Leveraging genetics and technology in EGFR-mutated lung cancer
Activating mutations in the epidermal growth factor receptor (EGFR) occur in a unique subset of patients with non-small cell lung cancers (NSCLC). In advanced disease, the response rates of these patients to EGFR inhibitors are as high as 75% in prospective trials and 100% in retrospective analyses. Such extraordinary results have led Lecia Sequist, MD, MPH (MGH), to initiate the first study of the EGFR inhibitor erlotinib (Tarceva) in early stage patients with EGFR mutations whose NSCLC has been resected; a novel feature of the trial is the use of new chip technology to capture circulating tumor cells (CTCs) for genetic analysis.
Objectives and importance of this trial
This phase II trial is the earliest adjuvant study in lung cancer to select exclusively for patients with confirmed activating EGFR mutations (either the exon 19 deletion or exon 21 L858R point mutation) and to intervene with a targeted therapy — oral erlotinib daily for up to two years. The primary objective of the study is to assess disease-free survival and, secondarily, to determine overall safety and tolerability of adjuvant erlotinib among these patients.
With the help of a microchip-based device developed at MGH, investigators are also examining the mechanisms of de novo and acquired resistance in patients whose tumors progress while on erlotinib, which have not been studied before in this population. The CTC chip is the size of a standard microscope slide; on it are etched approximately 80,000 micro-posts coated with antibodies to proteins expressed on tumor cells. As a pneumatic pump propels blood across the chip, the CTCs adhere to the posts. The exquisitely sensitive device detects one CTC per billion blood cells, counts the number of CTCs, and gently extracts their fragile DNA for EGFR mutation analysis.
To study CTCs over time, investigators obtain blood samples from patients at baseline and every six months thereafter. “If cancer recurs, we’re hoping the CTC analysis may shed light on the genetics of recurrence in this population,” says Sequist, the overall PI of the multi-site study. Previous research on resistance to EGFR inhibitors, done primarily in patients with metastatic disease, has shown that the T790M mutation accounts for about 50% of patients who progress while on Tarceva, while MET amplification accounts for another 20%, explains Sequist. “We’re hoping to understand what happens in the remaining 30% of cases.”
In the event of recurrence, patients’ biopsies, which are optional, will help investigators conduct more definitive genetic tests and serve as the “gold standard” with which to compare the CTC findings. “We want to be able to validate whether the CTCs are an accurate representation of the EGFR mutational changes in the tumor,” says Sequist. In addition to EGFR, correlative science analyses will examine a host of other biomarkers and how they interact. “This is an opportunity to learn which biomarkers are stronger predictors of relapse or of benefit from Tarceva,” says Sequist.
While she hopes for a low rate of recurrence for the patients on this study, she also is optimistic that investigators can learn something new about the mechanisms of resistance in those who do relapse. Her patients have curable disease, says Sequist, so the risk-benefit ratio of this treatment is unclear. “We’re hoping to show that targeted therapy in the adjuvant setting is effective and well tolerated.”
A Phase II Trial of Adjuvant Erlotinib in Patients With Resected, Early Stage Non-Small Cell Lung Cancer (NSCLC) With Confirmed Mutations in the Epidermal Growth Factor Receptor
Lecia Sequist, MD, MPH (MGH)
For eligibility criteria, contact information, and sites, go to NCT00567359 on ClinicalTrials.gov.