Natural history of SCLC patients treated in third-line and beyond: A retrospective real world study.

OBJECTIVES: To describe treatment patterns and estimate outcomes among real-world small cell lung cancer (SCLC) patients in the US who received three or more lines of therapy. MATERIALS AND METHODS: We conducted a retrospective analysis of adult patients with SCLC who received a front-line platinum-based regimen and two additional lines of therapy (ie., a cohort of at least three lines of therapy). De-identified patients were selected from a United States Flatiron Health oncology database of electronic health records. Treatment patterns were captured by line of therapy. Outcomes evaluated by line of therapy included real-world overall survival (rwOS), real-world progression free survival (rwPFS), real-world response rate (rwRR) and real-world duration of response (rwDOR). RESULTS: The analysis included 326 3L SCLC patients, of which 103 (32 %) received 4L treatment, and 38 % (39/103) of 4L treated received 5L of therapy. Among the 3L cohort, the average age was 67 years, 49 % were male, and nearly all had a history of smoking (96 %). In the 3L setting, the median rwOS was 5.3 months (95 % Confidence Interval (CI): 4.5, 6.0), median rwPFS was 2.5 months (95 % CI: 2.1, 2.7), rwRR was 19.3 % (95 % CI: 15.2, 24.0) and median DOR was 3.4 months (95 % CI: 2.8, 4.4). No differences were seen in outcomes between the overall cohort and a subgroup of patients treated with front-line platinum-based regimen with an anti-programmed cell death ligand 1 (PD-L1) agent (atezolizumab or durvalumab), in each respective line of therapy. CONCLUSION: Results from this large, real-world study of US patients with SCLC in the 3L setting and beyond highlight the poor treatment outcomes in advanced SCLC patients with existing therapies and underscore the dire need for new therapies for SCLC patients.

Natural History and Real-World Treatment Outcomes for Patients With NSCLC Having EGFR Exon 20 Insertion Mutation: An International Association for the Study of Lung Cancer-American Society of Clinical Oncology CancerLinQ Study.

Introduction: EGFR exon 20 insertion (ex20ins) mutations account for approximately 10% of EGFR mutations in lung adenocarcinoma. Patients with ex20ins mutation do not respond to standard EGFR tyrosine kinase inhibitor therapy. In this work, we analyzed the characteristics, treatment patterns, and outcomes in this subgroup of patients with NSCLC. Methods: The American Society of Clinical Oncology CancerLinQ Discovery data set was queried to identify patients with initial diagnosis of NSCLC between the years 1995 and 2018 and with EGFR ex20ins mutations. Data were extracted on patient demographics, tumor characteristics, treatments, and outcomes, and compared using chi-square and analysis of variance. Kaplan-Meier curves were generated to compare overall survival with log-rank tests. All analyses were performed using Python 3.6 (Python Software Foundation). Results: A total of 357 patients were eligible. Patient characteristics include a median age of 68 years comprising female sex of 54%, White race of 63%, and Black race of 9%. Approximately 62% of total patients had stage 4 disease, and 30% of all patients had brain metastasis. There were 54% of patients who were treated with chemotherapy and 15% with immune checkpoint inhibitors (ICIs). In patients with brain metastasis, 16% were treated with ICI, 18% with targeted therapy, and 59% with chemotherapy. The median survival of the entire group was 23.8 months. Among patients with stage 4 disease (n = 222): 51% were women, 64% were white, 37% had brain metastasis, 18% were treated with ICI, 14% had targeted therapy, and 60% were treated with chemotherapy. Stage 4 patients treated with targeted therapy had better survival compared with those who did not receive targeted therapy (20.6 versus 16.1 mo, p = 0.02). Univariate and multivariate analyses suggested favorable outcomes for patients treated with immunotherapy. Conclusions: EGFR ex20ins mutation represents a unique subset of NSCLC; it is associated with a higher propensity for brain metastases and a relatively modest overall survival. Novel treatment approaches are urgently needed to improve patient outcomes.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC.

BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR-tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).

Histological characterization and development of mesial surface sulci in the human brain at 13-15 gestational weeks through high-resolution histology.

Cellular-level anatomical data from early fetal brain are sparse yet critical to the understanding of neurodevelopmental disorders. We characterize the organization of the human cerebral cortex between 13 and 15 gestational weeks using high-resolution whole-brain histological data sets complimented with multimodal imaging. We observed the heretofore underrecognized, reproducible presence of infolds on the mesial surface of the cerebral hemispheres. Of note at this stage, when most of the cerebrum is occupied by lateral ventricles and the corpus callosum is incompletely developed, we postulate that these mesial infolds represent the primordial stage of cingulate, callosal, and calcarine sulci, features of mesial cortical development. Our observations are based on the multimodal approach and further include histological three-dimensional reconstruction that highlights the importance of the plane of sectioning. We describe the laminar organization of the developing cortical mantle, including these infolds from the marginal to ventricular zone, with Nissl, hematoxylin and eosin, and glial fibrillary acidic protein (GFAP) immunohistochemistry. Despite the absence of major sulci on the dorsal surface, the boundaries among the orbital, frontal, parietal, and occipital cortex were very well demarcated, primarily by the cytoarchitecture differences in the organization of the subplate (SP) and intermediate zone (IZ) in these locations. The parietal region has the thickest cortical plate (CP), SP, and IZ, whereas the orbital region shows the thinnest CP and reveals an extra cell-sparse layer above the bilaminar SP. The subcortical structures show intensely GFAP-immunolabeled soma, absent in the cerebral mantle. Our findings establish a normative neurodevelopment baseline at the early stage.

Ni doping induced property enhancement in laser ablated BaSnO3 films suitable for optoelectronic applications.

Pulsed laser deposition is a straightforward approach for preparing films with superconducting to dielectric properties with atomic layer precision. The deep-seated mechanisms involved in the particle transport from target to substrate and subsequent film formation still need to be fully comprehended. This manuscript reports the property enhancement observed in laser ablated perovskite BaSnO3 films with Ni doping. Films' crystallinity improvement is observed, and an intensity enhancement of 1150% is observed on 3 mol% Ni-doping. The optimum Ni-doping concentration in BaSnO3 is found to be 3 mol%. Herein, Ni-doped BaSnO3 films deposited by PLD showed an unusual increase in film thickness (i.e., from 615 nm in the pure film to 1317 nm in the film with 7 mol% Ni-doping as revealed by lateral SEM analysis and spectroscopic ellipsometry). We propose an "Induced Magnetic field-assisted Particle Convergence (IMPC)" effect for this superficial growth enhancement. The film's optical properties are modified with an increased nickel doping level, and the bandgap energy shows renormalization. All the films show excellent transmittance (80-90%) in the Vis.-NIR region. Hall-effect measurement reveals the increased carrier concentration by three orders (2.98 × 1011 to 3.50 × 1014 cm-3). In addition, the enhancement in mobility from 3.13 to 20.93 cm2V-1s-1 and a decrease in electrical resistivity by six orders (i.e., from 4.05 × 109 to 1.13 × 103 Ω cm) are observed on 7 mol% Ni doping. XPS measurements reveals that the Ba, Sn and Ni ions are at 2+, 4+ and 2+ oxidation states. Using spectroscopic ellipsometric method, we estimated the optical constants of the films, the refractive index, dielectric constant, and extinction coefficient show a normal dispersion behavior. The high crystallinity, high transmittance, suitable surface topography, and improved electrical performances of the Ni-doped BaSnO3 films make them excellent candidates for optoelectronic devices and solar cells.

Strengthening of District/Taluk Level Hospitals Through Implementation of Post-graduate Medical Courses in Karnataka, India.

The World Health Organization (WHO) recommends the requirement of human resource for health (HRH) stands at 44.5 skilled health workers per 10,000 population. WHO recognizes India as one of the countries which has HRH crisis. Karnataka, a southern state in India, has the highest number of medical colleges yet faces the shortage of specialists in the public hospitals. We conducted desk review to understand the HRH crisis, particularly the medical specialists in India. Simultaneously, we conducted secondary research to explore the initiatives taken by the Government of Karnataka (GoK) to mitigate the shortage of medical specialists in the rural areas. GoK scaled up the National Board of Examination in Medical Sciences (NBEMS) postgraduate and super-speciality courses such as Diplomate of National Board (DNB), Diploma, and Doctorate of National Board (DrNB) in district hospitals (minimum 250-500 bedded) and taluk hospitals (minimum 100 bedded) by utilizing the existing resources. Karnataka is the first state in India to expand the NBEMS (DNB and Diploma) courses in taluk hospitals and to begin DrNB courses in district hospitals. The paper documents the process of implementation of the NBEMS courses at district and taluk hospitals of Karnataka, which has supported in strengthening these hospitals in the state.

Production, optimization and characterization of partially purified anti-mycotic compound from marine soil derived streptomycetes originating at unexplored region of Bay of Bengal, India.

Sixty-eight morphologically distinct isolates of marine actinomycetes were derived from seashore, mangrove, and saltpan ecosystems located between the Palk Strait and Gulf of Mannar region, Bay of Bengal, Tamilnadu. Twenty-five (36.8%) isolates exhibited anti-mycotic activity against Candida albicans and Cryptococcus neoformans in preliminary screening, and 4 isolates with prominent activity were identified and designated at the genus level as Streptomyces sp. VPTS3-I, Streptomyces sp. VPTS3-2, Streptomyces sp. VPTSA1-4 and Streptomyces sp. VPTSA1-8. All the potential antagonistic isolates were further characterized with phenotypic and genotypic properties including 16S rRNA gene sequencing and identified species level as Streptomyces afghaniensis VPTS3-1, S. matensis VPTS3-2, S. tuirus VPTSA1-4 and S. griseus VPTSA1-8. In addition, the active fractions from the potential antagonistic streptomycetes were extracted with organic solvents by shake flask culture method and the anti-mycotic efficacies were evaluated. The optimization parameters for the production of the anti-mycotic compound were found to be pH between 7 and 8, the temperature at 30ᵒC, the salinity of 2%, incubation of 9 days, and starch and KNO3 as the suitable carbon and nitrogen sources respectively in starch casein medium.

DNA topoisomerase II inhibition potentiates osimertinib's therapeutic efficacy in EGFR-mutant non-small cell lung cancer models.

Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, synergistically decreased cell survival, with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells; suppressed the growth of osimertinib-resistant tumors; and delayed the emergence of osimertinib-acquired resistance. Mechanistically, osimertinib decreased Topo IIα levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines that possess elevated levels of Topo IIα. Increased Topo IIα levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their susceptibility to osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.

A plain language summary of the PHAROS study: the combination of encorafenib and binimetinib for people with BRAF V600E-mutant metastatic non-small-cell lung cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI®) and binimetinib (MEKTOVI®). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC). NSCLC is the most common type of lung cancer. Metastatic means that the cancer has spread to other parts of the body. All people in this study had a type of NSCLC that has a change in a gene called BRAF termed a BRAF V600E mutation. A gene is a part of the DNA that has instructions for making things that your body needs to work, and the BRAF V600E mutation contributes to the growth of the lung cancer. WHAT WERE THE RESULTS?: In this study, 98 people with BRAF V600E-mutant metastatic NSCLC were treated with the combination of encorafenib and binimetinib (called encorafenib plus binimetinib in this summary). Before starting the study, 59 people had not received any treatment for their metastatic NSCLC, and 39 people had received previous anticancer treatment. At the time of this analysis, 44 (75%) out of 59 people who did not receive any treatment before taking encorafenib plus binimetinib had their tumors shrink or disappear. Eighteen (46%) out of 39 people who had received treatment before starting encorafenib plus binimetinib also had their tumors shrink or disappear. The most common side effects of encorafenib plus binimetinib were nausea, diarrhea, fatigue, and vomiting. WHAT DO THE RESULTS MEAN?: These results support the use of encorafenib plus binimetinib combination treatment as a new treatment option in people with BRAF V600E-mutant metastatic NSCLC. The side effects of encorafenib plus binimetinib in this study were similar to the side effects seen with encorafenib plus binimetinib in people with a type of skin cancer called metastatic melanoma.

Association between body composition and mortality in patients requiring extracorporeal membrane oxygenation support.

AIM: To ascertain the association between body composition, including muscle mass and adiposity, and patient mortality in those requiring extracorporeal membrane oxygenation (ECMO) for acute respiratory failure. MATERIALS AND METHODS: A retrospective study was undertaken of all patients with acute respiratory failure requiring veno-venous (VV) ECMO between January 2015 and December 2019. Automated image segmentation software was used to quantify the cross-sectional area and average radiodensity (in Hounsfield units) of different muscle and fat compartments at the L3 level of whole-body computed tomography (CT) images taken within 48 h of initiation of ECMO support. The primary endpoint was 30-day post-ECMO initiation all-cause mortality. Logistic regression was used to analyse the correlation between CT measurements, co-morbidities, and 30-day survival. RESULTS: The study included 189 patients (age = 43.8 ± 14.6, sex = 42.3% female). There was no significant association between 30-day survival status and cross-sectional area of muscle or fat. Muscle attenuation (psoas, long spine, and abdominal muscles respectively) at the L3 level were significantly lower in those who died within 30 days of ECMO cannulation (p<0.05). On multivariable analysis including age, sex, and pre-existing respiratory comorbidities, psoas muscle attenuation was an independent predictor of survival at 30 days (OR 0.97; 95% CI 0.94 to 1.00; p=0.047). CONCLUSIONS: Reduced psoas muscle attenuation is associated with poorer survival outcomes at 30 days post-ECMO cannulation in patients who received VV ECMO support for respiratory failure. Cross-sectional areas of muscle and fat compartments did not correlate with survival outcomes at 30 days even when corrected for height and sex.

Incidence, Correlates, and Prognostic Significance of Mixed Response in Advanced Non-small Cell Lung Cancer.

BACKGROUND: Mixed response (MR), a scenario featuring discordant tumor changes, has been reported primarily with targeted therapies or immunotherapy. We determined the incidence and prognostic significance of MR in advanced non-small cell lung cancer (NSCLC) treated with cytotoxic chemotherapy. PATIENTS AND METHODS: We analyzed patient-level data from ECOG-ACRIN E5508 (carboplatin-paclitaxel + bevacizumab induction followed by randomization to maintenance therapy regimens). For patients with at least 2 target lesions and available measurements after cycle 2, we characterized response as homogeneous response (HR, similar behavior of all lesions), MR (similar behavior but >30% difference in magnitude of best and least responding lesions), or true mixed response (TMR, best and least responding lesions showing different behavior: ≥10% growth versus ≥10% shrinkage). We compared category characteristics using Mann-Whitney U and Chi-square tests, and overall survival (OS) using log-rank test and Cox models. RESULTS: Among 965 evaluable patients, HR occurred in 609 patients (63%), MR in 208 (22%), and TMR in 148 (15%). Median OS was 13.6 months for HR, 12.0 months for MR, and 7.6 months for TMR (P < .001). Compared to HR, TMR had inferior OS among stable disease cases (HR 1.62; 95% CI, 1.23-2.12; P < .001) and a trend toward inferior OS among progressive disease cases (HR 1.39; 95% CI, 0.83-2.33; P = .2). In multivariate analysis, TMR was associated with worse OS (HR 1.48; 95% CI, 1.22-1.79; P < .001). CONCLUSION: True mixed response occurs in a substantial minority of lung cancer cases treated with chemotherapy and independently confers poor prognosis.

Long-term benefit of sotorasib in patients with KRAS G12C-mutated non-small-cell lung cancer: plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a study called CodeBreaK 100. The CodeBreaK 100 study included patients with non-small-cell lung cancer that had spread outside the lung (advanced). Lung cancer is one of the most common forms of cancer. CodeBreaK 100 specifically looked at patients with a particular change(mutation) in the KRAS gene resulting in the mutated protein called KRAS G12C. The KRAS G12C mutation can lead to development and growth of lung cancer. Patients received a treatment called sotorasib, which has accelerated approval or full approval in over 50 countries for patients with non-small-cell lung cancer with the KRAS G12C mutation. The CodeBreaK 100 study looked at whether sotorasib is a safe and effective treatment for advanced non-small-cell lung cancer. Sotorasib is designed to specifically target and lock the mutated KRAS protein in the inactive state to treat non-small-cell lung cancer. WHAT WERE THE RESULTS?: In total, 174 adults were treated with sotorasib. Treatment-related side effects were seen in 70% of patients and were severe in 21% of patients. The most common side effects included diarrhea, increased liver enzymes, nausea and tiredness. 70 (41%) patients responded to sotorasib and 144 (84%) patients had tumors that either remained stable or shrunk in size. 29 (41%) patients who responded to sotorasib responded for over 12 months. After 2 years, 9 patients with a response remained on sotorasib; there were no notable increases in tumor size or development of new tumors over this time. There were 5patients who received sotorasib for more than 2 years and continued to respond. Long-term benefit was seen for some patients. Patients also benefitted from treatment when the tumor expressed different amounts of a protein called PD-L1.In total, 33% of patients were still alive after 2 years. WHAT DO THE RESULTS MEAN?: Results show the long-term benefit of sotorasib therapy for people with advanced KRAS G12C-mutated non-small-cell lung cancer. Clinical Trial Registration: NCT03600883 (CodeBreaK 100) (ClinicalTrials.gov).

Longitudinal Circulating Tumor DNA Modeling to Predict Disease Progression in First-Line Mutant Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer.

This exploratory, post hoc analysis aimed to model circulating tumor DNA (ctDNA) dynamics and predict disease progression in patients with treatment-naïve locally advanced/metastatic epidermal growth factor receptor mutation (EGFRm)-positive non-small cell lung cancer, from the FLAURA trial (NCT02296125). Patients were randomized 1:1 and received osimertinib 80 mg once daily (q.d.) or comparator EGFR-TKIs (gefitinib 250 mg q.d. or erlotinib 150 mg q.d.). Plasma was collected at baseline and multiple timepoints until treatment discontinuation. Patients with Response Evaluation Criteria in Solid Tumors (RECIST) imaging data and detectable EGFR mutations (Ex19del/L858R) at baseline and ≥ 3 additional timepoints were evaluable. Joint modeling was conducted to characterize the relationship between longitudinal changes in ctDNA and probability of progression-free survival (PFS). A Bayesian joint model of ctDNA and PFS was developed solving differential equations with the ctDNA dynamics and the PFS time-to-event probability. Of 556 patients, 353 had detectable ctDNA at baseline. Evaluable patients (with available imaging and ≥ 3 additional timepoints, n = 320; ctDNA set) were divided into training (n = 259) and validation (n = 61) sets. In the validation set, the model predicted a median PFS of 17.7 months (95% confidence interval (CI): 11.9-28.3) for osimertinib (n = 23) and 9.1 months (95% CI: 6.3-14.8) for comparator (n = 38), consistent with observed RECIST PFS (16.4 months and 9.7, respectively). The model demonstrates that EGFRm ctDNA dynamics can predict the risk of disease progression in this patient population and could be used to predict RECIST-defined disease progression.

Targeted treatment for unresectable EGFR mutation-positive stage III non-small cell lung cancer: Emerging evidence and future perspectives.

Epidermal growth factor receptor (EGFR) mutations are detected in up to one third of patients with unresectable stage III non-small cell lung cancer (NSCLC). The current standard of care for unresectable stage III NSCLC is consolidation durvalumab for patients who have not progressed following concurrent chemoradiotherapy (the 'PACIFIC regimen'). However, the benefit of immunotherapy, specifically in patients with EGFR mutation-positive (EGFRm) tumors, is not well characterized, and this treatment approach is not recommended in these patients, based on a recent ESMO consensus statement. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated significant improvements in patient outcomes in EGFRm metastatic NSCLC. The benefits of these agents have also translated to patients with EGFRm early-stage resectable disease as adjuvant therapy. The role of EGFR-TKIs has yet to be prospectively characterized in the unresectable setting. Preliminary efficacy signals for EGFR-TKIs in unresectable EGFRm stage III NSCLC have been reported from a limited number of subgroup and retrospective studies. Several clinical trials are ongoing assessing the safety and efficacy of EGFR-TKIs in this patient population. Here, we review the current management of unresectable EGFRm stage III NSCLC. We outline the rationale for investigating EGFR-TKI strategies in this setting and discuss ongoing studies. Finally, we discuss the evidence gaps and future challenges for treating patients with unresectable EGFRm stage III NSCLC.

Pan-Tumor Analytical Validation and Osimertinib Clinical Validation in EGFR Mutant Non-Small-Cell Lung Cancer, Supporting the First Next-Generation Sequencing Liquid Biopsy in Vitro Diagnostic.

Comprehensive genotyping is necessary to identify therapy options for patients with advanced cancer; however, many cancers are not tested, partly because of tissue limitations. Next-generation sequencing (NGS) liquid biopsies overcome some limitations, but clinical validity is not established and adoption is limited. Herein, clinical bridging studies used pretreatment plasma samples and data from FLAURA (NCT02296125; n = 441) and AURA3 (NCT02151981; n = 450) pivotal studies to demonstrate clinical validity of Guardant360 CDx (NGS LBx) to identify patients with advanced EGFR mutant non-small-cell lung cancer who may benefit from osimertinib. The primary end point was progression-free survival (PFS). Patients with EGFR mutation as identified by NGS LBx had significant PFS benefit with first-line osimertinib over standard of care (15.2 versus 9.6 months; hazard ratio, 0.41; P < 0.0001) and with later-line osimertinib over chemotherapy (8.3 versus 4.2 months; hazard ratio, 0.34; P < 0.0001). PFS benefits were similar to the original trial cohorts selected by tissue-based EGFR testing. Analytical validation included accuracy, precision, limit of detection, and specificity. Analytical validity was established for EGFR mutation detection and pan-tumor profiling. Panel-wide limit of detection was 0.1% to 0.5%, with 98% to 100% per-sample specificity. Patients with EGFR mutant non-small-cell lung cancer by NGS LBx had improved PFS with osimertinib, confirming clinical validity. Analytical validity was established for guideline-recommended therapeutic targets across solid tumors. The resulting US Food and Drug Administration approval of NGS LBx demonstrated safety and effectiveness for its intended use and is expected to improve adherence to guideline-recommended targeted therapy use.

Harnessing CD8 T cell responses using PD-1-IL-2 combination therapy.

There is considerable interest in developing more effective programmed cell death (PD)-1 combination therapies against cancer. One major obstacle to these efforts is a dysfunctional/exhausted state of CD8 T cells, which PD-1 monotherapy is not able to overcome. Recent studies have highlighted that PD-1+ T cell factor (TCF)-1+ stem-like CD8 T cells are not fate locked into the exhaustion program and their differentiation trajectory can be changed by interleukin (IL)-2 signals. Modifying the CD8 T cell exhaustion program and generating better effectors from stem-like CD8 T cells by IL-2 form the fundamental immunological basis for combining IL-2 with PD-1 therapy. Many versions of IL-2-based products are being tested and each product should be carefully evaluated for its ability to modulate dysfunctional states of anti-tumor CD8 T cells.

Platinum-based chemotherapy attenuates the effector response of CD8 T cells to concomitant PD-1 blockade.

PURPOSE: Combination of chemotherapy (CT) with programmed cell death (PD)-1 blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how CT affects the response of exhausted CD8 T cells to PD-1 blockade. EXPERIMENTAL DESIGN: We used the well-established mouse model of T cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of CT (cisplatin+pemetrexed) on T cell response to PD-1 blockade, in the absence of the impact of CT on antigen release and presentation observed in tumor models. RESULTS: When concomitantly administered with PD-1 blockade, CT affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of interferon (IFN)-γ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared to PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed CT, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by CT partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant CT, ultimately resulting in impaired overall CD8 T cell effector functions. CONCLUSIONS: In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T cell functions.