Scientific Highlights from Other Meetings

10th International Lung Cancer Congress

Kohala Coast, Hawaii
June 17-20, 2009

By David Gandara, MD
Co-chair, 10th International Lung Cancer Congress
University of California, Davis Cancer Center

Roy S. Herbst, MD, PhD
Co-chair, 10th International Lung Cancer Congress
The University of Texas M. D. Anderson Cancer Center

David J. Lee, PhD
Physicians’ Education Resource

The 10th Annual International Lung Cancer Congress, organized by David Gandara, MD, of the University of California, Davis, and Roy Herbst, MD, PhD, of M. D. Anderson Cancer Center, highlighted recent advances in the diagnosis and treatment of thoracic malignancies, including data presented at the 2009 ASCO Annual Meeting. Approximately 200 attendees gathered for the event, with significant representation of physicians from European and Asian lung cancer cooperative groups. Morning sessions featured state-of-the-art didactic lectures followed by the presentation of recent research results, expert debates, and case-based discussions. At afternoon workshops, renowned oncology experts discussed novel therapeutic agents in the pipeline and conducted a multidisciplinary tumor board. During a special session, representatives from North American, European, and Japanese lung cancer cooperative groups presented updates from ongoing clinical trials and discussed potential intercontinental scientific collaborations.

Early-stage Non-small Cell Lung Cancer
Heather Wakelee, MD, of Stanford University, discussed the (Neo)Adjuvant Taxol/Carboplatin Hope (NATCH) trial evaluating preoperative or postoperative carboplatin/paclitaxel or observation in patients with resected non-small cell lung cancer (NSCLC).¹ The results demonstrated no significant difference in the primary endpoint of five-year disease-free survival between the patients who were randomized to surgery alone, adjuvant, or neoadjuvant chemotherapy. Of note is the fact that approximately 75% of the patients on this trial had clinical stage I disease, a patient subgroup that has been shown to receive the least benefit from perioperative chemotherapy.

Maintenance Therapy
Karen Kelly, MD, of the University of Kansas, presented the results of phase III studies on maintenance therapy, also referred to as early second-line therapy, in patients with advanced NSCLC. These studies investigated pemetrexed, single-agent erlotinib (Sequential Tarceva^® in Unresectable NSCLC [SATURN] trial), and the addition of erlotinib to maintenance bevacizumab (AVF3671g [ATLAS]) in patients who achieved a response or stable disease after a frontline regimen.^2-4 All three trials met the primary endpoint of improved progression-free survival compared to the placebo arm. Pemetrexed also demonstrated improved overall survival compared to placebo; with regards to efficacy, the benefit was restricted to patients with nonsquamous histology. In the SATURN trial, an overall survival benefit for erlotinib versus placebo was announced in a press release, with details to be presented at the 13th World Conference on Lung Cancer. Survival information from the ATLAS trial is still pending.

Epidermal Growth Factor Receptor Inhibitors
Paul A. Bunn, Jr., MD, of the University of Colorado, summarized the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patient populations selected for response to this class of agents. This trial, known as the Iressa™ Pan-Asia Study (IPASS) study, was conducted in Asia and compared gefitinib to carboplatin/paclitaxel in never smokers or light ex-smokers with adenocarcinoma.⁵ In this trial, gefitinib demonstrated superior progression-free survival compared to chemotherapy; however, biomarker analysis revealed that even in these patients clinically selected to favor EGFR TKI therapy, only those with EGFR mutations derived a significant progression-free survival benefit from gefitinib compared to chemotherapy.

Román Pérez-Soler, MD, from the Albert Einstein College of Medicine, reviewed recent data on the use of EGFR antibodies in patients with lung cancer. Biomarker analyses were performed to examine correlations between efficacy and KRAS mutations or EGFR status (mutations, gene copy number, protein expression). Unlike what was observed in colorectal cancer, retrospective analyses of the First-line in Lung Cancer with Erbitux^® (FLEX) and BMS-099 trials did not show KRAS mutations as a negative predictive marker for cetuximab in NSCLC.^6,7 Additionally, EGFR gene copy number by fluorescence in situ hybridization (FISH) did not correlate with treatment outcomes with cetuximab in either trial. However, these biomarker analyses were limited in statistical power by the small sample size.

Multidisciplinary Tumor Board
A new activity that had its debut at the event was a multidisciplinary tumor board held during one of the afternoon workshops. The distinguished panel included surgeon Harvey I. Pass, MD, of the New York University School of Medicine, radiation oncologist Walter Curran, Jr., MD, of Emory University School of Medicine, and medical oncologist Martin Edelman, MD, of the University of Maryland. Cases included resectable stage III disease, earlystage disease with poor pulmonary function, and prophylactic cranial irradiation in stage III disease. This session fostered interaction between community physicians and the multidisciplinary panel of lung cancer experts.

Cooperative Group Session
One of the unique features of the International Lung Cancer Congress is the special session for cooperative groups from the United States, Europe, and Asia to present current and planned clinical studies. Senior representatives from each cooperative group presented an overview of their group’s activities in various disease settings, thereby stimulating interaction between the different groups. The proceedings of this session will be summarized in a special peer-reviewed manuscript to be published in an upcoming issue of Clinical Lung Cancer.

References

1. Felip E, Massuti B, Alonso G, et al. J Clin Oncol. 2009; 27(suppl): 382s (Abstract 7500).
2. Belani CP, Brodowicz T, Ciuleanu T, et al. J Clin Oncol. 2009; 27(suppl):806s (Abstract CRA8000).
3. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. J Clin Oncol. 2009; 27(suppl):407s (Abstract 8001).
4. Miller VA, O’Connor P, Soh C, et al. J Clin Oncol. 2009; 27(suppl):799s (Abstract LBA8002).
5. Fukuoka M, Wu Y, Thongprasert S, et al. J Clin Oncol. 2009; 27(suppl):408s (Abstract 8006).
6. O’Byrne KJ, Bondarenko I, Barrios C, et al. J Clin Oncol. 2009; 27(suppl):408s (Abstract 8007).
7. Khambata-Ford S, Harbison C, Woytowitz D, et al. J Clin Oncol. 2009; 27(suppl):412s (Abstract 8021).

CALGB Summer Group Meeting

By Jeffrey Peppercorn, MD, MPH
Assistant Professor of Medicine
Division of Medical Oncology
Duke University Medical Center

The Cancer and Leukemia Group B (CALGB) 2009 Summer Group Meeting highlighted the role of cooperative groups in biomarker studies and updated members on recent progress in clinical trials. The new Group Chair-Elect was announced: Monica Bertagnolli, MD, Chief of Surgical Oncology at Brigham and Women’s Hospital and a researcher into the molecular biology of gastrointestinal cancers at the Dana Farber Cancer Institute, will take on the mantle of leadership from Richard L. Schilsky, MD, Professor of Medicine and Associate Dean for Clinical Research at the University of Chicago and ASCO Immediate Past President. Gini Fleming, MD, of the University of Chicago, was announced as the Group Vice Chair Designee.

The Role of Cooperative Groups in Biomarker Studies
During the Plenary Session, Dr. Schilsky presented a review of CALGB involvement in the development of clinical biomarkers, from exploratory studies to randomized trials using biomarkers to guide therapy. He highlighted the work of Dr. Bertagnolli in early stages of biomarker development. Dr. Bertagnolli and colleagues demonstrated that among patients with stage III colon cancer and a DNA mismatch repair deficiency in the primary tumor, outcomes were improved with the use of an adjuvant chemotherapy regimen containing irinotecan, moving the management of colorectal cancer further in the direction of personalized therapy.¹ In addition, Dr. Schilsky reviewed recently published studies by Daniel F. Hayes, MD, of University of Michigan, and colleagues that explored the role of endocrine receptor and HER2 biomarkers in predicting benefit from sequential taxane therapy after anthracyclines for adjuvant breast cancer management. ² Also discussed was the work of Martin J. Edelman, MD, of Greenebaum Cancer Center, and colleagues in demonstrating the negative prognostic impact of COX-2 in non-small cell lung cancer, leading to development of a randomized trial of COX-2 inhibition, CALGB 30203, in select patients.³

The cooperative groups are also playing an important role in conducting large multi-group trials involving biomarker validation. These trials are designed to demonstrate that a biomarker can guide choice of therapy and improve outcomes for patients on the basis of more personalized treatment approaches. One example is N0723, a study involving the North Central Cancer Treatment Group (NCCTG), CALGB, the Eastern Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG), the National Cancer Institute of Canada (NCIC), and collaboration with partners in industry to evaluate the role of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, in patients with and without overexpression of EGFR who receive pemetrexed as second-line therapy for metastatic non-small cell lung cancer. Another example is CALGB 30506, a randomized trial designed to evaluate the ability of genomic prognostic model developed by Anil Potti, MD, of Duke University, and colleagues to identify patients with stage I non-small cell lung cancer as candidates for adjuvant chemotherapy.⁴

Dr. Schilsky noted the challenges involved in biomarker studies, including the adequacy of biospecimen collection, sources of funding for research, regulatory requirements, and developing contractual agreements with commercial partners. However, cooperative groups have demonstrated that they have the capacity to conduct large biomarker studies, including formal validation trials, which can translate the emerging understanding of molecular differences between cancers into more personalized selection of therapy that can improve outcomes for patients.

New Understanding of an Old Drug
The theme of personalized medicine continued in the Breast Cancer Session, in which David Flockhart, MD, PhD, of Indiana University School of Medicine, spoke on the emerging evidence for the importance of the CYP2D6 genotype in tamoxifen metabolism for patients with breast cancer. Tamoxifen is metabolized to endoxifen by a hepatic enzyme, CYP2D6, and patients have genetic differences that can lead to greater or lesser degrees of metabolism. These differences have been shown to correlate with outcomes, though much of the work to date has been in small retrospective studies. ⁵ Dr. Flockhart discussed two studies presented at the 2009 ASCO Annual Meeting that evaluated the impact of concurrent use of tamoxifen and CYP2D6 inhibitors on breast cancer outcomes. In a study conducted by Dr. Flockhart and colleagues⁶ involving the Medco pharmaceutical claims database, patients receiving tamoxifen and a CYP2D6 inhibitor (typically one of the serotonin-specific reuptake inhibitors used for depression) had a higher risk of breast cancer recurrence over two years compared to those on tamoxifen alone (13.9% vs. 7.5%; HR 1.92, 95% CI 1.33–2.76, p<0.001).

Although a different group of investigators from the Netherlands conducted a similar study involving a pharmacy database and found no clear association between concurrent prescriptions for tamoxifen, CYP2D6 inhibitors, and differences in breast cancer outcomes, Dr. Flockhart noted both that methodological limitations restrict our ability to interpret the second study, and that at this time the potential for an adverse effect from the use of strong CYP2D6 inhibitors among patients taking tamoxifen for breast cancer suggests a reason to avoid overlap of these drugs until the data becomes more clear.⁷ In discussion, it was noted that some oncologists are currently using CYP2D6 testing to evaluate the potential benefits of tamoxifen, but the majority are waiting for the pending results of large randomized trials that will allow us to better determine if testing and alternative treatment strategies are appropriate for women with breast cancer and poor metabolism of tamoxifen.

Patient-reported Outcomes
Clinical trials are designed to test the safety and efficacy of a drug, and the severity, number, and frequency of adverse events are carefully recorded in all trials. However, some have questioned whether the experience of the patients participating in clinical trials is sufficiently reported such that future clinicians and patients can consider the tolerability of therapy from the patient’s perspective when making treatment decisions. Ethan Basch, MD, of Memorial Sloan- Kettering Cancer Center and a leader in the field of patient-reported outcomes (PRO) research, presented an update on national efforts to incorporate PRO into clinical trials and clinical practice. Dr. Basch reviewed data from his study published in Lancet Oncology demonstrating that there may be differences in the perception of the frequency and severity of symptoms among patients and physicians, particularly for more subjective symptoms, and that collection of PRO can improve our understanding of the side effects of treatment.⁸ Although there remains discussion of the value of adding PRO to the U.S. Food and Drug Administration (FDA) label of new drugs, which currently include investigator-reported outcomes, Dr. Basch argued that for many decisions we can consider expert opinion and public opinion and still draw meaningful conclusions.

Finally Dr. Basch presented the design of CALGB 70501, a companion trial linked to several CALGB randomized trials designed to assess the feasibility of collecting patient-reported outcomes within cooperative group trials and to compare patient vs. clinician reporting of outcomes. Patients from any of eight trials can participate in CALGB 70501.

References

1. Bertagnolli MM, Niedzwiecki D, Compton CC, et al. J Clin Oncol. 2009;27:1814-1821.
2. Hayes DF, Thor AD, Dressler LG, et al. N Engl J Med. 2007;357:1496-1506.
3. Edelman MJ, Watson D, Wang X, et al. J Clin Oncol. 2008;26:848-855.
4. Potti A, Mukherjee S, Petersen R, et al. N Engl J Med. 2006;355:570-580.
5. Goetz MP, Rae JM, Suman VJ, et al. J Clin Oncol. 2005;23:9312-8.
6. Aubert RE, Stanek EJ, Yao J, et al. J Clin Oncol. 2009;27:18s (Abstract CRA508).
7. Dezentje V, Van Blijderveen NJ, Gelderblom H, et al. J Clin Oncol. 2009;27:18s (Abstract CRA509).
8. Basch E, Iasonos A, McDonough T, et al. Lancet Oncol. 2006;7:903-09.