Advancing Precision Medicine Trials
The advances in cancer genomics achieved by The Cancer Genome Atlas(TCGA) project, Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, and other molecularly oriented cancer research projects are leading to new clinical trials for patients whose tumors will be extensively genomically tested and whose treatment will be based on the identified molecular abnormalities. These include the Lung-MAP, ALCHEMIST, and MATCH trials.
The Lung-MAP trial is evaluating patients with squamous cell lung cancer that does not respond to first-line therapy. The study divides patients into multiple treatment arms based on the molecular profiles of their cancers, uses targeted drugs and standard chemotherapeutic agents from several pharmaceutical companies, and compares these new approaches to standard second-line treatment. Promising results in any arm can lead to testing the drugs in that treatment arm in more patients, with the goal of more rapidly determining whether the new treatment represents a substantial advance over the standard treatment.
This trial is a public–private partnership between the NCI, several pharmaceutical companies, the Foundation for NIH, and Friends of Cancer Research.
ALCHEMIST will test the benefits of molecularly targeted adjuvant (post-surgical) treatment of patients with early-stage lung adenocarcinomas whose tumors have either an EGFR gene mutation or an anaplastic lymphoma kinase (ALK) gene rearrangement. Depending on the genetic abnormality in a tumor, the patient will receive the EGFR protein kinase inhibitor erlotinib (Tarceva) or the ALK protein kinase inhibitor, crizotinib (Xalkori). These molecularly targeted therapies are approved by the Food and Drug Administration (FDA) for advanced lung adenocarcinoma in patients with the relevant genetic changes.
The trial will test whether treating patients earlier in the course of the disease may give even better results. If patients develop resistance to these drugs, as eventually happens with most advanced tumors, the resistant tumors will be biopsied to identify the causes of resistance and to see whether, in future trials, the resistance might potentially be overcome or prevented by alternative treatment approaches.
It is expected that most patients with early lung adenocarcinoma who are screened will not be eligible for the therapeutic portion of this trial because their tumors will not have the necessary mutations. However, the tumor samples from these patients will be saved, and, if they relapse while on standard treatment, their tumors will be biopsied again and analyzed for insight into the progression of their disease and for potential therapeutic approaches suggested by this analysis.
Promising results in any arm [of the Lung-MAP trial] can lead to testing the drugs in that treatment arm in more patients, with the goal of more rapidly determining whether the new treatment represents a substantial advance over the standard treatment.
Although most trials study cancers arising at a particular anatomic site, the MATCH trial changes this paradigm by emphasizing the molecular abnormality and by testing a large number of chemotherapeutic agents in virtually any tumor type in which appropriate abnormalities are identified.
This umbrella protocol will examine between 20 and 25 drugs, including those that have been FDA-approved for the treatment of cancer at another tumor site or experimental agents that have shown activity against a known target at one or more tumor sites. If the response rate to a particular agent is high, the number of patients evaluated with that treatment will be expanded to further explore whether the targeted treatment represents a substantial advance over standard chemotherapy.
If a tumor becomes resistant to the first test drug, it will be re-biopsied to see if another targeted therapy might be effective and to understand the basis for resistance to the initial treatment. By studying multiple agents at the same time, a higher proportion of patients will be eligible for the trial, and efficient progress can be made in the assessment of clinical benefit.