ABSTRACT: Erlotinib (Tarceva) is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor initially approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic non–small-cell lung cancer after failure of at least one prior chemotherapy regimen. In this report, we present the pivotal study that led to the approval of erlotinib in combination with gemcitabine(Drug information on gemcitabine) (Gemzar) in patients with locally advanced/metastatic chemonaive pancreatic cancer patients. The combination demonstrated a statistically significant increase in overall survival accompanied by an increase in toxicity. Physicians and patients now have a new option for the treatment of locally advanced/metastatic adenocarcinoma of the pancreas.
The prognosis of advanced pancreatic carcinoma has not improved in the past 20 years. The most recent drug approved by the US Food and Drug Administration (FDA) for the treatment of advanced pancreatic carcinoma was gemcitabine (Gemzar), approximately 10 years ago. The approval was based on two clinical trials in patients with locally advanced or metastatic pancreatic cancer. In the multicenter, prospective, single-blinded, two-arm, randomized pivotal trial, chemonaive patients received gemcitabine or fluorouracil(Drug information on fluorouracil) (5-FU).[1,2] Patients treated with gemcitabine not only had a statistically significant increase in clinical benefit response (a composite endpoint that reflects a measure of clinical improvement based on analgesic consumption, pain intensity, performance status, and weight change) but also experienced increases in survival and time to disease progression compared to 5-FU. This increase in survival was not associated with any evidence of tumor response.[2]
Although initial efforts to combine gemcitabine with other agents failed to demonstrate significant benefit, a few recent studies suggested that some gemcitabine-containing combination regimens may benefit patients with advanced adenocarcinoma of the pancreas.[3,4] Moreover, a recent meta-analysis[5] suggests that gemcitabine combinations improve overall survival compared with gemcitabine alone. Despite all these efforts, novel therapies are desperately needed for the treatment of this disease.
Erlotinib (Tarceva; OSI Pharmaceuticals, Inc, Melville, NY, and Genentech, Inc, South San Francisco, Calif) inhibits epidermal growth factor receptor (EGFR) tyrosine kinase (TK) autophosphorylation by inhibition of the intracellular domain. Studies in cell lines and enzyme assays have both shown that erlotinib inhibits EGFR at concentrations significantly lower than those needed to inhibit c-src and v-abl.[6] While erlotinib was more selective for EGFR TK than it was for several other tyrosine kinases tested, several other TKs in the same family as EGFR may be sensitive to erlotinib. On November 2004, erlotinib received FDA approval as monotherapy for the treatment of patients with locally advanced or metastatic non–small-cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen.[7,8]
Survival of erlotinib-treated patients was superior to that of placebo-treated patients. Exploratory univariate analyses showed a larger survival prolongation in two subsets of patients: those who never smoked and those with EGFR-positive tumors. Moreover, patients who developed rash during therapy demonstrated better survival.[7,8] Skin rash and diarrhea were the most common erlotinib adverse events (AEs). In order to increase the antitumor effect of erlotinib, several combinations were tested in patients with lung cancer. In two large controlled, randomized trials in first-line NSCLC patients, the addition of erlotinib to doublet, platinum-based chemotherapy did not show any benefit.[9,10] Therefore, erlotinib is not indicated for use in this setting.
In this report, we present the pivotal study that led to the approval of erlotinib in combination with gemcitabine in patients with locally advanced/metastatic chemonaive pancreatic cancer patients. The combination demonstrated a statistically significant increase in overall survival accompanied by an increase in toxicity. This is the first time that a small-molecule TK inhibitor demonstrated an increase in survival when combined with chemotherapy for the treatment of solid tumors. The combination of gemcitabine and erlotinib is a new treatment option for this patient population.
Patients and Methods
Patients
Eligible patients had histologically or cytologically confirmed adenocarcinoma of the pancreas that was unresectable, locally advanced, or metastatic. No prior systemic chemotherapy was allowed. However, patients could have received prior radiation treatment for management of local disease providing that disease progression had been documented, all toxicities had resolved, and the last fraction of radiation treatment was completed at least 4 weeks prior to randomization. Patients were not eligible if they had received prior chemotherapy other than 5-FU (with or without folinic acid) or gemcitabine given concurrently with radiation treatment as a radiosensitizer. Patients were required to have adequate renal, liver, and bone marrow reserve and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
Design
This was a randomized, double-blind, placebo-controlled, multi-institutional phase III study of erlotinib plus gemcitabine (EG) vs gemcitabine plus placebo (PG) in patients with incurable advanced or metastatic pancreatic cancer. This multinational trial was conducted by the National Cancer Institute of Canada Clinical Trials Group in collaboration with OSI Pharmaceuticals, Inc.[11]
Although the dose of erlotinib used at selected Canadian centers was 150 mg po qd, the dose used worldwide was 100 mg po qd. Because of the small number of patients in the 150-mg groups (48 on the EG arm and 24 on the PG arm), this review will discuss the results for the 100-mg group only.
A total of 521 patients were randomized to gemcitabine plus erlotinib (n = 261, EG arm) or to gemcitabine plus placebo (n = 260, PG arm) in a 1:1 ratio. Randomization was stratified by center, performance status (ECOG 0/1 vs 2), and extent of the disease (locally advanced vs distant metastases). Efficacy was evaluated by periodic assessments of survival. In addition, serial measurements of all disease sites were performed every 8 weeks, and tumor response was assessed using the response evaluation criteria in solid tumors (RECIST).
Safety was assessed every 4 weeks by evaluating changes in hematology and biochemistry parameters, changes in physical examination, and by monitoring the incidence, severity, and relationship of adverse events. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria (NCI CTC), version 2.0. After discontinuing protocol treatment, patients were evaluated at 4 weeks, and survival status was assessed every 12 weeks until death.
Efficacy Endpoints
The primary endpoint was overall survival. Secondary endpoints were tumor response, tumor response duration, and progression-free survival. The expression of EGFR levels at diagnosis was correlated with outcomes and response to treatment.
Statistical Methods
The primary survival analysis was survival time, defined as time from randomization to death, using the log-rank test stratified by the randomization stratification factors (extent of the disease [locally advanced vs distant metastases] and ECOG performance status [0/1 and 2]). Median survival was estimated using Kaplan-Meier estimates, and the 95% confidence interval was computed using the method of Brookmeyer and Crowley. No interim efficacy analysis was conducted in this study.
Analysis of a secondary endpoint, progression-free survival (defined as the time from randomization to the first observation of disease progression or death due to any cause), was conducted using the stratified log-rank test. Response rate was defined as the proportion of patients evaluable for response who met the criteria of complete or partial response. The Fisher's exact test (2-sided) was used to compare tumor response rates between the two treatment arms.
Results
Patient Baseline Characteristics
Demographic and Disease Characteristics: 100-mg cohortBaseline demographic and disease characteristics of the 100-mg cohort are shown in Table 1. The initial sample size estimate was based on 381 events for the final analysis. However, a total of 569 patients were randomized and 551 events had occurred at the time of final analysis, including the 100- and 150-mg erlotinib cohorts.
In the 100-mg cohort, a total of 261 patients were randomized to the EG group and 260 patients were randomized to the PG group. Treatment groups were well balanced with respect to baseline characteristics (see Table 1). Only 17% of patients had ECOG PS 2. Also, half of the patients had a pain intensity score ≤ 20 (data not shown). Of note, PS 2 and pain intensity scores ≥ 20 portend poor prognosis. Median age was 64 and 63 years old, respectively, in the EG and PG treatment groups. With respect to extent of disease at baseline, approximately 25% had locally advanced pancreatic carcinoma. Most patients were < 6 months from time of initial diagnosis to randomization. Almost all patients had surgery before therapy. This includes any surgical procedure such as biopsy of the pancreas.
Approximately one-third of the patients were diagnosed by cytology (fine-needle aspiration), as can be expected for this type of tumor. Approximately 8% of patients received radiation therapy alone or in combination with radiation sensitization doses of chemotherapy.
The expression of EGFR (as measured by immunohistochemistry [IHC]), the main target for erlotinib, is presented in Table 1. A positive EGFR expression was defined as having at least 10% of tumor cells staining for EGFR using the DAKO EGFR pharmDX kit. Pathology blocks or slides were available and the results were interpretable for only 27% of patients in the EG arm and for 24% of patients in the PG arm. In the EG arm, 16% of patients' tumors (representing 56% of patients with known EGFR status) had a positive EGFR expression and 13% (44% of patients with known status) had a negative expression, compared with 11% and 12% (representing 46% and 54% of patients with known status) in the placebo arm. Of note, tissue collection was not a mandatory inclusion criterion.
Causes of Ineligibility Due to Pathology EvaluationIn a blinded fashion, the FDA assessed the eligibility criteria for all 521 cases. Two FDA reviewers assessed the available pathology, surgical, and radiologic reports for all patients. In 18 cases, the diagnosis of pancreatic carcinoma was incorrect or unproven. Based on this information, the FDA performed sensitivity analyses excluding these ineligible patients (Table 2). The major protocol violations that the FDA observed were as follows: no pathology reports (n = 2), lack of confirmation of malignancy (n = 3), metastatic disease without proof of pancreatic origin as determined by computed tomography or surgical reports (n = 3); and other primary malignancy in the biopsy report (n = 10).
Cases with other primary malignancies were ampula of vater (n = 5), acinar cell carcinoma (n = 2), and adenocarcinoma of nonpancreatic origin, colon cancer, or gastric cancer (1 case each). Thus, there were three analysis populations for this study (see Table 3): all randomized patients (n = 521); analysis population excluding major protocol violations (n = 503), and safety population (patients who received study drug, n = 515). Patient disposition is described in Table 4. Of note, 62% discontinued due to disease progression in the EG arm as compared to 71% in the PG arm. However, a higher number of patients in the EG arm had discontinuation of drug due to adverse events, patient refusal or death.
