Background. Both gefitinib and erlotinib are orally-administered reversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) used in the treatment for advanced non-small cell ...lung cancer (NSCLC). Erlotinib has a disease control rate of 30% for NSCLC which acquired resistance to gefitinib. However, it is not known whether erlotinib has any clinical benefit for patients who experienced disease progression with gefitinib. We previously reported the effectiveness of readministration of gefitinib in 24 patients with recurrent NSCLC who had already been treated with gefitinib. We considered that the effectiveness is mainly associated with the regrowth of EGFR-TKI sensitive cells during the TKI-free interval. We retrospectively examined 17 cases beginning treatment with erlotinib the next day after terminating gefitinib. There are no reports concerning only cases with no TKI-free interval. Materials and Methods. The study included advanced or recurrent NSCLC patients who had received one or more chemotherapy regimens and subsequent gefitinib monotherapy, or gefitinib as first line treatment. We started treatment with erlotinib the day after terminating gefitinib. We retrospectively examined 17 cases for responses and time to treatment failure. Results. Patients characteristics were as follows: female/male: 9/8; median age: 70 years (56-83); smoking status, never/former: 9/8; all cases were adenocarcinoma; positive/negative EGFR mutation was 14/3; stages and recurrence cases were IIIB/IV/recurrent: 2/9/6; the number of prior chemotherapy treatment were 0/1/2/3/4/5: 3/6/5/2/0/1. No patients obtained partial response, stable disease was observed in 9 patients, with improvement of multiple brain metastasis in 4 cases. The median times to treatment failure were 160 days (53-350). On the other hand, 7 of 8 cases having progressive disease with erlotinib had EGFR major mutation (exon 19 deletion or exon 21 L858R), good response with a long duration to prior gefitinib therapy. Conclusions. Erlotinib seems to be a potential therapeutic option for advanced NSCLC after gefitinib failure. In particular, a change to erlotinib may be beneficial for patients who do not have good response to gefitinib therapy or have central nerve lesions.
Introduction:
Anticancer therapy for disease recurrence in medically inoperable stage I lung adenocarcinoma patients receiving stereotactic body radiotherapy (SBRT) has not been previously reported. ...Gefitinib is tolerable and effective in patients with active epidermal growth factor receptor (EGFR) mutations who have an advanced age and/or a low performance status, but whether gefitinib improves the survival of such patients with disease recurrence after SBRT remains unclear.
Patients and methods:
We retrospectively evaluated overall survival after disease recurrence in patients with active EGFR mutations who received gefitinib (GEF group) and patients without active EGFR mutations who did not receive gefitinib (non-GEF group).
Results:
During a follow-up period with a median time of 36.0 months, disease recurrence occurred in 10 of 20 patients with medically inoperable stage I lung adenocarcinoma who received SBRT (2 cases with local tumor recurrence alone and 8 cases with lymph node and/or distant metastasis). The median age or the median Charlson comorbidity index score were 84 years and 2 in the GEF group (n=4) and 81 years and 2 in the non-GEF group (n=6), respectively. Two cases in the GEF group received chemotherapy after first-line gefitinib therapy. Two cases in the non-GEF group received chemotherapy, but the others received best supportive care alone. The median overall survival time from disease recurrence was significantly different between the 2 groups (27.3 vs. 3.6 mo,
P
=0.038). Two cases with grade 2 radiation pneumonitis did not have a recurrence of pneumonitis during gefitinib therapy.
Conclusions:
Gefitinib might be useful as a salvage therapy in patients who desire to continue anticancer treatment.
To evaluate the safety and efficacy of second-line chemotherapy with docetaxel and cisplatin for non-small cell lung cancer (NSCLC), we performed a phase II study.
The subjects were 25 patients with ...NSCLC, 75 years or younger, without organ dysfunction (performance status PS, 0 to 2) in whom treatment with cisplatin and irinotecan had been ineffective or had been followed by recurrence or relapse. Four weeks or more after the end of the previous therapy, 60 mg/m2 of cisplatin and 60 mg/m2 of docetaxel were administered at intervals of 3 weeks.
Observed toxicities of grade 3 or 4 included anemia (24% of patients), leukocytopenia (48%), neutropenia (76%), thrombocytopenia (4%), hepatic dysfunction (8%), and electrolyte abnormalities (4%). However, no severe nonhematologic adverse reactions occurred. The overall response rate was 32% (95% confidence interval, 13.7-50.3). The median time to disease progression was 98 days, and the median survival time was 257 days.
Our results suggest that cisplatin and docetaxel can be used as second-line chemotherapy against NSCLC. But further, comparative, study of this combination should be performed in patients with good PS and organ function who have responded to prior platinum-based chemotherapy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose: To evaluate the efficacy and toxicity of a novel combination treatment using concurrent radiotherapy with cisplatin plus
UFT, which is comprised of uracil and tegafur, in locally advanced ...non-small cell lung cancer (NSCLC) patients.
Experimental Design: In this Phase II trial, patients with unresectable stage III NSCLC were treated with the oral administration of UFT (400
mg/m 2 /d tegafur) on days 1–14 and days 29–42 whereas 80 mg/m 2 cisplatin was administered i.v. on days 8 and 36. Radiotherapy, with a total dose of 60 Gy, was delivered in 30 fractions
from day 1.
Results: Seventy patients were enrolled and eligible, as follows: 57 males/13 females; mean age 61 ranging from 36 to 74; performance
status 0/1:45/25; stage IIIA/IIIB, 14/56. A complete response was observed in two patients and a partial response in 54 patients,
and the overall response rate was 81% (95% confidence interval; 70–89%). The median survival, the 1- and 2-year survival rates
were 16.5 months, 67% and 33%, respectively. Grade 3/4 leukopenia occurred in 14%/1% of the patients. Grades 3 non-hematological
toxicities were only reported in three patients with nausea, two with esophagitis and one with pneumonitis whereas no grade
4 non-hematological toxicity was observed.
Conclusions: UFT plus cisplatin with concurrent radiotherapy is considered to be a feasible and effective treatment for locally advanced
NSCLC patients. Additional study of this concurrent chemoradiotherapy is warranted.
Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with ...oral erlotinib at a standard dose of 150mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C > T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.
Abstract
Introduction: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, a 150 mg daily dose of which has been shown to be effective for improving overall survival in ...non-small-cell lung cancer (NSCLC) patients who had failed at least 1 prior chemotherapy regimen. Furthermore, erlotinib demonstrated significant prolongation of progression-free survival versus standard chemotherapy in EGFR mutation positive NSCLC patients. However, skin rash and diarrhea often occurs, and these toxicities lead to discontinuation of therapy or dose reduction in many patients. Several population pharmacokinetics (PK) analyses have reported large interindividual variabilities in erlotinib blood exposure and its toxicities. However, none of those analyses clearly explains the determinants of these large interindividual variabilities. Here, aiming to develop a dose regimen that would maintain the clinical benefits of erlotinib while minimizing its adverse effects, we analyzed single nucleotide polymorphisms (SNPs) of PK-related genes and investigated the relationships between genotypes and interindividual variabilities in the PK and adverse effects.
Methods: We performed a multicenter study of 50 patients treated with 150 mg erlotinib as a second-line or later treatment. PK and toxicity were assessed. For PK analyses, blood samples were collected from 28 patients at 5 to 18 time points, and trough blood samples were collected from 20 patients at 1 time point. SNPs in genes encoding metabolizing enzymes or efflux transporters (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, GSTT1, ABCB1, and ABCG2) were analyzed. Population PK analyses were carried out using NONMEM. SNPs were tested as covariates in a population PK model. The effects of these SNPs and erlotinib exposure on toxicity were evaluated.
Results and Discussion: A 2-compartment model with first order absorption and linear elimination described the erlotinib PK. Only the ABCB1 1236C>T polymorphism was a statically significant covariate for CL/F, showing a 29.4% decrease in CL/F for the TT genotype as compared with the CC and the CT genotypes. The interindividual variability in CL/F decreased by 10.6% after inclusion of the TT genotype as a covariate in the model. This result indicates that a dose reduction to 100 mg for the TT genotype group could equalize the erlotinib exposure between each genotype group. A higher incidence of adverse effects (mainly diarrhea) was observed in the TT genotype group.
Conclusions: Of the 20 SNPs that are related to erlotinib PK, only ABCB1 1236C>T influenced the exposure of erlotinib. This SNP was suggested to be related to the risk of adverse events. Individual dosing based on ABCB1 genotype might reduce the adverse effects. Further clinical trials are needed to investigate the toxicity and the clinical outcome of this dose regimen.
Citation Format: Chihiro Endo-Tsukude, Ji-ichiro Sasaki, Sho Saeki, Norihiro Iwamoto, Megumi Inaba, Sunao Ushijima, Hiroto Kishi, Shinji Fujii, Hiroshi Semba, Kosuke Kashiwabara, Yukari Tsubata, Yuki Kai, Hideyuki Saito, Takeshi Isobe, Hirotsugu Kohrogi, Akinobu Hamada. Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5481. doi:10.1158/1538-7445.AM2015-5481
Background
Uridine 5′‐diphospho‐glucuronosyltransferase 1A1 (UGT1A1*27) is known to impair the effect of UGT in basic research; however, little clinical investigation has been conducted. To evaluate ...the effect of the UGT1A1*27 polymorphism in irinotecan therapy, we conducted a prospective study.
Methods
Eligibility criteria included: lung cancer patients; scheduled irinotecan therapy doses of single ≥ 80, combination ≥ 50, radiation with single ≥ 50, or radiation with combination ≥ 40 mg/m2; age ≥ 20; and Eastern Cooperative Oncology Group performance score (PS) 0–2. Patients were examined for UGT1A1*28 and *6 polymorphisms and received irinotecan. When the UGT1A1*28 polymorphism was detected, a search for UGT1A1*27 was conducted. Fifty patients were enrolled, with 48 patients determined eligible.
Results
UGT1A1 polymorphisms *28/*28, *6/*6, *28/*6, *28/−, *6/−, −/− observed 0 (0%), 1 (2%), 1 (2%), 7 (15%), 17 (35%) and 22 (46%), respectively. UGT1A1*27 were examined in nine patients including one ineligible patient; however, no polymorphisms were found. The study ceased after interim analysis. In an evaluation of the side effects of irinotecan, patients with UGT1A1*28 and UGT1A1*6 polymorphisms had a higher tendency to experience febrile neutropenia than wild type (25% and 32% vs. 14%). Incidences of grade 3/4 leukopenia and neutropenia were significantly higher in patients with UGT1A1*28 polymorphisms compared with wild type (75% vs. 32%, P = 0.049; 75% vs. 36%, P = 0.039, respectively).
Conclusion
Our prospective study did not locate the UGT1A1*27 polymorphism, suggesting that UGT1A1*27 does not significantly predict severe irinotecan toxicity in cancer patients.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We analyzed the association of ABCB1 polymorphisms with erlotinib-induced toxicity and the pharmacokinetics in patients with non-small-cell lung cancer.
After erlotinib 150 mg was administered to 50 ...patients, ABCB1 polymorphisms were analyzed via either TaqMan(®) assays or direct nucleotide sequencing. Plasma concentrations were measured by HPLC.
The trough concentration at steady state in patients with the ABCB1 1236TT-2677TT-3435TT genotype was higher compared with others groups (p = 0.021) and patients carrying this genotype had a higher risk of developing higher grade 2 toxicity (p = 0.012).
The present study suggested that the ABCB1 1236TT-2677TT-3435TT genotype was associated with higher plasma concentration and the risk of developing higher toxicity in patients treated with erlotinib.
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