Researchers intensify efforts to solve mysteries of exceptional responders

Exceptional responders — those patients with cancer who demonstrate sustained benefit from a therapy on which almost all others fail — have been observed in clinical trials for decades.

“This is the basis of the urban legend story that everyone has heard — someone was given 2 months to live, but was given a drug and had a miraculous recovery,” William C. Hahn, MD, PhD, chief of the division of molecular cellular oncology at Dana-Farber Cancer Institute, told HemOnc Today.

Because of recent strides in genomic sequencing, however, the phenomenon has evolved from a series of unexplained individual success stories into a collection of tremendously valuable case studies.

Consequently, Dana-Farber and many other cancer centers are initiating protocols and pilot studies to retrospectively and prospectively identify and evaluate outlier responders.

The hope is that researchers armed with genetic data can identify mutations that triggered the exceptional responses. That knowledge could further the quest for personalized medicine, potentially leading to the resurrection of failed orphan drugs or a better understanding of how a drug approved for one indication could benefit patients with other malignancies.

William C. Hahn, MD, PhD, 

William C. Hahn

“For the first time, we are starting to have the infrastructure to not only identify this amazing response in a patient but have a good hypothesis as to why the patient responded,” Hahn said. “If we can do this in a systematic way, eventually this should allow us to find more patients across cancer subtypes who will respond to that same therapy.”

Yet, the feasibility of sequencing exceptional responders — and subsequently screening other patients for the same mutations — in an era of limited research funding remains unclear. Other challenges include the ease with which this information can be shared, as well as how lessons learned from select individuals can be applied to larger patient populations.

HemOnc Today spoke with several physician–scientists about the programs in place to evaluate exceptional responders, what researchers hope to learn, and how their findings could transform clinical trials and advance cancer care.

Setting the stage

The recent focus on exceptional responders has been fueled by a finding by Milowsky and colleagues, who evaluated the use of everolimus (Afinitor, Novartis) in patients with metastatic urothelial cancer.

Overall, the trial was deemed negative, as only two of 45 patients achieved a response by RECIST criteria. But one of those two patients, a 75-year-old woman, is still in a remission that has endured for 4 years.

Iyer and colleagues performed an analysis of this outlier response beginning with the sequencing of select candidate genes to identify the source for the woman’s exceptional response. When that revealed no clues, they sequenced her entire tumor genome.

From the 17,000-plus mutations identified through sequencing, researchers focused on two, TSC1 and NF2. When mutated, these genes activate mTOR, which everolimus targets.

The evaluation of exceptional responders adds to the growing knowledge of the biologic and genetic bases for tumor response and resistance, according to David B. Solit, MD, director of developmental therapeutics at Memorial Sloan-Kettering Cancer Center. 

The evaluation of exceptional responders adds to the growing knowledge of the biologic and genetic bases for tumor response and resistance, according to David B. Solit, MD, director of developmental therapeutics at Memorial Sloan-Kettering Cancer Center.

Source: Photo courtesy of Memorial Sloan-Kettering Cancer Center

“It turned out that this patient had a somatic mutation in the same gene that patients with tuberous sclerosis have in their germline, [so the fact] patients with tuberous sclerosis and our patient both benefit from everolimus isn’t surprising,” David B. Solit, MD, director of developmental therapeutics at Memorial Sloan-Kettering Cancer Center and the senior researcher on the Iyer study, told HemOnc Today. “What made our patient’s response surprising was our lack of knowledge prior to treatment with everolimus that TSC1 was mutated in her tumor. The major advance here is that the technology has advanced to the point that we can probably figure out the basis of all outlier responses by analyzing the entire genome.”

Solit and colleagues at Memorial Sloan-Kettering used targeted sequencing to screen for TSC1 mutations in an additional 109 patients with bladder cancer. They found that approximately 8% of patients had TSC1 mutations, and that mutation in this gene was associated with sensitivity to everolimus.