Based on the above preclinical findings, erlotinib has undergone extensive evaluation in numerous clinical trials and has gained approval for use in both NSCLC and pancreatic caricnoma. The original phase I trials of this agent were conducted in previously treated patients with a broad range of solid tumors and allowed for the establishment of optimal dosing and toxicity profiles. In one such study, Hidalgo et al evaluated erlotinib as a single agent in 40 patients with advanced solid malignancies in doses ranging from 25 to 200 mg daily, in continuous and intermittent schedules, and established a maximum tolerated daily dose of 150 mg (Hidalgo et al 2001
). 59% of patients (23/39) on study developed grade 1–2 dermatologic toxicity, including 41% (9/22) at the 150 mg once-daily dosing schedule. Although no grade 3–4 dermatologic toxicity was reported, 3 patients, including 1 at the 150 mg daily dosing, required termination of treatment because of clinically intolerable rash. Rash and diarrhea were the dose-limiting toxicities at doses higher than 150 mg. Other principal toxicities included mucositis, hyperbilirubinemia, and headache. Pharmacokinetic analysis indicated that a dose of 150 mg daily produced plasma concentrations greater than 0.5 μg/mL in most patients, corresponding to the level expected to result in antitumor activity from the preclinical studies described above.
A phase I study initially presented at the 2004 annual meeting of the American Society of Clinical Oncology (ASCO), since published, evaluated escalating doses of erlotinib in combination with standard-dose gemcitabine (1000 mg/m2
weekly x 7, then weekly x 3 every 4 weeks) in 26 patients, the majority (n = 15) of whom had pancreatic cancer (Porterfield et al 2004; Dragovich et al 2007
). Two sequential cohorts were enrolled, the first cohort receiving erlotinib at 100 mg daily and the second 150 mg daily. Because 3 of 9 patients at the 100 mg dose level developed grade 3 transaminitis, the study protocol was subsequently amended to increase the stringency of entry criteria, limiting patients to no more than one prior chemotherapy regimen, transaminases less than 1.5× upper limits of normal, and a bilirubin within normal range. The most common non-hematologic toxicity was skin rash, occurring in 18 of 26 patients (69%), none higher than grade 2. Incidence of skin rash was similar at the 100 mg and 150 mg dose levels (67% and 71%, respectively). Other common toxicities included diarrhea in 14 patients (54%), 3 of whom had grade 3; nausea in 11 patients (42%), one of whom had grade 3; and fatigue in 14 patients (54%), 4 of whom had grade 3. Four patients (15%) also developed grade 3 neutropenia. There was 1 fatal episode of pulmonary toxicity in a patient with NSCLC previously treated with chemoradiation. On the whole, the toxicity profile of this combination appeared acceptable, with patients able to tolerate gemcitabine plus erlotinib at 150 mg daily with manageable side effects. Moreover, of the 12 patients with pancreatic cancer evaluable for response, 1 had a partial response (8%), and 9 had stable disease for more than 3 months (75%).
The pivotal study upon which the FDA approval of erlotinib for use in pancreatic cancer was based was PA.3, a phase III trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Results of this study were first presented at the ASCO Gastrointestinal Cancers Symposium in 2005 and have since been recently published (Moore et al 2007b
). PA.3 compared gemcitabine plus erlotinib with gemcitabine plus placebo as first-line therapy in patients with advanced pancreatic cancer. The study was a randomized, double-blind, placebo-controlled international trial with 176 centers in 17 countries. Enrollment consisted of 569 patients with locally advanced or metastatic adenocarcinoma of the pancreas, measurable disease, and an ECOG performance status (PS) between 0 and 2. Prior radiotherapy for local disease was allowed with fluorouracil or gemcitabine given concurrently as a radiosensitizer; patients could not have been previously treated with chemotherapy for advanced disease. Appropriate stratifications were made for both PS and disease stage; approximately 80% of patients on each arm had an ECOG PS of 0 or 1, and 75% had metastatic disease. Of note, EGFR overexpression was not required for enrollment.
All patients received gemcitabine 1000 mg/m2 by 30-minute infusion weekly for 7 weeks followed by 1 week rest in cycle 1. Subsequent cycles were administered weekly for 3 weeks followed by 1 week rest. Patients were randomized to receive erlotinib (285 patients) or placebo (284 patients). The vast majority of patients on the study arm received erlotinib at a dose of 100 mg daily until disease progression or unmanageable toxicity. During the latter portion of the study, a small Canadian cohort of 48 patients received erlotinib at 150 mg daily to assess the tolerability of this higher dose.
The PA.3 study was powered for overall survival as the primary endpoint. Secondary endpoints included PFS, response rate, response duration, toxicity, quality of life (QOL), and correlation of tumor EGFR expression with clinical outcome. Analysis of results showed median survival in patients randomized to gemcitabine plus erlotinib was 6.24 months as opposed to 5.91 months in the gemcitabine plus placebo group; one year survival was 23% versus 17%, respectively (p = 0.23). The hazard ratio (HR) for overall survival was 0.82 (p = 0.038). PFS was also significantly improved in the erlotinib arm (3.75 months) as compared with the placebo arm (3.55 months) with HR of 0.77 for progression (p = 0.004). Response rates were not significantly different between treatment groups (8.6% versus 8.0%), although a trend towards improved rate of disease control was observed for patients in the erlotinib arm (57.5% versus 49.2%, p = 0.07). There was no difference in response duration between groups. depicts Kaplan-Meier curves for overall survival and progression-free survival in the PA.3 study.
Toxicity analysis showed treatment to be well-tolerated in both treatment groups. Patients in the erlotinib arm had higher incidence of rash, diarrhea, infection, and stomatitis. Skin rash was the most common toxicity, occurring in 203 of 282 of patients (72%) on the erlotinib-containing arm, fully half (36%) of whom were categorized as having grade 2 or higher. The incidence of grade 3–4 rash was 6% versus 1% in the erlotinib versus placebo arms, respectively.
As for non-dermatologic toxicity, the incidence of grade 3–4 diarrhea was 6% versus 2%. No differences in grade 3–4 hematologic toxicity were observed between the two arms. Of note, the incidence of interstitial lung disease (ILD) syndromes was 2.1% in the erlotinib arm versus 0.4% in the placebo arm. For comparison, the incidence of ILD was reported to be less than 1% in the Tarceva Lung Cancer Evaluation Trial (TALENT) which evaluated gemcitabine plus cisplatin with or without erlotinib in patients with advanced lung cancer (Gatzemeier et al 2007
). In the PA.3 study, there were 6 protocol-related deaths overall, all of which occurred in the erlotinib arm. Two deaths were attributed to treatment complications (ILD and sepsis), while 4 were attributed to cancer complications combined with possible treatment-related effects.
Dose reductions for toxicity were required in 16% of patients in the erlotinib arm as opposed to 5% in the placebo arm. Dose reductions were more common in the small cohort of patients receiving the higher 150 mg dose of erlotinib (48% of patients at this level required a dose reduction) compared to those receiving a dose of 100 mg daily (dose reduction required in 13%).
Despite these differences in toxicity profiles, there was no difference in global QOL scores using the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionaire C30 (EORTC QLQ-C30) instrument. Individual domain scores were also equivalent with the exception of diarrhea which was reported as worse in the erlotinib arm (p < 0.001). Of note, the EORTC QLQ-C30 instrument does not specifically address quality of life issues relating to skin toxicity. Given that even mild-to-moderate rash can confer impairment and distress, its effects on quality of life may be significant (Gridelli et al 2007
The PA.3 study also assessed EGFR expression in 162 tumor samples adequate for immunohistochemical EGFR analysis. Of these tumors, 86 (53%) were EGFR positive (as defined by at least 10% of cells staining positive) and 76 (47%) were EGFR negative. EGFR status was not significantly associated with response to erlotinib. Interestingly, subgroup analysis was notable for skin rash being associated with disease control with erlotinib (p = 0.05). Median survival for patients with grade 0, 1, and 2+ rash were 5.3, 5.8, and 10.5 months, respectively, with 1-year survival rates of 16%, 9%, and 43% (p < 0.001) ().
In conclusion, the PA.3 study showed that erlotinib in combination with gemcitabine results in a statistically significant improvement in overall survival in patients with advanced pancreatic cancer in the first-line setting. Although the absolute benefit in overall survival was modest with a median survival difference between the two arms of only 2 weeks, the hazard ratio of 0.82 corresponds to a 22% improvement in survival overall (Moore et al 2007b
). The hazard ratio may represent a more clinically meaningful parameter in a rapidly-progressive disease like pancreatic cancer in that it measures risk over a time continuum and may better reflect differences in survival than a static time point such as the median. Ultimately, the PA.3 study represents the first phase III study to demonstrate a survival benefit of combination therapy over gemcitabine monotherapy in advanced pancreatic cancer.
A number of questions arise in evaluating the results of this trial. The high incidence of ILD in the erlotinib arm is noteworthy, particularly by comparison to the lower incidence seen in TALENT which also used erlotinib in combination with gemcitabine. This finding raises the possibility of an additive toxicity with these agents in combination. Also worth pointing out are the subgroup analysis findings identifying female gender as being significantly associated with longer overall survival. This is particularly relevant given the gender imbalance between treatment arms (52.3% females in the erlotinib arm compared to 43.0% in the placebo arm). The authors report that treatment effect remained significant when adjusted for sex, but these data were not presented. The optimal dose of erlotinib in this study also remains in question; the authors recommend a starting dose of 100 mg daily with consideration of dose escalation to 150 mg daily as tolerated. Dose reductions for toxicity in the 150 mg group greatly exceeded those in the 100 mg group, however, suggesting that dose escalations must be undertaken with caution.
Most importantly, the question remains how to identify patients who will benefit from the addition of erlotinib. Although there was no relationship between clinical outcome and EGFR expression by immunohistochemistry, subgroup analysis in the PA.3 study did identify the development of rash as a significant predictor of response, a finding that has been observed in studies evaluating other EGFR inhibitors in other tumor types. This subject will be discussed in further detail in a subsequent section.
In addition to PA.3, smaller studies have evaluated erlotinib in other settings and combinations for advanced pancreatic cancer. A phase II study presented at the annual meeting of ASCO in 2005 evaluated the combination of capecitabine and erlotinib as a second-line regimen in 28 patients with metastatic pancreatic cancer after failure of front line therapy with gemcitabine (Blaszkowsky et al 2005
). This study reported a well-tolerated toxicity profile as well as a promising median survival of 6.7 months. Three patients (11%) were assessed as having a partial response and an additional 16 (57%) demonstrated stable disease. Another phase II study presented at the annual meeting of ASCO in 2006 randomized 58 previously untreated patients with advanced pancreatic cancer to treatment arms consisting of bevacizumab (B) and gemcitabine (C) plus either erlotinib (E) or cetuximab (C) (Kindler et al 2006
). Preliminary analysis suggested activity of both regimens (GBE and GBC) with overall responses of 21% and 19%, respectively; similar six-month survival rates (38% and 41%); and minimal differences in toxicity profiles. A separate phase I study of erlotinib and gemcitabine in combination with bevacizumab is now underway (Gomez-Martin et al 2007
). Erlotinib may also have very modest activity as a single agent or in combination with bevacizumab for patients who have progressed on prior chemotherapy (Epelbaum et al 2007
; Ko et al 2007
). Clinical trials of erlotinib in advanced pancreatic cancer are reviewed in .
Clinical trials of erlotinib in advanced pancreatic cancer