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Introduction: The role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced NSCLC with EGFR mutation or ALK translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR and ALK wild-type versus those with EGFR or ALK mutations. Methods: In this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results (EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR and ALK wild-type and EGFR or ALK mutant NSCLC. Secondary objectives include overall survival according to EGFR or ALK mutation and programmed death-ligand 1 (PD-L1) expression. Results: Among 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 male individuals (81.4%) and 63 female individuals (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histologic types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. Most of the patients (n = 288, 85%) achieved partial response to CCRT, two (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding four patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1 to 49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% confidence interval [CI]: 17.3–25.3) for the EGFR/ALK wild-type group and 21.0 months (95% CI: 15.7–not available [NA]) for the EGFR or ALK mutant group with no difference (p = 0.74). Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5–NA), 18.7 (95% CI: 15.1–26.9), and 24.7 (95% CI: 20.7–NA) months for TPS of 0, 1–49, and 50 or higher, respectively (p = 0.02). Conclusions: Durvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

Introduction: SCLC has traditionally been considered to arise from toxic exposure factors, such as smoking. Recent evidence has revealed that germline mutations may also affect the development of SCLC; however, these alterations remain understudied. We sought to identify novel germline mutations in SCLC including germline copy number variations (CNVs) in our cohort of patients. Methods: We designed a custom hybrid-capture gene panel to evaluate germline alterations in 192 cancer-predisposition and frequently mutated genes in SCLC. We applied this panel to germline analysis of a treatment-naive cohort of 67 patients with SCLC at our institution. Subsequently, we annotated the variants using the American College of Medical Genetics criteria and further classified variants of uncertain significance using a set of in silico tools, including DeepMind AlphaMissense, MutationTaster, SIFT, and Polyphen2. Results: We identified American College of Medical Genetics pathogenic or likely pathogenic alterations in seven of 67 patients. Five (71%) were novel alterations (BCORL1, FANCC, ATR, and BBC3) and a novel CNV (SLFN11) with two (29%) previously described mutations (CHEK1 and BRIP1). We also identified 191 variants of uncertain significance in 60 of 67 patients, of which, depending on the in silico tool, 5% to 14% were predicted to be pathogenic. Patients with SCLC with the seven pathogenic alterations were observed to have a numerically longer overall survival (hazard ratio = 0.50) and progression-free survival (hazard ratio = 0.45) though not statistically significant compared with the remaining cohort. Conclusions: Our study identifies novel germline alterations, including a CNV, and provides additional evidence that germline factors could be important contributing factors to the development of SCLC.

Introduction: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the “last patient in” date. Methods: Adult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. Results: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23–0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08–0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. Conclusions: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Background: Lung cancer, especially non-small cell lung cancer (NSCLC), poses a significant health challenge globally due to its high mortality. Afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has shown superior efficacy over traditional chemotherapy in NSCLC treatment. However, issues like secondary resistance and adverse effects call for alternative therapies. HAD-B1, comprising 4 herbal medicines, has shown promise in lung cancer treatment in both preclinical and clinical settings. This study assesses the combination of HAD-B1 and Afatinib in advanced NSCLC patients to potentially improve outcomes by addressing the limitations of current EGFR-TKI therapies. Method: A randomized, open-label trial evaluated the efficacy and safety of HAD-B1 with Afatinib in 90 EGFR-mutation-positive NSCLC patients. Participants were divided into treatment and control groups, receiving Afatinib with or without HAD-B1. The study focused on the initial dose maintenance rate and disease control rate (DCR) of Afatinib, alongside secondary outcomes like survival rates and quality of life, under continuous safety monitoring. Results: Among the 90 participants, no significant difference was found in initial dose maintenance (60.98% in the treatment group vs 52.50% in the control, P = .4414) or DCR (80.49% vs 90.00%, P = .2283). Secondary outcomes like PFS, TTP, and OS showed no notable differences. However, physical functioning significantly improved in the treatment group ( P = .0475, PPS group). The control group experienced higher rates of adverse events of special interest and adverse drug reactions ( P = .01), suggesting HAD-B1 with Afatinib might enhance physical function without increasing adverse effects. Conclusion: Combining HAD-B1 with Afatinib potentially improves quality of life and reduces adverse events in advanced NSCLC patients. Further research is necessary to confirm the long-term benefits of this combination therapy, aiming to advance NSCLC treatment outcomes. Trial registration: Clinical Research Information Service (CRIS) of the Republic of Korea, https://cris.nih.go.kr/ (ID: KCT0005414).

Background: Strategies to minimize the impact of the COVID-19 pandemic led to a reduction in diagnostic testing. It is important to assess the magnitude and duration of this impact to plan ongoing care and avoid long-lasting impacts of the pandemic. Objective: We examined the association between the COVID-19 pandemic and the rate of diagnostic tests for breast, cervical, and colorectal cancer in Manitoba, Canada. Design and Participants: A population-based, cross-sectional study design with an interrupted time series analysis was used that included diagnostic tests from January 1, 2015 until August 31, 2022. Setting: Manitoba, Canada. Main Outcomes: Outcomes included mammogram, breast ultrasound, colposcopy, and colonoscopy rates per 100,000. Cumulative and percent cumulative differences between the fitted and counterfactual number of tests were estimated. Mean, median, and 90th percentile number of days from referral to colonoscopy date by referral type (elective, semiurgent, urgent) were determined. Results: In April 2020, following the declaration of the COVID-19 public health emergency, bilateral mammograms decreased by 77%, unilateral mammograms by 70%, breast ultrasounds by 53%, colposcopies by 63%, and colonoscopies by 75%. In Winnipeg (the largest urban center in the province), elective and semiurgent colonoscopies decreased by 76% and 39%, respectively. There was no decrease in urgent colonoscopies. As of August 2022, there were an estimated 7270 (10.7%) fewer bilateral mammograms, 2722 (14.8%) fewer breast ultrasounds, 836 (3.3%) fewer colposcopies, and 11 600 (13.8%) fewer colonoscopies than expected in the absence of COVID-19. As of December 2022, in Winnipeg, there were an estimated 6030 (23.9%) fewer elective colonoscopies, 313 (2.6%) fewer semiurgent colonoscopies, and 438 (27.3%) more urgent colonoscopies. Conclusions: In Manitoba, the COVID-19 pandemic was associated with sizable decreases in diagnostic tests for breast, colorectal, and cervical cancer. Two and a half years later, there remained large cumulative deficits in bilateral mammograms, breast ultrasounds, and colonoscopies.

Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK-positive or ALK-negative advanced NSCLC, respectively. Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: In the avelumab plus lorlatinib group (ALK-positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group (ALK-negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%–70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%–57%) with avelumab plus crizotinib (all partial responses). Conclusions: Avelumab plus lorlatinib treatment in ALK-positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK-negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group. ClinicalTrials.gov identifier: NCT02584634

Objectives: This study aimed to build a comprehensive deep-learning model for the prediction of radiation pneumonitis using chest computed tomography (CT), clinical, dosimetric, and laboratory data. Introduction: Radiation therapy is an effective tool for treating patients with lung cancer. Despite its effectiveness, the risk of radiation pneumonitis limits its application. Although several studies have demonstrated models to predict radiation pneumonitis, no reliable model has been developed yet. Herein, we developed prediction models using pretreatment chest CT and various clinical data to assess the likelihood of radiation pneumonitis in lung cancer patients. Methods: This retrospective study analyzed 3-dimensional (3D) lung volume data from chest CT scans and 27 features including dosimetric, clinical, and laboratory data from 548 patients who were treated at our institution between 2010 and 2021. We developed a neural network, named MergeNet, which processes lung 3D CT, clinical, dosimetric, and laboratory data. The MergeNet integrates a convolutional neural network with subsequent fully connected layers. A support vector machine (SVM) and light gradient boosting machine (LGBM) model were also implemented for comparison. For comparison, the convolution-only neural network was implemented as well. Three-dimensional Resnet-10 network and 4-fold cross-validation were used. Results: Classification performance was quantified by using the area under the receiver operative characteristic curve (AUC) metrics. MergeNet showed the AUC of 0.689. SVM, LGBM, and convolution-only networks showed AUCs of 0.525, 0.541, and 0.550, respectively. Application of DeLong test to pairs of receiver operating characteristic curves respectively yielded P values of .001 for the MergeNet–SVM pair and 0.001 for the MergeNet–LGBM pair. Conclusion: The MergeNet model, which incorporates chest CT, clinical, dosimetric, and laboratory data, demonstrated superior performance compared to other models. However, since its prediction performance has not yet reached an efficient level for clinical application, further research is required. Contribution: This study showed that MergeNet may be an effective means to predict radiation pneumonitis. Various predictive factors can be used together for the radiation pneumonitis prediction task via the MergeNet.

Introduction: The purpose of this study was to compare the transcriptomes of poorly cohesive carcinoma (PCC; diffuse-type) and well-differentiated tubular adenocarcinoma (WD; intestinal-type) using gastric cancer (GC) tissues and cell lines and to evaluate the prognostic role of HIV-1 Tat Interactive Protein 2 (HTATIP2). Materials and Methods: We performed next-generation sequencing with 8 GC surgical samples (5 WD and 3 PCC) and 3 GC cell lines (1 WD: MKN74, and 2 PCC: KATOIII and SNU601). Immunohistochemistry was used to validate HTATIP2 expression. We performed functional analysis by HTATIP2 overexpression (OE). Kaplan-Meier survival plots and the PrognoScan database were used for survival analysis. Results: The genes with significantly reduced expression in PCC versus WD (in both tissues and cell lines) were HTATIP2, ESRP1, GRHL2, ARHGEF16, CKAP2L, and ZNF724. According to immunohistochemical staining, the HTATIP2-OE group had significantly higher number of patients with early GC (EGC) (T1) ( P = .024), less lymph node (LN) metastasis ( P = .008), and low TNMA stage ( P = .017) than HTATIP2 underexpression (UE) group. Better survival rates were confirmed in the HTATIP2 OE group by Kaplan-Meir survival and PrognoScan analysis. In vitro, HTATIP2-OE in KATO III cells caused a significant decrease in cancer cell migration and invasion. Decreased Snail and Slug expression in HTATIP2 OE cells suggested that epithelial-mesenchymal transition is involved in this process. Conclusion: HTATIP2 might be a good prognostic marker and a candidate target for GC treatment.

Introduction: In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly (p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604. Methods: Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire—Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ—Lung Cancer Module 13. Two-sided, nominal p values are reported. Results: A total of 439 patients completed at least one QLQ-C30 and QLQ—Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3–12.1) for pembrolizumab plus EP and 4.2 (0.9–7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2–8.7], p = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9–not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56–1.14], p = 0.208). Conclusions: First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC.

Vaping use among Canadian youth is rising but the long-term sequelae of cannabidiol (CBD) vaping are not yet elucidated. Vaping aerosols contain carcinogens; however, owing to the latency period between carcinogen exposure and clinical presentation of malignancies, at present, there is a paucity of reported CBD vaping–associated lung cancers. We present the case of a 24-year-old female with nonspecific respiratory symptoms who developed multifocal NSCLC attributable to extensive CBD vaping.

Purpose We aimed to identify the differently expressed genes or related pathways associated with good responses to anti-HER2 therapy and to suggest a model for predicting drug response in neoadjuvant systemic therapy with trastuzumab in HER2-positive breast cancer patients. Methods This study was retrospectively analyzed from consecutively collected patient data. We recruited 64 women with breast cancer and categorized them into 3 groups: complete response (CR), partial response (PR), and drug resistance (DR). The final number of patients in the study was 20. RNA from 20 core needle biopsy paraffin-embedded tissues and 4 cultured cell lines (SKBR3 and BT474 breast cancer parent cells and cultured resistant cells) was extracted, reverse transcribed, and subjected to GeneChip array analysis. The obtained data were analyzed using Gene Ontology, Kyoto Gene and Genome Encyclopedia, Database for Annotation, Visualization and Integrated Discovery. Results In total, 6,656 genes differentially expressed between trastuzumab-susceptible and trastuzumab-resistant cell lines were identified. Among these, 3,224 were upregulated and 3,432 were downregulated. Expression changes in 34 genes in several pathways were found to be related to the response to trastuzumab-containing treatment in HER2-type breast cancer, interfering with adhesion to other cells or tissues (focal adhesion) and regulating extracellular matrix interactions and phagosome action. Thus, decreased tumor invasiveness and enhanced drug effects might be the mechanisms explaining the better drug response in the CR group. Conclusions This multigene assay-based study provides insights into breast cancer signaling and possible predictions of therapeutic response to targeted therapies such as trastuzumab.

Purpose: Endobronchial electromagnetic transponder beacons (EMT) provide real-time, precise positional data of moving lung tumors. We report results of a phase 1/2, prospective, single-arm cohort study evaluating the treatment planning effects of EMT-guided SABR for moving lung tumors. Methods and Materials: Eligible patients were adults, Eastern Cooperative Oncology Group 0 to 2, with T1-T2N0 non-small cell lung cancer or pulmonary metastasis ≤4 cm with motion amplitude ≥5 mm. Three EMTs were endobronchially implanted using navigational bronchoscopy. Four-dimensional free-breathing computed tomography simulation scans were obtained, and end-exhalation phases were used to define the gating window internal target volume. A 3-mm expansion of gating window internal target volume defined the planning target volume (PTV). EMT-guided, respiratory-gated (RG) SABR was delivered (54 Gy/3 fractions or 48 Gy/4 fractions) using volumetric modulated arc therapy. For each RG-SABR plan, a 10-phase image-guided SABR plan was generated for dosimetric comparison. PTV/organ-at-risk (OAR) metrics were tabulated and analyzed using the Wilcoxon signed-rank pair test. Treatment outcomes were evaluated using RECIST (Response Evaluation Criteria in Solid Tumours; version 1.1). Results: Of 41 patients screened, 17 were enrolled and 2 withdrew from the study. Median age was 73 years, with 7 women. Sixty percent had T1/T2 non-small cell lung cancer and 40% had M1 disease. Median tumor diameter was 1.9 cm with 73% of targets located peripherally. Mean respiratory tumor motion was 1.25 cm (range, 0.53-4.04 cm). Thirteen tumors were treated with EMT-guided SABR and 47% of patients received 48 Gy in 4 fractions while 53% received 54 Gy in 3 fractions. RG-SABR yielded an average PTV reduction of 46.9% (P < .005). Lung V5, V10, V20, and mean lung dose had mean relative reductions of 11.3%, 20.3%, 31.1%, and 20.3%, respectively (P < .005). Dose to OARs was significantly reduced (P < .05) except for spinal cord. At 6 months, mean radiographic tumor volume reduction was 53.5% (P < .005). Conclusions: EMT-guided RG-SABR significantly reduced PTVs of moving lung tumors compared with image-guided SABR. EMT-guided RG-SABR should be considered for tumors with large respiratory motion amplitudes or those located in close proximity to OARs.

Introduction: High-dose total body irradiation (TBI) is often part of myeloablative conditioning in acute leukemia. Modern volumetric modulated arc therapy (VMAT)-based plans employ arcs to the inferior-most portion of the body that can be simulated in a head-first position and use 2D planning for the inferior body which can result in heterogeneous doses. Here, we describe our institution's unique protocol for delivering high-dose TBI entirely with VMAT and retrospectively compare dosimetric outcomes with helical tomotherapy (HT) plans. Additionally, we describe our method of oropharyngeal mucosal sparing that was implemented after fatal mucositis occurred in two patients. Methods: Thirty-one patients were simulated and treated in head-first (HFS) and feet-first (FFS) orientations. Patients were treated with VMAT (n = 26) or HT (n = 5). In VMAT plans, to synchronize doses between the orientations, images were deformably registered and the HFS dose was transferred to the FFS plan and used as a background dose when optimizing plans. Six to eight isocenters with two arcs per isocenter were generated. HT was delivered with an established technique. Patients were treated to 13.2 Gy over eight twice daily fractions. Dosimetric outcomes and toxicities were retrospectively compared. Results: Prescription dose and organ at risk (OAR) constraints were met for all patients. Lower lung doses were achieved with VMAT relative to HT plans (7.4 vs 7.7 Gy, P = .009). Statistically significant improvement in mucositis was not achieved after adopting a mucosal-sparing technique, however lower doses to the oropharyngeal mucosal were achieved (6.9 vs 14.1 Gy, P = .009), and no further mucositis-related deaths occurred. Conclusions: This full-body VMAT method of TBI achieves dose goals, eliminates risk of heterogenous doses within the femur, and demonstrates that selective OAR sparing with the purpose of reducing TBI-related morbidity and mortality is possible at any institution with a VMAT-capable linear accelerator.

Introduction: EGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. Methods: We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab. Results: Quantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab. Conclusions: Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.

Introduction: Lorlatinib is a potent, third-generation inhibitor of ALK. In the planned interim analysis of the ongoing, phase 3, randomized, global CROWN trial (NCT03052608), lorlatinib resulted in significantly longer progression-free survival than crizotinib in patients with previously untreated, advanced, ALK-positive NSCLC. Here, we present a subgroup analysis of Asian patients in the CROWN study. Methods: Patients received lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. The primary end point was progression-free survival assessed by blinded independent central review. Objective response rate (ORR), intracranial ORR, safety, and select biomarkers were secondary end points. Results: At data cutoff (September 20, 2021), 120 patients were included in the Asian intention-to-treat subgroup (lorlatinib n = 59; crizotinib n = 61). At 36 months, 61% (95% confidence interval [CI]: 47–72) and 25% (95% CI: 12–41) of patients in the lorlatinib and crizotinib groups, respectively, were alive without disease progression (hazard ratio for disease progression by blinded independent central review or death: 0.40; 95% CI: 0.23–0.71). ORR was 78% (95% CI: 65–88) versus 57% (95% CI: 44–70) for patients treated with lorlatinib and crizotinib, respectively. In patients with measurable, nonmeasurable, or both measurable and nonmeasurable brain metastases at baseline, intracranial ORR was 73% (95% CI: 39–94) versus 20% (95% CI: 4–48) for patients treated with lorlatinib and crizotinib, respectively. The definition of nonmeasurable brain metastases is: a brain lesion less than 10 mm in MRI scan is defined as nonmeasurable brain metastasi based on RECIST criteria (Clinical trial evaluation criteria). Hypercholesterolemia, hypertriglyceridemia, and edema were the most frequently reported adverse events with lorlatinib. Conclusions: Lorlatinib efficacy and safety in the Asian subgroup of CROWN were consistent with those in the overall population.

Purpose: This study aimed to develop a routine quality assurance method for a dose accumulation technique provided by a radiation therapy platform for online treatment adaptation. Methods and Materials: Two commonly used phantoms were selected for the dose accumulation QA: Electron density and anthropomorphic pelvis. On a computed tomography (CT) scan of the electron density phantom, 1 target (gross tumor volume [GTV]; insert at 6 o'clock), a subvolume within this target, and 7 organs at risk (OARs; other inserts) were contoured in the treatment planning system (TPS). Two adaptation sessions were performed in which the GTV was recontoured, first at 7 o'clock and then at 5 o'clock. The accumulated dose was exported from the TPS after delivery. Deformable vector fields were also exported to manually accumulate doses for comparison. For the pelvis phantom, synthetic Gaussian deformations were applied to the planning CT image to simulate organ changes. Two single-fraction adaptive plans were created based on the deformed planning CT and cone beam CT images acquired onboard the radiation therapy platform. A manual dose accumulation was performed after delivery using the exported deformable vector fields for comparison with the system-generated result. Results: All plans were successfully delivered, and the accumulated dose was both manually calculated and derived from the TPS. For the electron density phantom, the average mean dose differences in the GTV, boost volume, and OARs 1 to 7 were 0.0%, –0.2%, 92.0%, 78.4%, 1.8%, 1.9%, 0.0%, 0.0%, and 2.3%, respectively, between the manually summed and platform-accumulated doses. The gamma passing rates for the 3-dimensional dose comparison between the manually generated and TPS-provided dose accumulations were >99% for both phantoms. Conclusions: This study demonstrated agreement between manually obtained and TPS-generated accumulated doses in terms of both mean structure doses and local 3-dimensional dose distributions. Large disagreements were observed for OAR1 and OAR2 defined on the electron density phantom due to OARs having lower deformation priority over the target in addition to artificially large changes in position induced for these structures fraction-by-fraction. The tests applied in this study to a commercial platform provide a straightforward approach toward the development of routine quality assurance of dose accumulation in online adaptation.

Introduction: In recent years, programmed cell death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy was found to have favorable clinical outcomes in patients with extensive-stage SCLC (ES-SCLC). The usefulness of early tumor shrinkage (ETS) has been reported in various types of cancers. Nevertheless, there have been few reports evaluating ETS in ES-SCLC. Therefore, this study aimed to evaluate the role of ETS in the clinical outcomes of patients with ES-SCLC receiving chemoimmunotherapy. Methods: We prospectively identified 46 patients with ES-SCLC who received PD-L1 inhibitor plus platinum-etoposide chemotherapy at 10 institutions in Japan between September 2019 and October 2021. Of them, 35 patients were selected for analyses. Results: The responders (progression-free survival [PFS] ≥ 6.0 mo) had significantly greater tumor shrinkage at the first evaluation than the nonresponders (PFS < 6.0 mo) (65.0% versus 53.7%, p = 0.03). We defined the cutoff value for ETS as a 57% change from the baseline on the basis of the receiver operating characteristic results to determine the optimal tumor shrinkage rate at the first evaluation for identifying responders. The patients with ES-SCLC who achieved ETS had longer PFS and overall survival than those who did not achieve ETS (5.6 versus 4.0 mo, log-rank test p = 0.001 and 15.0 versus 8.3 mo, log-rank test p = 0.02). In the multivariate analyses, ETS was significantly associated with PFS and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.12–0.63, p = 0.002 and hazard ratio = 0.34, 95% confidence interval: 0.13–0.85, p = 0.02). Conclusions: Our prospective observational study indicated that ETS was related to favorable clinical outcomes for patients with ES-SCLC receiving PD-L1 inhibitor plus platinum-etoposide chemotherapy.

Introduction: Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunotherapy in patients with advanced lung adenocarcinoma. Methods: This multicenter prospective observational study included 58 patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy across 10 institutions in Japan. The expression of TTF-1 in pretreatment tumors was determined using immunohistochemistry. Results: The objective response rate of combined chemoimmunotherapy was significantly higher in TTF-1–positive groups than in TTF-1–negative groups (p = 0.02). The median progression-free survival (PFS) and overall survival were significantly longer in TTF-1–positive groups than in TTF-1–negative groups (10.9 versus 5.0 mo; p = 0.01). Multivariate analysis revealed that TTF-1 expression was an independent favorable prognostic factor for PFS. Moreover, TTF-1 expression in patients with lung adenocarcinoma is significantly associated with programmed death-ligand 1 expression (p = 0.003). The TTF-1–positive group with programmed death-ligand 1 tumor proportion score greater than or equal to 50% had a significantly longer PFS than the other groups (p = 0.02). Conclusions: TTF-1 positivity is associated with better clinical outcomes in patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy.

Purpose: Non-small cell lung cancer (NSCLC) is a deadly malignancy that is frequently diagnosed in patients with significant medical comorbidities. When delivering local and regional therapy, an exceedingly narrow therapeutic window is encountered, which often precludes patients from receiving aggressive curative therapy. Radiation therapy advances including particle therapy have been employed in an effort to expand this therapeutic window. Here we report outcomes with the use of proton therapy with curative intent and immunotherapy to treat patients diagnosed with high-risk NSCLC. Methods and Materials: Patients were determined to be high risk if they had severe underlying cardiopulmonary dysfunction, history of prior thoracic radiation therapy, and/or large volume or unfavorable location of disease (eg, bilateral hilar involvement, supraclavicular involvement). As such, patients were determined to be ineligible for conventional x-ray–based radiation therapy and were treated with pencil beam scanning proton beam therapy (PBS-PBT). Patients who demonstrated excess respiratory motion (ie, greater than 1 cm in any dimension noted on the 4-dimensional computed tomography simulation scan) were deemed to be ineligible for PBT. Toxicity was reported using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Overall survival and progression-free survival were calculated using the Kaplan-Meier method. Results: A total of 29 patients with high-risk NSCLC diagnoses were treated with PBS-PBT. The majority (55%) of patients were defined as high risk due to severe cardiopulmonary dysfunction. Most commonly, patients were treated definitively to a total dose of 6000 cGy (relative biological effectiveness) in 30 fractions with concurrent chemotherapy. Overall, there were a total of 6 acute grade 3 toxicities observed in our cohort. Acute high-grade toxicities included esophagitis (n = 4, 14%), dyspnea (n = 1, 3.5%), and cough (n = 1, 3.5%). No patients developed grade 4 or higher toxicity. The majority of patients went on to receive immunotherapy, and high-grade pneumonitis was rare. Two-year progression-free and overall survival was estimated to be 51% and 67%, respectively. COVID-19 was confirmed or suspected to be responsible for 2 patient deaths during the follow-up period. Conclusions: Radical PBS-PBT treatment delivered in a cohort of patients with high-risk lung cancer with immunotherapy is feasible with careful multidisciplinary evaluation and rigorous follow-up.

Purpose: Hypofractionated stereotactic radiosurgery (HF-SRS) with or without surgical resection is potentially a preferred treatment for larger or symptomatic brain metastases (BMs). Herein, we report clinical outcomes and predictive factors following HF-SRS. Methods and Materials: Patients undergoing HF-SRS for intact (iHF-SRS) or resected (rHF-SRS) BMs from 2008 to 2018 were retrospectively identified. Linear accelerator-based image-guided HF-SRS consisted of 5 fractions at 5, 5.5, or 6 Gy per fraction. Time to local progression (LP), time to distant brain progression (DBP), and overall survival (OS) were calculated. Cox models assessed effect of clinical factors on OS. Fine and Gray's cumulative incidence model for competing events examined effect of factors on LP and DBP. The occurrence of leptomeningeal disease (LMD) was determined. Logistic regression examined predictors of LMD. Results: Among 445 patients, median age was 63.5 years; 87% had Karnofsky performance status ≥70. Fifty-three % of patients underwent surgical resection, and 75% received 5 Gy per fraction. Patients with resected BMs had higher Karnofsky performance status (90-100, 41 vs 30%), less extracranial disease (absent, 25 vs 13%), and fewer BMs (multiple, 32 vs 67%). Median diameter of the dominant BM was 3.0 cm (interquartile range, 1.8-3.6 cm) for intact BMs and 4.6 cm (interquartile range, 3.9-5.5 cm) for resected BMs. Median OS was 5.1 months (95% confidence interval [CI], 4.3-6.0) following iHF-SRS and 12.8 months (95% CI, 10.8-16.2) following rHF-SRS (P < .01). Cumulative LP incidence was 14.5% at 18 months (95% CI, 11.4-18.0%), significantly associated with greater total GTV (hazard ratio, 1.12; 95% CI, 1.05-1.20) following iFR-SRS, and with recurrent versus newly diagnosed BMs across all patients (hazard ratio, 2.28; 95% CI, 1.01-5.15). Cumulative DBP incidence was significantly greater following rHF-SRS than iHF-SRS (P = .01), with respective 24-month rates of 50.0 (95% CI, 43.3-56.3) and 35.7% (95% CI, 29.2-42.2). LMD (57 events total; 33% nodular, 67% diffuse) was observed in 17.1% of rHF-SRS and 8.1% of iHF-SRS cases (odds ratio, 2.46; 95% CI, 1.34-4.53). Any radionecrosis and grade 2+ radionecrosis events were observed in 14 and 8% of cases, respectively. Conclusions: HF-SRS demonstrated favorable rates of LC and radionecrosis in postoperative and intact settings. Corresponding LMD and RN rates were comparable to those of other studies.

Introduction: Genomic alterations in the juxtamembrane exon 14 splice sites in NSCLC lead to increased MET stability and oncogenesis. We present the largest cohort study of MET Exon 14 (METex14) using whole transcriptome sequencing. Methods: A total of 21,582 NSCLC tumor samples underwent complete genomic profiling with next-generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, whole transcriptome sequencing). Clinicopathologic information including programmed death-ligand 1 and tumor mutational burden were collected and RNA expression for mutation subtypes and MET amplification were quantified. Immunogenic signatures and potential pathways of invasion were characterized using single-sample gene set enrichment analysis and mRNA gene signatures. Results: A total of 533tumors (2.47%) with METex14 were identified. The most common alterations were point mutations (49.5%) at donor splice sites. Most alterations translated to increased MET expression, with MET co-amplification resulting in synergistic increase in expression (q < 0.05). Common coalterations were amplifications of MDM2 (19.0% versus 1.8% wild-type [WT]), HMGA2 (13.2% versus 0.98% WT), and CDK4 (10.0% versus 1.5% WT) (q < 0.05). High programmed death-ligand 1 > 50% (52.5% versus 27.3% WT, q < 0.0001) and lower proportion of high tumor mutational burden (>10 mutations per megabase, 8.3% versus 36.7% WT, p < 0.0001) were associated with METex14, which were also enriched in both immunogenic signatures and immunosuppressive checkpoints. Pathways associated with METex14 included angiogenesis and apical junction pathways (q < 0.05). Conclusions: METex14 splicing alterations and MET co-amplification translated to higher and synergistic MET expression at the transcriptomic level. High frequencies of MDM2 and CDK4 co-amplifications and association with multiple immunosuppressive checkpoints and angiogenic pathways provide insight into potential actionable targets for combination strategies in METex14 NSCLC.

Introduction: We report brigatinib long-term efficacy and safety from phase 1/2 and phase 2 (ALTA) trials in ALK–rearrangement positive (ALK+) NSCLC. Methods: The phase 1/2 study evaluated brigatinib 30 to 300 mg/d in patients with advanced malignancies. ALTA randomized patients with crizotinib-refractory ALK+ NSCLC to brigatinib 90 mg once daily (arm A) or 180 mg once daily (7-d lead-in at 90 mg; arm B). Results: In the phase 1/2 study, 79 of 137 brigatinib-treated patients had ALK+ NSCLC; 71 were crizotinib pretreated. ALTA randomized 222 patients (n = 112 in arm A; n = 110 in arm B). Median follow-up at phase 1/2 study end (≈5.6 y after last patient enrolled) was 27.7 months; at ALTA study end (≈4.4 y after last patient enrolled), 19.6 months (A) and 28.3 months (B). Among patients with ALK+ NSCLC in the phase 1/2 study, median investigator-assessed progression-free survival (PFS) was 14.5 months (95% confidence interval [CI]: 10.8–21.2); median overall survival was 47.6 months (28.6–not reached). In ALTA, median investigator-assessed PFS was 9.2 months (7.4–11.1) in arm A and 15.6 months (11.1–18.5) in arm B; median independent review committee (IRC)-assessed PFS was 9.9 (7.4–12.8) and 16.7 (11.6–21.4) months, respectively; median overall survival was 25.9 (18.2–45.8) and 40.6 (32.5–not reached) months, respectively. Median intracranial PFS for patients with any brain metastases was 12.8 (9.2–18.4) months in arm A and 18.4 (12.6–23.9) months in arm B. No new safety signals were identified versus previous analyses. Conclusions: Brigatinib exhibited sustained long-term activity and PFS with manageable safety in patients with crizotinib-refractory ALK+ NSCLC.

Antibody-drug conjugates targeting receptor tyrosine-protein kinase erbB-2 (ERBB2, HER2) have emerged as promising targeted options for HER2-mutant NSCLC. Among antibody-drug conjugates targeting HER2, trastuzumab deruxtecan was found to have the most impressive efficacy and is a potential new standard of care. Drug-related interstitial lung disease remains a serious unpredictable identified risk for patients treated with trastuzumab deruxtecan, requiring careful monitoring and multidisciplinary management. We report the first two cases of drug-related cardiotoxicity with acute myocarditis that developed after the first trastuzumab deruxtecan cycle. Routine cardiovascular risk screening is advisable, with close collaboration between cardiology specialists and oncologists.

Sotorasib is a KRASG12C inhibitor that recently received approval for use in locally advanced or metastatic KRASG12C-mutated NSCLC. CodeBreaK100, the phase 2 clinical trial leading to the approval of sotorasib, excluded patients with untreated brain metastases; there have been no reports describing efficacy of sotorasib on untreated brain metastases. We present a case of a patient with active untreated brain metastases with resulting disorientation and weakness who has radiographic response and complete resolution of neurologic symptoms with sotorasib. Our case illustrates the intracranial activity of sotorasib, but additional studies are needed to characterize the intracranial response rate and duration of response in these patients.

Introduction We aimed to evaluate the efficacy and toxicity of the combination of 6 cycles of chemotherapy and radiation therapy compared with chemotherapy alone as postoperative adjuvant therapy for patients with stage III endometrial cancer. Methods This retrospective cohort study included patients with stage III endometrial cancer who received postoperative chemoradiotherapy or chemotherapy alone at 6 hospitals between January 2009 and December 2019. The progression-free survival (PFS) and overall survival (OS) for each treatment group were analyzed using the Kaplan–Meier method. We also assessed differences in toxicity profiles between the treatment groups. Results A total of 133 patients met the inclusion criteria. Of these, 80 patients (60.2%) received adjuvant chemoradiotherapy and 53 (39.8%) received chemotherapy alone. The PFS and OS did not differ significantly between the groups. For patients with stage IIIC endometrioid subtype, the chemoradiotherapy group had significantly longer PFS rate than did the chemotherapy alone group (log-rank test, P = .019), although there was no significant difference in the OS (log-rank test, P = .100). CRT was identified as a favorable prognostic factor for PFS in multivariate analysis (adjusted HR, .37; 95% CI, .16-.87; P = .022). Patients treated with chemoradiotherapy more frequently suffered from grade 4 neutropenia (73.8% vs 52.8%; P = .018) and grade 3 or worse thrombocytopenia (36.3% vs 9.4%; P = .001) compared with the chemotherapy alone group. There were no differences between the 2 treatment groups in the frequency of toxicity-related treatment discontinuation or dose reduction. Conclusion We confirmed that chemoradiotherapy yields longer progression-free survival than does chemotherapy alone for patients with stage IIIC endometrioid endometrial cancer, with an acceptable toxicity profile.

Purpose: Preoperative radiation therapy (RT) for pancreatic adenocarcinoma reduces positive surgical margin rates, and when delivered to an ablative dose range it may improve local control and overall survival for patients with unresectable disease. Use of stereotactic body RT to achieve a higher biologically effective dose has been limited by toxicity to adjacent radiosensitive structures, but this can be mitigated by stereotactic magnetic resonance image guided adaptive radiation therapy (SMART). Methods and Materials: We describe our single-institution experience of high biologically effective dose SMART before resection of localized pancreatic adenocarcinoma. Toxicity was evaluated according to Common Terminology Criteria for Adverse Events (V 5.0). Tumor response was evaluated according to the College of American Pathologists tumor regression grading criteria. Results: We analyzed 26 patients with borderline resectable (80.8%), locally advanced (11.5%), and resectable (7.7%) tumors who received ablative dose SMART (A-SMART) followed by surgical resection. Median age at diagnosis was 68 years (range, 34-86). Most patients received chemotherapy (80.8%) before RT. All patients received A-SMART to a median dose of 50 (range, 40-50) Gy in 5 fractions. Toxicity data were collected prospectively and there were no acute grade 2+ toxicities associated with RT. The median time to resection was 50 days (range, 37-115), and the procedure types included Whipple (69%), distal (23%), or total pancreatectomy (8%). The R0 resection rate was 96% and no perioperative deaths occurred within 90 days. Pathologic response was observed in 88% of cases. The time from RT to surgery was associated with tumor regression grade (P = .0003). The median follow-up after RT was 16.5 months (range, 3.9-26.2). The derived median progression-free survival from RT was 13.2 months. Conclusions: The initial surgical and pathologic outcomes after A-SMART are encouraging. Preoperative A-SMART was associated with low toxicity rates and no surgical or RT-associated mortality. The surgical morbidity was comparable to historic rates after upfront resection. These data also suggest that the time from stereotactic body RT to surgical resection is associated with pathologic response.

Introduction: Fucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1. Methods: CA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival. Results: Patients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 [90%]). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval [CI]) was higher with BMS-986012 plus nivolumab (38% [20.7%–57.7%]) than with monotherapy (4% [0.8%–11.0%]). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4–not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%–20.7%) and 39.3% (21.7%–56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0–7.3) and 18.7 (8.2–37.3) months, respectively. Conclusions: BMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880).

Introduction: The aim of this study was to evaluate the efficacy of pemetrexed and platinum plus pembrolizumab by baseline tumor burden. Methods: A total of 616 patients in the intention-to-treat population of the KEYNOTE-189 study were included in this analysis. Baseline tumor burden subgroups were identified on the basis of extent of distant metastasis (M1a versus M1b), median number (≤3 versus >3) of organ systems with lesions, or symptom severity score of patient-reported lung cancer-associated symptoms (≤median versus >median). Overall survival (OS), progression-free survival (PFS), and PFS-2 were evaluated by Kaplan-Meier and univariate Cox methods. Objective response rate was analyzed using logistic regression models, and duration of response was analyzed descriptively. Efficacy outcomes were also analyzed according to the programmed death-ligand 1 expression levels. Results: OS and PFS were significantly improved with pemetrexed and platinum plus pembrolizumab in all baseline tumor burden subgroups (M1a stage: OS hazard ratio [HR] = 0.54, p = 0.0037; PFS HR = 0.48, p = 0.0001; M1b stage: OS HR = 0.58, p ≤ 0.0001; PFS HR = 0.51, p ≤ 0.0001; number of organ systems with lesion ≤ 3: OS HR = 0.49, p ≤ 0.0001 PFS HR = 0.41, p ≤ 0.0001; >3: OS HR = 0.67, p = 0.0068; PFS HR = 0.59, p = 0.0001; symptom severity score ≤ median: HR = 0.51, p ≤ 0.0001; PFS HR 0.49, p ≤ 0.0001; > median: OS HR = 0.60, p = 0.0003; PFS HR = 0.48, p ≤ 0.0001). PFS2 and objective response rate were also improved with pemetrexed and platinum plus pembrolizumab in all baseline tumor burden subgroups. Efficacy outcomes were generally consistent regardless of programmed death-ligand 1 expression levels. Conclusions: Pemetrexed and platinum plus pembrolizumab were found to have relevant efficacy regardless of the extent of baseline tumor burden and the variables used to define it. These results further support pemetrexed and platinum plus pembrolizumab as the standard of care in the first-line treatment of metastatic nonsquamous NSCLC.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is the frontline standard in the treatment of metastatic EGFR-mutant NSCLC. Although osimertinib is effective, disease progression occurs in virtually all patients, mediated by a heterogeneous array of resistance mechanisms. Activation of the MET signaling pathway by means of amplification has been implicated in resistance to osimertinib, but activation caused by point mutations in MET has not been well described.Here, we present the case of a 65-year-old female with metastatic EGFR-mutant NSCLC whose disease progressed on osimertinib owing to emergence of MET Y1003N mutation. She subsequently received capmatinib in combination with osimertinib and achieved a partial response. This case illustrates a potential role for dual EGFR/MET inhibition in EGFR-mutated NSCLC with resistance driven by activating MET mutations.

Introduction: Crizotinib provided meaningful clinical benefit in the initial analysis of a phase 2 study in East Asian patients with advanced ROS1-positive NSCLC (NCT01945021). Nevertheless, overall survival (OS) data were immature. Here, we present the final OS, quality of life (QoL), and safety data after an additional 3 years of follow-up. Methods: In this phase 2, open-label, single-arm trial, East Asian patients with ROS1-positive advanced NSCLC who had received less than or equal to three systemic therapies previously were treated with crizotinib 250 mg twice daily on a continuous daily dosing schedule in 28-day cycles. The OS (secondary end point) was analyzed for the total population, by country, and by number of previous chemotherapy regimens. QoL and safety were also evaluated. Results: With a median duration of follow-up of 56.1 months, the median OS was 44.2 months (95% confidence interval: 32.0–not reached) for the total population (N = 127). Differences in median OS were observed among individual countries and with number of previous regimens. The improvement in QoL found in the previous analysis was maintained with the extended follow-up. Treatment-related adverse events led to crizotinib dose reductions or permanent treatment discontinuations in 17.3% and 2.4%, respectively, of the patients. Conclusions: This is the largest trial of an ALK/ROS1 inhibitor to treat patients with ROS1-positive advanced NSCLC and provides a new benchmark for OS in East Asian patients. The QoL and safety profile with long-term follow-up were consistent with previous reports and support the continued use of crizotinib in the treatment of patients with ROS1-positive advanced NSCLC.

Viscum album var. coloratum (Kom.) Ohwi is a traditional herbal medicine used in East Asia to treat hypertension, skeletal muscle disorders, and cancer. The inhibitory effects of Viscum album (VA) extract on chemokines and its therapeutic potential in erlotinib-induced skin rash were investigated in this study. ELISA was used to measure the levels of chemokines, MCP-1 and RANTES, which are thought to be mediators of erlotinib-induced skin rash in RAW264.7 cells. Western blot analysis was used to look into the activation of signaling pathways like AKT, MAPK, and EGF. In order to investigate the active compounds in VA extract, solvent fractionation and preparative HPLC were performed sequentially. VA extract significantly reduced the production of TNF-α, MCP-1, and RANTES but not IL-1. Furthermore, macrophage transmigration was inhibited without causing cell toxicity. VA extract had no effect on the phosphorylation of EGF receptors stimulated by EGF or suppressed by erlotinib in both A549, a non-small cell lung cancer cells, and Hacat, a human skin keratinocyte. The isolated viscumneoside III and viscumneoside V from VA extract significantly suppressed the expression of MCP-1, according to activity guided fractionation with organic solvent fractionation and preparative HPLC. These findings suggest that VA extract and its active compounds, viscumneoside III and viscumneoside V, regulate MCP-1 production and may have the potential to suppress erlotinib-induced skin toxicity by modulating macrophage activity without neutralizing anti-cancer efficacy.

Objective: This study aimed to evaluate the association between vitamin D receptor (an essential component in the vitamin D signaling pathway) and serum vitamin D as well as its clinical significance in papillary thyroid cancer. Methods: This prospective cohort study comprised patients with thyroid tumors who visited our hospital, from 2017 to 2018. The level of vitamin D receptor expression from thyroid tissue was measured in patients with thyroid tumor and evaluated for correlation with serum vitamin D levels and clinicopathologic characteristics of papillary thyroid cancer. Data from 501 patients with papillary thyroid cancer from The Cancer Genome Atlas database were analyzed. Results: Increased vitamin D receptor protein and mRNA expression were observed in papillary thyroid cancer compared to those in normal and benign tissues. Lower vitamin D receptor protein expression was associated with high TNM stage papillary thyroid cancer and low p21 protein expression. Lower relative vitamin D receptor mRNA expression in papillary thyroid cancer was associated with low serum 25-hydroxyvitamin D level. The Cancer Genome Atlas database showed a positive correlation among mRNA expression of vitamin D receptor, CYP24A1, and p21. Conclusions: An association between decreased vitamin D receptor protein expression and advanced stage papillary thyroid cancer, and a correlation between low vitamin D receptor mRNA expression with low serum 25-hydroxyvitamin D level was observed. Low vitamin D receptor expression in papillary thyroid cancer was shown to positively correlate with low serum vitamin D level and disease aggressiveness.

Objectives The objective is to evaluate the prognostic value of serum human epididymis protein 4 (HE4) as a tumor marker in patients with cervical cancer. Methods Sixty-seven patients with cervical cancer treated at Seoul National University Bundang Hospital from September 2014 to May 2018 were retrospectively reviewed. Serum HE4 levels were measured by immunoassay before starting primary treatment. A mean serum HE4 level of 72.6 pmol/L was used to divide the patients into low and high HE4 groups. Patient characteristics, clinicopathological variables, and survival outcomes were compared between the two groups. Results The low and high HE4 groups included 55 (82.1%) and 12 (17.9%) patients at diagnosis, respectively. Higher HE4 levels were significantly associated with older age at diagnosis (age

Purpose: The medical trainee perspective regarding the prior authorization process has not been previously assessed. Here we evaluate the perceptions of radiation and medical oncology trainees regarding the prior authorization process and its effect on their training and patient care. Methods and Materials: A 12-question, nonincentivized, electronic national survey of radiation and medical oncology trainees at all Accreditation Council for Graduate Medical Education accredited oncology programs was conducted. Participation, perspectives, and experiences with the prior authorization process were assessed by Likert scale, free response, and multiple response selection. Results: Between January and March of 2019, the survey was distributed to 1505 trainees at 76 institutions with responses from 174/616 radiation (28.2%) and 139/889 medical oncology trainees (15.6%). The majority (69.2%) reported participating in the prior authorization process (radiation: 78.2% vs medical: 57.6%; P < .01). Most trainees (71%) reported concern for decline in the quality of patient care due to the prior authorization process. The majority of trainees (77.1%) reported decreased enthusiasm for work and choice of profession, with a higher incidence in medical oncology trainees (83.1% vs 73.7%, P = .04). The most commonly recommended modifications by trainees included that the insurance reviewer be in the same specialty as the ordering provider (87.7%), providers be compensated for participation (82.7%), and turnaround time be more rapid (74.3%). Conclusions: These data indicate that trainees in US oncology programs are active participants in the prior authorization process and report that prior authorization approvals negatively influence their medical training and the quality of patient care. Additional efforts to revise the insurance approval process are warranted.

Purpose To evaluate the clinical course and long-term outcomes of patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) and identify independent prognostic factors for further recurrence. Methods In this retrospective study, we reviewed the records of 327 patients who experienced IBTR after undergoing BCS for breast cancer at Asan Medical Center during 1990–2013. Overall survival (OS) after IBTR and cumulative incidence rates of recurrences after IBTR were calculated. The association of clinicopathological factors with survival and the development of further recurrence after IBTR was determined in multivariate analysis. Results At a median follow-up of 127.7 months, 97 patients experienced recurrence after IBTR. The 5-year and 10-year cumulative incidence rates of recurrence after IBTR were 32% and 41%, respectively. The 5-year and 10-year OS rates after IBTR were 86.6% and 70.3%, respectively. In multivariate analysis, hormone receptor negativity was associated with decreases in OS after IBTR (hazard ratio [HR] 2.83, 95% confidence interval [CI] 1.18–6.78). Patients with longer disease-free interval (DFI) had decreased risks of second recurrence (HR .99, 95% CI .99–1.00), and second locoregional recurrence (LRR) (HR .98, 95% CI .97–.99). Lymphovascular invasion (LVI) of IBTR was associated with increased recurrence rates (second recurrence-free survival, HR 3.58, 95% CI 2.16–5.94; second LRR free survival, HR 5.21, 95% CI 2.77–9.78; second distant metastasis-free survival, 2.11, 95% CI 1.04–4.30) and lower survival rates (OS after IBTR, HR 4.64, 95% CI 2.23–9.67). Conclusions Despite subsequent recurrences during long-term follow-up, the survival rates after IBTR remained high. Patients with hormone receptor-negative tumors, shorter DFI, and tumors that present LVI of IBTR had higher risks for recurrence and poor survival rates after IBTR. The study findings may help in understanding the course and prognosis of IBTR patients and identifying high-risk IBTR to establish management strategies.

Introduction: Alectinib is a preferred first-line treatment option for advanced ALK-positive NSCLC. Combination regimens of alectinib with immune checkpoint inhibitors are being evaluated for synergistic effects. Methods: Adults with treatment-naive, stage IIIB/IV, or recurrent ALK-positive NSCLC were enrolled into a two-stage phase 1b study. Patients received alectinib 600 mg (twice daily during cycle 1 and throughout each 21-d cycle thereafter) plus atezolizumab 1200 mg (d8 of cycle 1 and then d1 of each 21-d cycle). Primary objectives were to evaluate safety and tolerability of alectinib plus atezolizumab. Secondary objectives included assessments of antitumor activity. Results: In total, 21 patients received more than or equal to 1 dose of alectinib or atezolizumab. As no dose-limiting toxicities were observed in stage 1 (n = 7), the starting dose and schedule were continued into stage 2 (n = 14). Median duration of follow-up was 29 months (range: 1–39). Grade 3 treatment-related adverse events occurred in 57% of the patients, most often rash (19%). No grade 4 or 5 treatment-related adverse events were reported. Confirmed objective response rate was 86% (18 of 21; 95% confidence interval [CI]: 64–97). Median progression-free survival was not estimable (NE) (95% CI: 13 mo–NE), neither was median overall survival (95% CI: 33 mo–NE). Conclusions: The combination of alectinib and atezolizumab is feasible, but increased toxicity was found compared with the individual agents. With small sample sizes and relatively short follow-up, definitive conclusions regarding antitumor activity cannot be made.

Purpose: Understanding patterns of relapse for primary central nervous system lymphoma (PCNSL) may inform mechanisms of recurrence and optimal consolidation strategies. In this study, we report patterns of relapse among patients with PCNSL who achieved a complete response to high-dose methotrexate (HD-MTX)-based chemotherapy with or without consolidation radiation therapy (RT). Methods and Materials: We conducted an institutional retrospective analysis of patients with PCNSL who received HD-MTX-based chemotherapy between November 2001 and May 2019. Relapses were characterized as in-field (within original T1 contrasted lesion), marginal (within T2 fluid-attenuated inversion recovery but not T1), local (in-field or marginal), distant brain (no overlap), or distant (distant brain, cerebrospinal fluid, vitreous or extra-axial) and further characterized with respect to periventricular location (≤10 mm of ventricles). Results: Seventy-eight patients with PCNSL met inclusion criteria, of whom 29 (37%) underwent consolidation RT. Median progression-free survival and overall survival were 57.0 and 66.7 months, respectively. After a median follow-up of 38.9 months, a total of 32 patients (41%) experienced recurrence. Most patients (21 [65.6%]) had a periventricular failure. Surprisingly, local recurrences (n = 11) were exclusively observed within periventricular lesions, whereas distant recurrences (n = 21) were seen in both periventricular and nonperiventricular locations (P= .009). The median time to progression was shorter for locally recurrent lesions compared with distant recurrences (13.8 vs 26.1 months; P= .03). Conclusions: After complete response to HD-MTX, few failures occurred within initial T1 contrast-enhancing lesions and many of these may have been alternatively classified as periventricular failures. These observations argue against the use of purely focal RT consolidation for patients who achieve a complete response after HD-MTX-based chemotherapy and suggest that periventricular reseeding may have a central role in PCNSL recurrence.

Purpose: Yttrium-90 (90Y) radioembolization with an escalated dose has been shown to improve clinical outcomes compared with standard dose radioembolization, but there are few data on the local control of primary liver tumors. We reported the clinical outcomes of patients with unresectable primary liver tumors treated with 90Y radioembolization with an escalated dose. Methods and Materials: Clinical data of patients with unresectable hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and biphenotypic tumors (cHCC-CC) treated with radioembolization with an escalated dose (≥150 Gy) between 2013 and 2020 with >3 months follow-up were retrospectively reviewed. The primary endpoint was freedom from local progression. Clinical response was defined by Modified Response Evaluation Criteria in Solid Tumours and toxic effects were assessed using Common Terminology Criteria for Adverse Events version 5.0. Results: Fifty-three patients with HCC and 15 patients with CC/cHCC-CC were analyzed. The median dose delivered was 205 Gy (interquartile range, 183-253 Gy) and 198 Gy (interquartile range, 154-234 Gy) for patients with HCC and CC/cHCC-CC, respectively. The 1-year freedom from local progression rate was 54% (95% confidence interval [CI], 38%-78%) for patients with HCC and 66% (95% CI, 42%-100%) for patients with CC/cHCC-CC. For patients with HCC, United Network for Organ Sharing nodal stage 1 (P = .01), nonsolitary tumors (P = .02), pretreatment α-fetoprotein of >7.7 ng/mL (P = .006), and ≤268 Gy dose delivered (P = .003) were predictors for local progression on multivariate Cox analysis. No patients with HCC who received a dose >268 Gy had a local tumor progression. The 1-year overall survival for patients with HCC was 74% (95% CI, 61%-89%). After radioembolization, 5 (7%) patients had grade 3 ascites, and 4 (6%) patients had grade 3/4 hyperbilirubinemia. Conclusions: Treatment of unresectable primary liver tumors with 90Y radioembolization with an escalated dose was safe and well tolerated. Delivery of >268 Gy may improve local tumor control of HCC. Determination of the maximum tolerated dose needs to be performed in the context of future prospective dose-escalation trials to further evaluate the safety and efficacy of such an approach.

Introduction: The aim of this study was to perform a clinicopathologic analysis of PHLPP1 expression in gastric cancer patients and analyze AKT activity with chemotherapy drug treatment in cancer subtypes. Materials and Methods: Surgically resected gastric cancer tissue specimens were obtained from 309 patients who underwent gastrectomy, and PHLPP1 expression was validated by tissue microarray analysis with immunohistochemistry. We assessed whether PHLPP1 selectively dephosphorylates Ser473 of AKT in an in-vitro study. Results: We found that the PHLPP1 overexpression (OE) group showed significantly greater proportions of differentiated subtype samples and early T stage samples, lower lymph node metastasis, and lower TNM stage than the PHLPP1 underexpression (UE) group. The overall survival of the PHLPP1-OE group was significantly higher (53.39 ± 0.96 months) than that of the PHLPP1-UE group (47.82 ± 2.57 months) ( P = .01). In vitro analysis, we found that the PHLPP1-OE group showed a significant decrease in relative AKT S-473 levels in both cell lines (MKN-74 and KATO-III). We found that treatment with chemotherapy drugs decreased the activity of Ser473 in the MKN-74 cell line with PHLPP1 OE, but it did not affect the activity of Ser473 in KATO-III cells. Conclusion: We found that patients who overexpressed PHLPP1 showed low recurrence and good prognosis. PHLPP1 was found to work by lowering the activity of AKT Ser473 in gastric cancer. Additionally, we found a clue regarding the mechanism of chemotherapeutic drug resistance in a cell line of signet ring cell origin and will uncover this mechanism in the future.

Background: Head and neck cancer patients often suffer from dysphagia after surgery and radiotherapy. A singing-enhanced swallowing protocol was established to improve their swallowing function. This study aimed to evaluate the beneficial effects of therapeutic singing on dysphagia in head and neck cancer (HNC) patients. Methods: Patients who participated in this study were allocated to the intervention group (15 patients) and the control group (13 patients). Patients assigned to the intervention group received therapeutic singing 3 times per week for 4 weeks. Each group was divided into 2 subgroups, including the oral cavity cancer group and the pharyngeal cancer group. The patients’ vocal functions were evaluated in maximum phonation time, pitch, intensity, jitter, shimmer, harmonics to noise ratio, and laryngeal diadochokinesis (L-DDK). To evaluate swallowing function, videofluoroscopic swallowing study was done, and the results were analyzed by videofluoroscopic dysphagia scale (VDS) and dynamic imaging grade of swallowing toxicity (DIGEST). Results: Among the voice parameters, L-DDK of the intervention group significantly increased compared to that of the control group. Swallowing functions of the intervention group were significantly improved in VDS and DIGEST after the intervention. Detailed items of VDS and DIGEST showed improvements especially in the pharyngeal phase score of VDS, such as laryngeal elevation, pharyngeal transit time, and aspiration. In addition, the pharyngeal cancer group showed significant improvements in VDS and DIGEST scores after the intervention. Conclusions: Our outcomes highlight the beneficial effects of singing for HNC patients with dysphagia. The notable improvements in the pharyngeal phase suggest that therapeutic singing would be more appropriate for HNC patients who need to improve their intrinsic muscle movements of vocal fold and laryngeal elevation.

Introduction Not much is known regarding the disparities in cancer care between women with and without disabilities. Objectives The aim of this study was to investigate the potential disparities in the diagnosis, treatment, and survival of women with cervical cancer with and without disabilities. Methods We performed a retrospective cohort study and linked the National Disability Database, Korean Central Cancer Registry, and Korean National Health Insurance claims database. Charlson comorbidity index was used for adjusting the comorbidity. The study population comprised 3 185 women with disabilities (physical/brain, communication, mental, cardiopulmonary, and other impairment) who were diagnosed with cervical cancer and 13 582 age- and sex-matched women without disability who were diagnosed with cervical cancer for comparison. Results Distant metastatic stage (7.7% vs 3.7%) and unknown stage (16.1% vs 7.0%) were more common in cervical cancer women with grade 1 disabilities, compared with women without disabilities. Women with cervical cancer with disabilities were less likely to undergo surgery (adjusted odds ratio (aOR) 0.81, 95% confidence interval (CI) 0.73–0.90) or chemotherapy (aOR 0.86, 95% CI 0.77–0.97). Lower rate of surgery was more evident in patients with physical/brain impairment (aOR 0.46, 95% CI 0.37–0.58) and severe mental impairment (aOR 0.57, 95% CI 0.41–0.81). The overall mortality risk was also higher in patients with disabilities (adjusted hazard ratio (aHR) 1.36, 95% CI 1.25–1.48). Conclusion Women with cervical cancer with disabilities, especially with severe disabilities, were diagnosed at later stages, received less treatment, and had higher mortality rates, compared with patients who lacked disabilities. Social support and policies, along with education for women with disabilities, their families, and healthcare professionals, are needed to improve these disparities.

Background : High tumor mutational burden (TMB-H) has been reported as a predictive marker to immunotherapy or prognostic marker in various tumor types. However, there has been little study of the role of TMB-H in advanced biliary tract cancer (BTC). Methods : We analyzed 119 advanced BTC patients who received Gemcitabine/Cisplatin (GP) as a first-line treatment between November 2019 and April 2021. Next-generation sequencing (NGS), including TMB analysis, as a routine clinical practice was performed in 119 patients. The TruSight TM Oncology 500 assay from Illumina was used as a cancer panel. Results : Among 119 patients, 18 (18.5%) had a tumor with high TMB (≥ 10 Muts/Mb). There were no significant differences between the status of TMB and clinical outcomes with GP, including objective response rate (ORR) ( P = .126), disease control rate (DCR) ( p = .454), and median progression-free survival (PFS) ( p = .599). The median overall survival (OS) was not different between patients with TMB-H and no TMB-H ( p = .430). In subgroup analysis of 32 patients receiving immune checkpoint inhibitor (ICIs), there were significant differences in ORR ( p = .034) and median PFS ( p = .025) with ICIs between patients with and without TMB-H. Conclusions : This study revealed that TMB-H in advanced BTCs did not have a prognostic or role in the standard first-line treatment. However, TMB-H might be a predictive biomarker for response to ICIs in advanced BTC.

Purpose: Small cell carcinoma of the cervix (SCCC) represents 1% to 5% of cervical cancers, with limited data on management and outcomes. We evaluated patterns of care and outcomes for SCCC using the National Cancer Database. Methods and Materials: This retrospective cohort study of SCCC (2004-2011) included 542 cases. Patient demographic, diagnosis, treatment information, and overall survival (OS) were compared with descriptive statistics, logistic regression, Kaplan-Meier, and Cox models. Clinical reasoning was used to select variables for multivariable models to avoid overfitting. Results: SCCC had more comorbidities, higher grade, and advanced stage than other histologies. SCCC received neoadjuvant chemotherapy (36%) more often than squamous cell carcinoma (23%) and adenocarcinoma (13%, P