ATR2C ala2 from Arabidopsis-infecting downy mildew requires 4 TIR-NLR immune receptors for full recognition.

Arabidopsis Col-0 RPP2A and RPP2B confer recognition of Arabidopsis downy mildew (Hyaloperonospora arabidopsidis [Hpa]) isolate Cala2, but the identity of the recognized ATR2Cala2 effector was unknown. To reveal ATR2Cala2, an F2 population was generated from a cross between Hpa-Cala2 and Hpa-Noks1. We identified ATR2Cala2 as a non-canonical RxLR-type effector that carries a signal peptide, a dEER motif, and WY domains but no RxLR motif. Recognition of ATR2Cala2 and its effector function were verified by biolistic bombardment, ectopic expression and Hpa infection. ATR2Cala2 is recognized in accession Col-0 but not in Ler-0 in which RPP2A and RPP2B are absent. In ATR2Emoy2 and ATR2Noks1 alleles, a frameshift results in an early stop codon. RPP2A and RPP2B are essential for the recognition of ATR2Cala2. Stable and transient expression of ATR2Cala2 under 35S promoter in Arabidopsis and Nicotiana benthamiana enhances disease susceptibility. Two additional Col-0 TIR-NLR (TNL) genes (RPP2C and RPP2D) adjacent to RPP2A and RPP2B are quantitatively required for full resistance to Hpa-Cala2. We compared RPP2 haplotypes in multiple Arabidopsis accessions and showed that all four genes are present in all ATR2Cala2-recognizing accessions.

Real-world treatment patterns and clinical outcomes in patients with stage III NSCLC in Korea: The KINDLE study.

OBJECTIVE: KINDLE-Korea is part of a real-world KINDLE study that aimed to characterize the treatment patterns and clinical outcomes of patients with stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The KINDLE was an international real-world study that explores patient and disease characteristics, treatment patterns, and survival outcomes. The KINDLE-Korea included stage III NSCLC patients diagnosed between January 2013 and December 2017. RESULTS: A total of 461 patients were enrolled. The median age was 66 years (range: 24-87). Most patients were men (75.7%) with a history of smoking (74.0%), stage IIIA NSCLC (69.2%), and unresectable disease (52.9%). A total of 24.3% had activating EGFR mutation and 62.2% were positive for PDL1 expression. Broadly categorized, 44.6% of the patients received chemoradiation (CRT)-based therapy, 35.1% underwent surgery, and 20.3% received palliative therapies as initial treatment. The most commonly adopted approaches for patients with stage IIIA and IIIB disease were surgery and CRT, respectively. The median PFS was 15.2 months and OS was 66.7 months. Age >65 years, adenocarcinoma histology, and surgery as the initial treatment were significantly associated with longer OS. CONCLUSION: This study revealed the heterogeneity of treatment patterns and survival outcomes in patients with stage III NSCLC before durvalumab consolidation came into clinical practice. There is an unmet need for patients who are not eligible for surgery as an initial therapy. Novel therapeutic approaches are highly warranted to improve clinical outcomes.

Impact of PIK3CA and cell cycle pathway genetic alterations on durvalumab efficacy in patients with head and neck squamous cell carcinoma: Post hoc analysis of TRIUMPH study.

OBJECTIVES: This study aimed to investigate whether genetic alterations in PI3KCA and the cell cycle pathways influence the efficacy of durvalumab, an immune checkpoint inhibitor, in patients with head and neck squamous cell carcinoma (HNSCC) who had previously failed platinum-based treatment. MATERIALS AND METHODS: We obtained data from a phase II umbrella trial of patients with HNSCC who failed platinum-based treatment (TRIUMPH, NCT03292250). Patients receiving durvalumab treatment comprised those with PIK3CA alterations (Group A), those with cell cycle pathway alterations such as CDKN2A (Group B), and those with no druggable genetic alterations (Group C). We analyzed the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in each group and evaluated the potential predictive factors for durvalumab. RESULTS: We analyzed the data of 87 patients: 18, 12, and 57 in groups A, B, and C, respectively. The ORRs were 27.8 %, 8.3 %, and 15.8 % in Groups A, B, and C, respectively (P = 0.329), and the median PFS for each group was 2.3, 1.6, and 1.7 months, respectively, with no significant differences between the groups (P = 0.24). Notably, patients with lower neutrophil-lymphocyte ratio (NLR) (≤5.8) had longer PFS (median, 2.8 vs 1.6 months, P < 0.001), while those with lower platelet-lymphocyte ratio (PLR) (≤491.2) exhibited longer PFS (median, 1.8 vs 1.2 months, P < 0.001). CONCLUSION: Durvalumab's efficacy was similar, irrespective of the presence of PIK3CA or cell cycle pathway genetic alterations in patients with platinum-resistant HNSCC. The NLR and PLR may be promising predictive biomarkers.

A nationwide real-world study for evaluation of effectiveness and safety of T-DM1 in patients with HER2-positive metastatic breast cancer in Korea (KCSG BR19-15).

Purpose: This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC). Methods: We included patients with HER2-positive mBC who received T-DM1 as a palliative therapy between August 2017 and December 2018. The safety and outcomes of T-DM1, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) for mortality or progression to HER2-positive mBC. Results: In total, 824 patients were enrolled during the study period. The mean age of patients was 58 years, and 516 (62.6%) patients relapsed after curative treatment. Excluding a history of endocrine therapy, 341 (41.4%) patients previously received none or first-line chemotherapy, 179 (21.7%) received second-line therapy, and 303 (36.9%) received third-or later-line chemotherapy before T-DM1 therapy. During a median follow-up of 16.8 months, the ORR was 35%, the median PFS was 6.6 months, and the median OS was not reached. The clinical factors associated with the hazard of progression were age (<65 years), poor performance status (⩾2), advanced line of palliative chemotherapy (⩾2), prior pertuzumab use, and treatment duration of palliative trastuzumab (<10 months). Common grade 3-4 adverse events were thrombocytopenia (n = 107, 13.2%), neutropenia (n = 23, 2.8%), anemia (n = 21, 2.6%), and elevated liver enzyme (n = 20, 2.5%). Hypokalemia (⩽3.0 mmol/L) and any-grade bleeding events occurred in 25 (3.1%) and 94 (22.6%) patients, respectively. Conclusion: This is the first nationwide real-world study of T-DM1 use in patients with HER2-positive mBC in Korea. The effectiveness and toxicity profiles of T-DM1 in real-world practice were comparable to those in randomized trials. Moreover, patient factors and previous anti-HER2 therapy could predict the outcomes of T-DM1 therapy.

Personalized Biomarker-Based Umbrella Trial for Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC. METHODS: In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment. RESULTS: Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths. CONCLUSION: To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.

A Phase II Trial of Nintedanib in Patients with Metastatic or Recurrent Head and Neck Squamous Cell Carcinoma: In-Depth Analysis of Nintedanib Arm from the KCSG HN 15-16 TRIUMPH Trial.

PURPOSE: Precision oncology approach for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) is necessary due to its dismal prognosis. We performed a genomic profile-based umbrella trial of patients with platinum-refractory HNSCC (KCSG-TRIUMPH). Here, we present an in-depth report of the the nintedanib arm (arm 3) of the current trial. MATERIALS AND METHODS: The TRIUMPH study was a multicenter, open-label, single-arm phase 2 trial, in which patients were assigned to treatment arms based on next-generation sequencing (NGS)-based, matching genomic profiles. Patients whose tumors harbor fibroblast growth factor receptor (FGFR) alteration were enrolled in the nintedanib arm (arm 3) as part of the TRIUMPH study. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), safety, and biomarker analysis. RESULTS: Between October 2017 and August 2020, 207 were enrolled in the TRIUMPH study, and eight were enrolled in the nintedanib arm. ORR and disease control rate were 42.9% and 57.1%, respectively. The median PFS was 5.6 months and the median duration of response was 9.1 months. Median OS was 11.1 months. One patient maintained the partial response for 36 months. Overall, the toxicity profiles were manageable. CONCLUSION: Single-agent nintedanib has demonstrated significant efficacy in FGFR-mutated, recurrent or metastatic HNSCC patients, with tolerable toxicity profiles. The results from the study have provided the basis for routine NGS screening and FGFR-targeted therapy. Because of the small number of patients due to slow accrual in this study, further studies with a larger cohort are warranted for statistical power.

Pemetrexed plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer (KCSG-BR15-17): A randomized, open-label, multicenter, phase II trial.

INTRODUCTION: Metastatic breast cancer refractory to anthracycline and taxanes often shows rapid progression. The development of effective and tolerable combination regimens for these patients is needed. This phase II trial investigated the efficacy of pemetrexed plus vinorelbine in patients with metastatic breast cancer. METHODS: This randomized, open-label, phase II trial was conducted in 17 centers in Korea. Patients with advanced breast cancer who had previously been treated with anthracyclines and taxanes were randomly assigned in a 1:1 ratio to receive either vinorelbine or pemetrexed plus vinorelbine. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included the objective response rate, overall survival, safety, and quality of life. RESULTS: Between March 2017 and August 2019, a total of 125 patients were enrolled. After a median follow-up duration of 14.1 months, 118 progression events and 88 death events had occurred. Sixty-two patients were assigned to the pemetrexed plus vinorelbine arm, and 63 were assigned to the vinorelbine arm. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine (5.7 vs. 1.5 months, p < 0.001). The combination arm had higher disease control rate (76.8% vs. 45.9%, p = 0.001) and a tendency toward longer overall survival (16.8 vs. 10.5 months, p = 0.102). Anemia was more frequent in the pemetrexed plus vinorelbine arm per cycle compared with vinorelbine (7.9% vs. 1.9%, p < 0.001), but there was no difference in the incidence of grade 3-4 neutropenia per cycle between the pemetrexed plus vinorelbine arm and the vinorelbine single arm (14.7% vs. 19.5%, p = 0.066). CONCLUSIONS: This phase II study showed that pemetrexed plus vinorelbine led to a longer PFS than vinorelbine. Adverse events of pemetrexed plus vinorelbine were generally manageable.

Genomic analysis of plasma circulating tumor DNA in patients with heavily pretreated HER2 + metastatic breast cancer.

We explored accumulated genomic alterations in patients with heavily treated HER2 + metastatic breast cancer enrolled in the KCSG BR18-14/KM10B trial. Targeted sequencing was performed with circulating tumor DNAs (ctDNAs) collected before the treatment of 92 patients. ctDNAs collected at the time of disease progression from seven patients who had a durable response for > 12 months were also analyzed. Sixty-five genes were identified as pathogenic alterations in 99 samples. The most frequently altered genes were TP53 (n = 48), PIKCA (n = 21) and ERBB3 (n = 19). TP53 and PIK3CA mutations were significantly related with shorter progression free survival (PFS), and patients with a higher ctDNA fraction showed a worse PFS. The frequency of homologous recombination deficiency (HRD)-related gene mutations was higher than that in matched tumor tissues, and these mutations tended to be associated with shorter PFS. New pathogenic variants were found at the end of treatment in all seven patients, including BRCA2, VHL, RAD50, RB1, BRIP1, ATM, FANCA, and PIK3CA mutations. In conclusion, TP53 and PIK3CA mutations, as well as a higher ctDNA fraction, were associated with worse PFS with trastuzumab and cytotoxic chemotherapy. The enrichment of HRD-related gene mutations and newly detected variants in ctDNA may be related to resistance to treatment.

A Multicenter, Prospective, Observational Study to Evaluate Ethanol-Induced Symptoms in Patients Receiving Docetaxel Chemotherapy.

PURPOSE: Several previous studies and case reports have reported ethanol-induced symptoms in patients receiving anticancer drugs containing ethanol. Most docetaxel formulations contain ethanol as a solvent. However, there are insufficient data on ethanol-induced symptoms when docetaxel-containing ethanol is administered. The primary purpose of this study was to investigate the frequency and pattern of ethanol-induced symptoms during and after docetaxel administration. The secondary purpose was to explore the risk factors for ethanol-induced symptoms. MATERIALS AND METHODS: This was a prospective, multicenter, observational study. The participants filled out ethanol-induced symptom questionnaire on the day of chemotherapy and the following day. RESULTS: Data from 451 patients were analyzed. The overall occurrence rate of ethanol-induced symptoms was 44.3% (200/451 patients). The occurrence rate of facial flushing was highest at 19.7% (89/451 patients), followed by nausea in 18.2% (82/451 patients), and dizziness in 17.5% (79/451 patients). Although infrequent, unsteady walking and impaired balance occurred in 4.2% and 3.3% of patients, respectively. Female sex, presence of underlying disease, younger age, docetaxel dose, and docetaxel-containing ethanol amount were significantly associated with the occurrence of ethanol-induced symptoms. CONCLUSION: The occurrence of ethanol-induced symptoms was not low in patients receiving docetaxel-containing ethanol. Physicians need to pay more attention to the occurrence of ethanol-induced symptoms and prescribe ethanol-free or low-ethanol-containing formulations to high-risk patients.

Oligomerization of a plant helper NLR requires cell-surface and intracellular immune receptor activation.

Plant disease resistance involves both detection of microbial molecular patterns by cell-surface pattern recognition receptors and detection of pathogen effectors by intracellular NLR immune receptors. NLRs are classified as sensor NLRs, involved in effector detection, or helper NLRs required for sensor NLR signaling. TIR-domain-containing sensor NLRs (TNLs) require helper NLRs NRG1 and ADR1 for resistance, and helper NLR activation of defense requires the lipase-domain proteins EDS1, SAG101, and PAD4. Previously, we found that NRG1 associates with EDS1 and SAG101 in a TNL activation-dependent manner [X. Sun et al., Nat. Commun. 12, 3335 (2021)]. We report here how the helper NLR NRG1 associates with itself and with EDS1 and SAG101 during TNL-initiated immunity. Full immunity requires coactivation and mutual potentiation of cell-surface and intracellular immune receptor-initiated signaling [B. P. M. Ngou, H.-K. Ahn, P. Ding, J. D. G. Jones, Nature 592, 110-115 (2021), M. Yuan et al., Nature 592, 105-109 (2021)]. We find that while activation of TNLs is sufficient to promote NRG1-EDS1-SAG101 interaction, the formation of an oligomeric NRG1-EDS1-SAG101 resistosome requires the additional coactivation of cell-surface receptor-initiated defense. These data suggest that NRG1-EDS1-SAG101 resistosome formation in vivo is part of the mechanism that links intracellular and cell-surface receptor signaling pathways.

Preliminary Attainability Assessment of Real-World Data for Answering Major Clinical Research Questions in Breast Cancer Brain Metastasis: Framework Development and Validation Study.

BACKGROUND: In recent decades, real-world evidence (RWE) in oncology has rapidly gained traction for its potential to answer clinical questions that cannot be directly addressed by randomized clinical trials. Integrating real-world data (RWD) into clinical research promises to contribute to more sustainable research designs, including extension, augmentation, enrichment, and pragmatic designs. Nevertheless, clinical research using RWD is still limited because of concerns regarding the shortage of best practices for extracting, harmonizing, and analyzing RWD. In particular, pragmatic screening methods to determine whether the content of a data source is sufficient to answer the research questions before conducting the research with RWD have not yet been established. OBJECTIVE: We examined the PAR (Preliminary Attainability Assessment of Real-World Data) framework and assessed its utility in breast cancer brain metastasis (BCBM), which has an unmet medical need for data attainability screening at the preliminary step of observational studies that use RWD. METHODS: The PAR framework was proposed to assess data attainability from a particular data source during the early research process. The PAR framework has four sequential stages, starting with clinical question clarification: (1) operational definition of variables, (2) data matching (structural/semantic), (3) data screening and extraction, and (4) data attainability diagramming. We identified 5 clinical questions to be used for PAR framework evaluation through interviews and validated them with a survey of breast cancer experts. We used the Samsung Medical Center Breast Cancer Registry, a hospital-based real-time registry implemented in March 2021, leveraging the institution's anonymized and deidentified clinical data warehouse platform. The number of breast cancer patients in the registry was 45,129; it covered the period from June 1995 to December 2021. The registry consists of 24 base data marts that represent disease-specific breast cancer characteristics and care pathways. The outcomes included screening results of the clinical questions via the PAR framework and a procedural diagram of data attainability for each research question. RESULTS: Data attainability was tested for study feasibility according to the PAR framework with 5 clinical questions for BCBM. We obtained data sets that were sufficient to conduct studies with 4 of 5 clinical questions. The research questions stratified into 3 types when we developed data fields for clearly defined research variables. In the first, only 1 question could be answered using direct data variables. In the second, the other 3 questions required surrogate definitions that combined data variables. In the third, the question turned out to be not feasible for conducting further analysis. CONCLUSIONS: The adoption of the PAR framework was associated with more efficient preliminary clinical research using RWD from BCBM. Furthermore, this framework helped accelerate RWE generation through clinical research by enhancing transparency and reproducibility and lowering the entry barrier for clinical researchers.

Knowledge, attitudes, and behaviors toward fertility preservation in patients with breast cancer: A cross-sectional survey of physicians.

Background: Fertility is an important issue for young women with breast cancer, but studies about physicians' knowledge, attitudes, and practices toward fertility preservation (FP) are largely based on Western populations and do not reflect recent international guidelines for FP. In this international study, we aimed to assess the knowledge, attitudes, and practices of physicians from South Korea, other Asian countries, and Latin America toward FP in young women with breast cancer, and identify the related barriers. Methods: The survey was conducted anonymously among physicians from South Korea, other Asian countries, and Latin America involved in breast cancer care between November 2020 and July 2021. Topics included knowledge, attitudes, and perceptions toward FP; practice behaviors; barriers; and participant demographics. We grouped related questions around two main themes-discussion with patients about FP, and consultation and referral to a reproductive endocrinologist. We analyzed the relationships between main questions and other survey items. Results: A total of 151 physicians completed the survey. Most participants' overall knowledge about FP was good. More than half of the participants answered that they discussed FP with their patients in most cases, but that personnel to facilitate discussions about FP and the provision of educational materials were limited. A major barrier was time constraints in the clinic (52.6%). Discussion, consultations, and referrals were more likely to be performed by surgeons who primarily treated patients with operable breast cancer (FP discussion odds ratio [OR]: 2.90; 95% confidence interval [CI]: 1.24-6.79; FP consultation and referral OR: 2.98; 95% CI: 1.14-7.74). Participants' knowledge and attitudes about FP were significantly associated with discussion, consultations, and referrals. Conclusion: Physicians from South Korea, other Asian countries, and Latin America are knowledgeable about FP and most perform practice behaviors toward FP well. Physicians' knowledge and favorable attitudes are significantly related to discussion with patients, as well as consultation with and referral to reproductive endocrinologists. However, there are also barriers, such as limitations to human resources and materials, suggesting a need for a systematic approach to improve FP for young women with breast cancer.

Effector-dependent activation and oligomerization of plant NRC class helper NLRs by sensor NLR immune receptors Rpi-amr3 and Rpi-amr1.

Plant pathogens compromise crop yields. Plants have evolved robust innate immunity that depends in part on intracellular Nucleotide-binding, Leucine rich-Repeat (NLR) immune receptors that activate defense responses upon detection of pathogen-derived effectors. Most "sensor" NLRs that detect effectors require the activity of "helper" NLRs, but how helper NLRs support sensor NLR function is poorly understood. Many Solanaceae NLRs require NRC (NLR-Required for Cell death) class of helper NLRs. We show here that Rpi-amr3, a sensor NLR from Solanum americanum, detects AVRamr3 from the potato late blight pathogen, Phytophthora infestans, and activates oligomerization of helper NLRs NRC2 and NRC4 into high-molecular-weight resistosomes. In contrast, recognition of P. infestans effector AVRamr1 by another sensor NLR Rpi-amr1 induces formation of only the NRC2 resistosome. The activated NRC2 oligomer becomes enriched in membrane fractions. ATP-binding motifs of both Rpi-amr3 and NRC2 are required for NRC2 resistosome formation, but not for the interaction of Rpi-amr3 with its cognate effector. NRC2 resistosome can be activated by Rpi-amr3 upon detection of AVRamr3 homologs from other Phytophthora species. Mechanistic understanding of NRC resistosome formation will underpin engineering crops with durable disease resistance.

Comparison of Treatment Patterns and Clinical Outcomes by Gender in Locally Advanced Head and Neck Squamous Cell Carcinoma (KCSG HN13-01).

We aimed to compare treatment modalities and outcomes by gender in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC). We characterized the sex-specific differences and compared the overall survival (OS) between male and female patients in a multicenter cohort of LA-HNSCC. To minimize the observed confounding, propensity score matching was utilized. The study included 445 patients; 385 (86.5%) were men and 60 (13.5%) were women. In terms of age, smoking habits, drinking habits, and primary tumor locations, there was a significant imbalance in sex before the matching. Propensity score matching yielded 60 patient pairs, with no statistical difference between the sexes in terms of their characteristics. As for the treatment strategies, there were no significant differences between the sexes before (p = 0.260) and after (p = 0.585) the propensity score matching. When comparing the survival probabilities between the sexes, OS was not significantly different in the overall (HR 1.02; 95% CI 0.59-1.76; p = 0.938) and propensity-score-matched population (HR 1.46; 95% CI 0.68-3.17; p = 0.331). These results suggest that there was no difference in prognosis by gender in the treatment modalities and outcomes of LA-HNSCC in real-world practice.

Treatment Patterns, Clinical Outcomes and Health Care Resource Utilisation in Patients with EGFR-mutated Metastatic Non-Small Cell Lung Cancer: A Real-World Study in South Korea.

BACKGROUND: Despite the dynamic treatment landscape for EGFR mutant-positive metastatic non-small cell lung cancer (EGFRm+ mNSCLC), most of the earlier studies have focused on US or Western populations. OBJECTIVE: The objective of this study was to explore real-world treatment patterns and outcomes of South Korean patients with EGFRm+ mNSCLC. METHODS: Retrospective chart review of adult patients with EGFRm+ mNSCLC who received systemic treatment between January-2019 and June-2019. RESULTS: A total of 162 patients were included from 21 hospitals, with a median follow-up of 15.6 months. Median age was 65.0 years, 22% had central nervous system metastasis, and 57% and 38% had exon 19 deletion and exon 21 L858R, respectively. Among 144 patients (89%) who received first-line EGFR-tyrosine kinase inhibitor, afatinib was most the common (44%), followed by gefitinib (28%) and erlotinib (13%). First-line chemotherapy was more common when an EGFR-mutation was detected after versus before first-line treatment initiation (31% vs 5%). Discontinuation of first-line treatment was mostly due to disease-progression (81%) and toxicity (7%). Among 58 (78%) patients who received second-line treatment, osimertinib was the most common (40%). Most (60%) patients reported ≥1 Grade ≥3 adverse event during first-line treatment. Following initiation of first-line treatment, physician visits and chest X-rays were the most frequent healthcare utilisation events. Rates of emergency-room visits and hospitalization were 12% and 16%, respectively, with a mean length-of-stay of 10.4 days. At 12 months, overall survival rate was 95%, and numerically worse for patients with exon 21 versus 19 mutations. CONCLUSIONS: Characteristics and clinical outcomes of Korean patients with EGFRm+ mNSCLC in real-world practice were comparable to those observed in clinical trials. As osimertinib was not reimbursed for first-line treatment before study completion, further investigation is warranted to explore evolving treatment practice.

Sensor NLR immune proteins activate oligomerization of their NRC helpers in response to plant pathogens.

Nucleotide-binding domain leucine-rich repeat (NLR) immune receptors are important components of plant and metazoan innate immunity that can function as individual units or as pairs or networks. Upon activation, NLRs form multiprotein complexes termed resistosomes or inflammasomes. Although metazoan paired NLRs, such as NAIP/NLRC4, form hetero-complexes upon activation, the molecular mechanisms underpinning activation of plant paired NLRs, especially whether they associate in resistosome hetero-complexes, is unknown. In asterid plant species, the NLR required for cell death (NRC) immune receptor network is composed of multiple resistance protein sensors and downstream helpers that confer immunity against diverse plant pathogens. Here, we show that pathogen effector-activation of the NLR proteins Rx (confers virus resistance), and Bs2 (confers bacterial resistance) leads to oligomerization of their helper NLR, NRC2. Activated Rx does not oligomerize or enter into a stable complex with the NRC2 oligomer and remains cytoplasmic. In contrast, activated NRC2 oligomers accumulate in membrane-associated puncta. We propose an activation-and-release model for NLRs in the NRC immune receptor network. This points to a distinct activation model compared with mammalian paired NLRs.

Data collection framework for electronic medical record-based real-world data to evaluate the effectiveness and safety of cancer drugs: a nationwide real-world study of the Korean Cancer Study Group.

Background: Electronic medical records (EMRs) have the highest value among real-world data (RWD). The aim of the present study was to propose a data collection framework of EMR-based RWD to evaluate the effectiveness and safety of cancer drugs by conducting a nationwide real-world study based on the Korean Cancer Study Group. Methods: We considered all patients who received ramucirumab plus paclitaxel (RAM/PTX) for gastric cancer and trastuzumab emtansine (T-DM1) for breast cancer at relevant institutions in South Korea. Standard operating procedures for systematic data collection were prospectively developed. Investigator reliability was evaluated using the concordance rate between the recommended input value for representative fictional cases and the input value of each investigator. Reliability of collected data was evaluated twice during the study period at three institutions randomly selected using the concordance rate between the previously collected data and data collected by an independent investigator. The reliability results of the investigators and collected data were used for revision of the electronic data capture system and site training. Results: Between the starting date of medical insurance coverage and December 2018, a total of 1063 patients at 56 institutions in the RAM/PTX cohort and 824 patients at 60 institutions in the T-DM1 cohort were included. Mean investigator reliability in the RAM/PTX and T-DM1 cohorts was 73.5% and 71.9%, respectively. Mean reliability of collected data in the RAM/PTX and T-DM1 cohort was 90.0% for both cohorts in the first analysis and 89.0% and 84.0% in the second analysis, respectively. Mean missing values of the RAM/PTX and T-DM1 cohorts at the time of simulation of fictional cases and final data analysis decreased from 20.7% to 0.46% and from 18.5% to 0.76%, respectively. Conclusion: This real-world study provides a framework that ensures relevance and reliability of EMR-based RWD for evaluating the effectiveness and safety of cancer drugs.

Totality outcome of afatinib sequential treatment in patients with EGFR mutation-positive non-small cell lung cancer in South Korea (TOAST): Korean Cancer Study Group (KCSG) LU-19-22.

Background: Irrespective of the first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor chosen, acquired resistance to therapy is inevitable. Therefore, a key consideration when assessing therapeutic choices is the availability of subsequent treatment options following disease progression. We assessed clinical outcomes in patients who received first-line afatinib treatment with various second-line treatments including osimertinib for patients acquiring the T790M mutation. Methods: A total of 737 EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) patients receiving first-line afatinib treatment were categorized by second-line treatment: T790M+ sequentially treated with osimertinib (cohort A, n=116); T790M- given chemotherapy or others (cohort B, n=143); patients with unknown T790M status (cohort C, n=111); and patients who were undergoing afatinib treatment at the time of data collection, were dead, had discontinued afatinib treatment due to serious adverse events or were lost to follow-up (cohort D, n=367). The primary outcomes were total time on treatment (TOT) and TOT for first-line (TOT-1) and second-line treatments (TOT-2). Secondary outcomes were objective response rates (ORR), overall survival (OS), and central nervous system (CNS) efficacy. Results: Median total TOT in cohorts A, B, C, and D were 35.10 months [95% confidence interval (CI): 30.09-43.53 months], 18.80 months (95% CI: 16.92-20.20 months), 12.00 months (95% CI: 10.22-14.98 months), and 42.60 months (95% CI: 30.95-59.23 months), respectively. The ORR of patients given afatinib was 75.7%. In patients with initial brain metastasis without local treatment, the CNS response rate was 67.0% and CNS progression-free survival was 24.70 months (95% CI: 19.84-33.15 months). Conclusions: This study showed that sequential approach of afatinib followed by second line treatment is an effective therapeutic strategy for EGFR M+ NSCLC patients.

A Multicenter Two-arm, Phase II Trial Assessing the Safety and Efficacy of First-line Lazertinib and Locally Ablative Radiotherapy in Patients With Synchronous Oligo-metastatic EGFR-mutant Non-small Cell Lung Cancer (ABLATE, KCSG-LU21-11).

BACKGROUND: The current standard treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation is upfront EGFR targeted therapy. However, patients invariably experience disease progression at primary tumors or metastatic sites. Adding stereotactic body radiation therapy (SBRT) to systemic therapy can improve progression-free survival (PFS) and overall survival (OS). This multicenter, 2-arm, phase II study aims to evaluate the efficacy and safety of lazertinib, a third generation EGFR tyrosine kinase inhibitor, combined with upfront locally ablative radiotherapy in EGFR-mutant NSCLC patients with synchronous oligometastatic disease (ClinicalTrials.gov: NCT05167851). PATIENTS AND METHODS: Key inclusion criteria are biopsy-proven EGFR-mutated adenocarcinoma with synchronous, oligometastatic (≤5 metastases) NSCLC. Patients will be randomized 1:1 to receive lazertinib or lazertinib + SBRT to the primary tumor and metastatic sites. The primary endpoint is PFS according to RECIST: Response Evaluation Criteria in Solid Tumor version 1.1, and the secondary endpoints are OS, objective response rate, and safety. RESULTS: Patient enrolment began in January 2021 and is ongoing at 7 sites in the Republic of Korea. CONCLUSION: This trial will provide valuable information on the efficacy and safety of lazertinib in combination with SBRT in patients with synchronous, oligometastatic EGFR-mutant NSCLC.