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Sequencing Explains Another Extraordinary Response Outlier in Targeted Drug Trial

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A sequencing study of a bladder cancer patient from a Phase I clinical trial of Novartis' mTOR inhibitor Afinitor (everolimus) in combination with GlaxoSmithKline's VEGF inibitor Votrient (pazopanib) has found the most likely culprit for that patient's extraordinary response to the drug combo among a cohort with comparatively disappointing responses.

The results, published this month in Cancer Discovery by a team led by the Dana-Farber Cancer Institute, pointed to two concurrent mTOR mutations as most likely responsible for the patient's sensitivity to treatment, resulting in a 14-month complete response marked by a near-disappearance of the patient's cancer in radiologic imaging.

Efforts to understand the molecular basis of such response outliers in the context of otherwise disappointing or failed drug trials is a growing effort, according to Jonathan Rosenberg, a senior author of the study.

"The mTOR mutations we saw in this patient tend to be quite rare [and] they are unlikely to be found in large numbers in patients with any disease," Rosenberg told PGx Reporter this week.

"But [this study] does show that doing this type of research may give us some fundamental insights into these [cancers]" as well as how response to emerging and established targeted cancer therapies can be linked increasingly to rare mutations, he said.

In the case of the group's recent discovery, Rosenberg said the impetus to sequence the highly responsive patient in question was prompted by an earlier study of everolimus, in which, similarly, only a single patient showed a dramatic positive response in a Phase II trial of the drug in bladder cancer.

In this previous study, sequencing found that the likely cause of the patient's extraordinary response was a mutation in the tumor suppressor gene TSC1. "Based on that [previous] result, we felt that this new patient should be investigated further to see if TSC1 was responsible," Rosenberg said. "But in this case it wasn’t. [We found that] it was these mTOR mutations, most likely."

In the study, Rosenberg and his colleagues performed whole-exome sequencing on the highly responsive patient's tumor DNA, identifying, among many candidates, two mutations in mTOR that appeared most likely to be the cause of the patient's sensitivity to everolimus. According to the authors, neither mutation had been previously reported in human cancer.

Because the study was initiated retrospectively, the team did not sequence any other patients from the trial, Rosenberg said, so an understanding of why those patients failed to respond to the drugs nearly as well as the one patient is limited.

Among the four other bladder cancer patients enrolled in the study, three showed stable disease for about four to five months.

"This is [slightly] longer than you might expect with cytotoxic chemotherapy," Rosenberg said, "So there may be a signal there that the combination may have some activity – but there was only one patient that had this dramatic outcome."

While rare mutations, like the mTOR mutations identified in the highly-responsive patient in this trial, may not prove to be a practical tool for predicting patient response or guiding treatments, identifying them in studies like this continues to confirm that response to targeted inhibitors, like everolimus, may often be limited to small subsets of patients with a particular tumor type.

In bladder cancer, Rosenberg said that the group's recent result, as well as the earlier study of the TSC1 mutated superresponder, suggest that identifying and defining these subsets is going to be the "theme for bladder cancer research over the next years."

"There are clearly, at a minimum, a small number, and maybe a modest number of patients who benefit from targeting the PI3K/MTOR pathway," Rosenberg said.

"I think we are still struggling for the right agents … The benefits will be there for a subset, [but] the question is to what is the degree? There are some who will do better than others even within these molecularly defined subsets," he added.

This paints a tricky picture for drugmakers looking to find new indications for already marketed drugs or bring new mTOR-targeted inhibitors to market for bladder or other solid tumors.

While success stories like Pfizer's Xalkori (crizotinib) — which is marketed for a subset of about 4-7 percent of non-small cell lung cancer patients with ALK translocations — have been shown in studies to be efficacious in even smaller molecular subsets of lung cancer patients, launching a separate development program for each new, exceedingly rare molecularly-defined cancer indication may not be financially feasible for a pharmaceutical company.

According to the study authors, multiple activating alterations in the mTOR/PI3K pathway, including mTOR, TSC1/2, and STK11 have proved likely to confer sensitivity to clinical mTOR inhibition. Routine screening of patients with bladder and other cancers for these alterations could "help to identify a subset of patients who may respond to targeted therapies against mTOR, including everolimus … as well as direct mTOR kinase inhibitors now in clinical trials," the group wrote.

"I don't know about development plans on [Novartis'] side for everolimus," Rosenberg said. "I would say, though, that if there is interest in moving forward with an mTOR inhibitor for a bladder cancer indication [at this point], they should really be thinking about a select population based on these studies."

"It would be a small population," he added. "But it may be possible to do that study and get a drug approved in that context. The issue for the company is that it may not be worth their time and effort."

In an email to PGx Reporter, a Novartis spokesperson said that the company does not currently have plans for a registration trial in bladder cancer, but continues to explore everolimus sensitivity in multiple cancers.

Currently, everolimus is approved by the US Food and Drug Administration for the treatment of pediatric and adult patients with subependymal giant cell astrocytoma, hormone receptor-positive HER2/neu-negative advanced breast cancer in combination with Exemestane, unresectable or metastatic neuroendocrine tumors of pancreatic origin, and advanced renal cell carcinoma.

Meanwhile, research efforts to find the mechanisms behind extraordinary responders to targeted drugs are growing and becoming more prospective and more systematic, Rosenberg said.

For example, in addition to these now two studies of everolimus superresponders, another recent effort by Ohio State University found a mutation, ARAF S214C, which researchers believed to be responsible for a lung cancer patient's extraordinary response to the cancer drug Nexavar (sorafenib).

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