Abstract
Background: Several pre-clinical and clinical studies suggest a potential predictive role of epidermal growth factor receptor (EGFR) mutation in responsiveness to cytotoxic chemotherapy. The aim of this phase II study was to evaluate the efficacy and safety of pemetrexed–carboplatin combination as first-line chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) limited to EGFR-wild-type cases. Patients and Methods: In this single-arm, multicenter clinical trial, patients received pemetrexed (500 mg/m2) and carboplatin (area under the curve=6) intravenously on day 1 every 3 weeks for three to six cycles. The objective response rate (ORR) was the primary end-point; secondary end-points included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: A total of 54 patients were enrolled and 53 patients received therapy. No complete response was observed and partial response was observed in 19 (35.8%) cases, resulting in an ORR of 35.8% [95% confidence interval (CI)=23.1-50.2%]. Stable disease was observed in 20 (37.7%) patients and therefore the DCR was 73.6% (95% CI=59.7-84.7%). The median PFS was 5.4 months (95% CI=4.1-6.8 months) and the median OS was 12.7 months (95% CI=9.3-16.1 months). Treatment-related grade 3 or 4 hematological toxicities were neutropenia, leukopenia, anemia and thrombocytopenia in 35.8%, 11.3%, 30.2%, and 32.1% of patients, respectively. No grade 3 febrile neutropenia was observed, and grade 3 or 4 non-hematological toxicities were mild. There was no treatment-related death. Conclusion: The pemetrexed–carboplatin combination was effective and well-tolerated in patients with EGFR-wild-type non-squamous NSCLC (UMIN-CTR number: UMIN000003393).
Lung cancer is the leading cause of cancer-related mortality in the world (1). In recent years, the discovery of epidermal growth factor receptor (EGFR) mutations in patients with non-small cell lung cancer (NSCLC) and their association with remarkable response to EGFR tyrosine kinase inhibitors have revolutionized the management of advanced NSCLC with EGFR mutation (2-8). Meanwhile, the prognosis of patients with EGFR-wild-type NSCLC still needs to be improved due to the limited number of treatment options. Therefore, the poor prognosis of patients with EGFR-wild-type NSCLC has prompted a search for new platinum-based combination regimens and new chemotherapeutic agents.
Pemetrexed is a multitargeted antifolate that inhibits three enzymes in the folate pathway involved in nucleotide synthesis: thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase (9). For chemo-naive patients with advanced non-squamous NSCLC, pemetrexed in combination with cisplatin or carboplatin have comparable efficacy and better tolerability when compared with other platinum-based doublet chemotherapy (10-14). With regard to platinum agents, carboplatin has been widely used in combination treatments as a substitute for cisplatin because of its more favorable toxicity profile and convenient administration in out-patient treatment settings.
Recently, several clinical studies have shown that patients with EGFR-wild-type NSCLC are generally less sensitive to cytotoxic chemotherapeutic agents, not only to EGFR tyrosine kinase inhibitors (4, 15-19). In a retrospective study, Wu et al. demonstrated that patients with EGFR-wild-type adenocarcinoma had a worse response rate and shorter progression-free survival (PFS) with pemetrexed than those with EGFR-mutant adenocarcinoma (19). These reports imply the necessity for examining treatment efficacy of combined therapy with pemetrexed and platinum agents in patients with EGFR-wild-type NSCLC. However, EGFR mutation status had not been confirmed in previous large phase III prospective studies on combined therapy with pemetrexed and carboplatin, and there are no specific prospective studies on this combination therapy limited to EGFR-wild-type non-squamous NSCLC (13-14, 20).
With this background, we conducted a phase II study assessing the efficacy and safety of this combination as first-line treatment only for patients with EGFR-wild-type non-squamous NSCLC.
Patients and Methods
Patient selection. The study protocol was approved by the Institutional Review Board of each institute. This trial is registered at UMIN-CTR (UMIN number: UMIN000003393). Key eligibility criteria were as follows: i) Histologically proven or cytological diagnosis of NSCLC that is defined as other than predominantly squamous cell histology; ii) no EGFR mutation (exon 18 G719X, exon 19 deletion, exon 21 L858R/L861Q or exon 20 T790M) diagnosed by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method (Mitsubishi Chemical Corporation, Japan); iii) stage IIIB or IV, or recurrent disease after surgery and was not a candidate for curative radiotherapy; iv) no prior chemotherapy (including those who had received postoperative chemotherapy); v) measurable lesion by response evaluation criteria in solid tumors (RECIST) version 1.1 (21); vi) age ≥20 and <75 years; vii) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; viii) adequate organ function; ix) anticipated survival of more than 3 months; x) signed informed consent from the patient. Key exclusion criteria were as follows: i) Active systemic infection; ii) fever (≥38.0°C); iii) serious comorbidity (cardiac disease, pulmonary fibrosis, interstitial lung disease, bleeding tendency, poorly controlled hypertension and diabetes mellitus etc.); iv) active double cancer; v) symptomatic brain metastasis; vi) poorly controlled body cavity fluid retention; vii) severe drug allergy; viii) pregnancy or lactation; ix) participation considered to be inappropriate by the attending doctor.
Patients' characteristics.
Tumor responses experienced by patients treated with first-line pemetrexed and carboplatin.
Study design and treatment. This study was a multicenter, open-label, phase II study of first-line pemetrexed and carboplatin for patients with EGFR-wild-type NSCLC. We recruited patients over the period from March 2009 to February 2012. Patients began taking oral folic acid supplements (0.5 mg/day) and intramuscular vitamin B12 injection (1000 mg once every 9 weeks) at least 1 week before the first dose and continued until 3 weeks after the last dose of pemetrexed. Pemetrexed at 500 mg/m2 was infused over 10 minutes, followed by a 60-minute infusion of carboplatin on day 1 at an area under the concentration–time curve (AUC) of 6.0 mg/ml×min calculated based on the Calvert formula. Each treatment cycle was repeated every 21 days for 3-6 cycles. Maintenance or second-line chemotherapy, radiotherapy or surgery was not permitted except on disease progression after study treatment completion.
Study endpoints. The primary endpoint of this study was the overall response rate (ORR). The tumor responses were evaluated according to RECIST 1.1 every two cycles during the protocol treatment and required confirmation at least 4 weeks after initial documentation. The secondary endpoints were the disease control rate (DCR), PFS, overall survival (OS), and toxicity. Stable disease (SD) was defined as disease control maintained for at least 6 weeks. Toxicity was evaluated in according with the National Cancer Institute's Common Toxicity Criteria for Adverse Events, version 3.0 (22).
Kaplan–Meier curves of progression-free (PFS) (A) and overall (OS) (B) survival for patients with epidermal growth factor receptor (EGFR)-wild-type non-squamous non-small cell lung cancer treated with pemetrexed plus carboplatin.
Statistical analysis. The primary objective of this study was to determine the ORR. According to the 23.5% of RR to carboplatin plus paclitaxel for patients with EGFR-wild-type NSCLC in the Iressa Pan-Asia study (IPASS) trial (4), achievement of an ORR of more than 30% was considered a result worthy of further development of this combination therapy, whereas an ORR of less than 15% was insufficient for further investigation. Simon's minimax phase II study design was used to permit early termination if preliminary results indicated minimal efficacy (23). The estimated power of this design is 80% with a type I error of 0.05. The planned accrual for this study was 48 assessable patients. An interim analysis was conducted after enrolment of the first 23 assessable patients. Assuming that about 10% of patients would not qualify, at least 53 patients were to be recruited. Statistical analyses were carried out using SPSS version 19.0 (IBM Corporation, Armonk, NY, USA).
Results
Patients' characteristics. Fifty-four patients were enrolled in this study from 13 institutes. One patient withdrew consent before study treatment, hence 53 patients received treatment according to the study protocol. Forty-one patients were male (77%), and the median age was 65.5 years (range=43-73 years). Forty-seven patients had adenocarcinoma (89%), three (6%) had large cell carcinoma, and three (6%) had tumor not otherwise specified. Twenty-six (49%) patients had an ECOG performance status of 0 (Table I).
Efficacy. Fifty-three patients received a median of four courses (range=1-6 courses) study treatment. The ORR was 36.0% (95% CI=23.1-50.2%), and the DCR was 73.6% (95% CI=59.7-84.7%) (Table II). The median PFS was 5.4 months (95% CI=4.1-6.8 months) and the median OS was 12.7 months (95% CI=9.3-16.1 months) (Figure 1).
Adverse events experienced by patients treated in this study with first-line pemetrexed and carboplatin (N=53).
Toxicity. Adverse events of all 53 patients who received treatment are listed in Table III. Hematological toxicities reaching grade 3 or higher were neutropenia (35.8%), thrombocytopenia (32.1%), anemia (30.2%), and leukopenia (11.3%). Nonhematological toxicities reaching grade 3 or higher were vomiting (11.3%), anorexia and infection (7.5%, respectively), nausea (5.6%), and fatigue (3.8%), constipation, skin rash, stomatitis, aspartate aminotransferase elevation, alanine aminotransferase elevation and creatinine elevation (1.9%, respectively). No treatment-related deaths were observed.
Discussion
To our knowledge, this is the first phase II study based on combination therapy with pemetrexed and carboplatin specifically dedicated to the management of patients with EGFR-wild-type advanced non-squamous NSCLC. In this study, the ORR was 36.0%, thus our study successfully met its primary end-point. With regard to additional efficacy results, the DCR of 73.6%, the median PFS of 5.4 months, and the median OS of 12.7 months are demonstrative of good efficacy. Importantly, the regimen exhibited an acceptable and manageable toxicity profile. These findings demonstrate that this combined therapy represents an effective doublet in first-line treatment of advanced EGFR-wild-type non-squamous NSCLC.
While comparisons of efficacy results between studies may be problematic, it is notable that our results compared favorably to those reported in previous large studies. In terms of efficacy, the tumor response in our study (ORR=36.0%) was in accordance with those derived from a randomized phase III trial of pemetrexed and carboplatin versus docetaxel plus carboplatin for non-squamous NSCLC (ORR=34.0%) (14). In addition, compared with the median PFS and the median OS in the trial (median PFS=5.8 months and median OS=14.9 months, respectively), there is comparable activity. Furthermore, efficacy results of our study seem not to be inferior to those of pemetrexed plus cisplatin. The results of planned sub-analysis of the phase III randomized trial comparing pemetrexed plus cisplatin with gemcitabine plus cisplatin for NSCLC histological subtype has been reported (10). The ORR, median PFS, and median OS of patients with non-squamous histology in the pemetrexed plus cisplatin arm were 28.9%, 5.26 months, and 11.0 months, respectively.
Overall, observed toxicities in the present study were tolerable and the frequency of severe toxicities was lower than that of the pemetrexed plus carboplatin arm in the aforementioned phase III study (14). The most prevalent hematological toxicity reaching grade 3 or 4 in that study was neutropenia (35%) (14). The incidence of grade 3 or 4 neutropenia (35.8%) in our study was similar, and no clinical problems, such as infection or febrile neutropenia, occurred because of neutropenia. With regard to non-hematological toxicities in our study, only grade 3 or 4 vomiting was the only toxicity encountered in >10% of patients throughout the study treatment. Furthermore, there was no treatment-related death either. These results indicate that the toxicities of combined therapy with pemetrexed plus carboplatin are acceptable in patients with EGFR-wild-type non-squamous NSCLC.
Recent reports have suggested differences in the responses to cytotoxic chemotherapy between patients with mutant and those with wild-type EGFR. The IPASS trial, which compared the efficacy of gefitinib and paclitaxel plus carboplatin as a first-line treatment, showed that the response to paclitaxel plus carboplatin of patients with EGFR mutation was higher than that of patients without EGFR mutation (47.3% vs. 23.5%) (4). The reason for this might be molecular aberrations other than EGFR mutation that might influence sensitivity to cytotoxic chemotherapy. EGFR-wild-type tumors are heterogeneous tumors with regard to driver mutations, such as KRAS mutation. KRAS and EGFR mutation are mutually exclusive, and KRAS mutation has been suggested to be a negative predictor of response to first-line platinum-based chemotherapy in patients with non-squamous EGFR-wild-type NSCLC (24). Further prospective clinical trials are warranted to investigate whether responses to cytotoxic chemotherapy in patients with EGFR-wild-type NSCLC might differ by molecular alteration.
In conclusion, the combination of pemetrexed plus carboplatin exhibited favorable efficacy and manageable toxicity profiles in patients with EGFR-wild-type non-squamous NSCLC. Therefore, this combined therapy is a candidate as standard treatment for EGFR-wild-type non-squamous NSCLC.
Footnotes
↵This article is freely accessible online.
Conflicts of Interest
Tomoki Kimura and Hiroyuki Taniguchi received honoraria from Eli Lilly Japan K.K.
- Received January 25, 2016.
- Revision received March 14, 2016.
- Accepted March 22, 2016.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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