Clinical Experience With the HER1/EGFR Tyrosine Kinase Inhibitor Erlotinib

Erlotinib (Tarceva) is an inhibitor of HER1/epidermal growth factor receptor (EGFR) tyrosine kinase, a new class of targeted anticancer drugs currently being investigated in the clinical setting. The antitumor activity of erlotinib in preclinical studies provided strong support for an extensive clinical development program. This article summarizes earlyphase clinical investigations of erlotinib and describes ongoing trials in non-small-cell lung cancer. Erlotinib Phase I Trials Orally administered erlotinib has been evaluated as monotherapy in four phase I studies, consisting of two single-dose and multiple-dose studies in healthy volunteers and two multiple- dose studies of daily and weekly dosing in patients with refractory cancers, including non-small-cell lung cancer.[1,2] Diarrhea at the 200-mg/d dose in daily dosing studies was identified as the dose-limiting toxicity. Other observed toxicities consisted of a dose-related acneiform rash localized above the waist (grade 1 or 2), headache, and nausea/vomiting. No dose-limiting toxicities were observed in weekly dosing studies at doses of up to greater than 1,600 mg. The maximum tolerated dose of 150 mg/d in the daily dosing studies was identified for evaluation in subsequent phase II tri- als. Evidence of antitumor effect was observed in patients with refractory cancers, with 8 of 40 patients receiving daily doses exhibiting stable disease for longer than 5 months and 4 of 27 receiving weekly doses having stable disease for longer than 6 months. Similar findings were made in initial studies in Japanese patients. Evaluation of erlotinib pharmacokinetics in daily dosing studies showed dose-proportional maximum plasma concentrations (C_max) and area under the concentration-time curve (AUC), with no drug accumulation occurring with repeated daily dosing. High drug exposure was observed at the 150-mg dose, which resulted in C_max greater than 2,000 ng/mL; as shown in Figure 1, C_max and AUC values with erlotinib at 150 mg were comparable to those observed with gefitinib(Drug information on gefitinib) (Iressa) at 700 mg/d, a dose substantially higher than the currently accepted gefitinib dose of approximately 250 mg/d.[1,3] Erlotinib currently is being evaluated in phase I studies of combinations with chemotherapeutic agents and other targeted agents. Preclinical studies have shown at least additive antitumor effects of erlotinib in combination with other chemotherapeutic agents, with no increase in toxicity.[4] Ongoing phase Ib combination trials include those evaluating the combination of erlotinib with docetaxel(Drug information on docetaxel) (Taxotere), carboplatin(Drug information on carboplatin) (Paraplatin)/ paclitaxel(Drug information on paclitaxel), and cisplatin(Drug information on cisplatin)/gemcitabine (Gemzar).[5-7] Initial findings include absence of pharmacokinetic interactions between erlotinib and other agents and preliminary evidence of antitumor effects. Erlotinib Phase II Trials in Non-Small-Cell Lung Cancer Previously Treated Advanced Non-Small-Cell Lung Cancer
Erlotinib has been evaluated in a phase II trial in patients with previously treated non-small-cell lung cancer.[ 8] The primary objective of the trial was to determine the objective response rate in patients with HER1/ EGFR-positive advanced or recurrent non-small-cell lung cancer who had failed prior platinum-based chemotherapy. Secondary objectives included determining the stable disease rate, duration of response, progression- free, overall, and 1-year survival, and safety and tolerability. Eligible patients had histologically confirmed stage IIIB/IV disease, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and life expectancy of at least 12 weeks; all patients were required to be EGFR-positive. Erlotinib was given at 150 mg/d for up to 52 weeks or until clinical deterioration or disease progression. A total of 57 patients (34 female, 23 male) were studied: median age was 62 years (range: 31 to 83 years); ECOG performance status was 0 in 6 patients (11%), 1 in 44 (77%), and 2 in 7 (12%); 9 (16%) had stage IIIB disease and 48 (84%) had stage IV disease; and HER1/EGFR expression was strong in 32 patients (56%), weak to strong in 19 (33%), and weak in 6 (10.5%). The objective response rate was 12.3% (95% confidence interval [CI] = 5.1%-23.7%), with two complete responses and five partial responses being observed (Table 1). Stable disease was observed in 22 patients (38.6%), yielding an overall disease control rate of 51%. Response durations were 18 and 80 weeks in patients with complete response and 12, 14, 20, 24+, and 56 weeks in those with partial response; the median duration of response was 19.6 weeks (95% CI = 11.6-97.3 weeks). Median overall survival was 8.4 months (95% CI = 4.8-13.9 months) and the 1-year survival rate was 40% (95% = CI 28%-54%) (Figure 2), with 9 patients remaining alive over follow-up of greater than 18 months. Median progression-free survival was 9 weeks (95% CI = 8-15 weeks). Baseline predictors of response or overall survival included time from initial diagnosis, time from last chemotherapy, and ECOG performance status, but not extent of prior chemotherapy. Occurrence of grade 1 or 2/3 rash during treatment was predictive of survival. Treatment was well tolerated, with the most common adverse events being grade 1 or 2 rash and diarrhea (Table 2). No grade 4 toxicity was observed, and grade 3 toxicity consisted of pruritus in 2 patients and rash, diarrhea, and dry skin in 1 patient each. Five patients discontinued treatment due to toxicity. The disease control rate (51%) and survival rates (overall survival 8.4 months, 1-year survival 40%) observed with erlotinib in this trial compare favorably with those reported in the phase II IDEAL 1 and IDEAL 2 trials of gefitinib in advanced NSCLC. In the IDEAL 1 trial, disease control rates were 54%/51%, median overall survival durations were 7.6/8.0 months, and 1-year survival rates were 35%/30% with doses of 250 mg/500 mg per day; in IDEAL 2, disease control rates were 43%/36%, overall median survival durations were 6.5/5.9 months, and 1-year survival rates were 29%/24% with doses of 250 mg/ 500 mg per day.[9,10] The findings with erlotinib also compare well with the 54% disease control rate, 7.5-month median overall survival, and 37% 1-year survival rate observed with docetaxel 75 mg/m² treatment in a phase III trial vs best supportive care in this setting reported by Shepherd et al[11], recognizing, however, the limitations of comparing the results of a phase II trial with those of a phase III trial. Bronchioloalveolar Cell Carcinoma
In an ongoing phase II trial, the effects of erlotinib at 150 mg/d are being evaluated in patients with bronchioloalveolar cell carcinoma (BAC).[12,13] Eligibility requirements included disease characterized as pure BAC, BAC with focal invasion, or adenocarcinoma with BAC features; 0 or 1 course of prior chemo- chemotherapy; and Karnofsky performance status of at least 60. Thus far, data are available from a total of 50 evaluable patients (34 female, 16 male). Patient characteristics include median age 66 years (range 32 to 85 years); Karnofsky performance status of 90 or 100 in 17 (34%), 80 in 30 (60%), and 70 in 3 (6%); history of cigarette smoking (former/current smoker) in 37 (74%) vs no history (< 100 cigarettes lifetime) in 13 (26%); and no prior chemotherapy in 38 (76%) vs one prior course in 12 (24%). Of these patients, 13 (26%, 95% CI = 13%-40%) have exhibited a partial response; the median duration of follow up for responding patients is 6 months, and median duration of response has not yet been reached. One case of response is shown in Figure 3. Treatment was well tolerated, with the most significant adverse events consisting of 4 cases of grade 3 rash, 2 cases of intolerable grade 2 rash, grade 3 arthralgia in 1 patient, and grade 3 diarrhea in 1 patient. One patient discontinued treatment due to adverse events, and all other adverse events were managed by dose reduction or interruption. It is noteworthy that a strong trend was observed for response in patients with no history of smoking (46% vs 19%, P = .07). Multivariate analyses of gefitinib trials involving non-small-cell lung cancer patients have shown both presence of BAC features (P = .005) and absence of smoking history (P = .007) to be predictive of response.[14] Such findings suggest that BAC may have a different biology in patients with no history of smoking. Phase I/II Trial of Erlotinib/ Bevacizumab(Drug information on bevacizumab) in Non-Small-Cell Lung Cancer The combination of erlotinib and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin) currently is being evaluated in a phase II trial in patients with advanced non-small-cell lung cancer.[ 15,16] Preclinical data indicate that the combination of HER1/EGFR inhibitors and VEGF inhibitors pro- duces an at least additive antitumor effect. The rationale for such a combination includes the potential for improved tolerance with fewer nonspecific toxicities and augmentation of efficacy via the targeting of two pathways critical to tumor growth. In the phase I portion of the trial, patients with grade IIIB/IV locally advanced or metastatic non-squamous cell non-small-cell lung cancer who had received at least one prior chemotherapy regimen were treated with oral erlotinib once daily and intravenous bevacizumab on day 1 every 21 days at three dose levels: (1) erlotinib at 100 mg plus bevacizumab at 7.5 mg/kg; (2) erlotinib at 100 mg plus bevacizumab at 15.0 mg/kg; and erlotinib at 150 mg plus bevacizumab at 15.0 mg/kg. Dose escalation was performed according to a standard 3 + 3 study design, with three patients per cohort being treated unless doselimiting toxicity was observed. Among the 12 patients (8 female, 4 male) assessed in the phase I study: median age was 55 years (range: 37 to 72 years); 1 had stage IIIB and 11 had stage IV disease; 12 had prior chemotherapy, 5 had prior surgery, and 7 had prior radiation therapy; and the number of prior chemotherapy regimens was 1 in 2 patients, 2 in 7, and 3 or more in 3. Treatment was well tolerated, with no dose-limiting toxicities observed. The most frequent adverse events were grade 1/2 rash in 10 patients (83%), diarrhea in 9 (75%), nausea in 7 (58%), pruritus in 5 (42%), and proteinuria in 4 (33%), with no grade 3 toxicities observed. The maximum tolerated dose was defined as the highest dose studied, consisting of daily erlotinib at 150 mg plus bevacizumab at 15.0 mg/kg every 21 days. Antitumor activity was observed in the phase I study, with partial response occurring in 3 patients (25%) and stable disease observed in 5 (42%). An example of response in this portion of the study is shown in Figure 4. Preliminary data indicate absence of a pharmacokinetic interaction between erlotinib and bevacizumab. Additional patients have been recruited to the ongoing phase II portion of the trial. Ongoing Erlotinib Phase III Trials in Non-Small-Cell Lung Cancer Erlotinib has an additive antitumor effect in combination with cytotoxic agents, including cisplatin, paclitaxel, capecitabine(Drug information on capecitabine) (Xeloda), irinotecan(Drug information on irinotecan) (Camptosar), and gemcitabine(Drug information on gemcitabine) (Gemzar) in human cancer xenograft models. The toxicity profiles of erlotinib and chemotherapy (carboplatin/paclitaxel or gemcita- bine/cisplatin) are essentially nonoverlapping. Currently, two phase III trials of erlotinib combined with standard chemotherapy as first-line treatment of non-small-cell lung cancer are in progress (Figure 5). Both the TALENT and TRIBUTE trials enrolled patients with HER1/ EGFR-positive or -negative stage IIIB/ IV disease. In the TALENT trial, 1,137 patients were randomized to cisplatin/gemcitabine plus erlotinib at 150 mg/d or placebo for six cycles of chemotherapy followed by daily erlotinib or placebo until disease progression. In the TRIBUTE trial, 1,079 patients were randomized to carboplatin/ paclitaxel plus erlotinib at 150 mg/d or placebo for six cycles of chemotherapy followed by daily erlotinib or placebo until disease progression. Both trials have 80% power to detect a 25% survival benefit at an α = .05 level and similar power to detect a 33% difference between treatments in 1- year survival. Preliminary reports indicate that survival is negative, but formal presentation of the data is awaited. Erlotinib is also being evaluated as monotherapy in an ongoing National Cancer Institute of Canada phase III trial in patients with advanced, refractory non-small-cell lung cancer. In the BR.21 trial, patients with stage IIB/IV disease who have failed one or two prior chemotherapy regimens and have an ECOG performance status of 0 to 3 have been randomized 2:1 to erlotinib at 150 mg/d or placebo. Accrual to this trial is complete, with 731 patients having been randomized. The trial has 90% power to detect a 33% survival benefit. Results of this trial are also expected in early 2004. Conclusion Erlotinib is an active and well-tolerated agent in advanced non-smallcell lung cancer. It currently is being evaluated as part of combination treatment with cytotoxic chemotherapeutic agents as first-line treatment in advanced disease, as monotherapy in refractory disease, and in combination with the angiogenesis inhibitor bevacizumab in pretreated patients. Additional studies are under way or planned to identify predictors of response to erlotinib, to investigate combinations of erlotinib with other biologic agents, and to define optimal dosing strategies, including identification of optimal dosing in concurrent and sequential combination therapy regimens and development of potential weekly dosing schedules.