Welcome to the October edition of OncoFacts. I am going to be discussing lung cancer protocols as we continue in our series of emerging and important ongoing clinical trials in the United States for different major cancer types.

Adjuvant NSCLC Trials

RADIANT: A multi-center, randomized, double-blind, placebo-controlled, phase III study of single-agent erlotinib following complete tumor resection with or without adjuvant chemotherapy in patients with stage IB-IIIA non-small cell lung carcinoma who have EGFR-positive tumors

Why is this trial being done? Erlotinib is an orally active, potent, selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Erlotinib was approved in November 2004 by the FDA for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen.

Historically, the standard of care for patients with early-stage NSCLC has been complete resection of the tumor. The use of adjuvant chemotherapy following surgery has been the subject of intense controversy over the last decade. The controversy continued until several studies reported that the addition of platinum-based, adjuvant chemotherapy improves disease-free survival (DFS) and OS in patients with successfully resected NSCLC.

Four adjuvant trials have demonstrated a statistically significant increase in patient survival and/or DFS. In the International Adjuvant Lung Cancer Trial (IALT), patients were randomized to a treatment group, where they received 3 or 4 cycles of cisplatin-based chemotherapy, or to a control group. The chemotherapy options were vindesine, vinblastine, vinorelbine, or etoposide in combination with cisplatin. The National Cancer Institute of Canada (NCIC) study JBR.10 randomized patients between 4 cycles of vinorelbine plus cisplatin versus no adjuvant chemotherapy. In the Cancer and Leukemia Group B (CALGB) study, patients were randomized to receive 4 cycles of paclitaxel and carboplatin or to observation. The Adjuvant Navelbine International Trialist Association (ANITA) study randomized patients between 4 cycles of cisplatin plus weekly vinorelbine or observation. Despite the statistically significant improvement in OS and disease-free survival (DFS) associated with adjuvant chemotherapy, there is a continued need to improve survival outcomes for early stage disease. Novel therapies with potentially lower toxicities, such as the oral EGFR inhibitors, may have a role in this setting.

As a single agent in patients who failed at least 1 prior chemotherapy regimen for advanced or metastatic NSCLC, erlotinib has been shown to increase both OS (HR: 0.73) and PFS (HR: 0.59) and to lengthen time to deterioration of lung cancer symptoms. Survival of patients with EGFR-positive tumors by immunohistochemistry (IHC [HR: 0.68]) and by FISH (HR: 0.43) was longer in the erlotinib group than in the placebo group.

The current trial will evaluate whether treatment with erlotinib increases the DFS of patients with NSCLC with EGFR-positive tumors by IHC and/or FISH following complete surgical resection. In addition to evaluating the treatment effect of erlotinib on the DFS for the overall randomized population, a separate analysis for the purposes of the filing in the US will be conducted in the subset of patients determined to be EGFR-positive by FISH.

Primary Objective: The primary objectives of this study are to assess the efficacy of single-agent, oral, once daily, erlotinib (150 mg/day) at increasing the DFS following complete surgical resection with or without adjuvant chemotherapy in the following patient populations:

• Overall population: Patients who have EGFR-positive tumor tissue (by IHC and/or FISH)
• Selected subset population:
  • For regulatory submission in the US: Patients who have EGFR-positive tumor tissue by FISH.
  • For regulatory submission in the rest of the world (ROW): The subset population will be prospectively defined in the statistical analysis plan before the first interim analysis. The reason for delaying the definition of the subset population until that time is that more information on which biomarkers are most suitable for identifying the subgroups of patients benefiting most from erlotinib therapy will become available from currently ongoing studies at that time, and therefore, the definition will be more informed than at the time of writing this protocol.

The secondary objectives, to be analyzed for both patient populations, are to:

• Compare the OS by study arm
• Evaluate the safety of erlotinib
• Explore the prognostic and predictive value of EGFR-related biomarkers and other biomarkers that may be associated with clinical outcomes following treatment with erlotinib

Who is eligible? To be eligible for participation in the screening portion of this study, patients must meet all of the following inclusion criteria:
A. Histologically confirmed diagnosis of stage IB-IIIA NSCLC.

• Patients with bronchoalveolar carcinoma that presents as a single, solitary, discrete nodule or mass may be included.
• Patients with preoperative radiological evidence of N2 disease by either positron emission tomography (PET) or CT scan (ie, radiological evidence of metastasis to ipsilateral mediastinal and subcarinal lymph nodes) that is confirmed as N2 disease histologically are excluded. However, patients determined to have microscopic N2 disease, that was not radiologically obvious preoperatively, can be included.
• Patients with histologically confirmed intralobar satellites (T4) are not eligible for this study.

B. Patients must have had a complete surgical resection defined as the appropriate pulmonary parenchymal resection including lobectomy, bilobectomy, sleeve lobectomy, and pneumonectomy with histologically confirmed negative bronchial margins. Patients treated by a segmentectomy or wedge resection are not eligible for this study. Additionally, patients must have had a nodal dissection of 2 separate mediastinal nodal stations or nodal sampling of 2 separate mediastinal nodal stations (levels 4, 7, and 9 for right-sided tumors and levels 5, 6, 7, and 9 for leftsided tumors are strongly suggested).

C. Age ≥18 years

D. Written informed consent to participate in the screening portion of the study.

Inclusion Criteria for Treatment: To be eligible for participation in the on-treatment portion of this study, patients must continue to meet all of the screening inclusion criteria as well as all of the following treatment inclusion criteria:

1. Primary tumor tissue from the patient’s surgical resection must be analyzed by the central laboratory and determined to be EGFR-positive by IHC and/or FISH. This is a mandatory requirement for entry.
2. Patients may have completed up to a total of 4 cycles of adjuvant chemotherapy using a standard (non-investigational), 2-drug, platinum-based regimen OR may not have received adjuvant chemotherapy for NSCLC. Patients who have received adjuvant chemotherapy must have recovered from the acute side effects before randomization
3. Ability to be randomized within the following timelines: 6 months (≤180 days) from the day of surgical resection for patients who receive adjuvant chemotherapy and 3 months (≤90 days) from the day of surgical resection for patients who do not receive adjuvant chemotherapy
4. Ability to take oral medications

Study Schema: Patients with completely resected stage IB-IIIA NSCLC who have EGFR-positive tumor tissue by IHC and/or FISH, who have completed up to 4 cycles of standard (non-investigational), 2-drug, platinum-based, adjuvant chemotherapy or who are chemonaïve will be eligible for randomization and treatment. Patients will receive erlotinib or placebo orally, once daily for 2 years or until 1 of the following: relapse, death, patient request or investigator decision to discontinue study drug, or intolerable toxicity. The randomization is 2:1 in favor of receiving erlotinib.

Statistical Outcome: This study is based on an event-driven analysis with at least 500 events required at the time of the final analysis in the overall population. The planned enrollment is a total of 945 eligible patients (2:1 randomization; 630 on the erlotinib arm, and 315 on the placebo arm) with approximately 330 (35% of total) patients in the selected subset population, estimated from the percentage of patients who have EGFR-positive tumors by FISH.

Approximately 1730 NSCLC patients with complete surgical resection will need to be screened to randomize 945 eligible patients.

The study will have 80% power to detect a 33% improvement in median DFS (HR = 0.75) with erlotinib (2-sided log-rank test with 2.5% level of significance) for all randomized patients. The final analysis of DFS will be approximately 4 years after the last patient is randomized, and at least 500 events are required at the time of final analysis.

For more information about this trial, please visit ClinicalTrials.gov. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00373425?term=Radiant+trial&rank=1. Accessed October 5, 2009.

References

1. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-132.
2. Hirsch FR, Bunn PA Jr. Epidermal growth factor receptor inhibitors in lung cancer: smaller or larger molecules, selected or unselected populations? J Clin Oncol. 2005;23(36):9044-9047
3. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-144.

E1505: Chemotherapy with or without bevacizumab in treating patients with stage IB, stage II or stage IIIA NSCLC that was removed by surgery.

Why is this trial being done? As stated with the previous trial, the standard of care for resected stage II-IIIA NSCLC includes adjuvant chemotherapy. The ECOG 4599 trial evaluated paclitaxel plus carboplatin with or without bevacizumab in patients with advanced NSCLC and showed a 2-month survival advantage (10.3 months vs 12.3 months). E1505 is being performed to assess the advantage of the addition bevacizumab to chemotherapy in the adjuvant setting.

Primary Objective: The primary objective is to compare the OS of patients with completely resected stage IB – IIIA NSCLC treated with adjuvant chemotherapy with or without bevacizumab.

Secondary objective: The secondary objectives include comparison of the DFS and toxicity of the regimens. In addition, the study will perform analysis of tissue and blood to establish factors that predict clinical outcome in patients treated with these regimens and to determine whether smoking status is linked to outcome.

Who is eligible? Patients must have a resected stage IB-IIIA NSCLC. Patients with stage IB must have tumors >4 cm. The surgical resection must have been completed within the last 6-12 weeks.

Study Schema: The study will enroll 1500 patients with stage IB-IIIA resected NSCLC, stratified by stage, histology, gender and chemotherapy regimen. Investigators may choose among 3 different cisplatin-based chemotherapy regimens. The regimen must be chosen prior to the randomization to bevacizumab.

Arm I: Patients receive 1 of 4 chemotherapy regimens

• Regimen 1: Patients receive vinorelbine days 1 and 8 and cisplatin day 1
• Regimen 2: Patients receive docetaxel along with cisplatin on day 1
• Regimen 3: Patients receive gemcitabine day 1 and 8 and cisplatin day 1
• Regimen 4: (Nonsquamous histology only) Patients receive pemetrexed and cisplatin day 1.

In all regimens, treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Arm II: Patients receive chemotherapy as in arm I. Patients also receive bevacizumab IV every 21 days for up to 1 year.

Statistical Outcome: 1500 patients will be enrolled to the study that has an 85% power to detect a HR of 0.79 (26.5% OS advantage) with the addition of bevacizumab. The final collection date for a survival outcome is estimated to occur in July 2015.

For more information about this trial, please visit ClinicalTrials.gov. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00324805?term=E1505&rank=1. Accessed October 5, 2009.

I hope you enjoyed this edition of OncoFacts looking at ongoing clinical trials for lung cancer.

OncoFacts™ Editor:

Christy Russell, MD

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