider continuing targeted treatment with almonertinib and adjuvant oral anticoagulant therapy with rivaroxaban for treatment. Outcomes: Two months later, the patient’s condition was followed up and it was found that the imaging manifestations of pulmonary embolism disappeared, but the coagulation indicators remained in a hypercoagulable state. The patient’s treatment plan remained unchanged, and the patient was hospitalized for follow-up every 6 to 8 weeks to closely observe changes in the condition. Lessons: There are many reasons for the occurrence of hypercoagulable blood in tumor patients, and there are very few reports of treatment-related pulmonary embolism events in patients who are treated with almonertinib targeted therapy. It is particularly important to determine whether the hypercoagulable blood in such patients is related to targeted therapy drugs in clinical practice, as this will affect the clinical benefits of patients in epidermal growth factor receptor tyrosine kinase inhibitors treatment and the clinical indicators which need to pay more attention in follow-up observation, to avoid serious pulmonary embolism events and thus affect the patient’s survival status and quality of life.

Impact of sequential (first- to third-generation) EGFR-TKI treatment on corrected QT interval in NSCLC patients.

To evaluate the impact of sequential (first- to third-generation) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment on top-corrected QT interval (top-QTc) in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the medical records of NSCLC patients undergoing sequential EGFR-TKI treatment at Shanghai Chest Hospital between October 2016 and August 2021. The heart rate (HR), top-QT interval, and top-QTc of their ECGs were extracted from the institutional database and analyzed. Logistic regression was performed to identify predictors for top-QTc prolongation. Overall, 228 patients were enrolled. Compared with baseline (median, 368 ms, same below), both first-generation (376 ms vs. 368 ms, p < 0.001) and sequential third-generation EGFR-TKIs (376 ms vs. 368 ms, p = 0.002) prolonged top-QT interval to a similar extent (p = 0.635). Top-QTc (438 ms vs. 423 ms, p < 0.001) and HR (81 bpm vs.79 bpm, p = 0.008) increased after first-generation EGFR-TKI treatment. Further top-QTc prolongation (453 ms vs. 438 ms, p < 0.001) and HR increase (88 bpm vs. 81 bpm, p < 0.001) occurred after treatment advanced. Notably, as HR elevated during treatment, top-QT interval paradoxically increased rather than decreased, and the top-QTc increased rather than slightly fluctuated. Moreover, such phenomena were more significant after treatment advanced. After adjusting for confounding factors, pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation during sequential third-generation EGFR-TKI treatment. First-generation EGFR-TKI could prolong top-QTc, and sequential third-generation EGFR-TKI induced further prolongation. Top-QT interval paradoxically increased and top-QTc significantly increased as HR elevated, which was more significant after sequential EGFR-TKI treatment. Pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation after sequential EGFR-TKI treatment.

Prognostic value of combining clinical factors, 18F-FDG PET-based intensity, volumetric features, and deep learning predictor in patients with EGFR-mutated lung adenocarcinoma undergoing targeted therapies: a cross-scanner and temporal validation study.

To investigate the prognostic value of 18F-FDG PET-based intensity, volumetric features, and deep learning (DL) across different generations of PET scanners in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma receiving tyrosine kinase inhibitor (TKI) treatment. We retrospectively analyzed the pre-treatment 18F-FDG PET of 217 patients with advanced-stage lung adenocarcinoma and actionable EGFR mutations who received TKI as first-line treatment. Patients were separated into analog (n = 166) and digital (n = 51) PET cohorts. 18F-FDG PET-derived intensity, volumetric features, ResNet-50 DL of the primary tumor, and clinical variables were used to predict progression-free survival (PFS). Independent prognosticators were used to develop prediction model. Model was developed and validated in the analog and digital PET cohorts, respectively. In the analog PET cohort, female sex, stage IVB status, exon 19 deletion, SUVmax, metabolic tumor volume, and positive DL prediction independently predicted PFS. The model devised from these six prognosticators significantly predicted PFS in the analog (HR = 1.319, p < 0.001) and digital PET cohorts (HR = 1.284, p = 0.001). Our model provided incremental prognostic value to staging status (c-indices = 0.738 vs. 0.558 and 0.662 vs. 0.598 in the analog and digital PET cohorts, respectively). Our model also demonstrated a significant prognostic value for overall survival (HR = 1.198, p < 0.001, c-index = 0.708 and HR = 1.256, p = 0.021, c-index = 0.664 in the analog and digital PET cohorts, respectively). Combining 18F-FDG PET-based intensity, volumetric features, and DL with clinical variables may improve the survival stratification in patients with advanced EGFR-mutated lung adenocarcinoma receiving TKI treatment. Implementing the prediction model across different generations of PET scanners may be feasible and facilitate tailored therapeutic strategies for these patients.

Machine-learning and mechanistic modeling of metastatic breast cancer after neoadjuvant treatment.

Clinical trials involving systemic neoadjuvant treatments in breast cancer aim to shrink tumors before surgery while simultaneously allowing for controlled evaluation of biomarkers, toxicity, and suppression of distant (occult) metastatic disease. Yet neoadjuvant clinical trials are rarely preceded by preclinical testing involving neoadjuvant treatment, surgery, and post-surgery monitoring of the disease. Here we used a mouse model of spontaneous metastasis occurring after surgical removal of orthotopically implanted primary tumors to develop a predictive mathematical model of neoadjuvant treatment response to sunitinib, a receptor tyrosine kinase inhibitor (RTKI). Treatment outcomes were used to validate a novel mathematical kinetics-pharmacodynamics model predictive of perioperative disease progression. Longitudinal measurements of presurgical primary tumor size and postsurgical metastatic burden were compiled using 128 mice receiving variable neoadjuvant treatment doses and schedules (released publicly at https://zenodo.org/records/10607753). A non-linear mixed-effects modeling approach quantified inter-animal variabilities in metastatic dynamics and survival, and machine-learning algorithms were applied to investigate the significance of several biomarkers at resection as predictors of individual kinetics. Biomarkers included circulating tumor- and immune-based cells (circulating tumor cells and myeloid-derived suppressor cells) as well as immunohistochemical tumor proteins (CD31 and Ki67). Our computational simulations show that neoadjuvant RTKI treatment inhibits primary tumor growth but has little efficacy in preventing (micro)-metastatic disease progression after surgery and treatment cessation. Machine learning algorithms that included support vector machines, random forests, and artificial neural networks, confirmed a lack of definitive biomarkers, which shows the value of preclinical modeling studies to identify potential failures that should be avoided clinically.

Development and validation of a deep learning-based model to predict response and survival of T790M mutant non-small cell lung cancer patients in early clinical phase trials using electronic medical record and pharmacokinetic data.

Epidermal growth factor receptor (EGFR) T790M mutation is the standard predictive biomarker for third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. While not all T790M-positive patients respond to third-generation EGFR-TKIs and have a good prognosis, it necessitates novel tools to supplement EGFR genotype detection for predicting efficacy and stratifying EGFR-mutant patients with various prognoses. Mixture-of-experts (MoE) is designed to disassemble a large model into many small models. Meanwhile, it is also a model ensembling method that can better capture multiple patterns of intrinsic subgroups of enrolled patients. Therefore, the combination of MoE and Cox algorithm has the potential to predict efficacy and stratify survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations. We utilized the electronic medical record (EMR) and pharmacokinetic parameters of 326 T790M-mutated NSCLC patients, including 283 patients treated with Abivertinib in phase I (n=177, for training) and II (n=106, for validation) clinical trials and an additional validation cohort 2 comprising 43 patients treated with BPI-7711. Furthermore, 18 patients underwent whole-exome sequencing for biological interpretation of CoxMoE. We evaluated the predictive performance for therapeutic response using the area under the curve (AUC) and the Concordance index (C-index) for progression-free survival (PFS). CoxMoE exhibited AUCs of 0.73-0.83 for predicting efficacy defined by best overall response (BoR) and achieved C-index values of 0.64-0.65 for PFS prediction in training and validating cohorts. The PFS of 198 patients with a low risk [median, 6.0 (range, 1.0-23.3) months in the abivertinib treated cohort; median 16.5 (range, 1.4-27.4) months in BPI-7711 treated cohort] of being non-responder increased by 43% [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.40-0.78; P=0.0013] and 50% (HR, 0; 95% CI, 0-0; P=0.01) compared to those at high-risk [median, 4.2 (range, 1.0-35) months in the abivertinib treated cohort; median, 11.0 (range, 1.4-25.1) months in BPI-7711 treated cohort]. Additionally, activated partial thromboplastin time (APTT), creatinine clearance (Ccr), monocyte, and steady-state plasma trough concentration utilited to construct model were found significantly associated with drug resistance and aggressive tumor pathways. A robust correlation was observed between APTT and Ccr with PFS (log-rank test; P<0.01) and treatment response (Wilcoxon test; P<0.05), respectively. CoxMoE offers a valuable approach for patient selection by forecasting therapeutic response and PFS utilizing laboratory tests and pharmacokinetic parameters in the setting of early-phase clinical trials. Simultaneously, CoxMoE could predict the efficacy of third-generation EGFR-TKI non-invasively for T790M-positive NSCLC patients, thereby complementing existing EGFR genotype detection.

Relationship between hand-foot skin reaction and external force on patients with hepatocellular carcinoma: A cohort study

PurposeHand-foot skin reaction (HFSR), a side effect of tyrosine kinase inhibitor (TKI) treatment, makes it difficult to walk and perform daily activities because of pain in the limbs. HFSR occurs predominantly in the sites where external forces (pressure and shear stress) are applied. This study aimed to determine whether pressure or shear stress induces the occurrence of HFSR. MethodsThis cohort study was conducted in patients who received TKI treatment for hepatocellular carcinoma. The external forces applied to the sole of the patients' foot while walking was measured, and its association with the occurrence of HFSR was examined. The degree of HFSR was assessed by the patient's response during the examination and by photographs of their feet. The patients' feet were divided into low (grade <2) or high (grade ≥2) HFSR foot group, and the differences in external forces between the groups were analyzed using t-test and Cox hazard analysis. ResultsAnalysis of the feet of 55 study participants (n = 110) showed no significant difference between the groups on t-test (p ≥ 0.05), however, Cox hazard analysis showed an increased risk of HFSR with higher peak shear stress values at the fifth metatarsal head (hazard ratio = 1.01, p = 0.047; 95% confidence interval = 1.00–1.02). ConclusionShear stress is possibly related to HFSR occurrence. Nurses should assess whether patients' shoes fit their feet before initiating TKI treatment. They should instruct patients to wear shoes that are fit of both diameter and width for their feet.

Prognostic impact of clinical and radiological factors on leptomeningeal metastasis from solid cancers.

The number of leptomeningeal metastasis (LM) patients has increased in recent years, as the cancer survival rates increased. An optimal prediction of prognosis is essential for selecting an appropriate treatment. The European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guidelines for LM proposed a classification based on the cerebrospinal fluid cytological findings and contrast-enhanced magnetic resonance imaging (MRI) pattern. However, few studies have validated the utility of this classification. This study aimed to investigate the prognostic factors of LM, including the radiological and cytological types. We retrospectively analyzed the data of 240 adult patients with suspected LM who had undergone lumbar puncture between April 2014 and September 2021. The most common primary cancer types were non-small-cell lung cancer (NSCLC) (143 (60%)) and breast cancer (27 (11%)). Positive cytology results and the presence of leptomeningeal lesions on contrast-enhanced MRI correlated with decreased survival in all patients. Nodular lesions detected on contrast-enhanced magnetic resonance were a poor prognostic factor in cytology-negative patients, while contrast-enhanced patterns had no prognostic significance in cytology-positive patients. Systemic therapy using cytotoxic agents and molecular-targeted therapy after LM diagnosis correlated with prolonged survival, regardless of the cytology results. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment and systemic chemotherapy after LM improved the survival of EGFR-mutated and wild-type NSCLC patients with positive cytology results. This study validated the efficacy of prognostication according to the EANO-ESMO guidelines for LM. Systemic therapy after LM diagnosis improves the survival of NSCLC patients.

Dynamic Changes in ABL1 Kinase Domain Mutations and Comparative Efficacy of Third-Generation Tyrosine Kinase Inhibitors across Different Stages in Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Blast Crisis Patients

*Drs.Zixuan Li and Danyue Peng contributed equally. Drs.Mei Hong and Qiuling Wu are co-corresponding authors Background The development of first-generation and second-generation tyrosine kinase inhibitors (TKIs) has played a crucial role in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). However, the emergence of mutations in the kinase domain (KD) of BCR-ABL1 has increasingly compromised the efficacy of TKIs and become the primary cause of TKI resistance. Testing BCR-ABL1 KD mutations in early phase accurately is of great value in predicting response and guiding therapeutic decisions. Next-generation sequencing (NGS) provided a more comprehensive and elaborate understanding of mutation status. Third-generation (3G) TKI has been designed to overcome resistance problems caused by BCR-ABL1 KD mutations, and it exhibited unique pharmacological profiles and response patterns relative to different mutations and disease characteristics. Therefore, the potential clinical relevance of mutations detected by NGS and the efficacy of 3G TKI are worth exploring. Methods NGS was used to analyze the dynamic changes of both clinically unreported mutations and reported resistant mutations in the ABL1 KD during three stages of the disease course (pretreatment, remission, and relapsed periods) in Ph+ ALL (n = 97) and chronic myeloid leukemia blast crisis (CML-BP) (n = 21) patients. Meanwhile, the comparative efficacy of three generations of TKIs in Ph+ ALL (n = 92) and CML-BP (n = 23) and the relationship between ABL1 KD mutations and different TKI selection were analyzed. Results In Ph+ ALL patients, single ABL1 KD unreported mutations were detected in 30.49% of patients before therapy and 39.73% in remission, which accounted for the highest proportion among other mutation types. Conversely, single ABL1 KD resistant mutations were found to be the most prevalent (54.5%) in relapsed patients ( P &amp;lt; 0.0001). Logistic analysis revealed that the presence of F401V/L in untreated Ph+ ALL patients was associated with a higher risk of relapse ( P &amp;lt; 0.1). Furthermore, through analyzing patients who received TKI treatment, we observed that 3G TKIs like olverembatinib exhibited advantages in prognosis, including achieving deep molecular response, rapid remission reduction, and decreased relapse probability, for both newly diagnosed and relapsed Ph+ ALL patients. Notably, 3G TKIs not only demonstrated strong inhibition against the T315I mutation, as previously reported, but also displayed superior effectiveness against certain ABL1 KD unreported mutations, such as R516L, K262T, and F401V. Similar trends were observed in CML-BP, although statistical significance was not reached likely due to the limited number of patients. Conclusion Overall, our findings indicate the prevalence and impact of ABL1 KD mutations in Ph+ ALL and CML-BP patients, highlighting the necessity for effective therapies targeting these mutations. The promising outcomes observed with 3G TKIs suggest their potential as a treatment option for both newly diagnosed and relapsed Ph+ ALL patients, offering advantages in terms of molecular response depth, rapid remission, and reduced relapse risk. Further investigations are warranted to explore the clinical significance of unreported ABL1 KD mutations and validate the effectiveness of 3G TKIs against them.

The Impact of Adding Rituximab to the Standard Chemotherapy + TKI Regimen in Adults with Philadelphia-Positive B Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study

Introduction: The addition of rituximab to the treatment of CD20-positive (CD20+) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) patients has demonstrated considerable benefits in terms of event-free survival in a large randomized clinical trial, as well as overall survival (OS) in retrospective analyses. Consequently, it is now an integral part of the standard care chemotherapy regimen for these patients. Conversely, Ph-positive (Ph+) B-ALL patients have been excluded from these trials and are typically managed with tyrosine-kinase inhibitors (TKI) in combination with chemotherapy, steroids, or novel agents such as blinatumomab. However, the potential benefits and concerns of adding rituximab to CD20+ Ph+ B-ALL patients remain uncertain, as there are worries about prolonged immunosuppression and potential infectious complications. Methods: We conducted a multicenter retrospective study involving five tertiary care centers in Mexico. The study included patients older than 16 years with newly diagnosed Ph-positive B ALL between January 2009 and June 2022, according to the WHO criteria. CD20+ was defined as CD20 expression ≥20% by flow cytometry. The decision to administer rituximab was based on the physician's discretion. The primary objective was to compare the 3-year OS between CD20-negative patients and CD20-positive patients who received or did not receive rituximab, and as secondary objectives to evaluate infection rates and mortality during induction with the addition of rituximab. Results: The study comprised 119 patients who met the inclusion criteria. The median age at diagnosis was 38 years (16 - 73), with 52.1% being male. The median white blood cell count (WBC) count was 114 x 10 9/L (0.5 - 466). Of these, 45 patients (37.8%) had CD20+ B-ALL, and 24 of them (53.3%) received rituximab. A total of 111 patients (93.2%) received TKI treatment, with imatinib being the most common (79%), followed by dasatinib (13.4%) and ponatinib (0.8%). The majority of the patients received either Hyper-CVAD (41.2%) or a local adult regimen (31.9%). There were no significant differences in age, WBC count, or treatment/TKI between patients who received rituximab and those who did not. Table 1 presents the characteristics of the population based on CD20 expression and treatment. Early mortality was 5.8%, with no significant difference observed between patients who received rituximab and those who did not (0% vs. 7.4%; OR 0.78, 95% CI 0.71 - 0.86, p=0.342). The rate of neutropenic fever during induction was 72.3%, and it was lower in patients who received rituximab (50.0% vs. 77.9%; OR 0.28, 95% CI 0.11 - 0.72, p=0.010). The intensive care unit (ICU) admission rate during induction was 11.8%, with no significant difference observed between patients with or without rituximab (8.3% vs. 12.6%; OR 0.62, 95% CI 0.13 - 3.01, p=0.733). Molecular response at 3 months was measured in 72 patients and the use of rituximab was associated with a non-significant higher rate: 83.3% vs 57.4% with an OR of 3.71 (95% CI, 0.96-14.33, p=0.056).The median OS for the entire cohort was 20 months (95% CI, 13.34 - 26.65), with a 3-year OS of 35.7%. The leading cause of death was disease progression (77.3%), while 10.7% died in remission: 7.7% of CD20- patients, 21.4% of CD20+ patients without rituximab, and 11.1% of CD20+ patients receiving rituximab (p=0.436). There was a trend towards a better OS in CD20+ patients who received rituximab: median OS not reached vs. 21 months (95% CI 13.27 - 28.72) in CD20- patients, and 13 months (95% CI 9.7 - 16.29) in CD20+ patients without rituximab. The 3-year OS rates for these groups were 52.7%, 34%, and 24.6%, respectively (p=0.222; Figure 1). Conclusions: In real-world practice, rituximab is added to the chemotherapy regimen and TKI in 53.3% of CD20+ Ph+ B-ALL cases. Rituximab is not associated with a higher incidence of infections, ICU admission, early mortality, or deaths in remission. Although there is no significant benefit observed, there is a trend towards better OS with the addition of rituximab to the standard treatment of CD20+ Ph+ ALL. There is an unmet need to explore the concomitant use of rituximab and TKI in prospective studies.

Improvement of Treatment-Free Remission Rate Following Discontinuation of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Phase, Chronic Myeloid Leukemia

Backgrounds: Several studies have shown that approximately one-half of patients with chronic phase chronic myeloid leukemia (CP-CML) who receive sufficient tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. The main factors affecting Treatment free remission (TFR) are the duration of TKIs treatment and the duration of DMR maintenance during TKI treatment. Aims: To investigate impact of longer duration of DMR, we analyzed the outcome of patients with CP-CML who maintained DMR for more than 6 years during TKIs treatment and discontinued TKIs. The clinical and molecular immunological application criteria were also investigated for safer and more successful TFR. Methods: Among patients newly diagnosed with CP-CML and treated at least one of TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib, and Radotinib) as the first treatment, patients who maintained MR4.5 (BCR::ABL1 IS ≤0.0032%) continuously for at least 6 years through qRT-PCR tests were enrolled in this study. After discontinuation, molecular responses were monitored for up to six months per month, up to 12 months every two months, and every three months thereafter using the qRT-PCR method. In the case of relapse, defined as loss of major molecular response (MMR), the last TKI therapy was reintroduced and molecular responses after resumption were monitored monthly until achievement of MMR using qRT-PCR. Results: Altogether 116 patients (50 males and 66 females) discontinued TKI. Median age at diagnosis was 43.0 years (range, 40.8-45.3) and the percentages of patients with low, intermediate and high Sokal risk scores ware 58 (50.0%), 35 (30.2%) and 18 (15.5%) patients, respectively with unknown Sokal risk scores in 5 (4.3%) patients. Prior to discontinuation, all patients received TKIs for a median of 120.6 months (range, 113.9-127.3), and the duration of sustained MR4.5 was 75.0 months (range, 70.7-79.3). At the time of discontinuation, 93 patients (80.2%) were receiving their first TKI (70 imatinib, 13 nilotinib, 6 radotinib, and 4 dasatinib) while 13 (11.2 %) and 10 (8.6%) patients were receiving their second and more than three TKIs respectively. All patients who received more than one TKI had changed to adverse events. After a median follow-up from treatment discontinuation of 42.2 months (range, 35.3-49.1), 28 (24.1%) patients have lost their response at a median of 8.4 months (range, 4.9-11.9) after discontinuation; 18 (64.3%) patients had molecular relapse within 6 months of TKI discontinuation and 7 (25.0%) patients lost MMR after 12 months from discontinuation. TFR rates at 12, 24, and 48 months were 81.9%, 76.0%, and 71.0%, respectively. No progression toward advanced-phase CML occurred, and when 28 patients who lost MMR were retreated with same TKI, 26 patients (92.9%) re-achieved MMR with a median of 5.6 months (range, 4.0-7.2). By univariate analysis, a TKI treatment duration of 10 years or more was the only significant predictor for maintained response (P&amp;lt;0.048). Conclusion: Our result demonstrates that TFR rate can be improved in patients who received TKI treatment for approximately 10 years and maintained DMR for more than 6 years regardless of the type of TKI. Based on results, we can confirm one of important factors for safer TFR in CP-CML patients.

CTIM-23. SAFETY RUN-IN RESULTS OF A PHASE I/II STUDY TO EVALUATE ATEZOLIZUMAB IN COMBINATION WITH CABOZANTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Immune checkpoint inhibitor therapy has shown limited efficacy in the treatment of glioblastoma (GBM) in both newly diagnosed and recurrent disease which underscores the need for rational combinatorial strategies. Atezolizumab is a humanized monoclonal antibody that targets PD-L1 and has been shown to enhance the magnitude of tumor-specific T cell responses. Combining PD-L1/PD-1 axis inhibition with targeted therapy like cabozantinib which has both anti-tumoral and immunomodulatory properties may result in synergistic effects. Cabozantinib may modulate the myeloid cell population to overcome resistance to anti-PD-1/PD-L1 therapy. METHODS Eligibility criteria were those with recurrent GBM, age &amp;gt;18 yrs with 1st or 2nd recurrence who were naïve to antiangiogenic and receptor tyrosine kinase inhibitor treatment. The primary objective of the phase I run-in was to evaluate the safety of atezolizumab in combination with cabozantinib. RESULTS 1 dose-limiting toxicity (DLT) of a grade 3 ALT elevation was observed in the first 6 DLT evaluable patients treated during the safety run-in phase. Regarding immune related adverse events, 1 of 6 patients developed atezolizumab-related grade 1 hypothyroidism. 1 of 6 patients developed study treatment-related grade 2 diarrhea. 2 patients after completion of 2 cycles of treatment had evidence of a partial radiographic response ( &amp;gt; 50% decrease). 1 patient had a near partial radiographic response (45% decrease). 2 patients had stable disease after completion of 2 cycles of the combinatorial treatment. 1 patient had only completed the first 28-day cycle, DLT period, and had not yet had imaging to reassess disease status. CONCLUSIONS The combination of atezolizumab with cabozantinib was tolerable, and no new safety signals were noted. In this small cohort of recurrent GBM patients, radiographic responses were observed. The phase II component of the trial is recruiting patients (n = 45) to evaluate clinical efficacy. Multi-omic correlative studies and fecal microbiome analyses are planned.

Overall signature of acquired KRAS gene changes in advanced non-small cell lung cancer patient with EGFR-TKI resistance.

Numerous scattered case studies continue to demonstrate a strong correlation between acquired KRAS mutations and epidermal growth factor receptor-tyrosine kinase inhibitor resistance in non-small cell lung cancer. However, the comprehensive understanding of the KRAS pathway following the failure of epidermal growth factor receptor-tyrosine kinase inhibitor therapy remains limited. We conducted a retrospective evaluation of the next generation sequencing data from 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations after experiencing progression with epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our analysis specifically focused on the acquired changes to the KRAS gene. Among the 323 patients with advanced non-small cell lung cancer and EGFR-activating mutations who experienced resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy, 14 individuals (4.3%) developed resistance due to acquired KRAS alterations. Of these 14 patients, 10 cases (71.4%) were due to KRAS missense mutations, 1 case (7.2%) was due to KRAS gene fusion and 3 cases (21.4%) were due to KRAS amplification. Notably, we identified one newly demonstrated KRAS gene fusion (KRAS and LMNTD1), one KRAS G13D and one KRAS K117N. The emergence of acquired KRAS alterations was often accompanied by novel mutations and high tumor mutation burden, with TP53, CNKN2A, PIK3CA, MYC, STK11, CDK4, BRCA2 and ERBB2 being the most frequently observed concurrent mutations. The median progression-free survival and overall survival for the 14 patients were 5.2 and 7.3months, respectively. Acquired KRAS missense variants were associated with significantly worse progression-free survival compared with other KRAS variant subtypes (P<0.028). This study provides significant evidence of the role of acquired KRAS variants in the development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy. Our results contribute to the growing body of knowledge on the mutational profiles associated with resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment. Furthermore, our study highlights the KRAS gene change as a significant mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Management of chronic myelogenous leukemia with COVID-19 and hepatitis B.

The application of immunosuppressive agents and targeted drugs has opened a novel approach for the treatment of hematological tumors, and the application of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia is one of the landmark breakthroughs that has considerably improved the prognosis of CML patients. However, with the extensive use of TKI, the co-infection of CML patients has become increasingly apparent, especially regarding infectious diseases such as hepatitis B and COVID-19. The underlying mechanism may be related to the inhibition of the immune function by TKI. Poor management, including disease progression due to the infectious disease or TKI dose reduction or discontinuation, may lead to adverse clinical outcomes and can even be life-threatening. Therefore, this review principally provides an overview of the pathogenesis and standardized management principles of CML patients with comorbid COVID-19 or hepatitis B in order to improve clinicians' awareness of the risks so as to more effectively diagnose and treat CML and improve the survival rate and quality of life of patients. In the past two decades, owing to the advent of imatinib, chronic myeloid leukemia (CML) has transformed into a chronic controllable disease, and even treatment-free remission can be anticipated. Earlier studies have indicated that tyrosine kinase inhibitor (TKI) exerts a peculiar inhibitory effect on the body's immune function. Therefore, with the widespread application of TKI, more and more attention has been paid to the comorbidity of infectious diseases in CML patients, especially in patients with progressive disease or non-remission. Despite some studies revealing that the proportion and severity of SARS-CoV-2 infection in CML patients receiving TKI treatment are lower than in patients with other hematological malignancies, CML patients with stable disease are still recommended to be vaccinated against SARS-CoV-2, while TKI may or may not be discontinued. Meanwhile, the management of CML patients during the epidemic of coronavirus disease 2019 (COVID-19) still necessitates further discussion. This article also provides an overview of TKI-related hepatitis B reactivation. If not managed, patients may face adverse consequences such as hepatitis B reactivation-related hepatitis, liver failure, and progression of CML after forced withdrawal of medication. Therefore, this review aimed to comprehensively describe the management of CML patients with comorbid COVID-19, the pathogenesis of hepatitis B reactivation, the indicated population for prophylactic antiviral therapy, the time of antiviral drug discontinuation, and drug selection.

Clinical features and prognosis of lung cancer in patients with connective tissue diseases: a retrospective cohort study.

Studies have demonstrated a close association between connective tissue diseases (CTDs) and lung cancer (LC). Evidence supports that poor survival may be associated with the presence of CTDs in patients with LC. This retrospective cohort study investigated 29 patients with LC with CTDs, and 116 patients with LC without CTDs were enrolled as case-matched control cohorts. Medical records, therapeutic efficacy of cancer, and outcomes were analyzed. The median duration from the diagnosis of CTDs to LC was 17 years. The Eastern Cooperative Oncology Group (ECOG) performance score for LC-CTD patients was worse than that for matched non-CTD LC patients. The median progression-free survival (mPFS) and overall survival (mOS) of first-line chemotherapy did not differ between patients with lung adenocarcinoma (AC) with and without CTDs. A significant difference was observed in mPFS [4 months vs. 17 months; hazard ratio (HR), 9.987; p = 0.004] and mOS (6 months vs. 35 months; HR, 26.009; p < 0.001) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment between patients with AC with and without CTDs. The presence of CTD, sex, ECOG performance status, and tumor-node-metastasis clinical stage were the independent prognostic factors in all patients with non-small cell LC (NSCLC). ECOG performance status was determined to be an independent prognostic factor in patients with LC-CTD. In patients with NSCLC with CTD (n = 26), sex (male) and worse ECOG score were the independent poor prognostic factors. CTDs were associated with poor survival in patients with LC. The therapeutic efficacy of first-line EGFR-TKI therapy was significantly worse in patients with lung AC with CTDs than in those without CTDs. ECOG performance status was determined as an independent prognostic factor for patients with LC and CTDs.

LncRNA LINC00969 promotes acquired gefitinib resistance by epigenetically suppressing of NLRP3 at transcriptional and posttranscriptional levels to inhibit pyroptosis in lung cancer

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment prolongs the survival of lung cancer patients harbouring activating EGFR mutations. However, resistance to EGFR-TKIs is inevitable after long-term treatment. Molecular mechanistic research is of great importance in combatting resistance. A comprehensive investigation of the molecular mechanisms underlying resistance has important implications for overcoming resistance. An accumulating body of evidence shows that lncRNAs can contribute to tumorigenesis and treatment resistance. By bioinformatics analysis, we found that LINC00969 expression was elevated in lung cancer cells with acquired gefitinib resistance. LINC00969 regulated resistance to gefitinib in vitro and in vivo. Mechanistically, gain of H3K4me1 and H3K27Ac led to the activation of LINC00969 expression. LINC00969 interacts with EZH2 and METTL3, transcriptionally regulates the level of H3K27me3 in the NLRP3 promoter region, and posttranscriptionally modifies the m6A level of NLRP3 in an m6A-YTHDF2-dependent manner, thus epigenetically repressing NLRP3 expression to suppress the activation of the NLRP3/caspase-1/GSDMD-related classical pyroptosis signalling pathways, thereby endowing an antipyroptotic phenotype and promoting TKI resistance in lung cancer. Our findings provide a new mechanism for lncRNA-mediated TKI resistance from the new perspective of pyroptosis via simultaneous regulation of histone methylation and RNA methylation. The pivotal role of LINC00969 gives it the potential to be a novel biomarker and therapeutic target for overcoming EGFR-TKI resistance in lung cancer.

Efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitors treatment failure

Objective: To investigate the efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer (NSCLC) who failed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. Methods: A retrospective analysis was made on the clinical data of 60 NSCLC patients who were treated with immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure in the Affiliated Cancer Hospital of Shandong First Medical University from January 2019 to March 2022. Patients were followed up by telephone or outpatient review up to October 1, 2022, with a median follow-up of 8.2 months (95%CI: 7.1-9.3). All 60 patients were followed up. The response evaluation criteria in solid tumors were used to evaluate the short-term efficacy. The adverse reactions of patients were evaluated according to the common terminology criteria for adverse events. The survival curve was drawn by Kaplan-Meier method. Cox proportional hazard regression models were utilized to analyze the influencing factors of progression-free survival (PFS). Results: Among the 60 NSCLC patients, 22 were males. The age ranged from 41 to 75 years, with a median age of 61 years. Eleven patients had partial response, 19 patients had stable disease and 30 patients had progressive disease. The median PFS was 8.2 months (95%CI: 7.2-9.2). The median PFS of patients with low expression of programmed death receptor-ligand 1 (PD-L1) [Tumor cell Proportion Score (TPS)<1%], moderate expression of PD-L1 (1%≤TPS≤49%), and high expression of PD-L1 (TPS≥50%) were 6.4 (95%CI: 4.8-8.0), 8.3 (95%CI: 7.3-9.3) and 10.6 months (95%CI: 7.2-14.1), respectively, and there were statistically significant differences (χ2=13.58, P<0.001). Multivariate Cox proportional risk regression model analysis showed that age>65 years old (HR=4.017, 95%CI: 1.468-10.992, P=0.007) was a risk factor for PFS in NSCLC patients who received immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure. Moderate expression of PD-L1 (HR=0.360, 95%CI: 0.139-0.930, P=0.035) and high expression of PD-L1 (HR=0.155, 95%CI: 0.039-0.625, P=0.009) were protective factors for PFS. Most of the treatment-related adverse reactions in the whole group were grade 1-2, including bone marrow suppression (n=24), nausea (n=25), decreased appetite (n=24), fatigue (n=22), vomiting (n=18), abnormal liver function (n=17), blood creatinine increased (n=10), and so on. These were tolerated by the patients. Conclusions: NSCLC patients who failed EGFR-TKIs treatment can tolerate adverse reactions related to immunotherapy combined with chemotherapy and bevacizumab treatment. PFS is significantly prolonged in those aged≤65 years and those with moderate and high expression of PD-L1.

Healthcare coverage affects survival of EGFR-mutant Thai lung cancer patients.

Despite significant benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in patients with EGFR-mutated NSCLC, access remains limited in Thailand and elsewhere. Retrospective analysis of patients with locally advanced/recurrent NSCLC and known EGFR mutation (EGFRm) status treated at Ramathibodi Hospital (2012-2017). Prognostic factors for overall survival (OS), including treatment type and healthcare coverage, were analyzed using Cox regression. Of 750 patients, 56.3% were EGFRm-positive. After first-line therapy (n=646), 29.4% received no subsequent (second-line) treatment. EGFR-TKI-treated EGFRm-positive patients survived significantly longer than EGFRm-negative patients without EGFR-TKIs (median OS [mOS] 36.4 vs. 11.9 months; hazard ratio HR=0.38 [95%CI 0.32-0.46], P<0.001). Cox regression indicated significantly longer OS in patients with comprehensive healthcare coverage that included reimbursement of EGFR-TKIs, versus basic coverage (mOS 27.2 vs. 18.3 months; adjusted HR=0.73 [95%CI 0.59-0.90]). Compared with best supportive care (BSC; reference), EGFR-TKI-treated patients survived significantly longer (mOS 36.5 months; adjusted HR (aHR)=0.26 [95%CI 0.19-0.34]), and versus chemotherapy alone (14.5 months; aHR=0.60 [95%CI 0.47-0.78]). In EGFRm-positive patients (n=422), relative survival benefit of EGFR-TKI treatment remained highly significant (aHR[EGFR-TKI]=0.19 [95%CI 0.12-0.29]; aHR(chemotherapy only)=0.50 [95%CI 0.30-0.85]; reference:BSC), indicating that healthcare coverage (reimbursement) affected treatment choice and survival. Our analysis describes EGFRm prevalence and survival benefit of EGFR-TKI therapy for EGFRm-positive NSCLC patients treated from 2012-2017, one of the largest such Thai datasets. Together with research by others, these findings contributed evidence supporting the decision to broaden erlotinib access on healthcare schemes in Thailand from 2021, demonstrating the value of local real-world outcome data for healthcare policy decision-making.

Profile of Exon 20 T790M Mutation Incidence Rate with Plasma ctDNA in Lung Adenocarcinoma Patients Receiving EGFR-TKI Treatment

Introduction: Patients with lung adenocarcinoma following epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment will develop acquired resistance after 7 to 16 months of starting the medication, indicated by the emergence of exon 20 T790M mutations. This study aimed to identify the clinical and demographical profile of acquired resistance in patients with lung adenocarcinoma receiving EGFR-TKI therapy through plasma circulating tumor deoxyribonucleic acid (ctDNA) examination. Methods: This was a descriptive study with a retrospective cross-sectional design involving 108 lung adenocarcinoma patients who received EGFR-TKI for more than six months. Exon 20 T790M EGFR mutations were identified as a sign of acquired resistance using the digital droplet polymerase chain reaction (ddPCR) approach to examine plasma ctDNA Utilizing the Statistical Package for the Social Sciences, statistical tests were used to examine the data (SPSS). The data were analyzed by statistical tests using the Statistical Package for the Social Sciences (SPSS). Results: A total of 31 patients were recruited as study participants. The majority of the research subjects were female (64.5%), aged 20-69 years old (58%), and non-smokers (67.7%). Exon 19 deletions were the most prevalent EGFR mutation (58.1%). The incidence of acquired resistance was found in 10 subjects (32.3%). Patients with acquired resistance were predominately female (70%), non-smokers (80%), and with gefitinib therapy (90%). The average time for EGFR-TKI treatment until acquired resistance occurred was 12.6 months. Conclusion: The incidence of acquired resistance was mainly found in women without a smoking history after 12.6 months of treatment with EGFR-TKI.

Reactivation of Hepatitis B Virus in Lung Cancer Patients Receiving Tyrosine Kinase Inhibitor Treatment.

(1) Background: We aimed to evaluate the risk of hepatitis B virus (HBV) reactivation in lung cancer patients treated with tyrosine kinase inhibitor (TKI), particularly in those with resolved HBV infection. (2) Methods: In this retrospective hospital-based cohort study, we screened all lung cancer patients with positive hepatitis B core antibodies (anti-HBc) receiving systemic antineoplastic treatment during the period from January 2011 to December 2020. Cumulative incidences of HBV reactivation, and their hazard ratios (HRs), were evaluated after adjusting patient mortality as a competing risk. (3) Results: Among 1960 anti-HBc-positive patients receiving systemic therapy, 366 were HBsAg-positive and 1594 were HBsAg-negative. In HBsAg-positive patients without prophylactic NUC, 3-year cumulative incidences of HBV reactivation were similar between patients receiving chemotherapy and patients receiving TKI (15.0%, 95% confidence interval (CI): 0−31.2% vs. 21.2%, 95% CI: 10.8−31.7%; p = 0.680). Likewise, 3-year cumulative incidences of HBV-related hepatitis were similar between the two groups (chemotherapy vs. TKI: 15.0%, 95% CI: 0−31.2% vs. 9.3%, 95% CI: 2.8−15.7%; p = 0.441). In 521 HBsAg-negative TKI users, the 3-year cumulative incidence of HBV reactivation was only 0.6% (95% CI: 0.0−1.9%). From multivariable regression analysis, we found that the only independent risk factor for HBV reactivation in TKI users was HBsAg positivity (HR 53.8, 95% CI: 7.0−412.9; p < 0.001). (4) Conclusion: Due to high risks of HBV reactivation in HBsAg-positive TKI users, NUC prophylaxis can be considered. However, in patients with resolved HBV infection, such risks are lower, and therefore regular monitoring is recommended.