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A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer.

ABSTRACT: Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer.This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status.Due to a low accrual rate in this study, the sample size (n = 50) was not reached. Sixteen patients were included in four centers, 50% had adenocarcinoma and 75% were male. Genomic alterations (7 patients studied) retrieved TP53 mutation in 2 patients and no EGFR mutation. Four weeks after radiotherapy, 3 patients (19%) had a partial response, 6 (38%) had a stable disease, and 7 had a progression (44%). Median overall survival was 11 months and median progression-free survival was 5 months. At the time of the last contact, 5 patients (31%) were still alive. Main toxicities were gastrointestinal (81%), cutaneous (81%), general (56%), and respiratory (50%). There were 12>G3 adverse events in 7 (47%) patients, and there was one toxic-death during the concomitant period due to an interstitial pneumonitis. There were two possible adverse events-related deaths during the chemotherapy period (pulmonary embolism (n = 1) and sudden death after the administration of the 3rd course of chemotherapy (n = 1)).The benefit of Gefitinib-RT could not be confirmed due to premature trial discontinuation. Further evaluation is required, especially in patients with EGFR mutated NSCLC.

SUBMITTER: Levy A

PROVIDER: S-EPMC5362534 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer.

Levy Antonin A Bardet Etienne E Lacas Benjamin B Pignon Jean-Pierre JP Adam Julien J Lacroix Ludovic L Artignan Xavier X Verrelle Pierre P Le Péchoux Cécile C

Oncotarget 20170201 9

<h4>Background</h4>Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer.<h4>Patients and methods</h4>This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status.<h4>Results</h4 ...[more]

PMID: 27764781

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Project description:PurposeTo study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM).MethodsIn this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and KRAS mutation status.ResultsFour hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% v 49.3%). Both groups received full chemotherapy dose intensity.ConclusionThe addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.

Project description:ImportanceUse of tyrosine kinase inhibitors (TKIs) is the standard therapy for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases. Several studies have shown that adding chemotherapy to EGFR-TKIs could improve progression-free survival (PFS) in patients with EGFR-mutant advanced NSCLC; however, the efficacy of these agents in patients with brain metastases remains unclear.ObjectiveTo investigate the efficacy and safety of gefitinib plus chemotherapy (pemetrexed with platinum) compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases.Design, setting, and participantsThis open-label prospective, multicenter, phase 3 randomized clinical trial was conducted in 6 centers in China from January 13, 2016, to August 27, 2021. The median follow-up time was 21.1 months (IQR, 13.5-31.8 months). Patients with untreated confirmed brain metastases and EGFR-sensitive mutated NSCLC were enrolled.InterventionsThe eligible patients were randomly assigned (1:1) to receive gefitinib plus chemotherapy or gefitinib alone.Main outcomes and measuresThe primary end point was intracranial PFS; secondary end points included PFS, overall survival (OS), intracranial objective response rate, overall objective response rate, and safety. Intention-to-treat analysis was performed.ResultsA total of 161 patients (87 [54.0%] women; mean [SD] age, 55 [9.8] years; range, 26-80 years) were enrolled and randomized to receive gefitinib (n = 81) or gefitinib plus chemotherapy (n = 80). The median intracranial PFS was 15.6 months (95% CI, 14.3-16.9 months) in the gefitinib plus chemotherapy group vs 9.1 months (95% CI, 8.0-10.2 months) in the gefitinib group (hazard ratio, 0.36; 95% CI, 0.25-0.53; P < .001). Similarly, the median PFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16.3; 95% CI, 14.4-18.2 months vs 9.5; 95% CI, 8.3-10.8 months; P < .001). Gefitinib plus chemotherapy had a better intracranial objective response rate (85.0%; 95% CI, 77.0%-93.0% vs 63.0%; 95% CI, 52.2%-73.7%; P = .002) and overall objective response rate (80.0%; 95% CI, 71.0%-89.0% vs 64.2%; 95% CI, 53.5%-74.9%; P = .03) than gefitinib alone. At data cutoff, the median OS was also significantly longer in the gefitinib plus chemotherapy group vs the gefitinib group (35.0 vs 28.9 months; hazard ratio, 0.65; 95% CI, 0.43-0.99; P = .04). Grade 3 or worse adverse events were more common with gefitinib plus chemotherapy, most of which were manageable.Conclusions and relevanceIn this randomized clinical trial, gefitinib plus chemotherapy significantly improved intracranial PFS, PFS, and OS compared with gefitinib alone in patients with untreated EGFR-mutant NSCLC brain metastases and could be an optional first-line treatment for these patients.Trial registrationClinicalTrials.gov Identifier: NCT01951469.

Project description:BackgroundPreoperative chemoradiotherapy (PCRT) followed by surgery and adjuvant chemotherapy is the current standard treatment for stage II/III rectal cancer. However, radiotherapy in the pelvic area is commonly associated with complications such as anastomotic leakage, sexual dysfunction, and fecal incontinence. Recently, the MERCURY study showed that preoperative high-resolution magnetic resonance imaging (MRI) helped to selectively avoid PCRT. It remains unclear whether PCRT is necessary in patients who can achieve a negative circumferential resection margin (CRM) with surgery alone and in patients with cT1-2N1 or cT3N0 without CRM involvement and lateral lymph node metastasis. This study aims to evaluate the efficacy of upfront radical surgery with total mesorectal excision (TME) followed by adjuvant chemotherapy with folinic acid (or leucovorin), fluorouracil, and oxaliplatin (FOLFOX) versus the current standard treatment in patients with surgically resectable, locally advanced rectal cancer.MethodsThis study, named TME-FOLFOX, is a prospective, open-label, multicenter, phase II randomized trial. Patients with locally advanced rectal cancer will be randomized to receive PCRT followed by TME and adjuvant chemotherapy (arm A) or upfront radical surgery with TME followed by adjuvant FOLFOX chemotherapy (arm B). Clinical stage II/III rectal cancer without CRM involvement and lateral lymph node metastasis will be defined using preoperative MRI. The primary endpoint is 3-year disease-free survival (DFS). Secondary endpoints include 5-year DFS, local recurrence rate, systemic recurrence rate, cost-effectiveness, and overall survival. We hypothesized that our experimental group (arm B) will have a 3-year DFS of 75% and a non-inferiority margin of 15%.DiscussionIdentifying whether patients require PCRT is one of the critical issues in locally advanced rectal cancer. This study aims to elucidate whether PCRT may not be required for all patients with stage II/III rectal cancer, especially for the MRI-based intermediate-risk group (with cT1-2N1 or cT3N0) without CRM involvement and lateral lymph node metastasis. If the findings indicate that our proposed treatment, which omits PCRT, is non-inferior to the standard treatment, then patients may avoid unnecessary radiation-related toxicity, have a shorter treatment duration, and save on medical costs.Trial registrationClinicalTrials.gov, NCT02167321. Registered on 19 June 2014.

Dataset Information

A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer.

Publications

A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer.

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