Introduction

Inhibition of the epidermal growth factor receptor (EGFR) pathway is an established strategy for the treatment of patients with advanced non-small cell lung cancer (NSCLC). Two major classes of EGFR inhibitors are under development: the small molecule tyrosine kinase inhibitors (TKI) and monoclonal antibodies directed against the EGFR. Approximately one year ago, Iressa® (gefitinib), a small-molecule EGFR TKI, was approved as monotherapy for patients with advanced stage NSCLC who recurred/progressed following platinum and Taxotere®-based chemotherapy regimens. The efficacy of Iressa® was established in two randomized phase II clinical trials (IDEAL 1 and IDEAL 2) that compared two different dose levels of Iressa® for patients with recurrent NSCLC.^[1],[2] Objective responses and improvements in quality of life were noted for patients in both trials. However, neither study included a control arm with placebo or supportive care alone.

Tarceva™ (erlotinib), another small molecule EGFR TKI, has previously demonstrated activity against NSCLC in a phase II clinical trial. To establish a definite role of Tarceva™ in previously treated NSCLC patients, a randomized, placebo-controlled phase III clinical trial was conducted by the National Cancer Institute of Canada (NCIC- JBR 21). The results of the trial were presented at the 40th Annual Meeting of the American Society of Clinical Oncology (ASCO) by Shepherd and colleagues and generated a lot of excitement.^[3]

National Cancer Institute of Canada (NCIC-JBR 21) Trial

This study included patients with advanced NSCLC who had progressed following 1 or 2 prior chemotherapy regimens. Patients were stratified based on enrolling center, performance status (0/1 vs. 2/3), response to prior chemotherapy, prior platinum-based chemotherapy (yes vs. no) and number of prior regimens (1 vs. 2). Eligible patients were randomized to receive treatment with Tarceva™ (150 mg PO QD) or placebo. The primary endpoint of the study was to determine overall survival and secondary endpoints included determination of response rate, progression-free survival, quality of life and safety of the agent. The study was designed to detect a 33% improvement in median survival for patients treated with Tarceva™ when compared to placebo. Patient enrollment (N= 731) occurred over a period of 30 months. The baseline patient characteristics were evenly distributed between the two groups. Approximately 92% of all patients had received prior platinum-based chemotherapy. Two-thirds of the patients in both groups were men and about 25% of the patients had an ECOG performance status of 2.

The response rate was 8.8% for patients treated with Tarceva™. The median survival was 6.7 months for patients treated with Tarceva™, which was superior to the 4.7 month survival seen with the placebo group (P< 0.0001). Progression-free survival was also superior with Tarceva™ (2.2 months vs. 1.8 months, P < 0.0001). Stabilization of disease was noted in 35% of the patients treated with Tarceva™, compared to 27% with placebo. The 1-year survival rates were 31% with Tarceva™ and 22% with placebo. The benefit from Tarceva™ was noted regardless of performance status and number of prior treatments. Skin rash was seen in 76% of Tarceva™-treated patients (9% grade 3), but 17% of patients in the placebo group also reported some degree of skin rash. Diarrhea was the other common toxicity noted with Tarceva™ (55%, 6% grade 3). Pneumonitis was noted in 3% of the patients, and mild ocular toxicities were reported in 28% of patients.

Overall, the treatment was well tolerated and only 5% of the patients stopped treatment due to toxicity. Approximately 30% of patients completed 6 cycles of treatment. Improvements in pain, dyspnea, cough and fatigue scores were also noted more frequently in patients treated with Tarceva™. The trial demonstrates superior survival and quality of life for Tarceva™ over placebo for patients with advanced NSCLC following progression with 1 or 2 prior chemotherapy regimens. The impressive results of this study will likely lead to the approval of Tarceva™ for the treatment of patients with recurrent NSCLC.

JBR 21: Results

TALENT & TRIBUTE Trials

Despite its efficacy as a single agent, Tarceva™ failed to improve efficacy when combined with chemotherapy. Two large randomized clinical trials (TALENT & TRIBUTE) were conducted to evaluate whether Tarceva™ given in combination with chemotherapy would improve outcome over chemotherapy alone for patients with previously untreated, advanced and metastatic NSCLC.^[4],[5] The disappointing results of both these trials were also presented at ASCO 2004. In the TALENT study, presented by Gatzemeier and colleagues, the regimen of Platinol® and Gemzar® was administered alone or in combination with Tarceva™.4 The study included 1,172 patients with advanced NSCLC from 164 sites across the world (with the exception of North America). The demographic characteristics were well balanced between study and control. The median overall survival was approximately 10 months for patients in both groups. There were no differences in time-to-progression and 1-year survival for patients who received Tarceva™ in combination with chemotherapy and those treated with chemotherapy alone.

Similar results were noted in the TRIBUTE study, which was conducted in North America and led by Herbst and colleagues.5 The chemotherapy regimen used in this study was the combination of Paraplatin® and paclitaxel. No differences were noted between the study and control in terms of overall survival, time-to-progression and 1-year survival rate. The results of this study confirmed the lack of enhanced efficacy when Tarceva™ was combined with chemotherapy for patients with advanced NSCLC. The reasons for this are not known. An interesting observation from the TRIBUTE study with regard to the smoking status of the patients was that for patients who were never-smokers (less than 100 cigarettes smoked during their lifetime) (N=69), the median survival was 23 months with the Paraplatin®-paclitaxel-Tarceva™ regimen.^[6] Never-smokers treated with chemotherapy (Paraplatin®-paclitaxel) alone, (N=44) had a median survival span of only 10 months. Improvement in outcome survival for never-smokers treated with EGFR-TKI in combination with chemotherapy is supported by other reports, noting the improved efficacy of the EGFR inhibitors in never-smokers.^[7],[8] These data are provocative, but need validation in larger studies. Identification of specific sub-groups of patients most likely to realize substantial benefit with TKIs will allow targeted patient selection in future trials and facilitate development of custom therapies and optimal use of novel agents.

Iressa® Update

Ochs and colleagues presented data on 21,064 patients treated with Iressa® on the Expanded Access Program (EAP).^[9] Patients who failed prior chemotherapy or those unable to tolerate chemotherapy were treated with 250 mg QD of Iressa® in the EAP. The median survival was 5.3 months with a 1-year survival rate of 30%. Twenty percent of the patients received the drug for more than 6 months. The study confirmed the efficacy of Iressa® in the ‘real-life’ setting for patients with advanced NSCLC.  Similar efficacy with Iressa® was noted in the EAP group of patients treated at Pittsburgh.^[10] This retrospective study reported improved survival for patients with a good performance status and those who developed a skin rash with Iressa®. The median survival was 11 months for those who had a rash of any grade compared to 4.5 months for those without a rash in this analysis of 199 patients. Other reports have also suggested higher efficacy of EGFR inhibitors in patients who develop skin rash.^[11],[12] The reasons for this are not clear.  The Eastern Cooperative Oncology Group is planning a study to evaluate if increasing the dose of Tarceva™ until development of skin rash will result in improved efficacy for patients with advanced NSCLC.

EGFR Mutations

Recent reports have demonstrated the presence of mutations in the EGFR among patients who responded to treatment with Iressa®.^[13],[14] In a report by Lynch and colleagues, archived tumor tissue from patients who responded to Iressa® was evaluated for the presence of EGFR mutations.¹³ The study demonstrated ‘gain of function’ mutations in the ATP binding domain of the EGFR, on exons 18-21; eight of nine responders had mutations while none of the seven non-responders had them. The mutations were confined to the tumor tissue and were not present in normal tissues. In separate experiments, investigators demonstrated that cell lines with the mutated transcript exhibited growth inhibition at lower doses of Iressa® compared to normal cells. Furthermore, the cell lines required a ligand to EGF for activation of the EGFR despite the presence of mutations. Thus, the mutation does not confer constitutive kinase activity to these cells, but enhances the response to natural ligands for EGFR.

Concurrently, Paez and colleagues studied tumor tissues from 58 patients with advanced NSCLC from Japan and 61 from the United States for the presence of the EGFR mutations.¹⁴ The prevalence of mutations was higher in Japanese patients when compared to Americans (26% vs. 2%). Mutations occurred more commonly in women (20%) and in patients with adenocarcinoma histology (21%). These differences within patient groups could certainly account for the higher susceptibility to Iressa® that has been noted in these subsets of patients.

EGFR Mutations^13,14

The identification of EGFR mutations represents a major step forward in our knowledge about small molecule EGFR TKIs. As is often the case, a gain in knowledge presents new questions, such as:  Are EGFR mutations necessary for response to therapy with Iressa®? Do tumors from patients who experience stable disease with Iressa® also have mutations? Can patients without the mutations be treated with higher doses of Iressa® in order to achieve benefit? Are there mutations at other sites in the EGFR that could account for the activity of the TKIs? What are the implications of the EGFR mutations for treatment with monoclonal antibodies against the EGFR? While much work remains to be done, it does appear that we may, finally, have identified the real target for EGFR TKIs.

Bronchoalveolar Carcinoma (BAC)

BAC represents a distinct subset of adenocarcinoma of the lung and accounts for about 3-10% of all adenocarcinomas. Patients with earlier stages of BAC tend to have a more indolent course compared to adenocarcinoma. However, BAC appears to be less responsive to systemic chemotherapy.^[15] Based on anecdotal activity of Iressa® for patients with BAC, prospective studies were undertaken to evaluate the role of EGFR TKIs for the treatment of BAC. The South West Oncology Group (SWOG), conducted a single arm phase II study for patients with BAC.^[16] The results of this study were updated by Dr. Jack West for the SWOG at ASCO 2004. Patients (N=145) with advanced BAC who were either chemonaive or had received prior chemotherapy were treated with Iressa® (500 mg PO QD). The higher dose of Iressa® was used because the results of the IDEAL 1 & 2 trials were not available (both of these studies showed no difference in efficacy between the 250 mg and 500 mg dose-levels) at the time of study initiation. The response rates were 19% for previously untreated patients and 9% for those who had received chemotherapy before. The median survival was similar (approximately 13 months) for both  subgroups of patients, but median survival was higher for patients who experienced a skin rash while on therapy with Iressa®  (13 months) compared to those without a rash (5 months). The investigators also evaluated the baseline tumor tissue for various markers of the EGFR pathway for patients who participated in the study. Patients whose tumors had low pMAPkinase and low ErB2 expression had superior survival duration. The expression of EGFR did not correlate with response to Iressa® therapy.

Kris and colleagues reported the preliminary results of their study in which Tarceva™ was administered at a dose of 150 mg QD for patients with a confirmed diagnosis of BAC.^[17] Fifteen out of 59 evaluable patients experienced a partial response (25%). There was also a correlation between smoking status and response to therapy. The response rate was 37% in never-smokers, compared to 15% to patients with a smoking history. The study is ongoing.

Based on the results of these two studies, treatment with an EGFR inhibitor is a reasonable first-line therapy for patients with advanced BAC. Ongoing and upcoming clinical trials will attempt to answer questions arising on the use and application of new agents, such as: How do EGFR inhibitors compare with chemotherapy for patients with BAC? What is the role for monoclonal antibodies against the EGFR for the treatment of BAC? Can chemotherapy be combined with EGFR inhibitors for patients with BAC?

Monoclonal Antibodies Against EGFR

Several monoclonal antibodies that target the EGFR are under development. Cetuximab  (Erbitux®) has already been approved for the treatment of patients with metastatic colorectal cancer. This agent is also currently under study for patients with advanced NSCLC. Rosell and colleagues conducted a randomized phase II study to evaluate the activity of cetuximab in patients with previously untreated advanced NSCLC.^[18] Patients with EGFR-positive tumors were randomized to treatment with Platinol® and Navelbine® alone or in combination with cetuximab. The study included 86 patients with 43 in each arm. The response rate was 35% for patients in the cetuximab arm, compared to 28% with chemotherapy alone. The median survival was 8.3 months with combination therapy and 7 months with chemotherapy alone. The 1-year survival and disease stabilization rates also favored the cetuximab arm. Based on the results of this study, a phase III clinical trial is being planned to compare the efficacy of chemotherapy with or without cetuximab for advanced NSCLC.

The single-agent activity of cetuximab against advanced NSCLC is being studied in a phase II study. Patients with advanced NSCLC who progress following treatment with a platinum-based regimen are eligible. At ASCO 2004, Lynch and colleagues reported the preliminary results of this study.^[19] Two of 33 patients experienced partial responses for a response rate of approximately 6% and 21% had stable disease. Interestingly, both of the responders did not harbor mutations in the EGFR ATP binding domain. It is possible that the presence of EGFR mutation is not critical in predicting response to monoclonal antibodies against the EGFR.

Panitumumab (ABX-EGF) is a fully humanized antibody against the EGFR. Crawford and colleagues reported the results of a phase I study that evaluated panitumumab in combination with Paraplatin® and paclitaxel.^[20] The study included 21 patients with previously untreated advanced NSCLC. Three dose levels of panitumumab were studied. The recommended dose for phase II studies was 2.5 mg/kg administered on a weekly basis in combination with the standard doses of Paraplatin® and paclitaxel. No pharmacokinetic interactions were noted between panitumumab and the chemotherapeutic agents. For the 19 evaluable patients, the median survival was an impressive 17 months, with a median time-to-progression of 7 months. These results are provocative and require confirmation in larger trials. A randomized phase II clinical trial to evaluate the activity of panitumumab in combination with Paraplatin® and paclitaxel has recently been completed. The study randomized patients (N=175) to treatment with Paraplatin® and paclitaxel alone or in combination with panitumumab. The results are eagerly awaited.

The data from the studies of monoclonal antibodies in combination with chemotherapy are very interesting and raise the issue that monoclonal antibodies against the EGFR may be more suited for combination with chemotherapy. Larger randomized clinical trials that will be conducted in the near future will provide the answer to this question.

Other Targeted Agents for NSCLC

Though the development of EGFR inhibitors has been in the forefront of targeted therapies for NSCLC, other targets are also being actively investigated. Avastin™ (bevacizumab), a monoclonal antibody against the vascular endothelial growth factor (VEGF) has  been evaluated in a large phase III trial by the Eastern Cooperative Oncology Group (ECOG 4599). Patients with non-squamous histology were randomized to treatment with carboplatin and paclitaxel alone or in combination with Avastin™. The study has accrued approximately 850 patients and the results are awaited.

Sandler and colleagues performed a phase I/II study to compare the combination of Avastin™ with Tarceva™ in advanced NSCLC  patients who progressed following platinum-based chemotherapy.^[21] The study demonstrated that Avastin™ (15 mg/kg every 3 weeks) can be safely combined with Tarceva™ (150 mg QD). For the 34 patients enrolled in the phase II part of the study, the response rate was 20%. The median survival was 12.6 months, with a 1-year survival rate of 52%. The regimen was well tolerated. Two patients developed grade 3 hypertension and 1 patient had grade 4 pulmonary toxicity. The impressive results of this study have prompted a 3-arm randomized phase II study that will evaluate the combination of Tarceva™ and Avastin™ as second-line therapy for patients with advanced NSCLC. The other 2 arms of the study are Taxotere® plus Avastin™ and Taxotere® alone.

Exisulind (Aptosyn), a non-steroidal anti-inflammatory drug that has also demonstrated the ability to induce apoptosis in NSCLC cells, was evaluated in combination with Paraplatin® and Gemzar® by the Eastern Cooperative Oncology Group in a phase II study.^[22] The results were disappointing, with a median survival of only 7.1 months. The combination of a COX-2 inhibitor with a chemotherapeutic agent or an EGFR inhibitor is being evaluated as second-line therapy for advanced NSCLC. Both celecoxib and rofecoxib have been studied in phase II trials that were reported at ASCO 2004.^{[23],[24],[25]} The preliminary results from these studies have demonstrated the safety of these agents. It will be interesting to see how effective these regimens are when the studies are completed.

Conclusion

In summary, targeted agents, primarily the EGFR inhibitors, have led to a new era in the treatment of patients with NSCLC. Qualitative and quantitative survival benefit has been demonstrated with Tarceva™ as a single agent for advanced NSCLC patients. The discovery of mutations in the EGFR has opened the door to proper selection of patients for therapy with EGFR inhibitors. Monoclonal antibodies against the EGFR have also demonstrated promising activity that warrants further studies of these agents. While an efficacy plateau has been reached with chemotherapy for NSCLC, the surface has barely been scratched for the targeted agents. The exciting developments reported at ASCO 2004 will lead to a number of studies that will enhance our ability to use these targeted agents in a more efficacious manner.

References