A Phase II Study of S‐1 and Paclitaxel Combination Therapy as a First‐Line Treatment in Elderly Patients with Advanced Non‐Small Cell Lung Cancer

Abstract

Lessons Learned.

• Coadministration of S‐1 and paclitaxel in elderly patients with advanced non‐small cell lung cancer showed favorable efficacy.

• Coadministration of S‐1 and paclitaxel in elderly patients with advanced non‐small lung cancer showed tolerable toxicity.

Background.

Although monotherapy with cytotoxic agents including docetaxel or vinorelbine are recommended for elderly patients with advanced non‐small cell lung cancer (NSCLC), the outcome is not satisfactory. We evaluated the efficacy and safety of S‐1 and paclitaxel (PTX) as a first‐line cotreatment in elderly patients with advanced NSCLC.

Methods.

Oral S‐1 was administered on days 1–14 every 3 weeks at 80, 100, and 120 mg per day for patients with body surface area < 1.25 m², 1.25–1.5 m², and > 1.5 m², respectively. PTX was administered at 80 mg/m² on days 1 and 8. The primary endpoint was response rate, and secondary endpoints were progression‐free survival (PFS), overall survival (OS), and safety.

Results.

Seventeen patients were enrolled with response and disease control rates of 47.1% and 88.2%, respectively. Median PFS and OS were 5.6 and 35.0 months, respectively. Hematological grade 3 or 4 toxicities included leukopenia (55.8%), neutropenia (52.9%), febrile neutropenia (11.8%), and anemia (11.8%). Nonhematological grade 3 toxicities included stomatitis (23.5%), diarrhea (5.9%), and interstitial lung disease (5.9%), and grade 5 toxicities included interstitial lung disease (5.9%).

Conclusion.

This S‐1 and PTX cotherapy dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.

Discussion

Coadministration of S‐1 and PTX is expected to be especially effective in patients with NSCLC with epidermal growth factor receptor (EGFR) mutations, and four such patients included in this study showed prolonged survival in a subgroup analysis with a median OS of 49.8 months. In a pooled analysis of elderly patients with EGFR mutations, the median OS was 30.8 months [1]. Thus, the OS in our study was much longer than that reported previously, although our findings were obtained in a small sample in a subgroup analysis. Previous studies reported an inverse relationship between thymidylate synthase expression and fluorouracil (5‐FU) sensitivity in colorectal and gastric cancers [2], and the thymidylate synthase expression in patients with NSCLC with EGFR mutations has been reported to be significantly lower than that in wild‐type cases [3]. Moreover, thymidine phosphorylase converts 5‐FU to its more active form, fluorodeoxyuridylate, and a correlation between the expression of thymidine phosphorylase and efficacy of 5‐FU‐based chemotherapy has been observed [4]. Because PTX upregulated the expression of thymidine phosphorylase mRNA in human gastric cancer xenografts [5], we hypothesized that the combination of S‐1 with PTX would provide good anticancer effects.

In conclusion, cotherapy with S‐1 and PTX for elderly patients with advanced NSCLC showed favorable efficacy and tolerable toxicity. The results of this study met the criteria for the primary endpoint, suggesting that this regimen could be a treatment option for those patients. However, further studies are needed to compare this regimen with conventional therapy for elderly patients with advanced NSCLC.

Trial Information

Disease

Lung cancer – NSCLC

Stage of Disease/Treatment

Metastatic/advanced

Prior Therapy

None

Type of Study – 1

Phase II

Type of Study – 2

Single arm

Primary Endpoint

Overall response rate

Secondary Endpoint

Progression‐free survival

Secondary Endpoint

Overall survival

Secondary Endpoint

Safety

Additional Details of Endpoints or Study Design

 

The sample size was calculated at an α error of 0.05 and β error of 0.2. The expected response rate and threshold response rate are determined to be 35% and 10%, respectively. The estimated minimum sample size was 16, and considering the potential patient dropout, we planned to enroll 18 patients.

 

Investigator's Analysis

Active and should be pursued further

Drug Information

Drug 1

 

 Generic/Working Name

S‐1

 Company Name

Taiho Pharmaceutical Co., Ltd.

 Dose

40, 50, and 60 milligrams (mg) per squared meter (m²)

 Route

Oral (p.o.)

 Schedule of Administration

S‐1 was administered twice daily from day 1 to day 14. The dose of S‐1 was calculated according to the patient's body surface area as follows: 40, 50, and 60 mg/m² S‐1 for body surface areas of <1.25, 1.25–1.50, and ≥ 1.50 m², respectively.

Drug 2

 

 Generic/Working Name

Paclitaxel

 Company Name

Bristol‐Myers Squibb

 Dose

PTX was fixed as 80 mg/m²

 Route

IV

 Schedule of Administration

PTX was fixed as 80 mg/m² on days 1 and 8

Patient Characteristics

Number of Patients, Male

13

Number of Patients, Female

4

Stage

IIIB or IV

Age

Median (range): 79 (range, 72–84) years

Number of Prior Systemic Therapies

Median (range): not collected

Performance Status: ECOG

0 — 9

1 — 8

2 — 0

3 — 0

Unknown —

Cancer Types or Histologic Subtypes

Adenocarcinoma, 8; squamous cell carcinoma, 5; non‐small cell lung carcinoma, 4.

Primary Assessment Method

Title

Total patient population

Number of Patients Enrolled

17

Number of Patients Evaluable for Toxicity

17

Number of Patients Evaluated for Efficacy

17

Evaluation Method

RECIST 1.1

Response Assessment – CR

n = 0 (0%)

Response Assessment – PR

n = 8 (47.1%)

Response Assessment – SD

n = 7 (41.2%)

Response Assessment – PD

n = 2 (11.8%)

(Median) Duration Assessments – PFS

5.6 months; 95% CI, 1.6–6.8

(Median) Duration Assessments – OS

35.0 months; 95% CI, 9.1–NR

Adverse Events

Adverse Events Legend

The grade 3 or higher adverse events were leukopenia (58.9%), neutropenia (52.9%), anemia (11.8%), febrile neutropenia (11.8%), stomatitis (23.5%), diarrhea (5.9%), and interstitial pneumonia (11.8%). The median number of cotherapy cycles with S‐1 and PTX cycles was 4 (range 2–4). Four cycles of combination chemotherapy were completed by 52.9% (9/17) of the patients. The main reason for discontinuation was prolonged neutropenia. Dose reduction was necessary in 35.3% (6/17) of the patients.

Abbreviation: NC/NA, no change from baseline/no adverse event.

Serious Adverse Events

Serious Adverse Events Legend

One patient who developed pneumonitis exhibited respiratory failure, and the chest computed tomography showed ground‐glass opacity after 22 days of the four‐cycle treatment. He died after 28 days of the four‐cycle treatment, although he discontinued all suspected drugs, including S‐1, and received pulsed methylprednisolone therapy. The relationship between this event and the combination therapy cannot be ruled out.

Assessment, Analysis, and Discussion

Completion

Study completed

Investigator's Assessment

Active and should be pursued further

Lung cancer is the leading cause of cancer‐related deaths worldwide, and the number of elderly patients with lung cancer is increasing [6]. Non‐small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, and nearly 50% of patients with NSCLC are aged ≥70 years [7]. Approximately 50% of patients with NSCLC show metastasis at diagnosis [8], and platinum doublet therapy is recommended for patients with advanced NSCLC with good performance status. However, although platinum doublet therapy is effective in some elderly patients, it may not show adequate efficacy in others because of an unfavorable side effect profile [9], [10].

For elderly patients with advanced NSCLC without driver oncogene mutation, monotherapy with cytotoxic agents such as docetaxel, vinorelbine, or gemcitabine (GEM) are recommended, but the efficacy of these regimens has not been satisfactory [11], [12], [13]. Therefore, these patients require a more effective and safe treatment approach. Although platinum‐based combination therapy has been shown to improve the overall response rate (ORR) and prolonged progression‐free survival (PFS) or overall survival (OS) more than monotherapy does, coadministration may be intolerable for elderly patients because of severe toxicities [9]. Therefore, for elderly patients, it is important to select drugs without platinum agents to obtain better effects with less toxicity.

S‐1 (Taiho Pharmaceutical Co., Ltd, Tokyo, Japan) is an oral fluorinated pyrimidine formulation composed of tegafur, 5‐chloro‐2,4‐dihydroxy‐pyridine, a reversible inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate. In a phase II study of elderly patients with advanced NSCLC, S‐1 monotherapy as a first‐line treatment was reported to be effective and well tolerated [14] with an ORR and median OS of 27.6% and 12.1 months and no grade 4 toxicity.

Paclitaxel (PTX; Bristol‐Myers Squibb, NY) is a microtubule‐stabilizing taxane drug. It enhances tubulin polymerization and inhibits spindle fiber function, resulting in inhibition of mitosis and cell division. Several phase II studies on the efficacy and safety of PTX monotherapy for elderly patients with advanced NSCLC have been reported, with ORRs of 23%–41.2% and median OS values of 9.8–10.3 months [15], [16]. However, for elderly patients with advanced NSCLC, the combination of carboplatin and PTX was not significantly superior to PTX monotherapy and also showed more toxicity than the monotherapy did [9].

The combination of S‐1 and PTX is expected to show a greater synergistic effect than that of either drug alone. Thymidine phosphorylase (TP) converts fluorouracil (5‐FU) to fluorodeoxyuridylate, the more active metabolite. The efficacy of 5‐FU‐based anticancer agents is correlated with the expression of TP mRNA [4]. The expression levels of TP mRNA were upregulated by PTX in human gastric cancer xenografts [17], and significant tumor reduction was observed with PTX in combination with S‐1 in a mouse model of human breast cancer [18]. Moreover, some clinical studies have already reported that the combination of S‐1 and PTX is effective and tolerable for the treatment of patients with advanced NSCLC [19] as well as advanced gastric cancer [20], [21], [22].

We previously reported the results of a phase I study of S‐1 and PTX coadministration for elderly patients with advanced NSCLC [23]. We determined that the recommended dose of S‐1 and PTX was 80 mg/m² during days 1–14 and days 1 and 8, respectively. In this study, we conducted a phase II study of S‐1 and PTX cotherapy for elderly patients with advanced NSCLC.

The results of this phase II study revealed that it met the criteria for the primary endpoint. The S‐1 and PTX cotherapy was the treatment option for elderly patients with advanced NSCLC.

Combination chemotherapy regimens, both platinum‐ and non‐platinum‐based, improve patient prognoses significantly compared with monotherapy [9], [24]. However, compared with non‐platinum‐based chemotherapy, platinum‐based chemotherapy shows severe toxicities in elderly patients [25]. Therefore, non‐platinum‐based combination chemotherapies are promising for the treatment of elderly patients. In fact, non‐platinum‐based cotherapy such as S‐1 plus GEM has been reported to be effective and well tolerated [26], [27].

Furthermore, previous studies have reported ORR, median PFS, and median OS of 27.0%–40.0%, 4.2– 6.4 months, and 12.9–17.8 months, respectively, in elderly patients who received cotherapy with S‐1 and GEM [26], [27], and these results were not superior to those of our study (Fig. 1). Therefore, cotherapy with S‐1 and PTX seemed to be effective and well tolerated. The results of this study indicate that it met the criteria for the primary endpoint of ORR. In this study, the patients received a combination of S‐1 and PTX and developed several adverse events, with hematological toxicities such as neutropenia occurring frequently. However, the rates of adverse events were similar to those with docetaxel monotherapy [28], which has been recommended for elderly patients with advanced NSCLC. Moreover, the reported grade 3 or 4 hematological toxicities in elderly patients who received a combination of S‐1 with GEM were leukopenia (27.0%–29.0%), neutropenia (24.0%–45.9%), and anemia (0%–13.5%) [26], [27]. These results were equivalent to the findings of our study, indicating mild toxicities with S‐1 and PTX cotherapy.

Figure 1.

Kaplan‐Meier plots. (A): Kaplan‐Meier estimation of progression‐free survival. (B): Kaplan‐Meier estimation of overall survival.

Abbreviations: CI, confidence interval; NR, not reached; PFS, progression‐free survival.

Coadministration of S‐1 and PTX is expected to be especially effective in patients with NSCLC with epidermal growth factor receptor (EGFR) mutations, and four such patients included in this study showed prolonged survival in a subgroup analysis with a median OS of 49.8 months. In a pooled analysis of elderly patients with EGFR mutations, the median OS was 30.8 months [1]. Thus, the OS in our study was much longer than that reported previously, although our findings were obtained for a small sample in a subgroup analysis.

Previous studies reported an inverse relationship between thymidylate synthase expression and 5‐FU sensitivity in colorectal and gastric cancers [2]. Thymidylate synthase expression in patients with NSCLC with EGFR mutations has been reported to be significantly lower than that in wild‐type cases, suggesting that tumors in these patients may show greater sensitivity [3]. Moreover, thymidine phosphorylase converts 5‐FU to its more active form, fluorodeoxyuridylate, and a correlation between the expression of thymidine phosphorylase and efficacy of 5‐FU‐based chemotherapy has been observed [4]. In several phase II studies, the S‐1 plus paclitaxel combination was effective and tolerated by patients with advanced gastric cancer [20], [21], [22], and a retrospective study by Aono et al. showed that S‐1 and paclitaxel combination therapy is effective for pretreated advanced NSCLC, with a response rate of 32.6% and median PFS of 253 days [19]. Because PTX upregulated the expression of thymidine phosphorylase mRNA in human gastric cancer xenografts [5], the combination of S‐1 with PTX would provide good anticancer effects.

In conclusion, coadministration of S‐1 and PTX for elderly patients with advanced NSCLC showed favorable efficacy and tolerable toxicity. The results of this study met the criteria for the primary endpoint, suggesting that this regimen could be a treatment option for those patients. However, further studies are needed to compare this regimen with conventional therapy for elderly patients with advanced NSCLC.

Table

Table 1. Baseline characteristics of patients (n = 17).

Abbreviations: EGFR, epidermal growth factor receptor; PS, performance status.

Disclosures

Junji Uchino: Eli Lilly Japan K.K. (RF); Koichi Takayama: Chugai‐Roche Co. and Ono Pharmaceutical Co. (RF), AstraZeneca, Chugai‐Roche Co., MSD‐Merck Co., Eli Lilly Co., Boehringer‐Ingelheim Co., Daiichi‐Sankyo Co. (H). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board