In an accompanying editorial, Nasser H. Hanna, MD, of Indiana University, Indianapolis, suggested that although the question of two chemotherapy drugs vs one in this setting made sense at the time GOIRC 02-2006 was initiated, advances in understanding of the heterogeneity of non–small cell lung cancer (NSCLC) and in targeted therapies have reduced the value of these types of comparisons in advancing therapeutics. Dr. Hanna noted that a recent meta-analysis of two drugs vs one drug in second-line treatment of advanced NSCLC indicated that response rates and progression-free survival were improved with a two-drug approach, but overall survival was not improved and toxicity was increased with combination treatment.1
Are We Asking the Right Questions?
“Do we need additional studies of this nature?” Dr. Hanna asked. “In a time of substantial scientific advances, are we still asking the right questions? At the time the trial by Ardizzoni et al was conceived, my answer would have been yes. In 2012, the answer is no.”
He continued, “Our understanding of lung cancer has markedly advanced since the conception of [this] trial. Lung cancer is no longer only thought of as small-cell lung cancer, in which chemotherapy and radiation have substantial benefits, albeit short-lived in most patients, and NSCLC, in which chemotherapy and radiation have modest benefits. We must now think of NSCLC as nonsquamous non–small cell or squamous cell lung cancer. We must consider several issues including whether patients are bevacizumab [Avastin] eligible, their smoking history, and the presence of molecular abnormalities such as EGFR mutation, ALK gene rearrangement, ROS-1 gene rearrangement, or KRAS mutation. Should we give patients maintenance therapy, and if so, will it be switch maintenance, whereby we change to a different drug before disease progression in patients receiving first-line therapy, or continuation maintenance, whereby we continue one or more drugs given in the first-line therapy until disease progression or intolerable adverse effects? These are the key clinical questions that must be addressed for patients with advanced NSCLC.”
Further Considerations
Each of these questions continues to have an impact on development of approaches to treatment-naive patients with advanced lung cancer. Additional factors that need to be considered for second-line treatment include whether molecular status at diagnosis affects choices of second-line treatment or even reflects status of disease at progression and whether patients should undergo repeat biopsy at progression.
As stated by Dr. Hanna, given the array of new targets and targeted agents, researchers are now designing trials that ask which drugs should be used for which patients, rather than simply whether one vs two drugs should be used or how much of each drug should be used. He cites as an example in this regard a report from an MD Anderson Cancer Center Initiative for personalized medicine in which patients with identified molecular targets were matched with phase I trials of target-specific drugs; response rates were 27% in target-matched patients and 5% in empirically treated patients.2
With regard to the pooled analysis finding of overall and progression-free survival benefit with combination treatment in patients with squamous cell cancer, Dr. Hanna asked whether, given that pemetrexed (Alimta) is believed to have minimal activity in squamous cell disease, the outcome should be considered as providing a rationale for using carboplatin alone in this setting. He stated, “Because of the spoils of testable hypotheses today, it is doubtful that this question will or should be answered in a separate clinical trial.”
Conclusions
Dr. Hanna concluded, “The understanding of the molecular underpinnings of NSCLC has brought hope and more successful treatment, including the discovery of epidermal growth factor receptor tyrosine kinase inhibitors for patients with EGFR mutations and anaplastic lymphoma kinase inhibitors for patients with ALK gene rearrangements. For these patients, gains in survival are not measured in weeks or months but, in some cases, years. History teaches us that substantial gains in the treatment of NSCLC will not come from minor manipulations in dose, schedule, and sequencing of these newer agents, just as it has not for classic chemotherapy drugs. As the saying goes, those that do not know their history are destined to repeat it.” ■
Disclosure: Dr. Hanna has received research funding from AstraZeneca and Eli Lilly.
References
1. Hanna NH: Two drugs versus one drug in non–small-cell lung cancer: Are we asking the right questions (editorial)? J Clin Oncol 30:4454-4455, 2012.
2. Tsimberidou AM, Iskander NG, Hong DS, et al: Personalized medicine in a phase I clinical trials program: The M.D. Anderson Cancer Center Initiative. 2011 ASCO Annual Meeting. Abstract CRA2500. Presented June 3, 2011.
