Abstract
Background/Aim: No standard treatment is currently recommended for advanced biliary tract cancer (BTC) after first-line therapy with gemcitabine plus cisplatin. We aimed to evaluate the efficacy and safety of a pemetrexed and erlotinib combination in patients with BTC previously treated with gemcitabine. Patients and Methods: This phase II, open-label, single-arm study enrolled patients with BTC who had previously failed gemcitabine-based first-line chemotherapy. Patients were treated with pemetrexed as a 500 mg/m2 intravenous infusion on day 1 for three weeks and erlotinib 100 mg daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR). Results: The study enrolled 20 patients with BTC, including 12 (60%) with intrahepatic cholangiocarcinoma (IHCC), 3 (15%) with extrahepatic cholangiocarcinoma (EHCC), and 5 (25%) with gallbladder cancer (GBC). The ORR was 5%, and the disease control rate (DCR) was 55%. As of the cutoff point of March 31, 2023, the median progression-free survival (PFS) was 2.3 months [95% confidence interval (CI)=0.00-4.74] and the median overall survival (OS) was 5.6 months (95%CI=2.28-8.87). Patients with EHCC showed longer PFS and OS compared to patients with IHCC or GBC, but the differences were not significant. A baseline CEA greater than the upper normal limit was the only significant prognostic factor for a worse OS rate. The only treatment-related adverse event (TRAE) with severity grade ≥3 was anemia (5%). Conclusion: Salvage chemotherapy with pemetrexed plus erlotinib was well-tolerated and showed marginal clinical activity in BTC patients after failure to gemcitabine-based chemotherapy.
Biliary tract cancer (BTC) is a heterogeneous group of hepatic and peri-hepatic tumours, including extrahepatic and intrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary cancer (1, 2). Although BTC is generally uncommon, incidence varies worldwide, with a relatively higher incidence in Asia and Latin America. In South Korea, BTC ranks sixth in cancer incidence and third in cancer-related deaths in men (3). BTC is frequently not diagnosed until an advanced stage, and the median survival for patients with advanced BTC receiving the standard of care chemotherapy, gemcitabine plus cisplatin (GimCis), was shown to be <1 year (4). Recently, durvalumab plus GemCis was demonstrated to significantly improve progression-free survival (PFS) and overall survival (OS) compared to GemCis in a Phase III TOPAZ-1 trial (5). To date, several treatment options using fluorouracil, leucovorin, oxaliplatin, and liposomal irinotecan as a second-line therapy have shown survival time extensions of two to three months for PFS and six to seven months for OS after progression to first-line gemcitabine-based therapy (6, 7).
Pemetrexed is an antifolate agent that acts on folate metabolism essential for cell proliferation and has been proven effective for use as a standard treatment in lung cancer, pleural mesothelioma, and intraperitoneal mesothelioma (8-10). With a favorable toxicity profile, pemetrexed is well tolerated by elderly patients or patients with a relatively poor systemic condition who have previously failed chemotherapy (11, 12). The only clinical study that has used pemetrexed in patients with BTC was a Phase I study conducted in combination with gemcitabine (13), and further studies in patients with BTC are needed.
Erlotinib is an orally active tyrosine-kinase inhibitor of epidermal growth factor receptor (EGFR), which has been associated with improved outcomes in various cancers, including non-small-cell lung cancer and pancreatic cancer (10, 14). Previously, we conducted a Phase III trial in patients with advanced BTC using gemcitabine and oxaliplatin plus erlotinib, and it was confirmed that the addition of erlotinib to chemotherapy did not improve the primary goal of PFS but led to a significantly better objective response rate compared to chemotherapy alone (15). In addition, the combined administration of pemetrexed and erlotinib was tolerable in a previous lung cancer study (16).
Herein, we aimed to evaluate pemetrexed plus erlotinib in patients with advanced BTC who failed to respond to previous gemcitabine-containing chemotherapy (NCT03110484).
Patients and Methods
Study design and participants. The study was a prospective, open-label, single-arm, Phase II trial carried out at Samsung Medical Center in Seoul, Republic of Korea. The eligibility criteria were as follows: 1) a histologically confirmed diagnosis of unresectable or recurrent BTC (intrahepatic cholangiocarcinoma, extrahepatic bile duct cancer, or gallbladder cancer); 2) prior failure of first-line chemotherapy containing gemcitabine; 3) at least 19 years of age; 4) at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; 5) adequate organ function per protocol; and 6) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 and life expectancy of 12 weeks or longer. Patients with active central nervous system metastasis or infection, any other malignancies, or clinically significant comorbidities were excluded. The trial protocol was approved by the Institutional Review Board (No.2020-06-111) at Samsung Medical Center (Seoul, Republic of Korea) and was conducted in accordance with the Declaration of Helsinki and Guidelines for Good Clinical Practice.
Treatment procedures. A 10-minute intravenous infusion of 500 mg/m2 pemetrexed was administered every three weeks, and 100 mg of erlotinib administered orally every day until further disease progression or unacceptable toxicity. Seven days before starting chemotherapy, premedication for pemetrexed was administered; every day, vitamin B12 1 mg was administered via intramuscular injection and folic acid 1 mg was administered orally. Computed tomography scan was performed every two cycles to evaluate the tumor response according to the RECIST 1.1 criteria. Toxicities were defined and graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
Outcomes. The primary endpoint was the overall response rate (ORR) as determined by the RECIST (version 1.1). The secondary endpoints were OS, PFS, and safety profile. The PFS was defined as the time from the start of treatment until the date of disease progression or death from any cause. The OS was measured from the start of treatment to the date of death from any cause. The response rate was calculated as the percentage of patients experiencing a confirmed complete response (CR) or partial response (PR). Toxicity was assessed according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines, version 5.0.
Statistical analysis. According to Fleming’s two-stage design, the required sample size was calculated using the hypothesis that the ORR would be >25% with 80% power and by discarding the hypothesis that the ORR would be <10% with 5% significance. In total, 38 patients were required for the sample with an accrual period of 12 months and a follow-up duration of 6 months from the time of the enrollment of the last patient. Considering a dropout rate of 10%, we aimed to enroll 42 patients. Descriptive statistics were reported as proportions and medians, while survival outcomes were estimated using the Kaplan-Meier method and compared using the long-rank test. Univariable and multivariable analyses were performed using the Cox proportional hazard model. A two-sided p-value <0.05 was considered statistically significant. All statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS) for Windows (version 27.0; SPSS, Inc., Chicago, IL, USA).
Results
Patient characteristics. Between July 2021 and December 2022, 21 patients were screened; 1 of these patients withdrew before starting the first treatment cycle, so the remaining 20 were successfully enrolled to receive pemetrexed plus erlotinib. Among the 20 patients enrolled in the first stage of this study, 15 (75%) were male and 5 (25%) were female. The mean (+/−SD) age was 61.5 years (+/− 9.67 years), and 7 patients (35%) were older than 65 years. Baseline characteristics are shown in Table I. Most of the patients had an ECOG performance status of 1 [19 (95%)], and 60% were diagnosed with IHCC, followed by GBCC (25%) and EHCC (15%). The most common sites of metastasis were the lymph node [16 (80%)] and liver [15 (75%)]. The median carbohydrate antigen (CA) 19-9 value was 50.7 units per ml (range=2.0-32,387.0 ml), while the median carcinoembryonic antigen (CEA) was 3.5 ng per ml (range=1.35-555.00 ml) at baseline.
Patient characteristics (N=20).
Efficacy outcomes. At the time of the data cutoff on March 31, 2023, the median follow-up duration was 7.8 months [95% confidence interval (CI)=2.4-13.2]; none of the participants remained on the treatment after that date. The confirmed ORR was 5%, with only one patient having a partial response (Figure 1). Ten (50%) patients had stable disease, with a disease control rate of 55% (Table II). Since the ORR was <10%, the study was terminated after completing the first stage of enrollment. The median PFS was 2.3 months (95%CI=0.0-4.7), and the median OS was 5.6 months (95%CI=2.3-8.9) (Figure 2). Among all participants, patients with EHCC had the longest survival [median PFS: 6.4 months (95%CI=0.0-14.9); median OS: 12.0 months (95%CI=0.0-26.8)]. There were no statistically significant differences in the PFS and OS between patients with IHCC and those with EHCC or GBC (Figure 2). Univariable analyses of PFS and OS were performed for all patients and the results are included in Table III. Multivariable analysis identified high serum CEA [≥upper normal limit (UNL)] as an independent prognostic factor for OS.
The change in tumor volume of target lesions. *The tumor diameter of this patient did not change over time. The dashed lines represent a 20% increase or a 30% decrease in tumor diameter.
Clinical activity of pemetrexed plus erlotinib in patients with advanced biliary tract cancer.
Kaplan-Meier survival curves of all patients. (A) Progression-free survival (PFS) and (B) overall survival (OS). Kaplan-Meier survival curves for (C) PFS, and (D) OS by subtype with intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC).
Univariable analysis for prognostic factors.
Safety. Treatment-related adverse events (TRAEs) that occurred in any patient are listed in Table IV. The only TRAE with a severity grade ≥3 was anemia (5%), and the most common TRAEs of any grade were fatigue (30%), skin rash (20%), acneiform eruption (20%), dyspepsia (30%), and anorexia (15%). There was no death from treatment-related causes during this study.
Treatment-related adverse events.
Discussion
This prospective, Phase II study assessed the efficacy of pemetrexed and erlotinib as a salvage therapy in metastatic BTC patients who had previously progressed despite gemcitabine-containing chemotherapy. In the present study, 1 of 20 patients achieved a PR, revealing an ORR of 5.0%, which did not meet the primary endpoint goal of ORR >25%. Therefore, our findings did not support the use of pemetrexed plus erlotinib as a salvage treatment for BTC patients, although these drugs’ toxicity profiles were well-tolerated.
Currently, various options for second-line treatment in metastatic BTC have been used. Fluorouracil and oxaliplatin (FOLFOX) demonstrated a superior OS to active symptom control in patients treated with first-line gemcitabine and cisplatin (6), and second-line treatment with fluorouracil and irinotecan (FOLFIRI) also provided some benefits to patients (17). A recently updated analysis of the NIFTY trial showed a significantly longer OS of 8.6 months for the liposomal irinotecan plus fluorouracil/leucovorin (FU/LV) treatment compared with 5.3 months for the FU/LV treatment alone (18). Compared with these results, the efficacy of pemetrexed and erlotinib as a second-line treatment in this study for metastatic BTC were insufficient. However, considering a disease control rate of 55% and low toxicity with this regimen, pemetrexed and erlotinib treatment might be considered a subsequent therapy after fluorouracil-based second-line treatment.
Visual inspection of the PFS and OS curves showed separation according to the subtypes of BTC. Patients with EHCC in particular had a prolonged median PFS of 6.4 months and a median OS of 12.0 months, while patients with GBC showed a poor outcome with a median PFS of 1.3 months and a median OS of 3.5 months compared to those with cholangiocarcinoma (CCA). The result was compatible with the finding that gallbladder cancer was associated with a shorter median survival duration and a shorter survival duration after recurrence than was hilar CCA (19). However, this was not a statistically significant difference, and it might have been affected by the small number of patients in this study.
There were 8 patients who developed grade 1 skin rash or acneiform eruption. Although skin rash has been reported as an important predictive marker for erlotinib treatment success (20), no significant difference in PFS or OS was observed based on the presence or absence of rash in this study. The median PFS and OS values for patients with a rash were 2.5 months and 10.4 months, respectively, compared to 1.3 months and 4.2 months in those with no rash (p=0.868 and p=0.138, respectively).
Regarding the prognostic factors for pemetrexed and erlotinib treatment, baseline serum CEA level >5.74 ng/ml was significantly associated with worse overall survival, and our findings were compatible with those of a previous study (21).
This study has several limitations. First, the study was underpowered because it contained a smaller sample size than planned. In addition, the study regimen using pemetrexed and erlotinib was outdated compared to the current salvage treatments for BTC. Currently, FOLFOX, FOLFIRI, and liposomal irinotecan plus FU/LV are more commonly used as a second-line treatment after progression following standard first-line gemcitabine-based chemotherapy. Pemetrexed and erlotinib combination therapy might be considered for patients with EHCC; however, the present study only included three EHCC patients, so our results should be interpreted with caution.
In conclusion, the combined pemetrexed and erlotinib regimen did not demonstrate any clinical evidence of improved RR in patients with advanced BTC who had been previously treated with gemcitabine. Pemetrexed plus erlotinib might be beneficial for patients diagnosed with EHCC, so further research with a larger sample size of this subset of patients is warranted. As the combination of immunotherapy and gemcitabine-based chemotherapy has become a standard first-line treatment for advanced BTC, further research is warranted to improve the efficacy of the sequential salvage treatment.
Footnotes
Authors’ Contributions
Conceptualization/design: Seung Tae Kim; Provision of study material or patients: Sung Hee Lim, Jung Yong Hong, Joon Oh Park Young Suk Park, Seung Tae Kim; Collection and/or assembly of data: Sung Hee Lim, Jung Yong Hong, Joon Oh Park Young Suk Park, Seung Tae Kim; Data analysis and interpretation: Sung Hee Lim, Seung Tae Kim; Manuscript writing: Sung Hee Lim, Seung Tae Kim; Final approval of manuscript: Sung Hee Lim, Jung Yong Hong, Joon Oh Park Young Suk Park, Seung Tae Kim.
Conflicts of Interest
All Authors declare that they have no conflicts of interest that might be relevant to the contents of this article.
- Received June 21, 2023.
- Revision received July 19, 2023.
- Accepted July 20, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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