Non-small cell lung cancer (NSCLC) is the most common type of primary lung cancer. Recent laboratory research highlighted current treatment strategies, such as radiotherapy, immunotherapy, and traditional therapy (1). In the clinic, especially for non-oncogene-addicted advanced NSCLC patients without contraindications to immune checkpoint inhibitors (ICIs), chemotherapy in combination with immunotherapy has become the preferred first-line treatment strategy. However, most patients will develop resistance to ICI over time. To date, several combination therapies are under development to delay or manage the acquired resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming (2).

Thus far, conventional systemic chemotherapy alone or with antiangiogenic agents remains the mainstay treatment (3). To date, several options for second-line treatment are available, ranging from chemotherapy alone, in combination with an antiangiogenic agent, and immunotherapy. Docetaxel and pemetrexed are the most commonly used single agents. As a historical control, the response rate (RR) of docetaxel was approximately 10%, and the median progression-free survival (PFS) and overall survival (OS) were 2 to 4 months and 5.5 to 12.5 months, respectively (4–12). Since 2015, ICIs have become the preferred second-line option over docetaxel because of their significant improvement in OS, durable response, and better tolerability, with an ORR of 14% to 30%, a PFS of 2.3 to 4.0 months, and an OS of 9.2 to 13.8 months (7–10, 12, 13). However, the high cost of ICIs and low coverage of health insurance restrict ICI application in Chinese patients widely.

The roles of doublet chemotherapy in the second-line setting are still controversial. In one early meta-analysis (14), the combination arm showed a statistically significant improvement in ORR (15.1% vs. 7.3%) and PFS (14 weeks vs. 11.7 weeks), but no improvement difference in OS (37.3 weeks vs. 34.7 weeks) compared with single-agent therapy. However, most studies did not distinguish or categorize the patients by factors that might impact the potential benefit from the second-line combination chemotherapy. By contrast, platinum-based doublet chemotherapy was revealed to be the preferred second-line option over single-agent chemotherapy in clinical practice from two Chinese retrospective studies and conferred improved OS especially in patients with longer treatment-free interval (TFI) or time to progression from first-line chemotherapy (15, 16).

In East Asia, S-1 is another promising, well-tolerated, and cost-effective option in advanced NSCLC (17), which is a kind of oral compound anticancer drug composed of tegafur (FT), gimeracil (CDHP), and oteracil potassium (OXO). Furthermore, in comparison with pemetrexed, S-1 improved the synergistic therapeutic efficacy of anti-PD-1 antibodies by eliminating myeloid-derived suppressor cells and downregulating the expression of tumor-derived Bv8 and S100A8 (18). S-1 plus cisplatin or carboplatin demonstrated non-inferior OS as compared to paclitaxel or docetaxel plus platinum as first-line treatment in two randomized phase III trials (19, 20). Furthermore, S-1 was as effective as docetaxel in second-line therapy with less toxicity in the East Asia S-1 Trial in Lung Cancer (11). Several single-arm phase I/II trials evaluated the efficacy and safety of S-1 plus docetaxel or gemcitabine and had shown encouraging RR, OS, and non-overlapping toxicity profile (21–23). Data are still lacking about S-1 plus non-platinum doublet chemotherapy as a second-line option in Chinese advanced NSCLC patients. Therefore, we conducted a multicenter retrospective study to evaluate the efficacy and toxicity of S-1-based non-platinum combination chemotherapy in previously treated advanced NSCLC.

To our knowledge, this study was the first to explore the efficacy and safety of S-1-based non-platinum combination chemotherapy as a second-line treatment in non-oncogene-addicted advanced Chinese NSCLC patients. There were two major findings.

The first finding was that S-1-based non-platinum combination chemotherapy could be a promising second-line option. When compared with docetaxel as a historical control, as shown in Table 1 , this multicenter study provided encouraging benefit in response (22.89%), PFS (5.23 months), OS (14.40 months), and good tolerability. After adjustment by weight matching, there was still a dramatic improvement in PFS (7.90 months) and OS (19.37 months). The results of our study were consistent with most of the other Japanese cohort studies (21–23). The excellent ORR and PFS might be attributed to the combination of S-1 and docetaxel or gemcitabine and also S-1 maintenance. Furthermore, the median OS in patients who achieved response was significantly longer than those with stable disease or progression, which suggested the durable survival benefit from S-1-based doublet non-platinum chemotherapy once achieving response.

One exception was OLCSG trial 0503 (24), in which the single-agent docetaxel had a similar ORR and PFS, but an extraordinarily prolonged survival compared with docetaxel plus S-1 (22.9 months vs. 8.7 months). The much higher percentages of patients receiving poststudy EGFR TKI in the single docetaxel arm (42.9% vs. 16.7%) might contribute to this discrepancy. Poststudy treatment was very prevalent (81.82%) in our study, and nearly 30% of the patients received antiangiogenic treatment with bevacizumab, apatinib, or anlotinib. All of the above post-study drugs were considered to prolong the OS. In a recently published study (26), anlotinib plus S-1 as third- or later-line treatment showed very promising antitumor activity, with an ORR of 37.9%, a PFS of 5.8 months, and an OS of 16.7 months, supporting the use of S-1 and anlotinib either concomitantly or subsequently in the future. Also, in another prospective study (27), bevacizumab and S-1 combination chemotherapy showed high activity with an ORR of 28.3%, a PFS of 4.3 months, and an OS of 15.0 months, and tolerable toxicities.

The second finding was that TFST could predict the PFS benefit from S-1 doublet chemotherapy. The patients with a TFST of > 9 months had a much longer PFS (8.7 months) than those with a TFST of ≤ 9 months (5.0 months). In other words, TFST from first-line chemotherapy could distinguish the patients who might benefit the most from second-line therapy, which was confirmed in two previous Chinese retrospective studies (15, 16). Both a TFST of > 12 months and a TFI of > 6 months from first-line chemotherapy were independent predictive factors of favorable PFS and OS in advanced NSCLC patients who received platinum-based doublet chemotherapy in the second-line setting. With additional new drugs introduced into the first-line treatment in advanced NSCLC, especially CPIs (checkpoint inhibitors) and antiangiogenic agents, whether TFST from these new first-line combinations could predict the benefit of the subsequent treatment remains to be elucidated in the future.

Regarding safety, both hematological and non-hematological toxicity in our study were tolerable and could be well controlled through treatment interruption and/or symptomatic treatment and dose reduction. There were no treatment-related deaths. Common adverse events of S-1 with docetaxel or gemcitabine were anemia, nausea, and leukocytopenia. The most common grade 3/4 adverse event was neutropenia (14.94%). All the above toxicities were higher than those of docetaxel as a historical control (3–10), but consistent with the data of previous S-1 studies (11, 21–23).

New evidence showing that immunotherapy plus chemotherapy could substantially improve ORR, PFS, and OS when compared with immunotherapy (4) or chemotherapy (28, 29) alone has emerged. S-1 had been proven to have a synergistic effect with nivolumab in gastric cancer (30); thus, it can be expected that S-1 would be introduced to clinical trials of immunotherapy in advanced NSCLC in the future.

The present study had some limitations. First, our study is limited by its retrospective nature and patients’ heterogeneity. Selection bias could not be ignored, since patients who could not afford the cost of ICIs or refused the gene mutation analysis had more chances of receiving cytotoxic drugs as a second-line treatment. Second, during the study period, no patient received ICIs in the first-line setting; whether the efficacy of S-1-based doublet chemotherapy as second-line option could be generalized to those who failed immunotherapy needs to be explored. Actually, there may be no need to worry about it since subsequent S-1 or docetaxel after nivolumab was proved to be more effective than regimens without ICI pretreatment (31). Moreover, the high percentage of unknown driver mutation in our study precluded patients’ availability to targeted therapy. Indeed, in the NJLCG0804 trial (32), among NSCLC patients whose treatment with epidermal growth factor receptor tyrosine kinase inhibitors and platinum-based chemotherapy failed, S-1 and irinotecan combination therapy demonstrated high effectiveness; the ORR reached 52.0%, and PFS and OS were 5.0 and 17.1 months, respectively. Third, although we did not find a significant difference in survival benefit among patients from different centers, it should be noted that most patients in this study were from the sponsor’s cancer center, while platinum-based doublet chemotherapy as second-line option seemed to be more popular in other institutions from the same province (15).

In conclusion, S-1-based non-platinum combination had promising efficacy and manageable toxicity in advanced NSCLC patients who had failed platinum doublet chemotherapy, indicating a favorable second-line option.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Medical Ethics Association of Qilu Hospital of Shandong University (2015040). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Conception and design: JH and XWW; Administrative support: XWW; Provision of study materials or patients: TW, XLW, YC, JL, CY, XY, YW, TZ, FC, LQ, BY, HL, FD, SW, XBW, JH, and XWW; Collection and assembly of data: XLW, TW, and JH; Data analysis and interpretation: XLW, TW, and JH; Manuscript writing: All authors; All authors contributed to the article and approved the submitted version.