Phase II study of daily S-1 combined with weekly irinotecan in previously treated patients with advanced or recurrent squamous cell lung cancer: North Japan Lung Cancer Group 1101 (NJLCG1101)

Purpose This phase II study was designed to evaluate the ecacy and safety of S-1 combined with weekly irinotecan as second- or third-line treatment for patients with advanced or recurrent squamous cell lung cancer. Methods Patients received oral S-1 on days 1–14 at 80 mg/day for patients with a body surface area of < 1.25 m 2 , 100 mg/day for patients with a body surface area of 1.25–1.5 m 2 , and 120 mg/day for patients with a body surface area of > 1.5 m 2 and irinotecan (70 mg/m 2 ) on days 1 and 8 every 3 weeks. The primary endpoint was overall response rate, and the secondary endpoints were progression-free survival, overall survival, and the frequency and the degree of adverse effects. The trial was registered in the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000006065.


Introduction
Lung cancer is one of the leading causes of cancer-related death in Japan and worldwide (Sung et al. 2021). Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer and squamous cell carcinoma is the second most common subtype after adenocarcinoma. Squamous cell carcinoma accounts for 40% of male lung cancer and 15% of female lung cancer. S-1 is a novel oral uoropyrimidine agent that consists of tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate in a molar ratio of 1:0.4:1. Tegafur is a prodrug of 5-uorouracil (5-FU), whereas CDHP is an inhibitor of dihydropyrimidine dehydrogenase, the enzyme responsible for degradation of 5-FU. Compared with tegafur alone, tegafur plus CDHP increases 5-FU concentration in serum and tumor tissue. Potassium oxonate is expected to palliate the gastrointestinal toxicity of tegafur. S-1 is commonly used as treatment for gastrointestinal cancer, head and neck cancer, NSCLC, breast cancer, pancreatic cancer, and biliary tract cancer. In a phase II study of S-1 monotherapy in advanced NSCLC patients without prior chemotherapy, the overall response rate (ORR) was 22.0% (95% con dence interval [CI] 12.3-34.7%) and there were no irreversible, severe, or unexpected toxicity (Kawahara et al. 2001 (Okamoto et al. 2010). These ndings indicate that S-1 has good antitumor activity against NSCLC irrespective if given as monotherapy or combination therapy. It is also one of the good candidates for a non-platinum chemotherapy agent in patients with this disease.
Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I, which is used in the treatment of NSCLC and has different mechanism of antitumor activity from of S-1. Two randomized phase III trials of CPT-11 combined with cisplatin for advanced NSCLC showed comparable survival to cisplatin plus vindesine and concluded that a regimen containing CPT-11 is one of the most active and well tolerated for the treatment of advanced NSCLC (Negoro et al. 2003;Niho et al. 1999 It was suggested that thymidylate synthase (TS) expression levels in squamous cell carcinoma is higher than in adenocarcinoma, and high TS expression levels contributes to attenuation of antitumor effect. As a matter of fact, pemetrexed, which targets TS and exerts antitumor effects, should not be recommended for the treatment of squamous cell carcinoma because of the attenuation of antitumor effects (Scagliotti et al. 2009). S-1 also targets TS, however, it was suggested that there is no difference in e cacy between histological types when S-1 is combined with platinum (Yamamoto et al. 2010; Okamoto et al. 2010). For this reason, it was suggested that 5-FU has another mechanism involving RNA dysfunction by orotate phosphoribosyl transferase (OPRT) to uorouridine monophosphate (FUMP), and high OPRT level contributes to enhancement of antitumor effect for metastatic colorectal cancer (Ichikawa et al. 2003).
According to the investigation of OPRT levels in lung cancer, the OPRT level in squamous cell carcinoma was signi cantly higher than that in adenocarcinoma (Ishihama et al. 2009). Therefore, S-1 is considered to inhibit the RNA dysfunction pathway especially in squamous cell carcinoma. Furthermore, it was suggested that TS expression and topoisomerase I expression have positive correlation (Ichikawa et al. 1999), and TS expression is reduced by CPT-11 in a human colorectal cancer cell line in a preclinical model (Guichard et al. 1998). Based on these data, several studies on the combination of S-1 plus CPT-11 showed high e cacy and safety against advanced gastric and colorectal cancers (Narahara et al. 2011; Goto et al. 2006). These ndings led us to investigate the possibility of using CPT-11 combined with S-1 in patients with advanced NSCLC, especially squamous cell carcinoma. We previously reported the results of a Phase I study of daily S-1 combined with weekly CPT-11 in patients with advanced NSCLC. In this report, we found that the recommended dose (RD) of CPT-11 was 70 mg/m 2 (Ishimoto et al. 2009). In this study, we report the results of a Phase II study of daily S-1 (80mg/m 2 , days 1-14) combined with weekly CPT-11 (70 mg/m 2 days 1 and 8) in previously treated patients with advanced squamous cell carcinoma of lung. This study was registered at UMIN-CTR under the study ID UMIN000006065.

Patient eligibility
The main eligibility criteria were: (1) histologically or cytologically con rmed squamous cell lung cancer patients with a predominant squamous component or adenosquamous carcinoma with a predominant squamous component; (2) unresectable stage III disease without indication for curative irradiation, stage IV disease, or postoperative recurrence; (3) age more than 20 years old; (4) measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al. 2009); (5) previously treated with less than two regimens (including at least one platinum regimen, EGFR-TKIs are counted as one regimen, post operative chemotherapy is excluded); (6) radiologically con rmed progressive disease (PD) after previous treatments (four weeks or more after previous treatment, four weeks or more after chemoradiation for locally advanced squamous cell lung cancer, two weeks or more after palliative local radiation except at the primary lesion); (7) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; (8) adequate organ function de ned as absolute neutrophil count of 1500 ≧ mm 3 , platelet count ≧ 100,000mm 3 , hemoglobin ≧ 9.0g/dl, aspartate aminotransferase ≦ 2.5 × the institutional upper limit of the normal value, alanine aminotransferase ≦ 2.5 × the institutional upper limit of the normal value, total serum bilirubin ≦ 1.5 × the institutional upper limit of the normal value, creatinine ≦ 1.2mg/dl, creatinine clearance ≥ 60 mL/min, PaO 2 ≧ 60Torr or SpO 2 ≧ 94%; and (9) written informed consent.
The main exclusion criteria were: (1) evidence of interstitial pneumonia on chest radiography; (2) past history of hypersensitivity to drugs; (3) active double cancer; (4) pleural, peritoneal, and pericardial effusion requiring drainage; (5) serious complications (symptomatic cardiovascular disease, uncontrolled hypertension and diabetes, active infections); (6) symptomatic brain metastases; (7) previously treated with S-1, UFT, and CPT-11; (8) water diarrhea; (9) intestinal paralysis or intestinal obstruction; (10) treated with ucytosine; (11) treated with atazanavir sulfate; and (12) women who were pregnant, intending to become pregnant, or breast-feeding. The study protocol was approved by the institutional review board of each participating hospital and written informed consent was obtained from all patients prior to enrollment.

Treatment schedule
Every 21-day cycle, intravenous CPT-11 (70 mg/m 2 ) was administered on days 1 and 8, and oral S-1 was administered twice daily after a meal from days 1 to 14. The dose of S-1 was modi ed according to body surface area (BSA) as follows: 80 mg/day for patients with a BSA less than 1.25 m 2 , 100 mg/day for those with a BSA from 1.25 to 1.5 m 2 , and 120 mg/day for those with a BSA of more than 1.5 m 2 . The criteria for initiating the treatment cycle were provided, and cycle delays of up to three weeks were permitted. The criteria for giving CPT-11 on day 8 were provided and the administration of CPT-11 was skipped if the patient did not meet the criteria. The criteria for S-1 cessation and resumption were also provided. The dose reduction criteria were as follows. The dose of S-1 was reduced at rst dose reduction as follows: from 120 to 100 mg/day, from 100 to 80mg/day, and from 80 to 50 mg/day. The dose of CPT-11 was reduced at second dose reduction as follows: from 70 mg/m 2 to 60 mg/m 2 . Patients who required dose reduction received the reduced dose for the rest of the study. If a patient who required second dose reduction became eligible for further dose reduction, the patient was withdrawn from the study.

Assessment of Endpoints
The primary endpoint was investigator-assessed ORR, which was de ned as the proportion of con rmed complete response (CR) or a partial response (PR). Tumor response assessments were performed by using spiral computed tomography (CT) and evaluated using RECIST version 1.1 every four weeks from screening until PD was observed. After the discontinuation of treatment and the tumor response was con rmed as CR, PR, or stable disease (SD), CT was performed every eight weeks. The secondary endpoints were progression-free survival (PFS), OS, disease control rate (DCR), and toxicity. PFS was de ned as the time from randomization to disease progression according to RECIST version 1.1 or death due to any cause, whichever occurred rst. OS was de ned as the time from randomization to death due to any cause. The DCR was de ned as the proportion of occurrence of CR, PR, or SD according to RECIST version 1.1. The toxicities were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The investigators determined whether the toxicities were caused by the trial regimen.

Statistical Analysis
Several phase III studies on docetaxel and erlotinib with patients who were previously treated with platinum showed that the ORR was from 5.5-12.8%. Combination therapy containing CPT-11 given to patients who was previously treated with platinum showed that the ORR was from 10-20%. Based on these data, we assumed that an ORR of 20% in eligible patients indicates potential usefulness and an ORR of 5% is the lower limit of interest. Accordingly, the estimated accrual using the SWOG one arm binomial was 28 patients in each arm (one-sided alpha = 0.05; beta = 0.20). After allowing for dropouts, the accrual goal was determined to be 30 patients. The PFS and OS were estimated until 31 December 2019 by using the Kaplan-Meier method and were analyzed using the log-rank test. All statistical analyses were performed with EZR (Saitama Medical Centre, Jichi Medical University, Saitama, Japan).  Table 2). The median relative dose intensities were 83.3% (CPT-11) and 84.9% (S-1), respectively.

Safety
One patient was excluded due to a lack of data and 29 patients were included in the safety analysis.

Discussion
In the present study, we evaluated the e cacy and safety of CPT-11 plus S-1 in previously treated patients with advanced or recurrent squamous cell lung cancer. We obtained an ORR of 6.7%, while the median PFS and OS were 3.0 months and 10.5 months, respectively. To the best of our knowledge, there are two studies evaluating the e cacy and safety of CPT-11 plus S-1 in patients with previously treated advanced or recurrent NSCLC. Goya et al. reported that the ORR was 15.8% (90% CI 6.1-25.5) and the median PFS and OS were 4.5 months (95% CI 3.5-5.0) and 15.0 months (95% CI 9.5-20.6), respectively (2012).
Ikeumura et al. reported that the ORR was 6.5% (95% CI -2.6-15.5) and the median PFS and OS were 2.8 months (95% CI 2.3-3.4) and 12.6 months (95% CI 8.9-19.9), respectively (2015). In both studies, the dominant histological type was adenocarcinoma and a limited number of squamous cell lung cancer patients were included (15.8% and 22.6%, respectively). Therefore, our study is worthy of evaluating the e cacy and safety of CPT-11 plus S-1 particularly in patients with squamous cell lung cancer.
Although we planned that the CPT-11 will be given at a dose of 70 mg/m 2 on days 1 and 8 every 3 weeks (= 46.7 mg/m 2 /week) according to the result of the Phase I study of daily S-1 combined with weekly CPT-11 in patients with advanced NSCLC, the dominant histological type was adenocarcinoma and only one patient (7.7%) with squamous cell lung cancer was included in the study (Ishimoto et al. 2009). In the current study, the median relative dose intensity of CPT-11 was 83.3% and the actual dose intensity of CPT-11 was 38.9 mg/m 2 /week. The histological type and the discrepancy in the dose intensity of CPT-11 may have contributed to a lower ORR than what we expected.
The toxicity pro le of the adverse events was as expected. For instance, 6/29 (20.7%) patients experienced grade 3-4 leukopenia or neutropenia, which was consistent with previous studies with second-line treatment. In these studies, the rate of grade 3 or 4 neutropenia in patients treated with CPT-11 and S-1 combination was 9.7-17.9%. With respect to non-hematological toxicities, grade 3 or 4 diarrhea occurred in 2/29 (6.9%) patients, which seems to be within the acceptable range. One adverse event to note is that 5/29 (17.2%) experienced grade 3-4 anemia. Although no patient developed grade 4 anemia, we should keep in mind that anemia sometimes can be life threatening.
There are several limitations in this study. First, immunotherapy was introduced into clinical practice after this study and no patient was treated with immunotherapy as the initial therapy. Immune checkpoint inhibitors (ICI) monotherapy, ICI plus chemotherapy, and ICI combination therapy are standard treatment for advanced NSCLC these days. Therefore, our study does not re ect the situation of current advances in immunotherapy. Second, we had planned this study based on the hypothesis that the OPRT expression and TS expression of squamous cell carcinoma was different from that of adenocarcinoma, however, we did not evaluate the actual OPRT expression and TS expression of tumors.
In conclusion, CPT-11 plus S-1 does not surpass the results of the single agent regarding ORR. This combination could not be a candidate regimen for further phase III studies. On the other hand, the toxicity pro le was as expected, and this regimen might be considered if combination regimen of non-platinum agent were preferred because platinum-based regimen is sometimes toxic and intolerable. results of a west Japan oncology group study. J Clin Oncol 28:5240-5246  Figure 1 Kaplan-Meier analysis of progression-free survival Ticks indicate patients for whom data were censored on March 31, 2019 CI, con dence interval