The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin ...and TRT followed by nonpemetrexed doublet consolidation therapy.
Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m(2) and cisplatin 50 mg/m(2) intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05.
Enrollment was stopped early because of futility. Five hundred ninety-eight patients were randomly assigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated. Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median, 26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P < .001), during the overall treatment period.
Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer.
To identify tumor-derived exosomal biomarkers that are able to discriminate between adenocarcinoma and squamous cell carcinoma (SCC) as a noninvasive method in the early diagnosis of non-small cell ...lung cancer (NSCLC).
Tumor-derived exosomes from the plasma of early-stage NSCLC patients were isolated. Exosomal miRNA profiling of 46 stage I NSCLC patients and 42 healthy individuals was performed using miRNA-seq to identify and validate adenocarcinoma- and SCC-specific miRNAs. The diagnostic accuracy of select miRNAs was tested further with an additional 60 individuals.
There were 11 and 6 miRNAs expressed at remarkably higher levels, 13 and 8 miRNAs expressed at lower levels in adenocarcinoma and SCC patients, respectively, compared with healthy volunteers. Distinct adenocarcinoma- and SCC-specific exosomal miRNAs were validated. The reliability of miRNA-seq data was verified with several demonstrated diagnostic potential miRNAs for NSCLC and other carcinomas, as reported in previous studies, such as let-7, miR-21, miR-24, and miR-486. The results indicated that miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p were adenocarcinoma-specific, and miR-10b-5p, miR-15b-5p, and miR-320b were SCC-specific. The diagnostic accuracy of three combination miRNA panels was evaluated using an AUC value of 0.899, 0.936, and 0.911 for detecting NSCLC, adenocarcinoma, and SCC, respectively.
Tumor-derived exosomal miRNAs, adenocarcinoma-specific miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p, and SCC-specific miR-10b-5p, miR-15b-5p, and miR-320b were observed by next-generation sequencing, and their diagnostic accuracy were verified. These miRNAs may be promising and effective candidates in the development of highly sensitive, noninvasive biomarkers for early NSCLC diagnosis.
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On December 19, 2014, the FDA approved olaparib capsules (Lynparza; AstraZeneca) for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ...ovarian cancer who have been treated with three or more prior lines of chemotherapy. The BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.) was approved concurrently. An international multicenter, single-arm trial enrolled 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy. Patients received olaparib at a dose of 400 mg by mouth twice daily until disease progression or unacceptable toxicity. The objective response rate (ORR) was 34% with median response duration of 7.9 months in this cohort. The most common adverse reactions (≥20%) in patients treated with olaparib were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/upper respiratory infection, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Myelodysplatic syndrome and/or acute myeloid leukemia occurred in 2% of the patients enrolled on this trial.
A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer ...(NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND).
This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0–2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov, NCT02357992.
Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9–5·8). Overall survival was 91% (95% CI 85–98) at 3 years and 87% (79–95) at 5 years. SABR was tolerated well, with no grade 4–5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85–98) at 3 years and 84% (76–93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 95% CI 0·45–1·65, p=0·65) from a multivariable analysis.
Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended.
Varian Medical Systems and US National Cancer Institute (National Institutes of Health).
The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local ...treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.
Several biomarkers of response to immune checkpoint inhibitors (ICI) show potential but are not yet scalable to the clinic. We developed a pipeline that integrates deep learning on histology ...specimens with clinical data to predict ICI response in advanced melanoma.
We used a training cohort from New York University (New York, NY) and a validation cohort from Vanderbilt University (Nashville, TN). We built a multivariable classifier that integrates neural network predictions with clinical data. A ROC curve was generated and the optimal threshold was used to stratify patients as high versus low risk for progression. Kaplan-Meier curves compared progression-free survival (PFS) between the groups. The classifier was validated on two slide scanners (Aperio AT2 and Leica SCN400).
The multivariable classifier predicted response with AUC 0.800 on images from the Aperio AT2 and AUC 0.805 on images from the Leica SCN400. The classifier accurately stratified patients into high versus low risk for disease progression. Vanderbilt patients classified as high risk for progression had significantly worse PFS than those classified as low risk (
= 0.02 for the Aperio AT2;
= 0.03 for the Leica SCN400).
Histology slides and patients' clinicodemographic characteristics are readily available through standard of care and have the potential to predict ICI treatment outcomes. With prospective validation, we believe our approach has potential for integration into clinical practice.
Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, ...11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4
macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3
T cells with high proportion of TIGIT
cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.
Purpose The safety and efficacy of pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), were assessed in patients with programmed death ligand 1 (PD-L1)-expressing ...extensive-stage small-cell lung cancer (SCLC) in the multicohort, phase Ib open-label KEYNOTE-028 study ( ClinicalTrials.gov identifier: NCT02054806). Methods Patients with SCLC received pembrolizumab 10 mg/kg every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. PD-L1 expression was assessed by immunohistochemistry. PD-L1-positive patients had membranous PD-L1 expression in ≥ 1% of tumor and associated inflammatory cells or positive staining in stroma. Response was assessed by investigator per Response Evaluation Criteria in Solid Tumors version 1.1 every 8 weeks for the first 6 months and every 12 weeks thereafter. Adverse events (AEs) were reported per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Primary end points were safety, tolerability, and objective response rate (ORR). Secondary end points included progression-free survival, overall survival, and duration of response. Results Twenty-four patients with PD-L1-expressing SCLC were enrolled and received at least one pembrolizumab dose. At the data cutoff date (June 20, 2016), the median follow-up duration was 9.8 months (range, 0.5 to 24 months). All 24 patients experienced AEs; the most common were asthenia (n = 7), fatigue (n = 7), and cough (n = 6). Two patients experienced grade 3 to 5 treatment-related AEs: one patient had elevated bilirubin, and one patient had asthenia, grade 5 colitis, and intestinal ischemia. One patient had a complete response, and seven patients had partial responses, resulting in an ORR of 33% (95% CI, 16% to 55%). Conclusion The safety of pembrolizumab was consistent with the known safety profile in other tumor types. Pembrolizumab demonstrated promising antitumor activity in patients with pretreated, PD-L1-expressing SCLC.
Programmed cell death receptor-1 (PD-1) inhibitors are frontline therapy in advanced melanoma. Severe immune-related adverse effects (irAEs) often require immunosuppressive treatment with ...glucocorticoids (GCCs), but GCC use and its correlation with patient survival outcomes during anti-PD-1 monotherapy remains unclear.
In this multicenter retrospective analysis, patients treated with anti-PD-1 monotherapy between 2009 and 2019 and detailed GCC use, data were identified from five independent cohorts, with median follow-up time of 206 weeks. IrAEs were tracked from the initiation of anti-PD-1 until disease progression, initiation of a new therapy, or last follow-up. Correlations between irAEs, GCC use, and survival outcomes were analyzed.
Of the entire cohort of 947 patients, 509 (54%) developed irAEs. In the MGH cohort irAE(+)
= 90, early-onset irAE (within 8 weeks of anti-PD-1 initiation) with high-dose GCC use (≥60-mg prednisone equivalent once a day) was independently associated with poorer post-irAE PFS/OS (progression-free survival/overall survival) post-irAE PFS: HR, 5.37; 95% confidence interval (CI), 2.10-13.70;
< 0.001; post-irAE OS: HR, 5.95; 95% CI, 2.20-16.09;
< 0.001 compared with irAEs without early high-dose GCC use. These findings were validated in the combined validation cohort irAE(+)
= 419, post-irAE PFS: HR, 1.69; 95% CI, 1.04-2.76;
= 0.04; post-irAE OS: HR, 1.97; 95% CI, 1.15-3.39;
= 0.01. Similar findings were also observed in the 26-week landmark analysis for post-irAE-PFS but not for post-irAE-OS. A sensitivity analysis using accumulated GCC exposure as the measurement achieved similar results.
Early high-dose GCC use was associated with poorer PFS and OS after irAE onset. Judicious use of GCC early during anti-PD-1 monotherapy should be considered. Further prospective randomized control clinical trials designed to explore alternative irAE management options are warranted.
OBJECTIVE:To improve the prognostic accuracy of the eighth edition of AJCC staging system for pNETs with establishment and validation of a new staging system.
BACKGROUND:Validation of the updated ...eighth AJCC staging system for pNETs has been limited and controversial.
METHODS:Data from the SEER registry (1975–2016) (n = 3303) and a multi-institutional database (2000-2016) (n = 825) was used as development and validation cohorts, respectively. A mTNM was proposed by maintaining the eighth AJCC T and M definitions, and the recently proposed N status as N0 (no LNM), N1 (1–3 LNM), and N2 (≥4 LNM), but adopting a new stage classification.
RESULTS:The eighth TNM staging system failed to stratify patients with stage I versus IIA, stage IIB versus IIIA, and overall stage I versus II relative to long-term OS in both database. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the SEER (5-year OS, stage I 87.0% vs stage II 80.3% vs stage III 72.9% vs stage IV 57.2%, all P < 0.001), and multi-institutional (5-year OS, stage I 97.6% vs stage II 82.7% vs stage III 78.4% vs stage IV 50.0%, all P < 0.05) datasets. On multivariable analysis, mTNM staging remained strongly associated with prognosis, as the hazard of death incrementally increased with each stage among patients in the 2 cohorts.
CONCLUSION:A mTNM pNETs clinical staging system using N0, N1, N2 nodal categories was better at stratifying patients relative to long-term OS than the eighth AJCC staging.
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