Incorporating Novel Agents as Adjuvant Therapy
A pantheon of novel agents are currently being investigated for the treatment of NSCLC. Bevacizumab, a monoclonal antibody that targets angiogenesis, has been shown to improve patient survival when combined with chemotherapy in metastatic disease.10 Erlotinib, a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) pathway, has demonstrated survival benefit for previously treated patients with advanced NSCLC.66 First-line use of the EGFR inhibitors erlotinib and gefitinib in advanced disease is now being investigated, encouraged by the identification of clinical and molecular correlates of response. As novel agents demonstrate activity and benefit in metastatic disease, the question of whether and how to incorporate these agents in the earlier-stage setting remains to be answered. Ongoing trials of several of these agents are designed to address this issue.
Targeting Angiogenesis
ECOG trial 4599 was the first phase 3 trial to show improved survival when a novel agent was added to a standard platinum doublet therapy. A total of 878 patients with stage IIIB/IV nonsquamous NSCLC were randomized to receive either carboplatin, paclitaxel, and bevacizumab or carboplatin and paclitaxel alone. Median survival was 12.3 months in the chemotherapy plus bevacizumab arm compared with 10.3 months in the chemotherapy alone arm, and progression-free survival was 6.2 vs. 4.5 months.11
Angiogenesis is hypothesized to be an important target in earlier stages of lung cancer as well. Activation of angiogenesis is thought to be a discrete event in tumor development that occurs in the early steps of tumori-genesis.67 Antiangiogenic therapies may have the greatest effect against micrometastases, because in preclinical models lower doses are needed to prevent neovascularization than to regress a primary tumor.68
The ECOG is currently leading a trial of bevacizumab in the adjuvant setting, E 1505 (Figure 5). Patients with completely resected stage IB, II, or IIIA NSCLC will be randomized to receive adjuvant chemotherapy with or without bevacizumab. Target accrual is 1500 patients. Based on the results of CALGB trial 9633, enrollment will be limited to patients with stage IB tumors 4 cm or larger, because this was the subgroup in CALGB 9633 who, in post hoc analysis, appeared to benefit from adjuvant therapy.69 Allowed chemotherapy regimens will be cisplatin-vinorelbine, cisplatin-docetaxel, and cisplatin-gemcitabine. The primary endpoint is overall survival, with secondary endpoints of disease-free survival and toxicity. Analysis will be stratified based on chemotherapy regimen, squamous vs. nonsquamous histologic findings, and sex. This trial is currently accruing patients.
Neoadjuvant strategies incorporating bevacizumab are being tested as well and may provide insight into responses to such regimens. The Bevacizumab and Chemotherapy for Operable NSCLC (BEACON) trial at Memorial Sloan-Kettering Cancer Center is a phase 2 trial of patients with resectable stage IB to IIIA NSCLC. Patients with nonsquamous, peripheral tumors are given cisplatin, docetaxel, and bevacizumab before surgery, whereas those with squamous or central tumors are given cisplatin and docetaxel. Patients who experience at least a 10% reduction in tumor size based on World Health Organization criteria receive 2 more cycles of treatment (bevacizumab is not given in the final cycle). Bevacizumab is given for a year after surgery. The primary objective is to determine the rate of downstaging, with secondary objectives of determining survival and toxicity. A similar neoadjuvant strategy is being tested at the University of California, San Francisco, with a phase 2 trial of patients with non-squamous stage IB to IIIA NSCLC being given carboplatin, docetaxel, and bevacizumab before surgery.
Numerous vascular EGFR tyrosine kinase inhibitors are in development for the treatment of metastatic NSCLC. Examples include ZD6474, AZD2171, sunitinib, and sorafenib. Like bevacizumab, it is possible that these drugs could be tested in the adjuvant setting in the future, particularly if results in late-stage disease are promising.
Targeting EGFR
Erlotinib is currently approved for use in the second- and third-line setting in advanced NSCLC. Approval was based on BR.21, a randomized phase 3 trial that showed that erlotinib has survival benefit in previously treated patients with advanced NSCLC.66 Although gefitinib had reasonable response rates in phase 2 studies,70,71 a survival benefit was not shown in the randomized phase 3 trial Iressa Survival Evaluation in Lung Cancer (ISEL),72 and gefitinib in the United States is currently only used in patients who are having ongoing benefit or through clinical trials. In addition to clinical correlates of response to EGFR inhibition, mutations in the EGFR gene have been detected that appear to correlate with response and survival.73,74
Enthusiasm for the adjuvant use of EGFR inhibitors has been tempered by the results of Southwest Oncology Group (SWOG) trial 0023, which were reported at the 2005 meeting of the American Society of Clinical Oncology.75 Patients with inoperable stage III NSCLC were initially treated with cisplatin, etoposide, and radiation, followed by consolidation docetaxel. Patients were then randomized to maintenance gefinitib vs. placebo. This study was stopped early when an interim analysis showed that gefitinib therapy was very unlikely to improve survival even if complete accrual was reached and, in fact, suggested a nonsignificant decrement in survival in the gefitinib arm.75 Although SWOG 0023 was not an adjuvant trial, it raised the question of whether maintenance EGFR inhibitor therapy has benefit. Indeed, the National Cancer Institute of Canada closed BR.19, a phase 3 randomized trial of gefitinib vs. placebo in patients with resected stage IB, II, and IIIA NSCLC, at least partly based on consideration of SWOG 0023 and ISEL. A Japanese phase 3 study of gefitinib vs. placebo in patients with resected stage IB to IIIA NSCLC was also attempted, but this was closed early because of toxicity.76
Adjuvant Studies
Several trials are currently under way directly testing erlotinib in the adjuvant setting. RADIANT is a phase 3 randomized study to evaluate the effectiveness of erlotinib vs. placebo after surgical resection of stage IB to IIIA NSCLC among patients whose tumor is EGFR positive by immunohistochemical analysis or fluorescence in situ hybridization (Figure 6). Patients may have up to 4 cycles of chemotherapy after surgery and would start taking erlotinib either within 6 months of surgery if adjuvant chemotherapy is given or within 3 months of surgery if adjuvant chemotherapy is not given. Patients will be randomized 2:1 to receive erlotinib or placebo for 2 years. Planned accrual is 945 patients.77
In a population that is not selected by EGFR status, a pilot study at M.D. Anderson Cancer Center treats patients with stage I, II, or IIII NSCLC after surgical resection with chemotherapy (cisplatin-docetaxel for 3 cycles) followed by erlotinib for a year. A major unanswered question is the optimal adjuvant treatment of patients who have EGFR mutation-positive tumors.
Neoadjuvant Studies
Neoadjuvant approaches are being tested as well, and several phase 2 studies are ongoing to investigate the effect of erlotinib or gefitinib therapy on tumor size preoperatively. Memorial Sloan-Kettering Cancer Center presented results from such a trial at the 2006 meeting of the American Society of Clinical Oncology. Patients with stage I or II NSCLC with either adenocarcinoma with BAC features or a less than 15-pack-year smoking history were treated with gefitinib for 21 days followed by CT reevaluation and surgery. If response was seen, defined as a 25% reduction or greater in tumor size after 3 weeks of gefitinib, or if patients were EGFR mutation positive, gefitinib was given adjuvantly as well. As of June 2006, 23 patients were enrolled in the trial. Nine had response to neoadjuvant gefitinib, with 5 having EGFR mutations and 4 not having these mutations.78
In another ongoing neoadjuvant trial at New York Cornell Center, erlotinib is being given in a phase 2 trial to patients with stage I or II NSCLC for 3 weeks followed by surgery at week 4. Adjuvant chemotherapy can be given at the discretion of the treating physician. The primary aim of the study is to assess whether erlotinib can shrink tumors.
Conclusion
Numerous trials are currently under way to test the addition of novel targeted agents in the adjuvant setting. Whether this improves survival in addition to adjuvant chemotherapy alone or whether there are selected patient populations who may benefit remains to be seen.
Dr. Heist: Most of the trials incorporating novel agents as adjuvant therapy are either ongoing or planned. In fact, the study schemas of some of these trials have been changed based on some of the study results. For instance, in the adjuvant bevacizumab study, only stage 1B lesions greater than 4 cm are included.
Dr. Lynch: A couple of neoadjuvant studies of bevacizumab are ongoing, including some at Memorial Sloan-Kettering.
Dr Azzoli: Our study will determine whether bevacizumab is safe to deliver to early-stage patients, both before and after surgery. It will also measure the rate of lymph node clearance when you add bevacizumab to chemotherapy prior to surgery.
Dr. Lynch: Basically, bevacizumab and erlotinib are the 2 drugs that are the farthest along in the metastatic setting, but it is important to let people know that there are no firm data yet on adjuvant use.
Dr. Lanuti: What are we recommending to community oncologists about mutational analysis for EGFR?
Dr. Lynch: EGFR testing is helpful if you have metastatic disease and you're deciding on first-line or maybe even second-line therapy. Beyond that, it's really hard to know. In the adjuvant setting I have never treated somebody with adjuvant erlotinib. A genotype-directed adjuvant study makes sense in my opinion. Aside from that I don't have a clear rule for mutational testing yet. What do you test?
Dr. Heist: I test for the same reasons. One caveat is that there are some clinical predictors too. Sometimes you hedge with whether you're going to go with your clinical predictors for response or the EGFR mutation.