Thomassen described all (except finitely many) regular tilings of the torus
and the Klein bottle
into (3,6)-tilings, (4,4)-tilings and (6,3)-tilings. Many researchers made great e orts to investigate ...the crossing number of the Cartesian product of an
-cycle and an
-cycle, which is a special kind of (4,4)-tilings, either in the plane or in the projective plane. In this paper we study the crossing number of the hexagonal graph
(
≥ 2), which is a special kind of (3,6)-tilings, in the projective plane, and prove that
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Background In patients (pts) with non-metastatic NSCLC, surgery has curative potential but 30-80% who undergo resection experience recurrence. Neoadjuvant or adjuvant chemo is recommended ...for pts with high recurrence risk; however, benefits are modest and pathological complete response (pCR) with neoadjuvant chemo is low. Although immunotherapy targeting the PD-1 pathway has shown survival benefits in metastatic NSCLC, phase 3 trial results in resectable disease are yet to be reported. Recently, neoadjuvant NIVO, alone or in combination with chemo, has shown encouraging pCR rates in single-arm phase 2 studies. Here, we report the final analysis of one of the primary endpoints, pCR, of CheckMate 816 (NCT02998528)-a randomized, phase 3, open-label study evaluating NIVO + chemo vs chemo as neoadjuvant tx for resectable NSCLC.
Methods Adults with clinical stage IB (≥ 4 cm)-IIIA (per AJCC 7th ed), resectable NSCLC, ECOG PS 0-1, and no known EGFR/ALK alterations were randomized to either NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles, followed by surgery. Stratification was by disease stage (IB/II vs IIIA), PD-L1 (≥ 1% or < 1%), and sex. pCR by blinded independent pathological review (BIPR) and event-free survival by blinded independent central review (BICR) are the primary endpoints. pCR was defined as 0% viable tumor cells in resected lung and lymph nodes; pts who did not undergo surgery were counted as non-responders. Overall survival, major pathological response (MPR; ≤ 10% viable tumor in both lung and lymph nodes) per BIPR, and time to death or distant metastases are secondary endpoints. Key exploratory endpoints are objective response rate (ORR) per BICR and potential predictive biomarkers including PD-L1 and tumor mutational burden (TMB).
Results Baseline characteristics were balanced between arms (n = 179 each). Neoadjuvant NIVO + chemo significantly increased pCR rates vs chemo in the intent-to-treat population (ITT) (24.0% vs 2.2%; odds ratio 13.94 99% CI 3.49-55.75; P < 0.0001). Improvement in pCR with NIVO + chemo vs chemo was consistent across key subgroups including disease stage (IB/II 26.2% vs 4.8%; ≥ IIIA 23.0% vs 0.9%), PD-L1 (< 1% 16.7% vs 2.6%; ≥ 1% 32.6% vs 2.2%), and TMB (low 22.4% vs 1.9%; high 30.8% vs 2.7%). NIVO + chemo also improved MPR rates vs chemo in the ITT (36.9% vs 8.9%), as well as ORR (53.6% vs 37.4%) and radiographic down-staging rates (30.7% vs 23.5%). Definitive surgery occurred for 83.2% of pts treated with NIVO + chemo and 75.4% with chemo; surgery was cancelled rarely due to AEs (2 pts/arm) and due to disease progression in 12 and 17 pts, respectively. Grade 3-4 tx-related AEs and grade 3-4 surgery-related AEs were reported in 33.5% vs 36.9% and 11.4% vs 14.8% of pts in the NIVO + chemo vs chemo arms, respectively.
Conclusions CheckMate 816 met its first primary endpoint with a statistically significant improvement in pCR with neoadjuvant NIVO + chemo vs chemo alone per independent review. The safety profile of NIVO + chemo was consistent with the known profile of this combination regimen, and the addition of NIVO did not decrease the ability to perform surgery. CheckMate 816 is the first positive phase 3 trial demonstrating a significant improvement in pathologic response with neoadjuvant immunotherapy plus chemo in resectable NSCLC.
Citation Format: Patrick M. Forde, Jonathan Spicer, Shun Lu, Mariano Provencio, Tetsuya Mitsudomi, Mark M. Awad, Enriqueta Felip, Stephen Broderick, Julie Brahmer, Scott J. Swanson, Keith Kerr, Changli Wang, Gene B. Saylors, Fumihiro Tanaka, Hiroyuki Ito, Ke-Neng Chen, Cecile Dorange, Junliang Cai, Joseph Fiore, Nicholas Girard. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT003.
BackgroundWe explored whether the effectiveness of immune checkpoint inhibitors (ICIs) can be characterized by incorporating a composite of duration of response (DOR) to complement traditional ...Response Evaluation Criteria in Solid Tumors (RECIST) criteria for objective response rate (ORR) in an intent-to-treat (ITT) population. Furthermore, the correlation of this novel endpoint, characterized by the restricted mean time in response (RMTR), with overall survival (OS) will be examined.MethodsWe analyzed ORR alone or in combination with DOR (RMTR) in available phase I, II, and III trials evaluating nivolumab monotherapy or in combination with ipilimumab across solid tumor types. ORR was evaluated per RECIST V.1.1. DOR was estimated using individual patient data in ITT populations regardless of RECIST response, with non-responders imputed as zero. Associations between ORR alone or RMTR and OS were evaluated in the ITT population. DOR curves were generated using the Kaplan-Meier product limit method, and 6-month RMTR, a measure of response durability, was derived from the area under the curves. For ORR and RMTR in the ITT population, the strength of association with OS was analyzed using Pearson correlation coefficients (r).ResultsNivolumab treatment was associated with longer response durations than active control in responder and ITT populations. Similarly, ORR and RMTR were both significantly correlated with OS (ORR vs OS: r=0.684, p=0.02; RMTR vs OS: r=0.695, p=0.018).ConclusionsCombining ORR and DOR (RMTR) to objectively characterize tumor shrinkage in an ITT patient population is a novel approach that appears to correlate well with OS in patients treated with nivolumab monotherapy or in combination with ipilimumab. This endpoint may provide a more complete characterization of tumor shrinkage to incorporate into the design of future ICI clinical trials. However, confirmation of this approach will require further research.
BackgroundPathologic response assessment after neoadjuvant treatment is the potential analog to radiographic response for advanced disease, with regard to study design, clinical care, and accelerated ...regulatory approvals. A standardized system for assessing degree of pathologic response in the primary tumor (PT) and lymph nodes (LNs) as a survival surrogate is an unmet need. It is also a prerequisite for determining whether patients with versus without LN involvement benefit from neoadjuvant therapy. Here, in a pre-specified exploratory analysis from CheckMate 816, we report the first in-depth assessment of the full spectrum of percent residual viable tumor (RVT; beyond pathologic complete response) in both the PT and LNs and its association with event-free survival (EFS). This study represents the first prospective use of such a pan-tumor scoring system in a phase 3 registrational trial.MethodsPathologic response was prospectively assessed in the randomized phase 3 study of neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone in patients with resectable non-small cell lung carcinoma. Percentages of RVT, regression, and necrosis were quantified (0%-100%) in the PT and LNs using pan-tumor immune-related pathologic response criteria (irPRC). Pathologic features scored using this system were tested for association with EFS. An exploratory comparison between pathologic response, radiographic response, and circulating tumor DNA (ctDNA) clearance was performed.ResultsIn both treatment arms and regardless of pathologic evidence of LN involvement, EFS was improved in patients with 0% versus >0% RVT-PT (HR=0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (AUC=0.74); 2-year EFS rates were 90%, 60%, 57%, and 39% for patients with 0%-5%, >5%-30%, >30%-80%, and >80% RVT, respectively. Each 1% increase in RVT associated with a 0.017 increase in HR for EFS. Combining pathologic response from PT+LNs helped differentiate outcomes. An increase in%necrosis was not observed in paired pre- and on-treatment specimens in either treatment arm. Further, necrosis within the on-treatment specimens was associated with lower EFS rates, arguing against necrosis as a histologic feature of treatment effect. When pathologic response was compared to radiographic response and ctDNA clearance, pathologic response best approximated EFS.ConclusionsPercent RVT associates with improved EFS, supporting pathologic response as an emerging survival surrogate. Given the prognostic value of%RVT, its assessment using routine surgical pathology workflows, and a scoring system generalizable to any solid tumor type, it is also anticipated to become a biomarker for guiding subsequent adjuvant therapy. Further assessment of clinically-relevant%RVT cutoffs in PT+LN is warranted.AcknowledgementsFunding for this study was provided by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd.Trial RegistrationNCT02998528Ethics ApprovalThis study was approved by the Johns Hopkins University Institutional Review Board.
In this article, we provide some new results on the divisibility of certain coefficients of the chromatic polynomials of connected graphs, and characterize connected nonplanar graphs of order n that ...minimize the absolute values of coefficients of the chromatic polynomials. Moreover, we also present a sufficient condition that a graph is planar in term of certain coefficients of its chromatic polynomial.
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Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than ...without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.
In this paper it is provided that a functional equation for enumerating rooted nearly cubic planar maps with the valency of root-vertex, the size and the valency of root-face of the maps as three ...parameters. In particular, the number of rooted nearly cubic planar maps with the valency of root-vertex and the size as two parameters, as an answer to open problem in 1989, can be also derived.
Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with ...previously treated NSCLC.
CheckMate 078 was a randomized, open-label, phase III clinical trial in patients from China, Russia, and Singapore with squamous or nonsquamous NSCLC that had progressed during/after platinum-based doublet chemotherapy (ClinicalTrials.gov: NCT02613507). Patients with EGFR/ALK alterations were excluded. Patients (N = 504) were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), stratified by performance status, tumor histology, and tumor programmed death ligand 1 expression. The primary endpoint was overall survival (OS); secondary endpoints included objective response rate, progression-free survival, and safety.
OS was significantly improved with nivolumab (n = 338) versus docetaxel (n = 166); median OS (95% confidence interval): 12.0 (10.4–14.0) versus 9.6 (7.6–11.2) months, respectively; hazard ratio (97.7% confidence interval): 0.68 (0.52–0.90); p = 0.0006. Objective response rate was 17% with nivolumab versus 4% with docetaxel; median duration of response was not reached versus 5.3 months. Minimum follow-up was 8.8 months. The frequency of grade 3 or greater treatment-related adverse events was 10% with nivolumab and 48% with docetaxel.
This is the first phase III study in a predominantly Chinese population reporting results with a programmed death 1 inhibitor. In this population with previously treated advanced NSCLC, nivolumab improved OS versus docetaxel. Results were consistent with global CheckMate 017 and 057 studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nivolumab is the first anti–programmed death‐1 agent approved in China for treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC). Here, we characterize the population ...pharmacokinetics (PPK) of nivolumab monotherapy in Chinese patients with previously treated advanced/recurrent solid tumors, including NSCLC and nasopharyngeal cancer (NPC), using data from 2 predominantly Chinese (CheckMate 077 and 078), and 5 global (MDX1106‐01, CA209‐003, and CheckMate 017, 057, and 063) studies. The PPK model was developed by reestimating parameters of a prior global population model with Chinese patient data. Model reestimates showed nivolumab pharmacokinetics (PK) to be linear and dose proportional. Race did not have a clinically meaningful effect on nivolumab clearance. Body weight, Asian race, sex, and performance status had significant effects on clearance. Baseline clearance was 9% lower in the Asian versus the global population but not considered clinically relevant. Change in time‐varying clearance and predicted nivolumab exposures with 3 mg/kg every 2 weeks (Q2W) were similar in Chinese, non‐Chinese Asian, and non‐Asian patients. In Chinese patients, the predicted nivolumab exposure with a 240‐mg Q2W regimen was ∼25% higher than with 3 mg/kg Q2W, but ∼62% lower than that of a previously evaluated, well‐tolerated regimen of 10 mg/kg Q2W (global population). Differences in nivolumab baseline clearance and exposures between patients with NPC and NSCLC were not clinically meaningful (<20%). Overall, PPK analysis demonstrated that nivolumab was not sensitive to race when evaluated in Chinese and non‐Asian patients and exhibited similar PK in NSCLC and NPC.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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