Originally published Sept. 25.
NEW YORK (GenomeWeb) – The National Cancer Institute this week kicked off its exceptional responders program, in which researchers will sequence tumor tissue from patients who have had an outlier response to investigational treatments.
The NCI defines exceptional responders as the less than 10 percent of patients who received treatment in a failed drug trial and experienced a complete or partial response lasting at least six months. Although these exceptional or super responders are rare in drug trials, investigational therapies fail to reach the market all too frequently. NCI's long-term hope with this project is to advance understanding of what's driving these seldom seen responses and inform personalized treatment approaches in drug development.
In recent years, researchers have published on a handful of cases, in which with the help of genomic technologies they were able to uncover the reason for a super response. The most well known is the story of a 73-year-old woman with metastatic bladder cancer whose tumor disappeared in three months after treatment with the drug Afinitor (everolimus). Meanwhile, only a few of the 44 other patients in the study experienced limited responses and the trial was considered a failure.
The research team led by Memorial Sloan Kettering Cancer Center's David Solit performed whole-genome sequencing on the tumor of this bladder cancer patient and identified more than 17,000 mutations. From that, his group narrowed the cause of this woman's response down to alterations in two genes, TSC1 and NF2. These mutations caused loss of expression, which in turn activated mTORC1, the protein complex targeted by Afinitor, resulting in the woman having a durable response for more than two years.
Spurred by this study and others like it, the NCI decided to embark on its own search for super responders and store the molecular characterizations of these unique individuals' tumors in a database. Sifting through several hundred NCI-sponsored trials completed over the past decade, researchers have identified approximately 100 exceptional responders.
"We wanted to see from all those Phase II trials that we ran for drugs, especially those that didn't get approved for anything, if we could find some exceptional responders," Barbara Conley, associate director of the Cancer Diagnosis Program at NCI's Division of Cancer Treatment and Diagnosis (DCTD), told PGx Reporter. The project will be led by DCTD and NCI's Center for Cancer Genomics.
Tissue collection wasn't stipulated in some these older trials, and so molecular analysis may not be possible for all the super responders NCI has identified. Casting a wider net into the life sciences community, NCI is asking investigators in non-NCI trials, at pharma companies and at cancer centers, to submit tissue and data on exceptional responders to an experimental treatment or from patients who have an unexpectedly robust response to standard therapy.
NCI is planning to analyze the tissue samples using whole-exome sequencing and RNA-seq. Depending on how much tissue is left over, NCI may even perform deep targeted sequencing, whole-genome sequencing, and other types of analysis on samples.
The timeline for the exceptional responders project is currently in flux, since it remains unclear how many of these patients will have tissue for genomic analysis, how much tissue will be available, and whether the quality of the tissue is sufficient. Conley is optimistic that if NCI can gather tissue from 300 exceptional responders, researchers may be able to sequence at least 100 samples and put forth hypotheses as to why these patients responded as well as they did.
It might take up to two years to collect the tissue and then at least another year for sequencing and data analysis, she estimated. NCI is planning to analyze the data as the project progresses and issue periodic reports. The institute will store information about patients and their tumors in a controlled-access database, so researchers doing similar work can use it and possibly learn more than they would be able to at a single center. NCI is planning to provide access to the information from this project in the database of Genotypes and Phenotypes (dbGaP).
"We hope that others will pool their results with ours in some way," Conley said. "And we may learn that for patients in certain molecular subsets a drug may be more effective than another drug, and why." Once this hypothesis is generated in a single super responder and hopefully proven in other patients, other researchers, and eventually healthcare providers, could prospectively test patients for these markers and guide them to personalized treatment decisions or appropriate clinical trials.
In this way, the identification of super responders in the early 2000s to EGFR inhibitors, such as Iressa (gefitinib), has fueled the development of more potent lung cancer drugs and continues to spur research a decade later. For example, lung cancer and genetics research pioneer David Carbone, while he was at Vanderbilt University in 2002, sequenced the tumor of a patient whom he described as having a "Lazarus response" to Iressa. This patient became one of the first super responders with lung cancer in whom an EGFR mutation was identified. Scientists at leading cancer centers, such as Massachusetts General Hospital, also found exceptional responders with EGFR mutations.
It is now well known that EGFR mutations show up in 10 percent of non-Asian and 50 percent of Asian non-small cell lung cancer patients. And so, more than a decade later, when lung cancer patient Annie Cacciato came to Carbone for treatment at Ohio State University, he immediately tested her tumor to see if she had an EGFR mutation. Cacciato, a 51-year-old wife and mother of three girls, had been diagnosed on Thanksgiving Day 2013 with advanced lung cancer. Fortunately, the test revealed that she did have an EGFR mutation, which enabled her to enroll in a clinical trial comparing the combination of two powerful anti-cancer therapies, Avastin (bevacizumab) and Tarceva (erlotinib), against taking Tarceva by itself.
On New Year’s Eve, she joined the study, landing in the Avastin/Tarceva combination arm. Six weeks into 2014, her first scan already showed signs of improvement. Every scan since then looked better and better, until June, when Carbone told her that she was in remission. Cacciato's response is primarily attributable to the EGFR mutation driving her tumor, Carbone said, and because of the earlier research on super-responders, he could guide her to the right clinical trial.
Treatment guidelines now recommend that all patients with advanced lung adenocarcinomas should be tested for alterations in EGFR. Meanwhile, at the American Society of Clinical Oncology's annual meeting, drugmakers presented data on a number of next-generation EGFR inhibitors – AstraZeneca's AZD9291, Clovis Oncology's CO-1686, and Hanmi Pharmaceutical's HM61713 – which they believe can benefit patients who have developed resistance to first-generation drugs and can cause fewer side effects by more precisely hitting mutant EGFR tumor cells.
Not every hypothesis generated by NCI's exceptional responders project will turn out like the EGFR story. Not all cancer patients can benefit as Cacciato has from past research on super responders. Even fewer patients can be exceptional responders. However, the hope is that studying super responders will enable researchers to group more and more cancer patients into small, molecularly defined subsets that respond particularly well to a type of treatment or elucidate new treatment strategies.
It would be particularly interesting, Conley said, if the NCI project helped identify response markers associated with standard treatments, such as platinums and taxanes. "We don't to date have a very good way of predicting who might respond to those," she said. "But if you could identify that then you could move towards precision approaches for those drugs as well."
By gathering data on these individuals in one database, the institute is hoping to bolster the research community's collective learning in this regard. "If you use the EGFR example, those mutations are rare among lung cancer patients, and ALK mutations are even rarer," Conley noted. "But if you treat only those patients with mutations with the appropriate inhibitor then you get a much better response than you would in the general population. The [exceptional responders program] is trying to move this idea forward."