Erlotinib (Tarceva®) 2008:
Role in Lung Cancer Therapy

Giuseppe Giaccone, MD, PhD
National Cancer Institute, Bethesda, Maryland

Erlotinib is an orally available reversible inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase that blocks the adenosine triphosphate (ATP) binding site of the kinase cytoplasmic domain.⁴³ Preclinical data have shown that erlotinib has significant antitumor activity in non–small cell lung cancer (NSCLC). Given that EGFR overexpression is common in NSCLC and is associated with a poor prognosis, agents such as erlotinib that target this receptor have therapeutic potential for patients with EGFR-positive tumors, a hypothesis that has been well substantiated in clinical trials.

Activity in Non–Small Cell Lung Cancer Single-agent studies In the first phase II study of erlotinib in patients with advanced (stage IIIB or IV) NSCLC, a dose of 150 mg/day was administered continuously to 57 patients who had failed platinum-based chemotherapy.⁴⁴ This dose has been considered to be the maximum tolerated dose (MTD) of erlotinib. The response rate was 12.3% in this patient population. Survival correlated with the occurrence and severity of skin rash, which is the most common side effect with this class of agents.

Figure 1

A large phase III study (BR.21) evaluated erlotinib in 731 patients with advanced NSCLC who had failed one or two prior chemotherapy regimens and had a performance status (PS) of 0 to 3.⁴⁵ The study assigned patients to erlotinib or placebo in a 2:1 ratio, and erlotinib was administered at a dose of 150 mg/day. The response rate was 8.9% in the erlotinib group and <1% in the placebo group (P<0.001); median duration of response was 7.9 months and 3.7 months, respectively. Progression-free survival (PFS) was 2.2 months for patients treated with erlotinib and 1.8 months for those on placebo (P<0.001). Overall survival was 6.7 months and 4.7 months, respectively (P<0.001), demonstrating a 2-month survival increase with erlotinib (Figure 1). Skin rash and diarrhea were the major side effects. Five percent of patients dis continued erlotinib due to toxicity. Patients of female gender, those with adenocarcinoma histology, never-smokers, and East Asians responded best to erlotinib therapy.

Several other studies of erlotinib monotherapy have consistently shown major responses in about 10% of Caucasian patients. Response rates were greater in Asians for whom the frequency of EGFR mutations is about 3- to 4-fold higher than Caucasians. The presence of EGFR mutations has been associated with major responses in many studies employing EGFR small-molecule inhibitors.⁴⁵ Studies of erlotinib in the first-line setting have also been performed. A phase II trial in 53 unselected patients with advanced NSCLC demonstrated a major response rate of 23%.⁴⁷ The main side effects were skin rash (which correlated with positive outcome) and diarrhea; mucositis and nail toxicities were also observed.

A randomized phase II study was conducted to compare treatment with erlotinib to carboplatin-paclitaxel in patients with a PS of 2 who had received no prior chemotherapy.⁴⁸ Patients were assigned to erlotinib 150 mg daily until progression, or carboplatin (AUC 6) and paclitaxel (200 mg/m2) day 1 every 3 weeks for up to four cycles. Patients who experienced progression and those who did not tolerate or refused further chemotherapy were allowed to cross over to erlotinib. The primary endpoint was PFS. Fifty-two patients were randomly assigned to erlotinib and 51 to chemotherapy. Partial response rates were 2% and 12%, respectively. Median PFS was 1.9 months in the erlotinib arm and 3.5 months in the chemotherapy arm (P= 0.06), with median survival times of 6.5 and 9.7 months (P = 0.018). Sex, histology, skin rash, and smoking history predicted outcome with erlotinib therapy. Rash and diarrhea were more common with erlotinib. These results strongly suggest that without proper patient selection, chemotherapy may be superior to erlotinib monotherapy in patients with advanced NSCLC.

Another study (TORCH) is underway in which patients are ran domized to receive initial treatment with erlotinib followed by chemotherapy (cisplatin-gemcitabine) on progression, or else chemotherapy first followed by erlotinib on progression. The primary endpoint in this non-inferiority study is overall survival; target enrollment is 900 patients. The large SATURN study is investigating use of erlotinib as maintenance therapy in patients who did not progress after four cycles of platinum-based chemotherapy. Patient tissues will be collected to correlate various biomarkers with clinical outcome. Those who progress on chemo therapy will be included in the TITAN study and randomized to receive either chemotherapy (docetaxel or pemetrexed) or erlotinib.

Although activity is observed with erlotinib in unselected patients, a strategy for selection clearly would be more desirable. Phase II studies in patients with EGFR mutations or those positive for EGFR expression by fluorescence in situ hybridization (FISH) are underway to determine if these can serve as predictive markers. Randomized studies will eventually have to be performed to confirm that treatment with EGFR inhibitors is at least as effective as standard chemotherapy in these selected patients.

Selection of patients who are most likely to benefit from EGFR inhibition is clearly the preferred approach compared to treating unselected patients. To this end, a large randomized study in radically resected NSCLC patients is underway to evaluate erlotinib therapy in patients with EGFR overexpression (via FISH or immunohistochemistry). Patients will receive erlotinib 150 mg/day or placebo for 2 years, with erlotinib treatment commencing following completion of chemotherapy. Eligible patients may have received up to four cycles of adjuvant chemotherapy.

Erlotinib in combination with other agents

Two major randomized studies (TALENT and TRIBUTE) have compared two chemotherapy regimens (carboplatin-paclitaxel and cisplatin-gemcitabine) combined with either erlotinib 150 mg/day or placebo in the first-line treatment of advanced NSCLC. The major goal of these trials, each of which accrued over 1000 patients, was an increase in survival. Unfortunately, these two studies, as well as two additional trials with a similar design employing gefitinib instead of erlotinib (INTACT-1 and INTACT-2), were negative.⁴³ Interestingly, the survival curves revealed a potential inferior survival of the three-drug combinations in the phase of chemotherapy treatment, whereas a trend for improvement was observed after discontinuation of chemotherapy in the EGFR inhibitor arms. In the TRIBUTE study, the presence of KRAS mutations was associated with a worse response rate and survival with erlotinib therapy compared to patients with wild-type KRAS.⁴⁹

A phase I/II study was conducted to evaluate erlotinib in combination with the vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, an inhibitor of angiogenesis.⁵⁰ In the absence of dose-limiting toxicities, the doses used in phase II were the MTD for both agents (150 mg/day erlotinib, and 15 mg/kg bevacizumab every 21 days). This combination regimen resulted in a 20% response rate in 34 patients, suggesting the superiority of erlotinib plus bevacizumab to either agent alone. A randomized phase II study was then performed to compare this doublet to second-line chemotherapy (either docetaxel or pemetrexed) in combination with either bevacizumab or placebo.⁵¹Dosing consisted of erlotinib 150 mg/day and bevacizumab 15 mg/kg every 3 weeks. Interestingly, the two bevacizumab-containing arms had a higher response rate and survival than the chemotherapy-alone arm. While this study was not powered to detect differences in survival (N120), these results suggest that a combination of targeted agents may challenge the activity of chemotherapy in this setting (Table 1).

Table 1

Large, randomized studies are presently investigating the erlotinib-bevacizumab combination in several settings. The Beta trial is evaluating this regimen as second-line therapy, where patients are randomized to erlotinib-placebo or erlotinib-bevacizumab. The primary endpoint in this trial is overall survival, with secondary endpoints including PFS, safety, and evaluation of biomarkers.

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