Clinical Trial for Evaluating Efficacy and Safety of PDR001 in Concurrent Plus Consolidation Versus Consolidation Only in Addition to Standard Chemoradiotherapy in Unresectable Stage III NSCLC Patients (PASTURE)

2019 ◽  
Author(s):  
Keyword(s):  
Clinical Trial ◽  
Stage Iii ◽  
Efficacy And Safety ◽  
Unresectable Stage ◽  
Stage Iii Nsclc ◽  
Nsclc Patients

Thoracic radiotherapy PLUS durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy: Employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy—The TRADE-hypo trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS8585-TPS8585
Author(s):  
Farastuk Bozorgmehr ◽  
Jessica Juergens ◽  
Michaela Hammer-Hellmig ◽  
Christian Meyer Zum Bueschenfelde ◽  
Johannes Classen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Objective Response ◽  
Stage Iii ◽  
Hypofractionated Radiotherapy ◽  
Poor Performance Status ◽  
Thoracic Radiotherapy ◽  
Therapy Algorithm ◽  
Safety And Efficacy ◽  
Unresectable Stage ◽  
Stage Iii Nsclc

TPS8585 Background: Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide highlighting the importance of improving current therapeutic options. In particular, elderly and frail patients are not only underrepresented in clinical trials, but also frequently do not receive standard treatment regimens due to comorbidities. For example, patients with unresectable stage III NSCLC who are unfit for chemotherapy (CHT) do not benefit from the recent seminal therapy algorithm change for this disease, i.e. consolidation therapy with the immune checkpoint inhibitor (ICI) durvalumab after combined radiochemotherapy (RChT). Instead, these patients are treated with radiotherapy only, raising the serious concern of undertreatment. This issue is addressed by the TRADE-hypo clinical trial that investigates a novel therapy option for NSCLC stage III patients not capable of receiving CHT. To this end, thoracic radiotherapy (TRT) is administered together with durvalumab, employing the synergism created by the combination of restoring anti-tumor immune response by the ICI with the induction of immunogenicity by irradiation. The latter effect has been suggested to be further boosted by hypofractionated radiotherapy, which could also be more practicable for the patient. Taken these considerations into account, the TRADE-hypo trial addresses safety and efficacy of durvalumab therapy combined with either conventional or hypofractionated TRT. Methods: The TRADE-hypo trial is a prospective, randomized, open-label, multicentric phase II trial. Eligible patients are diagnosed with unresectable stage III NSCLC and not capable of receiving sequential RChT due to high vulnerability as reflected by a poor performance status (ECOG 2 or ECOG1 and CCI≥ 1) and/or high age (≥ 70)]. Two treatment groups are evaluated: Both receive durvalumab (1,5000 mg, Q4W) for up to 12 months. In the CON-group this is combined with conventionally fractionated TRT (30 x 2 Gy), while in the HYPO-group patients are treated with hypofractionated TRT (20 x 2.75 Gy). In the HYPO-arm, a safety stop-and-go lead-in phase precedes full enrollment. Here, patients are closely monitored with regard to toxicity (i.e., pneumonitis grade ≥ 3 within 8 weeks after TRT) in small cohorts of 6. The primary objective of the trial is safety and tolerability. As a primary efficacy endpoint, the objective response rate after 3 months will be evaluated. Further endpoints are additional parameters of safety and efficacy, as well as the comprehensive collection of biomaterials to be analyzed regarding treatment-induced changes and potential novel biomarkers. As of February 10, 2021, 9 patients of planned 88 patients have been enrolled in the TRADE-hypo trial. Clinical trial information: NCT04351256.

First subsequent treatment after discontinuation of durvalumab in unresectable, stage III NSCLC patients from PACIFIC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9054-9054 ◽  
Author(s):  
David Planchard ◽  
Byoung Chul Cho ◽  
Jhanelle Elaine Gray ◽  
Luis G. Paz-Ares ◽  
Mustafa Ozguroglu ◽  
...  
Keyword(s):  
Single Agent ◽  
Subsequent Treatment ◽  
Stage Iii ◽  
Smoking History ◽  
Molecular Profile ◽  
It Use ◽  
Unresectable Stage ◽  
Baseline Characteristics ◽  
Stage Iii Nsclc ◽  
Nsclc Patients

9054 Background: In the phase 3 PACIFIC trial of unresectable, stage III NSCLC patients (pts) without progression after concurrent chemoradiotherapy (cCRT), durvalumab (durva) significantly improved PFS and OS with similar safety compared to placebo (pbo). We performed exploratory analyses to characterize first subsequent treatment (Tx) after discontinuation of durva. Methods: Pts with WHO PS 0/1 and any tumor PD-L1 status were randomized (2:1) 1–42 days after ≥2 cycles of platinum-based cCRT to durva 10 mg/kg IV or pbo Q2W up to 12 months, stratified by age, sex and smoking history. Pts were classified by the use or not of first subsequent Tx and category of first systemic Tx (platinum doublet CT [PDCT], single-agent CT [SCT], immunotherapy [IT] or targeted therapy [TT]). Results: As of Mar 22, 2018, 216/476 (45.4%) and 153/237 (64.6%) in the durva and pbo arms, respectively, had a RECIST-based PFS event per BICR (5.7% and 8.4% due to death). 195 (41.0%) and 128 (54.0%) received first subsequent Tx, most of which were systemic Tx (158 [33.2%] and 109 [46.0%]): PDCT (16.4% and 19.0%), SCT (8.6% and 8.4%), IT (4.2% and 13.5%) or TT (3.8% and 5.1%); 7.8% and 8.0% received RT only. Time to first subsequent therapy or death (TFST) was longer with durva vs pbo (HR 0.58; 95% CI 0.47–0.72; median 21.0 vs 10.4 months). Baseline characteristics of pts with or without first subsequent Tx were similar, and similar across durva or pbo arms. Among pts with systemic Tx, baseline characteristics (including pre-cCRT PD-L1 status) were generally similar, except pts on TT, more of whom were EGFR+ (70.0% vs 0–6.6% of other systemic Tx groups) with commonly associated phenotypes (more females, Asians, non-smokers and non-squamous pts). Best overall response to first systemic Tx will be presented. Conclusions: Due to longer PFS and fewer progression events with durva vs pbo, fewer pts on durva required subsequent Tx and, per TFST, much later. With the exception of IT, use of each subsequent Tx was similar between the durva and pbo arms with PDCT the most common. Baseline characteristics were similar for pts with or without first subsequent Tx and pts who received first systemic Tx, except for pts who received TT, as expected due to their molecular profile.

Chemoradiation-induced pneumonitis in patients with unresectable stage III non-small cell lung cancer: A meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20532-e20532
Author(s):  
Christine Pierce ◽  
Yuting Kuang ◽  
Hsiu-Ching Chang ◽  
Arianna Nevo ◽  
Anne Deitz ◽  
...  
Keyword(s):  
Observational Studies ◽  
Meta Analysis ◽  
Stage Iii ◽  
Baseline Risk ◽  
Small Cell Lung ◽  
Unresectable Stage ◽  
Immune Mediated ◽  
Stage Iii Nsclc ◽  
Grade 3 ◽  
Nsclc Patients

e20532 Background: Recent clinical trials have shown positive results for therapies combining concurrent chemoradiation therapy (cCRT) and checkpoint immunotherapy in unresectable non-small cell lung cancer (NSCLC). cCRT is associated with an increased risk of pneumonitis, a severe and life-threatening inflammation of the lungs. To further inform clinical decision-making and support the evaluation of new therapies combining immunotherapies with cCRT, it is important to understand the baseline risk of pneumonitis associated with cCRT alone. The objective of this study was to quantify the incidence of cCRT-induced grade 3−5 pneumonitis (immune-mediated and radiation pneumonitis) in unresectable stage III NSCLC patients. Methods: A systematic literature review and meta-analysis were performed in accordance with PRISMA guidelines. MEDLINE, Embase, and the Cochrane Central Register were searched from 2014 to April 24, 2020. Chemotherapies of interest were cisplatin, pemetrexed, etoposide, carboplatin, and paclitaxel. Randomized controlled trials (RCTs), observational studies, and non-randomized trials were included. Bayesian meta-analysis using a binomial model random effects model was conducted with SAS 9.4. Results: Among 1,889 records identified from the search, 17 studies (6 RCTs, 8 observational studies, 3 single-arm trials) met inclusion criteria. Eleven studies were included in the meta-analysis (5 RCTs, 6 observational studies; 1,788 patients). All studies specified radiation-related pneumonitis (RP), although this is clinically indistinguishable from immune-mediated pneumonitis. Patient populations were comparable across studies; the most common chemotherapies were paclitaxel + carboplatin (n = 6) and pemetrexed + cisplatin (n = 5), and radiation doses ranged from 60–74 Gy. There was variation across studies in intervention, outcome reporting, and follow-up (median range: 12–73 months), but this variation was considered acceptable based on sensitivity analyses. The estimated pooled incidence of grade 3−5 RP in cCRT-treated unresectable stage III NSCLC patients was 3.62% [95% confidence interval (CI): 1.65−6.21] in RCTs and 5.98% [95% CI: 2.26−12.91] in observational studies. The pooled incidence of fatal (grade 5) RP was 0.37% [95% CI: 0−2.78] in RCTs and 1.73% [95% CI: 0.53−4.33] in observational studies. Conclusions: This study estimates that 3.62–5.98% of patients with unresectable stage III NSCLC develop grade 3−5 RP when treated with cCRT, with incidence varying by study design. Estimates of RP incidence were higher in the real-world setting compared to RCTs. These results can be used to contextualize the baseline risk of cCRT-induced pneumonitis in unresectable stage III NSCLC to better understand the adverse event of pneumonitis associated with novel immunotherapy treatments indicated for concomitant use with this modality.

Oncologist decision drivers in stage III non-small cell lung cancer: Outcomes of a web-based survey.

2019 ◽  
Vol 37 (27_suppl) ◽  
pp. 35-35
Author(s):  
Adam Yagui-Beltran ◽  
Kellie Ryan ◽  
Marnie L. Boron ◽  
Ion Cotarla ◽  
Daryl S. Spinner ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Decision ◽  
Small Cell ◽  
Stage Iii ◽  
Small Cell Lung ◽  
Web Based ◽  
Unresectable Stage ◽  
Stage Iii Nsclc ◽  
Nsclc Patients ◽  
To Receive

35 Background: Clinical guidelines seek to optimize patient care. We investigated how oncologists manage stage III non-small cell lung cancer (NSCLC) patients from diagnosis through treatment decision-making and drivers impacting guideline adherence. Methods: A sample of US medical oncologists (n=150) participated in a 38-question, 25-min web-based quantitative survey in January 2019. Participation required at least 3 yrs in practice and 3 stage III NSCLC patients treated in the prior 6-mo period. Results: Surveyed oncologists (82% community; 18% academic), on average, had 15 yrs of clinical experience and treated 20 stage III NSCLC patients in the prior 6 mos. Time from first treatment decision to initiation averaged >2–4 wks in 31% and >4 wks in 20% of patients, respectively. Oncologists recommend definitive concurrent chemoradiation therapy (cCRT) in 48% of unresectable stage III NSCLC patients. Reasons for not recommending cCRT include patient unlikely to tolerate cCRT (64% of oncologists), presence of a targetable mutation (41%), patient inability to travel consistently to receive treatment/inconvenient dosing (41%), and patient cost/affordability (34%). Eighteen percent of unresectable stage III NSCLC patients decline recommended cCRT. Fifty-five percent of patients who receive cCRT go on to receive consolidation immunotherapy (IO). Insurance challenges led to oncologists not recommending consolidation IO in 19% of patients. In the 85% of oncologists who conduct EGFR or PD-L1 testing, positive EGFR or negative PD-L1 tests are reasons for not recommending consolidation IO in 27% of patients (12% and 15%, respectively). Over half (55%) of unresectable stage III NSCLC patients who receive definitive cCRT also receive consolidation chemotherapy, which is no longer recommended in guidelines. Patients receiving consolidation CT were less likely to receive consolidation IO than the overall cohort of patients receiving cCRT (42% vs. 55%). Conclusions: Oncologists reported important variances in guidelines and standards of care related to the stage III NSCLC patient treatment journey. While some deviations from both are expected, there may be areas of focus for quality improvement initiatives.

scholarly journals Prognostic value of PD-L1 expression in patients with unresectable stage III non-small cell lung cancer treated with chemoradiotherapy

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Martina Vrankar ◽  
Izidor Kern ◽  
Karmen Stanic
Keyword(s):  
Prognostic Value ◽  
Performance Status ◽  
Immune Checkpoint Blockade ◽  
National Registry ◽  
Stage Iii ◽  
Clinicopathological Parameters ◽  
Unresectable Stage ◽  
Total Radiation Dose ◽  
Stage Iii Nsclc ◽  
Nsclc Patients

Abstract Background Expression of PD-L1 is the most investigated predictor of benefit from immune checkpoint blockade in advanced NSCLC but little is known about the association of PD-L1 expression and clinicopathological parameters of patients with unresectable stage III NSCLC. Methods National registry data was searched for medical records of consecutive inoperable stage III NSCLC patients treated with ChT and RT from January 2012 to December 2017. Totally 249 patients were identified that met inclusion criteria and of those 117 patients had sufficient tissue for PD-L1 immunohistochemical staining. Results Eighty patients (68.4%) expressed PD-L1 of ≥ 1% and 29.9% of more than 50%. Median PFS was 15.9 months in PD-L1 negative patients and 16.1 months in patients with PD-L1 expression ≥ 1% (p = 0.696). Median OS in PD-L1 negative patients was 29.9 months compared to 28.5 months in patients with PD-L1 expression ≥ % (p = 0.888). There was no difference in median OS in patients with high PD-L1 expression (≥ 50%) with 29.8 months compared to 29.9 months in those with low (1–49%) or no PD-L1 expression (p = 0.694). We found that patients who received a total dose of 60 Gy or more had significantly better median OS (32 months vs. 17.5 months, p < 0.001) as well as patients with PS 0 (33.2 vs. 20.3 months, p = 0.005). Conclusions In our patients PD-L1 expression had no prognostic value regarding PFS and OS. Patients with good performance status and those who received a total radiation dose of more than 60 Gy had significantly better mOS.

A phase II trial of consolidation nivolumab or nivolumab plus ipilimumab following concurrent chemoradiation in unresectable stage III NSCLC: BTCRC LUN16-081.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS179-TPS179 ◽  
Author(s):  
Greg Andrew Durm ◽  
Susan M. Perkins ◽  
Nasser H. Hanna
Keyword(s):  
Phase Ii ◽  
Stage Iv ◽  
Standard Of Care ◽  
Concurrent Chemoradiation ◽  
Stage Iii ◽  
Current Standard ◽  
Unresectable Stage ◽  
Secondary Endpoints ◽  
Stage Iii Nsclc ◽  
Nsclc Patients

TPS179 Background: Unresectable stage III NSCLC demonstrates poor 5-yr OS outcomes. The current standard of care for fit patients in this setting is concurrent chemoradiation. Previous studies evaluating the addition of induction or consolidation chemotherapy, EGFR-targeted agents, ant-angiogenic agents, and higher doses of radiation have failed to definitively improve OS over chemoradiation alone. Recently, a trial of consolidation PD-L1 inhibition demonstrated improved PFS over chemoradiation alone, and a second trial of consolidation PD-1 inhibition is awaiting data maturation. This may herald a change to the standard of care in this setting. The addition of CTLA-4 inhibition to anti-PD-1 monoclonal antibodies has shown improved OS in melanoma and has demonstrated encouraging early phase data in stage IV NSCLC. Therefore, we initiated a trial evaluating the addition of a CTLA-4 inhibitor to PD-1 inhibition for consolidation treatment of unresectable stage III NSCLC. Methods: This is a multi-center, randomized, phase II study of nivolumab or the combination of nivolumab and ipilimumab as consolidation therapy following concurrent chemoradiation in unresectable stage III NSCLC. Patients will receive concurrent chemoradiation with one of three standard chemotherapy backbones (Cis-Etop, Cis-Pem, or Carbo-Pac), and repeat imaging will be done 4-8 weeks following completion of therapy. Patients without progressive disease will be randomized 1:1 to receive either niv 480mg IV every 4 weeks or the combination of niv 3mg/kg IV every 2 weeks and ipi 1mg/kg IV every 6 weeks for up to 6 months. The trial will enroll a total of 108 patients with 54 in each arm. The two arms are non-comparator arms and will be compared with historical controls. The primary endpoint is the improvement of PFS at 18 months, and key secondary endpoints include OS and the toxicity of consolidation niv and niv/ipi. Exploratory endpoints will look at the correlation between multiple clinical, radiographic, and laboratory parameters and outcomes, as well as the association of these parameters with the development of pneumonitis. This trial opened to accrual in September 2017. Clinical trial information: NCT03285321.

Gemstone-301: A phase III clinical trial of CS1001 as consolidation therapy in subjects with locally advanced/unresectable (stage III) non-small cell lung cancer (NSCLC) who have not progressed after prior concurrent/sequential chemoradiotherapy (CRT).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS8572-TPS8572
Author(s):  
Yi-Long Wu ◽  
Ming Chen ◽  
Qing Zhou ◽  
Hao Li ◽  
Wenyi Sun ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Stage Iii ◽  
Transgenic Rat ◽  
Consolidation Therapy ◽  
Double Blind ◽  
Unresectable Stage ◽  
Stage Iii Nsclc

TPS8572 Background: In China, the standard of care for patients with unresectable Stage III NSCLC is platinum-based doublet chemotherapy given concurrently or sequentially with radiotherapy. However, the median progression-free survival (PFS) of those patients is poor (approximately 8-10 months) and 5-year overall survival (OS) rate is only 15%. Recently, treatment with durvalumab resulted in significantly longer PFS and OS than placebo for patients with locally advanced/unresectable NSCLC whose disease did not progress after definitive concurrent chemoradiotherapy (cCRT) in PACIFC trial. CS1001 is the first full-length, fully human programmed death ligand-1 (PD-L1) targeted immunoglobin G4 (IgG4, s228p) monoclonal antibody (mAb) developed by the OMT transgenic rat platform. The Phase Ia/Ib study (GEMSTONE-101, NCT03312842) demonstrated that CS1001 was well tolerated and had promising anti-tumor activities across a range of tumors including NSCLC. GEMSTONE-301 is a randomized, double-blind, Phase III study to compare the efficacy and safety of CS1001 versus placebo as consolidation therapy in Stage III unresectable NSCLC patients. This is the first Phase III trial on an anti-PD-(L)1 mAb initiated in China for this indication. Methods: In this trial, eligible patients with locally advanced/unresectable (Stage III) NSCLC who have not progressed after prior concurrent/sequential CRT are 2:1 randomized to receive CS1001 1200 mg, every 3 weeks or placebo, every 3 weeks. Stratification factors for randomization include ECOG status (0 versus 1), chemoradiotherapy (concurrent versus sequential) and total radiotherapy dose ( < 60 Gy versus ≥ 60 Gy). Study treatment will be given for up to 24 months or until disease progression, intolerable toxicity, consent withdrawal, or discontinuation for other reason. Tumor assessments will be performed every 9 weeks in the first year and every 12 weeks thereafter by RECIST v1.1. AEs will be monitored throughout the study and graded according to NCI-CTCAE v4.03. Primary endpoint is PFS evaluated by investigators according to RECIST v1.1. Secondary endpoints are PFS evaluated by Blinded Independent Center Review (BICR), objective response rate, OS, time to death/distant metastasis (TTDM), safety and pharmacokinetics (PK) profile. Enrollment is ongoing across sites in China and will continue until 402 patients are randomized. Clinical trial information: NCT03728556.

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