WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis.

Metastasis from lung adenocarcinoma can occur swiftly to multiple organs within months of diagnosis. The mechanisms that confer this rapid metastatic capacity to lung tumors are unknown. Activation of the canonical WNT/TCF pathway is identified here as a determinant of metastasis to brain and bone during lung adenocarcinoma progression. Gene expression signatures denoting WNT/TCF activation are associated with relapse to multiple organs in primary lung adenocarcinoma. Metastatic subpopulations isolated from independent lymph node-derived lung adenocarcinoma cell lines harbor a hyperactive WNT/TCF pathway. Reduction of TCF activity in these cells attenuates their ability to form brain and bone metastases in mice, independently of effects on tumor growth in the lungs. The WNT/TCF target genes HOXB9 and LEF1 are identified as mediators of chemotactic invasion and colony outgrowth. Thus, a distinct WNT/TCF signaling program through LEF1 and HOXB9 enhances the competence of lung adenocarcinoma cells to colonize the bones and the brain. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data.

Oral Chemotherapy Metric Performance in Quality Oncology Practice Initiative Practices: Updated Trends and Analysis.

BACKGROUND: Oral chemotherapy performance measures were first introduced into ASCO's Quality Oncology Practice Initiative (QOPI) in 2013. This study examined performance on these measures among QOPI-participating practices and evaluated whether it differed among practices based on meeting QOPI Certification Program standards. METHODS: A total of 192 QOPI-participating practices (certified, n=50 [26%]; not certified, n=142 [74%]) reported performance on oral chemotherapy measures in 2017 and 2018. Inclusion was limited to practices reporting on ≥3 charts for ≥1 oral chemotherapy measure. Performance was defined as the percentage of charts examined that adhered to the measure. Descriptive analyses were used to characterize performance within and across practices, and mixed-effects logistic regression models were conducted to compare performance based on certification status. RESULTS: Median performance across practices for the 9 oral chemotherapy measures examined ranged from 44% (education before the start of treatment addressing missed doses, toxicities, and clinical contact instructions [composite measure]) to 100% (documented dose, documented plan, and education about toxicities). Certified practices were more likely to provide education about clinic contact instructions than noncertified practices (odds ratio, 4.87; 95% CI, 1.00-24.0). Performance on all other measures was not significantly associated with certification status. CONCLUSIONS: There is wide variability in quality related to performance on oral chemotherapy measures across all QOPI-participating practices, and several areas were identified in which administration of oral chemotherapy could be improved. Our findings highlight the need for the development and implementation of appropriate standards that apply to oral chemotherapy and address the complexities that set it apart from parenteral treatment.

Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.

BACKGROUND: We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort. METHODS: This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070. FINDINGS: Between March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5-26·2). 11 (29·7% [95% CI 15·9-47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths. INTERPRETATION: Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted. FUNDING: Merck and the Yale Cancer Center.

EGFR mutation testing and treatment decisions in patients progressing on first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: The objective of this study was to investigate real-world EGFR mutation testing in patients with metastatic non-small cell lung cancer (NSCLC) upon progression on first-/second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI), and subsequent treatments received. METHODS: Flatiron Health electronic health records-derived database was used to identify adult patients with metastatic NSCLC treated with first-/second-generation EGFR-TKI from 11/2015-09/2017, with start of first EGFR-TKI defined as the index date. Patients were stratified by receipt of EGFR-TKI as first-line (1 L) or later-line (2 L+) treatment. Mutation testing and subsequent therapies following first-/second-generation EGFR-TKI were described. RESULTS: Overall, 782 patients (1 L = 435; 2 L+ =347) were included. Median age was 69.0 years, 63.6% were female, 56.3% were white, 87.1% were treated in community-based practices, and 30.1% of patients died during the study period; median follow-up was 309.0 days. Among the 294 (1 L = 160; 2L+ =134) patients who received subsequent therapies, treatments included chemotherapy only (1 L = 15.6%; 2L+ =21.6%), immunotherapy only (1 L = 13.8%; 2 L+ =41.0%), and targeted therapies (1 L = 70.0%; 2 L+ =36.6%). Specifically, 40 (25.0%) 1 L patients and 7 (5.2%) 2 L+ patients received osimertinib as subsequent therapy. Before the start of subsequent therapy, EGFR T790M resistance mutation testing was performed in 88 (29.9%) patients (1 L = 63 [39.4%]; 2 L+ =25 [18.7%]). Of these patients, 25 (28.4%) were T790M positive, among whom 24 (96.0%) received osimertinib. CONCLUSIONS: A third of patients received subsequent therapies on disease progression; only 30% of these were tested for EGFR-TKI resistance mutation, prior to receiving subsequent therapies. These results highlight the importance of choosing treatments in the 1 L setting that optimize benefits for patients with EGFR-mutated NSCLC.

Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non-Small Cell Lung Cancer in the Community Oncology Setting.

Importance: Broad-based genomic sequencing is being used more frequently for patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting. Objective: To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone. Design, Setting, and Participants: Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment. Exposures: Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment. Main Outcomes and Measures: Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received. Results: Among 5688 individuals with advanced NSCLC (median age, 67 years [interquartile range, 41-85], 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference -3.6% [95% CI, -18.4% to 11.1%]; P = .63). The results were consistent in the propensity score-matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73 to 1.11]; P = .40) vs unmatched cohort (hazard ratio, 0.69 [95% CI, 0.62 to 0.77]; log-rank P < .001). Conclusions and Relevance: Among patients with advanced non-small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

BACKGROUND: Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS: In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS: Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION: Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING: Merck and the Yale Cancer Center.

Big Decisions on Small Cell Lung Cancer: A Focus on Clinical Care Updates and Patient Perspectives.

Small cell lung cancer (SCLC) is an uncommon, aggressive high-grade neuroendocrine carcinoma, associated with tobacco use. It is a highly chemosensitive disease that initially responds quickly to systemic therapy, although patients with SCLC tend to develop relapse. Although the landscape of SCLC treatment has remained stagnant for many decades, the field has seen notable advances in the past few years, including the use of immunotherapy, the development of further lines of systemic therapy, the refinement of thoracic and intracranial radiotherapy, and-most recently-the promise of more targeted therapies. Patients with SCLC also must face unique psychosocial burdens in their experience with their cancer, distinct from patients with other lung cancer. In this article, we review the latest literature and future directions in the management and investigation of SCLC, as well as the critical decisions that providers and patients must navigate in the current landscape. We also present the perspectives of several patients with SCLC in conjunction with this summary, to spotlight their individual journeys in the context of this challenging disease.

Differential Effect of Consolidative Thoracic Radiation Therapy in Extensive-Stage Small Cell Lung Cancer Based on Sex.

Purpose: The landmark randomized trial on chest irradiation in extensive disease small cell lung cancer (CREST) demonstrated that consolidative thoracic radiation therapy (cTRT) improved overall (OS) and progression-free survival (PFS) after initial chemotherapy (chemo) in extensive-stage small cell lung cancer, with potentially increased benefit in women compared with men. It is unknown whether similar findings would apply after chemoimmunotherapy became the standard first-line treatment. In this analysis, we report national practice patterns and survival outcomes of cTRT according to patient sex. Methods and Materials: We included patients from de-identified electronic health record-derived database diagnosed with stage IV small cell lung cancer (2014-2021) who completed 4 to 6 cycles of first-line systemic therapy (platinum-doublet chemotherapy or chemoimmunotherapy). We evaluated OS and PFS using multivariable Cox proportional hazards regression with receipt of cTRT as an independent variable and stratified by sex. As a sensitivity analysis, we weighted the models by the inverse probability of receiving cTRT. Results: A total of 1227 patients were included (850 chemotherapy, 377 chemoimmunotherapy). There were no statistically significant differences in baseline characteristics between patients who did and did not receive cTRT. Among women, cTRT was associated with superior OS (adjusted hazard ratio [HR], 0.67; 95% CI, 0.52-0.87) and PFS (HR, 0.63; 95% CI, 0.49-0.82) compared with those not receiving cTRT. Conversely, no OS or PFS benefit with cTRT was observed in men (OS HR, 1.03; 95% CI, 0.80-1.31; PFS HR, 1.12; 95% CI, 0.85-1.47). Findings were similar in weighted analyses. Conclusions: The survival efficacy of cTRT may be moderated by sex, with female patients appearing more likely to benefit than male patients. These findings reflect sex-based survival trends with similar effect sizes to those observed in the CREST trial. Although the underpinnings of this association need to be elucidated, stratification by sex should be considered for randomized-controlled trials studying cTRT in extensive-stage small cell lung cancer.

A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6-Targeting Antibody-Drug Conjugate, in Patients With Small Cell Lung Cancer.

PURPOSE: Seizure-related homolog protein 6 (SEZ6) is a novel target expressed in small cell lung cancer (SCLC). ABBV-011, a SEZ6-targeted antibody conjugated to calicheamicin, was evaluated in a phase I study (NCT03639194) in patients with relapsed/refractory SCLC. We report initial outcomes of ABBV-011 monotherapy. PATIENTS AND METHODS: ABBV-011 was administered intravenously once every 3 weeks (Q3W) during dose escalation (0.3-2 mg/kg) and expansion. Patients with SEZ6-positive tumors (≥25% of tumor cells with ≥1+ staining intensity by immunohistochemistry) were preselected for expansion. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated. RESULTS: As of August 2022, 99 patients received ABBV-011 monotherapy (dose escalation, n=36; Japanese dose evaluation, n=3; dose expansion, n=60 [1 mg/kg, n=40]); median age was 63 years (range, 41-79). Thirty-two percent, 41%, and 26% of patients received 1, 2, and ≥3 prior therapies, respectively. The maximum tolerated dose was not reached through 2.0 mg/kg. Most common treatment-emergent adverse events (TEAEs) were fatigue (50%), nausea (42%), and thrombocytopenia (41%). Most common hepatic TEAEs were increased aspartate aminotransferase (22%), increased g-glutamyltransferase (21%), and hyperbilirubinemia (17%); 2 patients experienced veno-occlusive liver disease. Objective response rate (ORR) was 19% (19/98). In the 1-mg/kg dose-expansion cohort (n=40), ORR was 25%; median response duration was 4.2 months (95% CI, 2.6-6.7) and median progression-free survival was 3.5 months (95% CI, 1.5-4.2). CONCLUSIONS: ABBV-011 1.0 mg/kg Q3W monotherapy was well tolerated and demonstrated encouraging antitumor activity in heavily pretreated patients with relapsed/refractory SCLC. SEZ6 is a promising novel SCLC target and warrants further investigation.

Mediators of vascular remodelling co-opted for sequential steps in lung metastasis.

Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.

Associations of Early Completion of Advance Directives With Key End-of-Life Quality Measures: Analysis of an ASCO Quality Oncology Practice Initiative Patient Cohort.

PURPOSE: Despite the growing calls for early and ubiquitous completion of advance directives (ADs), studies exploring links between AD completion and their impact on outcomes of patients with cancer have mixed conclusions. We used the ASCO Quality Oncology Practice Initiative (QOPI) registry to compare end-of-life (EOL) quality measures and the effect of QOPI certification among patients with and without early AD completion, defined as completion within the first three oncology visits after cancer diagnosis. METHODS: Deidentified patient-level data were analyzed from the QOPI database from 2015 through 2017. Associations were assessed using Chi-square tests between early AD completion and patient enrollment in hospice < 7 days before death, chemotherapy receipt in the last 14 days of life, or with emergency room visits or intensive care unit admissions in the last 30 days of life. RESULTS: Data from 31,558 patients eligible for the AD question were analyzed. Patients treated at QOPI-certified practices had higher rates of early AD completion than patients at non-certified practices. Early AD completion was not associated with differences in hospice enrollment for < 7 days before death, chemotherapy receipt in the last 14 days of life, or emergency room visits or intensive care unit encounters in the last 30 days of life. CONCLUSION: The study found that QOPI certification is associated with higher rates of early AD completion. However, early AD completion was not associated with recognized EOL quality measures. Future research should focus on the timing, frequency, and content of AD conversations to demonstrate the impact on care at the EOL.

Pre-Treatment Staging Imaging in Rectal Cancer: Results From the Quality Oncology Practice Initiative.

PURPOSE: For patients with nonmetastatic rectal cancer, the National Comprehensive Cancer Network guidelines recommend initial staging using pelvic magnetic resonance imaging or endorectal ultrasound to determine the stage of the disease before initial therapy or surgery. This imaging workup helps determine the T and N staging, which is essential to determine optimal treatment for a patient. The current study examined practice concordance with this guideline using a quality measure in ASCO's Quality Oncology Practice Initiative (QOPI) that specifically addressed staging workup for patients with rectal cancer. METHODS: From Fall 2016 through Fall 2019, 103 QOPI-participating practices reported performance on QOPI measure Colorectal 78, which addresses staging workup for patients with rectal cancer. The percentage and 95% CI of patients who received guideline-concordant imaging were calculated for each of the seven assessment time points. Difference of concordance rates between subsequent time points and the initial time point was assessed using logistic regression with random-effects models. In addition, 69 practices that submitted data in 2016 and 2017 were surveyed to gain insight on potential reasons for nonconcordance and the results were described. RESULTS: At each time point, a total of 20-33 practices reported data across 1,158 unique patients. Adherence appeared to increase over time, with 38% of patients receiving guideline-recommended staging in Fall 2016, to 56% in Fall 2019. The practice survey revealed that nonconcordance was mostly because of lack of care coordination between oncology and surgery disciplines (n = 16 practices of 28, 57.1%) and a lack of awareness of appropriate staging scans (n = 8 practices, 28.6%). CONCLUSION: As one half to one third of patients still do not receive appropriate imaging, our findings highlight the need for concerted quality improvement efforts that involve the multidisciplinary team to close this gap.

Relationship Between Participation in ASCO's Quality Oncology Practice Initiative Program and American Board of Internal Medicine's Maintenance of Certification Program.

PURPOSE: Medical oncologists have a variety of options for demonstrating proficiency in providing high-quality patient care. Perhaps, the best-known opportunity for demonstrating individual expertise and lifelong learning is the American Board of Internal Medicine (ABIM) maintenance of certification (MOC) program. At the practice level, ASCO has offered the Quality Oncology Practice Initiative (QOPI) as a means of optimizing cancer care delivery. In this study, we assess the association between active involvement in MOC on an individual basis and whether that individual's practice is involved with the QOPI program. METHODS: We evaluated 13,600 US medical oncologists initially certified by the ABIM and divided them into those initially certified before 1990 (the year in which ABIM started to require periodic recertification), those from 1990 to 2007, and those from 2008 to 2016. It was then determined which of these had let their certificates expire by 2020. These data were then compared with practices that participated in QOPI from 2017 to 2019, resulting in the matching of 97% of physicians. RESULTS: Of individuals initially certified before 1990 (and technically with lifelong certification), 22% were in QOPI practices. Among those who did not have lifelong certification, there was an association between QOPI participation and maintenance of ABIM certification. For those initially certified between 1990 and 2007, 35% of oncologists with up-to-date ABIM certification were in QOPI practices, whereas only 11% with expired ABIM certification were QOPI participants (P < .0001). For those in the 2008-2016 category, the numbers were 36% v 16%, respectively (P < .0001). CONCLUSION: Our analysis identifies a relationship between participation in these ABIM and ASCO proficiency programs. The reasons for this are likely complex and based on a variety of institutional, professional, monetary, and personal factors.

Harnessing the Immune System to Tackle Small Cell Lung Cancer.

Immunotherapy has improved first-line therapy for small cell lung cancer and has activity in the relapsed setting as well. The immunobiology of small cell lung cancer poses challenges for immunotherapy, and efforts are underway to unlock to the potential of immunotherapy through the identification of meaningful disease subsets and the development of novel combination therapies.

Management of Pneumonitis and Neuropathy in Patients Receiving PD-1-Based Therapy for Non-Small-Cell Lung Cancer.

Immunotherapy with programmed cell death-1 (PD-1) receptor and programmed death ligand 1 (PD-L1) inhibitors has improved outcomes for certain patients with advanced lung cancer. As use of these therapies has expanded in first-line settings, in patients with different histologies, and in combinations with chemotherapeutic and targeted agents, more patients with lung cancer may benefit from these therapies. However, with expanded use comes greater potential exposure to the immune-related adverse events (irAEs) associated with these immune checkpoint inhibitors (ICIs). This article uses two case examples to illustrate the presentation, evaluation, and management of pulmonary and neurologic symptoms in two patients receiving PD-1-based therapy for non-small-cell lung cancer. These cases illustrate the challenges associated with recognizing pneumonitis and neuropathy in patients receiving ICIs for lung cancer. Although pneumonitis and neuropathy are relatively rare irAEs, they can have devastating or even fatal outcomes if not promptly recognized and managed appropriately. Specific use of guideline-based, multidisciplinary management is emphasized, as illustrated in the Immuno-Oncology Essentials Care Step Pathways.

Clinical Activity and Safety of Atezolizumab in a Phase 1 Study of Patients With Relapsed/Refractory Small-Cell Lung Cancer.

BACKGROUND: Programmed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study (NCT01375842) of atezolizumab, in a cohort of patients with relapsed/refractory SCLC. PATIENTS AND METHODS: Eligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed. RESULTS: Seventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS. CONCLUSION: Atezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC.

Randomized Phase II Study of Paclitaxel plus Alisertib versus Paclitaxel plus Placebo as Second-Line Therapy for SCLC: Primary and Correlative Biomarker Analyses.

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials.

Importance: The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti-PD-1 agents). However, little is known about how quickly anti-PD-1 agents agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials). Objectives: To assess the speed with which anti-PD-1 agents agents reached eligible patients in practice and to compare the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. Design, Setting, and Participants: This retrospective cohort study, performed from January 1, 2011, through August 31, 2016, included patients from the Flatiron Health Network who were eligible for anti-PD-1 agents treatment of selected cancer types, which included melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Main Outcomes and Measures: Cumulative proportions of eligible patients receiving anti-PD-1 agents treatment and their age distributions. Results: The study identified 3089 patients who were eligible for anti-PD-1 agents treatment (median age, 66 [interquartile range, 56-75] years for patients with melanoma, 66 [interquartile range, 58-72] years for patients with RCC, and 67 [interquartile range, 59-74] years for patients with NSCLC; 1742 male [56.4%] and 1347 [43.6%] female; 2066 [66.9%] white). Of these patients, 2123 (68.7%) received anti-PD-1 agents treatment, including 439 eligible patients with melanoma (79.1%), 1417 eligible patients with NSCLC (65.6%), and 267 eligible patients with RCC (71.2%). Within 4 months after FDA approval, greater than 60% of eligible patients in each cohort had received anti-PD-1 agents treatment. Overall, similar proportions of older and younger patients received anti-PD-1 agents treatment during the first 9 months after FDA approval. However, there were significant differences in age between clinical trial participants and patients receiving anti-PD-1 agents treatment in clinical practice, with more patients being older than 65 years in clinical practice (range, 327 of 1365 [60.6%] to 46 of 72 [63.9%]) than in pivotal clinical trials (range, 38 of 120 [31.7%] to 223 of 544 [41.0%]; all P < .001). Conclusions and Relevance: Anti-PD-1 agents rapidly reached patients in clinical practice, and patients treated in clinical practice differed significantly from patients treated in pivotal clinical trials. Future actions are needed to ensure that rapid adoption occurs on the basis of representative trial evidence.

Measuring the Impact of Academic Cancer Network Development on Clinical Integration, Quality of Care, and Patient Satisfaction.

PURPOSE: Many US academic centers have acquired community practices to expand their clinical care and research footprint. The objective of this assessment was to determine whether the acquisition and integration of community oncology practices by Yale/Smilow Cancer Hospital improved outcomes in quality of care, disease team integration, clinical trial accrual, and patient satisfaction at network practice sites. METHODS: We evaluated quality of care by testing the hypothesis that core Quality Oncology Practice Initiative measures at network sites that were acquired in 2012 were significantly different after their 2016 integration into the network. Clinical and research integration were measured using the number of tumor board case presentations and total accruals in clinical trials. We used Press-Ganey scores to measure patient satisfaction pre- and postintegration. RESULTS: Mean Quality Oncology Practice Initiative scores at Smilow Care Centers were significantly higher in 2016 than in 2012 for core measures related to improvement in tumor staging ( z = 1.33; P < .05), signed consent and documentation plans for antineoplastic treatment ( z = 2.69; P < .01; and z = 2.36; P < .05, respectively), and appropriately quantifying and addressing pain during office visits ( z = 2.95; P < .05; and z = 3.1; P < .01, respectively). A total of 493 cases were presented by care center physicians at the tumor board in 2017 compared with 45 presented in 2013. Compared with 2012, Smilow Care Center clinical trial accrual increased from 25 to 170 patients in 2017. Last, patient satisfaction has remained at greater than the 90th percentile pre- and postintegration. CONCLUSION: The process of integration facilitates the ability to standardize cancer practice and provides a platform for quality improvement.