Phase II Study of S-1 and Paclitaxel Combination Therapy in Patients with Previously Treated Non-Small Cell Lung Cancer.

LESSONS LEARNED: In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer.
BACKGROUND: Although monotherapy with cytotoxic agents, including docetaxel and pemetrexed, is recommended for patients with previously treated advanced non-small cell lung cancer (NSCLC), its outcomes are unsatisfactory. S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC.
METHODS: Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. Primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed.
CONCLUSION: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC. © AlphaMed Press; the data published online to support this summary are the property of the authors.

Discussion

Lung cancer is the leading cause of cancer deaths in the world. NSCLC accounts for approximately 85% of lung cancer cases. Treatment for advanced NSCLC is dramatically evolving owing to immune checkpoint inhibitors (ICIs) and molecular target drugs. Currently, ICIs are recommended in the standard initial treatments of advanced or recurrent lung cancer without driver oncogene mutations, as single agents and ICI‐platinum based combination chemotherapy [1], [2], [3]. When ICIs are used for primary treatment, cytotoxic anticancer drugs are options for second‐line treatment during recurrence. The role of cytotoxic anticancer drugs is still important. Docetaxel (DOC) and pemetrexed (PEM) are used as single agents in previously treated cases; combination treatment with ramucirumab is recommended for younger patients with good performance status (PS). However, this antiangiogenic agent is not suitable for some patients; the incidence of adverse events is sometimes higher with combination therapy [4]. Single‐agent DOC or PEM therapy is an option when angiogenesis inhibitors are unavailable, but the response rates for single‐agent therapy are low [5], [6]; therefore, new safe and effective therapies are much needed.

The ORR and disease control rates were 27.5% (95% confidence interval [CI], 14.6‐43.9) and 75.0% (95% CI, 58.8‐87.3), respectively.

Although nonplatinum combinations provide an alternative strategy, several randomized trials comparing single‐agent with doublet chemotherapy had insufficient power to detect potentially relevant differences in survival [7], [8].

We had previously conducted a phase I/II study of S‐1 and paclitaxel (PTX) combination therapy in previously untreated non‐small cell lung cancers among the elderly (≥70 years of age). In the phase II study at the recommended dose (RD; S‐1, 80 mg/m2; PTX, 80 mg/m2), the response and disease control rates were 53.3% and 93.3%, respectively, and the toxicities were mild [9], [10]. The present phase II study evaluated the efficacy and safety of S‐1 and PTX combination therapy after second‐line treatment in patients with previously treated NSCLC. These results warrant further evaluation of this combination in phase III trials.

Trial Information

Lung cancer – NSCLC

Metastatic/advanced

1 prior regimen

Phase II

Single arm

Overall response rate

Progression‐free survival

Overall survival

Safety

Active and should be pursued further

Drug Information

S‐1

Taiho Pharmaceutical Co., Ltd.

40, 50, and 60 mg/m2

p.o.

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

Paclitaxel

Bristol‐Myers Squibb

PTX was fixed as 80 mg/m2

IV

The RD of PTX, that is, 80 mg/m2, from the results of our phase I study was used. In each 21‐day cycle, 80 mg/m2 of PTX was administered on days 1 and 8.

Patient Characteristics

28

12

Presence of confirmed stage IIIB disease without any indications for radiotherapy or stage IV disease in patients who have experienced disease progression on at least one prior line of chemotherapy, including platinum‐based regimens

Median (range): 65 (35–83) years

0 — 14

1 — 21

2 — 5

3 —

Unknown —

Adenocarcinoma, 23; squamous cell carcinoma, 15; non‐small cell lung carcinoma, 2.

Primary Assessment Method

ORR

40

40

40

40

RECIST 1.1

n = 0 (0%)

n = 11 (27.5%)

n = 19 (47.5%)

n = 10 (25%)

n = 0 (0%)

6.5 months, CI: 3.2–8.5

20.7 months, CI: 8.1–25.0

Secondary Assessment Method

OS

40

40

40

40

20.7, CI: 8.1

Kaplan‐Meier plot. Overall survival (OS). The median survival time was 20.7 months (95% confidence interval, 8.1–25.0 months).

PFS

40

40

40

40

RECIST 1.1

6.5, CI: 3.2

Kaplan‐Meier plot. Progression‐free survival (PFS). The median PFS survival was 6.5 months (95% confidence interval, 3.2–8.5 months).

Adverse Events

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

Monotherapy with docetaxel (DOC) or pemetrexed (PEM) is recommended for the treatment of previously treated advanced non‐small cell lung cancer (NSCLC) cases. The results of the REVEL study demonstrated significantly prolonged progression‐free survival (PFS) with ramucirumab (RAM) compared with DOC alone [4]. A combination of DOC + RAM is currently recommended for treating younger patients with good performance status. However, RAM is often unsuitable for many patients, including those with hemoptysis, tumor vascular invasion, and postradiation therapy; adverse events such as neutropenia and febrile neutropenia (FN) may be difficult to manage. In cases unsuited for RAM therapy, single‐agent cytotoxic drugs are recommended. Controlled trials with DOC versus PEM [6] and DOC versus S‐1 [11] have been conducted to date, but none of the trials showed superiority, with response rates of around 8.3%–9.9%. Currently, there is no treatment that provides superior results to those of single‐agent DOC. A meta‐analysis of nonplatinum doublets reported that although the overall response rate (ORR) and PFS tended to be superior, overall survival (OS) was not improved; these doublets also demonstrated a higher incidence of adverse events [12].

In the present study combining S‐1 with paclitaxel, the ORR was 27. 5%, and the primary endpoint was met. This was more favorable than the response rates of single‐agent DOC or single‐agent S‐1, with confirmed noninferiority to single‐agent DOC [11]. The results also surpassed the response rate of DOC + RAM (23%) reported in the REVEL study. The study combination demonstrated a PFS of 6.5 months, which was better than the 4.5 months demonstrated by DOC + RAM. The OS was found to be 20.7 months, which possibly surpassed the results of the meta‐analysis [12].

In addition, this study found similar response rates in both nonsquamous and squamous cell carcinomas and may be effective in either histology. Angiogenesis inhibitors cannot be used in certain squamous cell carcinoma cases; squamous cell carcinomas had made up only 25% of the population in the REVEL study. We speculate that this study combination could be an effective treatment option, particularly for patients with previously treated squamous cell carcinomas.

In terms of safety, neutropenia above grade 3/4 was the most common with this combination, at 47.5%. In comparison, grade 3/4 neutropenia was reported in 49% of patients receiving DOC + RAM. FN was noted in 7% of this study cohort. This was less than that reported in the REVEL study (16%). The incidence of FN in the meta‐analysis of nonplatinum combination therapy was 7%, which was similar to our findings. Among nonhematologic toxicities, stomatitis and diarrhea tended to be more common compared with the results of other concomitant treatments. This could have been due to S‐1, but the incidence was higher than that reported with S‐1 alone [13] and with DOC + S‐1 combination therapy [14]. Conversely, in a report of a phase II study of S‐1 + PTX in gastric cancer, stomatitis of grade 3 or higher was reported in 28% [15]; caution should be exercised in interpreting these results as these mucosal lesions may have been increased owing to PTX. In this study, anticancer therapy could be continued with supportive treatment and was considered well tolerated. Also, when compared with our previous phase II study in older adults with similar tumors, neutropenia (47.5% vs. 52. 9%), FN (7% vs. 11. 8%), and stomatitis (5% vs. 23. 5%) were all lower in this study. These results demonstrate that this schedule and dose tailored for older adults was better tolerated by adults of all ages in this cohort, with similar efficacy. As a supplement, S‐1 is labelled for use in many European countries, and for head and neck cancer, colorectal cancer, and non‐small cell lung, breast, pancreatic, and biliary tract cancers in several countries in Asia [16]. It has not been approved by the U.S. Food and Drug Administration [16].

In conclusion, the results of this study met the criteria for the primary endpoint. Combination chemotherapy with S‐1 and PTX was found to be effective and well tolerated in patients with previously treated NSCLC. These results warrant further evaluation of this combination in phase III trials.