Cancer Chemotherapy and Pharmacology

, Volume 76, Issue 6, pp 1309–1314 | Cite as

Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer

  • Zheng Wu
  • Andrew Gabrielson
  • Jimmy J. Hwang
  • Michael J. Pishvaian
  • Louis M. Weiner
  • Tingting Zhuang
  • Lisa Ley
  • John L. Marshall
  • Aiwu Ruth He
Clinical Trial Report

Abstract

Purpose

Patients with metastatic, gemcitabine-refractory pancreatic cancer typically have poor survival. Erlotinib, a targeted therapy that inhibits epidermal growth factor receptor (EGFR) activity (overexpressed in 40–60 % of pancreatic cancers), was FDA approved for the treatment of patients with advanced pancreatic cancer. Human epidermal growth factor receptor 2 (HER-2), another member of the ErbB family of growth factor receptor tyrosine kinases, has also been a therapeutic target of interest in pancreatic cancer; HER-2 overexpression is found in 20 % of pancreatic cancers. Lapatinib is a tyrosine kinase inhibitor that binds to both EGFR and HER-2. We conducted a single-arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic, gemcitabine-refractory pancreatic cancer.

Methods

Seventeen patients with metastatic, unresectable pancreatic cancer whose disease had progressed on first-line gemcitabine-based therapy were selected for this study. Patients were required to have an adequate performance status (ECOG 0–2) and normal hepatic and renal function prior to being enrolled. Patients received lapatinib 1250 mg PO daily 1 h before or after meals, and capecitabine 1000 mg/m2 PO twice daily on days 1–14 of the 21-day cycle. The primary endpoint was median overall survival (OS), and the secondary endpoints were objective response rate, progression-free survival (PFS) and the safety profile of the combination therapy. Clinical toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. Radiographic response was evaluated by RECIST criteria.

Results

Clinically, six of the 17 patients treated had disease progression (PD) after two cycles, six of 17 patients had stable disease (SD) and received more than four cycles (SD, range 4–22 cycles). For all patients, median PFS was 2.6 months (95 % CI 1.3–3.8) and median OS was 5.2 months (95 % CI 3.4–9). Treatment-related toxicities were limited to three (17 %) patients developing grade 3 adverse events such as nausea, vomiting, diarrhea and fatigue. When stratifying patients by treatment response, we found a statistically significant difference in median PFS and OS: median PFS was 1.4 months (95 % CI 1.0–1.8) in the PD group versus 4.0 months (95 % CI 1.8–6.3) in the SD group (P value = 0.001). Median OS was 2.9 months (95 % CI 0–7.3) in the PD group versus 8.3 months (95 % CI 0–21.2) in the SD group (P value = 0.023).

Conclusions

The combination of lapatinib and capecitabine is a tolerable regimen for patients with gemcitabine-refractory pancreatic cancer; however, this observation is based on the small number of patients enrolled in the trial. A subset of the enrolled patients had clinical benefit from treatment. Predictive biomarkers that allow selection of patients that will respond to this regimen should be further investigated.

Keywords

Pancreatic cancer Lapatinib Capecitabine 

Introduction

Pancreatic cancer is the fourth leading cause of cancer-related death in the USA, and has the highest mortality rate of all major cancers [1]. Effective systemic therapy is the key to prolonging the survival of patients with advanced pancreatic cancer. Gemcitabine became the standard front-line therapy after a randomized trial showed modest improvement in the median OS and a better quality of life in patients treated with Gemcitabine when compared with 5-fluorouracil (5-FU) regimens [2]. Recently, two combination chemotherapies have shown improved treatment efficacy over gemcitabine treatment and replaced gemcitabine for first-line systemic chemotherapy for patients with advanced pancreatic cancer. One randomized phase III trial (MPACT) showed nab-paclitaxel plus gemcitabine improved OS in treatment-naïve patients compared with gemcitabine alone [3]; and another trial demonstrated that in patients with a good performance status, FOLFIRINOX resulted in an OS of 11.1 months compared to 6.8 months with gemcitabine alone [4], leading FOLFIRINOX to be the treatment of choice in these patients.

Additionally, the choice of second-line therapy after a patient’s pancreatic cancer failed gemcitabine-based chemotherapy has been limited and inconclusive. Oxaliplatin and 5-FU (OFF) were used in patients with gemcitabine-refractory pancreatic cancer, with an OS of 6.5 months compared to 3.3 months in 5-FU/FA (FF)-treated patients [5]. Single-agent capecitabine, a prodrug of 5-FU, as second-line therapy resulted in 2.2 month PFS and 7.5 month OS [6]. Different single-agent and combination chemotherapies have been tested in phase II studies in this population of patients. Median survival times ranged from 3.5 to 6.5 months, and objective response rates ranged from 3.8 to 24 % [7, 8, 9].

Taking previous, somewhat dismal, response data for patients with metastatic pancreatic cancer, it is of utmost importance to find innovative combinatorial therapies and identify patients who obtain the most benefit from currently available therapies if we are going to make any headway in the treatment of this disease.

Increased expression of the first-noted member of the ErbB family, EGFR, and its ligand have been detected in 40–60 % of human pancreatic cancers [9, 10, 11, 12]. Co-expression of this receptor and its ligand has been proven to predict poor prognosis [13, 14]. Targeting EGFR by using the tyrosine kinase inhibitor, erlotinib showed a modest survival benefit when combined with gemcitabine [15]. Human epidermal growth factor receptor 2 (HER-2; ErbB2)-targeted therapy has been shown to significantly improve clinical outcome in breast cancer and gastric cancer. Twenty percent of pancreatic cancers have overexpressed HER-2 [11]. Efficacy of targeting this receptor has been shown in studies of trastuzumab, an antibody to HER-2. Trastuzumab has been shown to inhibit tumor growth in HER-2 xenografts and prolong survival in a pancreatic cancer orthotopic model [16]. When monoclonal antibodies were used to target EGFR and HER-2 synergistically in xenograft models, an augmented inhibition of tumor progression was observed compared with single monoclonal antibody treatment (P = 0.006) or no treatment (P = 0.0004) and even some complete remissions were evident [17].

Given the lack of effective, non-toxic second-line therapy in gemcitabine-refractory pancreatic cancer, we initially proposed the concept of targeting both EGFR and HER-2 with a single compound. Lapatinib is a tyrosine kinase inhibitor, which binds to both EGFR and HER-2. Lapatinib leads to cell growth arrest by dual inhibition of EGFR and HER-2 and also apoptosis by inhibition of HER-2 [18]. In an international phase III trial of HER-2 positive breast cancers, lapatinib with capecitabine significantly improved the time to progression compared to capecitabine alone [19]. We therefore conducted a single-arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic pancreatic cancer.

Materials and methods

Patients and clinical study design

Patients were eligible to be included in the study if they were 18 years of age or older and had histologically and cytologically confirmed, radiographically measurable adenocarcinoma of the pancreas and had disease progression on first-line gemcitabine therapy for metastatic disease, or relapsed within 6 months after completion of gemcitabine adjuvant therapy. Prior capecitabine or 5-FU was allowed (but not required) in the setting of radiation. Cardiac ejection fraction was required to be within the institutional range of normal as measured by echocardiogram or MUGA scan. Other inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2 [17] and adequate bone marrow (absolute neutrophil count ≥1500/mm3; and platelets ≥100,000/mm3), liver function (total bilirubin ≤1.5 times the upper limit of normal range; aspartate transaminase and alanine transaminase ≤3.0 times the upper limit of normal range unless liver metastases are present, in which case ≤5.0 times the upper limit of normal range), and renal function (creatinine clearance ≥30 mL/min as calculated by the Cockroft-Gault Equation).

We conducted an open-label single-arm phase II trial using lapatinib and capecitabine as second-line treatment in patients with metastatic pancreatic cancer (IRB# 08-437). Patients eligible for this study took lapatinib PO as a single dose of 1250 mg daily and capecitabine PO at a dose of 1000 mg/m2 twice daily on days 1–14 of 21-day cycle.

At the start of every cycle, the patient’s status was assessed according to complete physical examination, ECOG performance status, complete blood counts, and blood chemical tests. Serum samples were collected prior and on day 1 of every cycle of treatment thereafter. Cardiac function was evaluated by echocardiogram or MUGA scan every four cycles (12 weeks) while on therapy and 12 weeks after discontinuation of study medication. A CT scan was performed every two cycles (6 weeks), and tumor responses and progressions were determined according to the Response Evaluation Criteria in Solid Tumors [21]. Toxicity was assessed at every visit using the National Cancer Institute Common Toxicity Criteria version 4.0 [20]. Patients were discontinued from the study in the event of disease progression, uncontrolled side effects, loss to follow-up, or withdrawal of consent. An institutional review board approved the ethical, legal, and social implications of the project.

Statistical analysis

The primary end point of this single-arm, phase II study was OS. The secondary endpoints included objective response rate, PFS and the safety profile of the combination therapy. The Kaplan–Meier methodology was used to analyze PFS and OS, and the log-rank test was used to compare the survival curves between those with stable disease and those with disease progression. Median PFS and OS were reported with a 95 % confidence interval (CI). A P value <0.05 was considered statistically significant.

Results

Patient characteristics

Between September 2009 and September 2011, 17 patients were accrued into the study. Due to slow accrual and change of practice in the first-line treatment of advanced pancreatic cancer from gemcitabine to FOLFIRINOX, we did not meet our goal of patient enrollment. The majority of the 17 patients enrolled were aged between 50 and 70 years, while four patients were older than 70 years. Two patients enrolled in the study had a performance status of 2; the rest of patients all had a performance status of 0 or 1. Twelve patients had metastatic pancreatic cancer at the initial diagnosis; while the other five patients had disease progression after a Whipple procedure for localized disease. Fourteen patients received gemcitabine alone as first-line therapy; the other three patients were treated with gemcitabine in combination with erlotinib, oxaliplatin, or nab-paclitaxel (Table 1).
Table 1

Baseline characteristics of enrolled patients

Characteristic

Patients (%)

Total number of patients

17

Gender

 Male

13 (76 %)

 Female

4 (24 %)

Age

 50–70

13 (76 %)

 >70

4 (24 %)

ECOG performance status

 0

3 (18 %)

 1

12 (70 %)

 2

2 (12 %)

Extension of disease at diagnosis

 Local

5 (29 %)

 Metastatic

12 (71 %)

Previous treatment

 Gemcitabine

14 (82 %)

 Gemcitabine + Erlotinib

1 (6 %)

 Gemcitabine + Oxaliplatin

1 (6 %)

 Gemcitabine + Abraxane

1 (6 %)

ECOG Eastern Cooperative Oncology Group

Survival and response

Patients participating in the study received a CT scan after every two cycles of treatment (about every 6 weeks). Six of the 17 patients had disease progression after two cycles (6 weeks from start of treatment; included in the PD group for data analysis purposes), and six patients had stable disease and received at least four cycles of treatment (12 weeks or more of treatment; included in the SD group for data analysis purposes, range 4–22 cycles) (Fig. 1a). Five patients were taken off the trial due to severe toxicity or death. None of the patients had partial response (30 % or more tumor shrinkage based on RECIST criteria) or complete response. For the entire cohort, median PFS was 2.6 months (95 % CI 1.3–3.8); median OS was 5.2 months (95 % CI 3.4–9) (Fig. 1b, c), which is comparable to the PFS and OS in patients treated with oxaliplatin and 5-FU (OFF) in the randomized phase III second-line study comparing OFF with 5-FU/folinic acid in patients who have progressed on gemcitabine treatment. When comparing patients who received two or fewer cycles of treatment (PD group) to those who received 4–22 cycles (SD group), we found a statistically significant difference in median PFS and OS: median PFS was 1.4 months (95 % CI 1.0–1.8) in the PD group versus 4.0 months (95 % CI 1.8–6.3) in the SD group (P value = 0.001) (Fig. 1d). Median OS was 2.9 months (95 % CI 0–7.3) in the PD group versus 8.3 months (95 % CI 0–21.2) in the SD group (P value = 0.023) (Fig. 1e).
Fig. 1

Objective response according to RECIST criteria and duration of response in patients treated with lapatinib and capecitabine combination treatment (a); Kaplan–Meier curves for PFS (b) and OS (c) for the entire cohort; Kaplan–Meier curves comparing PFS (d) and OS (e) in patients who had stable disease following treatment and those who did not

Toxicity

The majority of the patients participating in the trial tolerated the treatment well with mostly grade 1 toxicities as listed in Table 2. The most common adverse events were fatigue (47 %) and diarrhea (41 %). Three patients developed grade 3 GI symptoms (nausea, vomiting, and diarrhea) and fatigue after receiving one cycle of treatment. These three patients were admitted to hospital for dehydration and were taken off the study due to intolerance. Two patients died after enrollment into the study and received only a few days of treatment; both died from small bowel obstruction and failure to thrive as a result of their large tumor burden and cancer progression, not due to the toxicity of the treatment. Two patients developed deep vein thrombosis or pulmonary embolism, which was likely due to the prothrombotic nature of the malignancy. No significant cardiac toxicities were observed in patients receiving combination treatment (data not shown).
Table 2

Adverse events in patients receiving combination treatment

Clinical event

Number of patients (%)

Grade 1

Grade 2

Grade 3

Fatigue

5 (29 %)

2 (12 %)

1 (6 %)

Anorexia

0

1 (6 %)

0

Nausea, vomiting

1 (6 %)

0

2 (12 %)

Diarrhea

5 (29 %)

0

2 (12 %)

Hand-foot syndrome

3 (18 %)

0

0

Rash

2 (12 %)

0

0

Sensory neuropathy

1 (6 %)

0

0

Skin infection (Fungal)

2 (12 %)

0

0

Stomatitis

2 (12 %)

0

0

Thromboembolism

2 (12 %)

0

0

Reason for treatment discontinuation

Number of patients (%)

Grade 3 clinical toxicity

3 (18 %)

Death

2 (12 %)

Discussion

Overexpression of EGFR has been suggested to be associated with malignant transformation of pancreatic cancer, and the EGFR gene is overexpressed in the majority of pancreatic ductal adenocarcinomas and human pancreatic cancer cell lines [22, 23, 24]. However, the combination of the EGFR inhibitor erlotinib with gemcitabine only showed a small but not clinically meaningful improvement in efficacy compared with gemcitabine alone [25]. Dual inhibition of EGFR and HER-2 was proposed for pancreatic adenocarcinoma based on the observed high levels of EGFR/HER-2 heterodimers in pancreatic cancer cells [26]. We therefore conducted a single-arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic pancreatic cancer. The study was not completed due to difficulty in enrollment and change of clinical practice for this patient population. The median overall survival in patients who have progressed on first-line systemic treatment was 6 months in our study, comparable to results from other second-line studies [5, 6]. Most severe side effects (grade 3) were nausea, vomiting, diarrhea, and fatigue, which occurred in 17 % of the patients. Most patients tolerated treatment without dose adjustment. No cardiac side effects were reported. The combination of lapatinib and capecitabine is a tolerable alternative for patients who have failed gemcitabine-containing chemotherapy; however, the observation is based on small number of patients enrolled in the trial.

Interestingly, there was a subset of patients (6 out of 17 patients), who responded to the lapatinib and capecitabine treatment with a median OS of 8.3 months and PFS of 4.0 months. The present study demonstrates that a subset of pancreatic cancer patients receive benefit from lapatinib, a treatment aimed at the combined inhibition of both EGFR and HER-2 signaling pathways. Predictive biomarkers that allow selection of patients that will respond to this regimen should be further investigated.

Notes

Compliance with ethical standards

Conflict of interest

None.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Zheng Wu
    • 1
  • Andrew Gabrielson
    • 1
  • Jimmy J. Hwang
    • 1
  • Michael J. Pishvaian
    • 1
  • Louis M. Weiner
    • 1
  • Tingting Zhuang
    • 2
  • Lisa Ley
    • 1
  • John L. Marshall
    • 1
  • Aiwu Ruth He
    • 1
  1. 1.Division of Hematology and Oncology, Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA
  2. 2.Department of Biostatistics and BioinformaticsGeorgetown UniversityWashingtonUSA

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