God love smart scientists and doctors ! Back in February, this post covered some of the ground on medical treatments aimed at individual genomes. In August, this post reported on Abbbott and Pfizer working in creating a gene chip to screen patients with a specific type of cancer for specific genomic changes so that a clinical trial can be run using people with that specific genomic defect. In this week of focus on health care, it is just plain wonderful to read that similar approaches are starting to produce the "miracles" needed for some of the almost 1.5 million Americans who will be diagnosed with cancer this year.
The specifics ? Now coming on line are humane therapies – pills !- tailored to particular changes in individual genomes. These therapies are actually shrinking tumors, and are doing so without the incredible brutality of chemotherapy and bone marrow transplants. There are still issues and uncertainties ahead, but these types of results prove the merit to treating specific genomes.
Here are the absolute key quotes from an article this morning in the NYT:
"The trial of PLX4032 offers a glimpse at how doctors, patients and drug developers navigate a medical frontier as more drugs tailored to the genetic profile of a cancer are being widely tested on humans for the first time.
Throughout the fall, the only two patients on the trial whose tumors continued to grow were the ones who did not have the particular gene mutation for which the drug had been designed. They were removed from the trial. By late December, tumors in the 11 patients who did have the mutation had shrunk. Those involved in the trial held their collective breath waiting to see how long the remissions would last. "
The entire article is here; addtional key excerpts on the science are pasted below. The entire article is well worth reading for the human side of the story.
February 23, 2010
Target CancerAfter Long Fight, Drug Gives Sudden Reprieve By AMY HARMON
For the melanoma patients who signed on to try a drug known as PLX4032, the clinical trial was a last resort. Their bodies were riddled with tumors, leaving them almost certainly just months to live.
But a few weeks after taking their first dose, nearly all of them began to recover.
Lee Reyes, 30, of Fresno, Calif., who had begun using a feeding tube because of a growth pressing against his throat, bit into a cinnamon roll.
Rita Quigley, who had been grateful just to find herself breathing each morning since learning she had the virulent skin cancer, went shopping for new clothes with her daughters at a mall in Huntsville, Ala.
Randy Williams, 46, who drove 600 miles from his home in Jonesboro, Ark., to the M.D. Anderson Cancer Center in Houston to get the experimental drug, rolled out of bed. "Something’s working," he thought, "because nothing’s hurting."
It was a sweet moment, in autumn 2008, for Dr. Keith Flaherty, the University of Pennsylvania oncologist leading the drug’s first clinical trial. A new kind of cancer therapy, it was tailored to a particular genetic mutation that was driving the disease, and after six years of disappointments his faith in the promise of such a "targeted" approach finally seemed borne out. His collaborators at five other major cancer centers, melanoma clinicians who had tested dozens of potential therapies for their patients with no success, were equally elated.
In a kind of "pinch me" exercise, the six doctors sent one another "before and after" CT scans of their patients.
One was of Mark Bunting, 52, an airline pilot in Sandy, Utah. His initial scan in early October showed the cancer in his bones, an incursion considered virtually impossible to reverse. After two months on the drug, it had all but disappeared.
"Holy Cow!" Dr. Flaherty typed in reply to the slide from Dr. Antoni Ribas at the University of California, Los Angeles, that Dec. 17.
The trial of PLX4032 offers a glimpse at how doctors, patients and drug developers navigate a medical frontier as more drugs tailored to the genetic profile of a cancer are being widely tested on humans for the first time.
Throughout the fall, the only two patients on the trial whose tumors continued to grow were the ones who did not have the particular gene mutation for which the drug had been designed. They were removed from the trial. By late December, tumors in the 11 patients who did have the mutation had shrunk. Those involved in the trial held their collective breath waiting to see how long the remissions would last.
It was a far cry from where they had been a year earlier, when a previous incarnation of the drug had no effect. Urged on by Dr. Flaherty and Dr. Chapman, the companies that owned it had spent months devising a new formulation that could be absorbed at higher doses.
But the new drug, still in the earliest phase of testing, had to pass several more hurdles before federal regulators would determine whether it was safe and effective enough for widespread use.
In December, as the doctors added more patients to the Phase 1 trial, looking for the highest dose they could give without intolerable side effects, they scrambled to prepare slides with graphs and statistics to convince the Food and Drug Administration that the drug should be tested in a larger Phase 2 trial. The agency required a summary of any and all side effects — there had been only a few — and any deaths of patients on the study; thankfully, there had been none since the drug was reformulated. In a matter of days they needed to submit their findings for a prestigious meeting of clinical oncologists in June.
The trial in Bethesda, run by the National Cancer Institute, involved coaxing immune cells to grow in a test tube in a procedure that worked for only a small fraction of patients, Dr. Flaherty knew.
But there would be no point in Mr. Nelson taking PLX4032 if his tumor did not carry the right mutation. For now, the doctor had a slot for only one more patient on the trial, and he and his collaborators had agreed it was almost unethical to give the drug to people without that mutation.
He wished, not for the first time, that he could snap his fingers and know the genetic profile of his patient’s cancer cells. But getting a hospital that had operated on a patient months earlier to retrieve a tumor sample from storage could take days or weeks; the test for the gene mutation could take even longer. To speed the process, Mr. Nelson drove his tumor sample himself from Robert Wood Johnson University Hospital in New Brunswick, N.J., where it had been removed from his lymph nodes, to the laboratory at the University of Pennsylvania.
Once unleashed, however, any cancer seemed to rely on the protein made by a particular mutated gene to fuel its wild growth. In all of the PLX patients, that gene was B-RAF. And whatever the cause, they came to consider themselves, so far as it was possible with what has always been a virtually untreatable cancer, charmed.
Dialing Back
The side effects struck at the 1,120-milligram dose.
Many patients had been taking the reformulated drug for five months with no signs of relapsing. The doctors had hoped that by pushing up the dose they could shut down the cancer more effectively. Some patients were taking as many as 28 pills a day.
Ms. Adams, in Oklahoma City, woke up one morning covered in a rash. Frightened that she would be dropped from the trial, she tried to ignore it. But at work, her boss was horrified and insisted that she call the doctor. Another woman’s hand swelled up, and she could not make a fist. A Philadelphia patient had horrible nausea and diarrhea, and Mr. Bunting’s joints grew so stiff that he had to hand jars to his wife to remove the lids, even when they had already been opened. Maybe the drug, designed to turn off only the defective B-RAF protein, was, at high doses, also affecting its role in healthy cells. Or perhaps it was interfering with other proteins the body needed to function properly. On their next conference call, the doctors agreed that they had to dial back the dose.
As the side effects began to subside, many of the patients began to believe they had beaten their cancer. One evening, Mr. Bunting performed what had become his pill-taking ritual as his wife puttered around the kitchen.
One Step Forward …
When Mr. Nelson strolled into the University of Pennsylvania for a scheduled day of blood work and monitoring in mid-March, Ms. Redlinger greeted him as if he had risen from the dead.
Gazing out the window of the clinic room, he spied a hot dog stand.
He had never seen a melanoma patient who had been that sick improve that much. He was not sure he had ever seen a melanoma patient that sick who improved at all.
The first patient to respond in the trial, Elmer Bucksbaum, had been admitted to the hospital. The cancer had spread to his brain.
Dr. Flaherty stopped walking.
The drug, Dr. Flaherty knew, was powerless in the brain. But had the drug held off the cancer elsewhere in Mr. Bucksbaum’s body? Or would other patients, too, begin to relapse?
Mr. Bucksbaum died a few days later.
Wednesday: The Next Hurdle.