Intercalated Dosing Schedule of Erlotinib and Docetaxel as a Therapeutic Strategy to Avoid Antagonism and Optimize Its Benefits in Advanced Non–Small-Cell Lung Cancer. A Randomized Phase II Clinical Trial

Juan, Óscar; Aparisi, Francisco; Sánchez-Hernández, Alfredo; Muñoz-Langa, José; Esquerdo, G.; García-Sánchez, José; López, Á.; Garde, J.; Giner, Vicente

doi:10.1016/j.cllc.2014.11.006

Cited by 13 publications

(6 citation statements)

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“…Recently, however, some phase II studies have shown potential benefits of EGFR TKI treatment combined with chemotherapy in patients harbouring sensitizing EGFR mutations [ 29 ], [ 30 ]. It is also noteworthy that studies investigating the potential benefits of pharmacodynamics separation using intercalated dosing schedules of EGFR TKIs in combination with platinum-based doublet chemotherapy have recently reported promising results [ 31 ]–[ 33 ]. This includes the results of the subgroup analysis of the FASTACT-2 study, which showed significantly longer PFS and OS in patients receiving the combination of gemcitabine and carboplatin with intercalated erlotinib compared to patients receiving chemotherapy alone [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

et al. 2016

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PurposeThis study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC).MethodsThis was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily.ResultsThe maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group.ConclusionsCombination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups.Trial RegistrationClinicalTrials.gov NCT00702182

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Section: Discussionmentioning

confidence: 99%

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

et al. 2016

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“…To our knowledge this is the first study to report a clinically relevant inferior outcome in the experimental arm by intercalating erlotinib with docetaxel over docetaxel as standard treatment in EGFR-WT patients with NSQ-NSCLC. Earlier phase II trials reported no significant differences in outcome in control and experimental arms [7][8][9]. These trials did not reveal a detrimental effect of the combination therapy.…”

Section: Adverse Events (Grade 3 And4)mentioning

confidence: 73%

“…One trial showed no additional effect of the combination therapy in 147 randomized patients [7]. On the other hand, another study reported improved PFS, OS and disease control rate in the combination arm in 68 randomized patients [8]. Another phase II study conducted in male patients with squamous NSCLC was ended prematurely and showed no improvement in PFS at 6 months [9].…”

Section: Discussionmentioning

confidence: 99%

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Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma

et al. 2021

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Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC). Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m 2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m 2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2-16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity. Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5-7.1) versus 1.9 months (95% CI 1.4-3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16-5.43). Corresponding median OS was 10.6 months (95% CI: 7.0-8.6) versus 4.7 months (95% CI: 3.2-8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46-9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia. Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice.

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“…To be more concrete: it comes as no surprise that intercalated treatment was superior to chemotherapy alone for a population which included a substantial proportion of EGFR-mutant patients; 26 , 29 , 30 , 34 , 37 , 39 , 42 and superior to TKIs alone for a population of predominantly EGFR-wt patients. 36 , 40 It is not the intercalated approach, but inclusion of an effective drug into the schedule which may be responsible for the positive experience in these trials. We believe that on the basis of randomized clinical trials published so far, the question of superiority of intercalated schedules over the standard treatment cannot be answered.…”

Section: Discussionmentioning

confidence: 99%

Selection of non-small cell lung cancer patients for intercalated chemotherapy and tyrosine kinase inhibitors

Zwitter

Rossi

Maïo

et al. 2017

Radiology and Oncology

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BackgroundWhen treating patients with advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors and chemotherapy, intercalated schedule with time separation between the two classes of drugs should avoid their mutual antagonism. In a survey of published trials, we focus on relation between eligibility criteria and effectiveness of intercalated treatment.MethodsPublished documents were identified using major medical databases, conference proceedings and references of published trials. Median progression-free survival (PFS) was taken as the basic parameter of treatment efficacy. Correlation between characteristics of patients and median PFS was assessed through the Pearson’s correlation coefficient and the coefficient of determination, separately for first-line and second-line setting.ResultsThe series includes 11 single-arm trials and 18 randomized phase II or phase III trials with a total of 2903 patients. Treatment-naive patients or those in progression after first-line treatment were included in 16 and 13 trials, respectively. In 14 trials, only patients with non-squamous histology were eligible. Proportion of patients with non-squamous carcinoma (in first-line setting), proportion of never-smokers (both in first- and second-line setting) and proportion of epidermal growth factor receptor (EGFR) mutant patients (both in first- and second-line setting) showed a moderate or strong correlation with median PFS. In six trials of intercalated treatment applied to treatment-naive EGFR-mutant patients, objective response was confirmed in 83.1% of cases and median PFS was 18.6 months.ConclusionsMost suitable candidates for intercalated treatment are treatment-naive patients with EGFR-mutant tumors, as determined from biopsy or liquid biopsy. For these patients, experience with intercalated treatment is most promising and randomized trials with comparison to the best standard treatment are warranted.

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Intercalated Dosing Schedule of Erlotinib and Docetaxel as a Therapeutic Strategy to Avoid Antagonism and Optimize Its Benefits in Advanced Non–Small-Cell Lung Cancer. A Randomized Phase II Clinical Trial

Cited by 13 publications

References 23 publications

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules

Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma

Selection of non-small cell lung cancer patients for intercalated chemotherapy and tyrosine kinase inhibitors

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