By AMY HARMON

PHILADELPHIA - HIS PATIENT, A spunky Italian-American woman in her 60s, was waiting in an exam room for the answer: Was the experimental drug stopping her deadly skin cancer?

But as Dr. Keith Flaherty read out the measurements of her tumors from the latest CT scan, he could not keep the distress from his voice.

“She’s worse,” he said to the clinical trial nurse at the University of Pennsylvania’s melanoma clinic.

Like the 17 other patients on the drug trial, the woman known in the trial as Patient 18 was going to die, most likely within months.

He had been so optimistic. A radical departure from standard chemotherapy, the drug was designed to reverse the effect of a genetic mutation particular to the patient’s tumors. The approach represented what some oncologists see as the best bet for attacking all types of cancer.

And as he returned to his office that autumn afternoon two years ago, Dr. Flaherty was already calculating the next step: he wanted to test the drug at a more potent dose before giving it to more patients in a larger trial. It would require retooling the drug in a costly and complicated task that might not work, and he would have to make his case to two companies that had already poured hundreds of millions of dollars into the drug and were eager to move it forward.

“This,” he insisted to colleagues, “is the best drug we’re going to get.”

Dozens of such “targeted” drugs are emerging from the laboratory, rooted in decades of research and backed by unprecedented investment by pharmaceutical companies, which stand to profit from drugs that prolong life even by weeks.

But putting them to their truest test falls to a small band of doctors committed to running experimental drug trials for patients they have no other way to heal.

To chronicle the trial of the drug known as PLX4032 is to ride a roller coaster of breakthroughs and setbacks at what many oncologists see as a watershed moment in understanding the genetic changes that cause cancer.

Dr. Flaherty, 39, seemed buoyed by an innate optimism and a faith in the scientific logic underlying the approach. But at his clinic, where he gave vials of pills to patients whose tumors were often erupting, black and bumpy across their arms and legs, he told them only what he believed to be true.

“This,” he said, “is our best shot.” Healthy cells turned cancerous, biologists knew, when certain genes that control their growth were mutated, either by random accidents or exposure to toxins like tobacco smoke and ultraviolet light. Once altered, they constantly signaled cells to grow.

What mattered in terms of treatment was therefore not only where a tumor originated, like the lungs or colon, but also which set of these “driver” genes was fueling its growth. Drugs that blocked the proteins that carried the genes’ signals, some believed, could defuse a cancer without serious side effects.

Dr. Flaherty was convinced that what he called the “targeted therapy revolution” was around the corner. Melanoma, which the World Health Organization reports affects about 132,000 people each year, is easily treatable in its earliest stages, but almost always fatal within a year once it spreads beyond the skin.

When an article in the journal Nature brought news of what was almost surely one of the driver genes in melanoma in the spring of 2002, Dr. Flaherty could hardly contain himself. British scientists analyzing hundreds of tumor samples, he read, had found the same gene mutated in more than half of melanomas, and smaller numbers of other cancers as well. It was called B-RAF.

The presence of the same B-RAF mutation in so many cancers, he thought, meant it was one of the biggest genetic proofs yet identified in cancer. A drug that blocked the protein made by the defective gene might have enormous consequences for patients - and he knew of one that just might work.

“We have to jump on this,” he urged his mentor, Dr. Lynn Schuchter. She would make trials of drugs that homed in on B-RAF a top priority, she told him.

That first effort, however, was destined to fail.

Over the next four years, with the backing of his superiors at Penn, Dr. Flaherty enrolled several hundred patients in trials of the drug, developed by an academic pioneer in targeted therapy and now owned by Bayer.

While a single targeted drug was likely to hold off cancer for only a limited time, immunotherapy can be curative. But after decades of effort, the only such treatment approved for use in melanoma helped just a tiny fraction of patients.

To many of Dr. Flaherty’s colleagues, the failure of the Bayer drug indicated that melanoma would prove impervious to targeted therapy. And to many other oncologists, it was a blow to the notion that targeted therapy would work in any cancer as its proponents envisioned.

Dr. Flaherty brushed them off. “We just had the wrong drug,” he insisted whenever he could. “The principle holds.”


PLX4032

While some concluded that Dr. Flaherty was toiling in vain, a small biotechnology company in Berkeley, California, called Plexxikon was keeping close track of his work.

Ever since the B-RAF mutation had been identified as so prevalent in melanoma tumors, the company’s scientists had been working on a drug aimed at it, and when they invited him for a visit in early 2006, Dr. Flaherty could not fend off a wave of excitement.

One reason the Bayer drug had failed, he believed, was because it blocked proteins in healthy cells as well as cancerous ones, inducing nasty side effects .

The drug Plexxikon called PLX4032 was designed to bind to the B-RAF protein only in cancer cells.

An investment in the drug by Roche, the Swiss pharmaceutical giant, shortly after Dr. Flaherty signed on to lead its first human trial alleviated his concern that Plexxikon might not have the resources to pull it off.

But the partnership also raised the financial stakes. Roche was to dole out nearly $700 million to Plexxikon as it passed certain milestones on the way to the hoped-for approval by the Food and Drug Administration. The first hurdle was the completion of the trial Dr. Flaherty was to run, known as Phase 1, in which the goal was to determine the highest dose humans could tolerate.

The trial opened in December 2006. Whenever possible, Dr. Flaherty and his co-investigator, Dr. Paul Chapman of Memorial Sloan-Kettering Cancer Center in New York, agreed, they would screen tumors first for the B-RAF mutation, and offer a spot on the trial for those who had it.

Dr. Flaherty and Dr. Chapman started the first three patients on 200 milligrams per day. After two months with no side effects - and no response - they doubled it. Two more months passed, still nothing. They gave three more patients 800 milligrams .

Dr. Flaherty pounced on the scans when they arrived. In some patients, tumors had remained the same size. “Maybe we’re starting to see something,” he could not help thinking. But at the next set of scans, the disease had progressed. By the time they had doubled the dose four times, Dr. Flaherty could not help wondering if the targeted therapy skeptics were right. Already, the two doctors had seen some patients on the trial die.

The higher doses, Dr. Flaherty and Dr. Chapman realized, were not getting from the digestive tract into their patients’ bloodstreams. The Phase 1 trial had accomplished its official goal: it had established that the drug was safe at the maximum dose the body could absorb. Yet everyone involved in the trial had hoped to see the tumors shrink.

The only recourse was to try to reformulate the drug so that patients could absorb a higher dose . In December 2007, the companies halted the trial. They would wait while Roche chemists tried to reformulate the drug.

Elmer Bucksbaum, 89, came to see Dr. Flaherty at the melanoma clinic in the spring of 2008. He was accompanied by his son-in-law, Marc Lovitz, whose own father had died of melanoma just one month after the diagnosis. “We know he doesn’t have long,” he told Dr. Flaherty.

Dr. Flaherty eventually secured him a spot on an immune therapy trial. By the time Mr. Bucksbaum returned, a few months later, Dr. Flaherty had received the new PLX4032 from Roche. It was, the company promised, 10 times as potent as the previous one, packaged in a way the body could more easily absorb.

Mr. Bucksbaum’s tumor had tested positive for the B-RAF mutation. But the other trial had given him colitis. Yet he took his first PLX pills on September 30, 2008. When Mr. Bucksbaum returned to Dr. Flaherty’s clinic at the end of October, his skin lesions were gone. But the internal tumors were what mattered.

When Dr. Flaherty saw the scans, he thought he had opened the wrong file. He strained to see any tumor at all.


A Reprieve

A few weeks after taking their first dose, nearly all of the patients began to recover.

It was a sweet moment, in autumn 2008, for Dr. Flaherty. 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 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 December 17.

“Are you sure it is the same patient??” added Dr. Jeffrey A. Sosman at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

By late December, tumors in the 11 patients who did have the mutation had shrunk. Doctors 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. In a matter of days they needed to submit their findings for a prestigious meeting of clinical oncologists in June.

First, though, Dr. Flaherty needed to respond to a desperate phone message from a patient named Christopher Nelson, 42, of Jackson, New Jersey. It came the day after Christmas.

“Dr. Flaherty,” the message said, “I need to get onto your trial.”

When Dr. Flaherty saw Mr. Nelson a few months later, he did not need the required blood test to tell that his numbers were off the charts. His eyes were yellow, a sign that his liver was at the edge of failure. He had, at the most, the doctor thought, a month to live. He was soon given the drug after having tested positive for the mutation.


Dialing Back the Dosage

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.

In Oklahoma City, Kerri Adams, 30, woke up one morning covered in a rash. Another woman’s hand swelled up, and she could not make a fist. A Philadelphia patient had horrible nausea and diarrhea, and Mr. Bunting had such stiff joints that he had to hand jars to his wife to remove the lids, even when they had already been opened.

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.

In Mr. Nelson’s room, Dr. Flaherty broke into a wide smile. He had never seen a melanoma patient who had been that sick improve that much.

In mid-May, right before he was to fly to Orlando, Florida, to present the trial’s data, Dr. Flaherty received a message on his BlackBerry . The first patient to respond in the trial, Elmer Bucksbaum, had been admitted to the hospital. The cancer had spread to his brain.

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. It had been not quite eight months.


‘The Right Combination’

In the weeks leading up to the annual oncologists’ conference in Orlando, Florida, several of the patients on the trial of PLX4032 had relapsed. One had died. Mr. Nelson had lost his appetite .

The drug’s ability to stop the melanoma, on average, Dr. Flaherty told the crowd, “appears to be approximately six months.”

“I was hoping we’d get more time,” said Dr. Grant McArthur, one of the six oncologists on the trial team .

However briefly, PLX4032 had held off the cancer by blocking a particular protein in its cells that was spurring them to multiply. If such “targeted” drugs were ever to provide a lasting benefit, many oncologists believed they would need to be combined with others .

“We just need,” Dr. Flaherty said, “to find the right combination.”

The problem was that while PLX4032 blocked the protein made by one mutated gene, a second mutation now seemed to be driving the cancer’s growth. If that mutation could be identified, they believed, its protein could also be blocked.

The most expedient approach would be to test PLX4032 in combination with other experimental drugs that targeted other mutations .

But the standard practice among pharmaceutical companies is to get each drug approved individually before combining it with others. Dr. Flaherty would work to convince the pharmaceutical industry that the fastest path to finding a combination that really worked would require changing their standard business procedure.


A Bitter Pill

At 4:40 p.m. June 25, Mr. Nelson waited with his wife in the melanoma clinic at Penn.

“The cancer,” Dr. Flaherty said, “is starting to wake up again.” But he gave them a new hope. One theory, he told them, was that the mutant B-RAF protein was managing to activate another protein on the same pathway in the cancer’s cells. And a space was about to open up in the trial of a new drug developed by Glaxo SmithKline that was designed to block the second protein.

Even if some combination of targeted drugs could put melanoma into hibernation, it might take a cocktail of five or more such drugs to treat any given case. And it can take 10 years for even one drug to reach the market.

“If they do it the way they’ve always done it,” Dr. Flaherty complained in e-mail messages and calls to colleagues, “it will delay by years how quickly we can figure this out.”

Such frustration, he knew, went beyond melanoma specialists . Dr. Flaherty urged the leading melanoma researchers to form an alliance to make it easier and cheaper for drug companies to conduct several trials at one time.

But a Roche official told Dr. Flaherty that the best interest of patients would be served by getting its B-RAF drug approved for sale as quickly as possible. “That has to be our focus right now,” she insisted.


A Death in the Family

At an appointment in mid-November, the tumors on Mr. Nelson’s neck and inside his heart had shrunk. “Aren’t you excited?” Mrs. Nelson crowed.

“I’m happy, Sharl,” he said slowly. “But how long do you think it will last?”

A few weeks later, when Dr. Flaherty again made the pitch for a combination trial, this time at a meeting with Glaxo, an executive hinted that the company would sponsor such a trial soon. The company had a pragmatic reason: Roche was likely to get its B-RAF drug approved first, but Glaxo might take the lead if it had a combination that could do a better job. It was becoming clearer that some targeted drugs might find a market only if combined.

“The culture is changing,” the Glaxo executive agreed.

It would be too late, however, for Mr. Nelson. On January 5, Mrs. Nelson wheeled him on a stretcher to his appointment at Penn. Three days later, an ambulance took him to hospice at a local hospital.

At his wake, Mrs. Nelson told relatives she felt blessed that he had lived longer than expected. “It’s a year I would never trade in,” she said.

One year, Dr. Flaherty thought, when he heard the news. Certainly no triumph. But it was something. Something to be built on.

Novartis and Bristol-Myers had agreed to schedule teleconferences for late February to talk about combination trials. He checked the dates on his electronic calendar. A meeting with Pfizer was also pending.

PETER MACCALLUM CANCER CENTER

Dr. Keith Flaherty oversees the testing of PLX4032 to treat melanoma. A patient’s tumors, left, shrank in 15 days. / ANGEL FRANCO/THE NEW YORK TIMES

The drug known as PLX4032 deactivates a defective protein that leads to cell growth causing cancer. / HEIDI SCHUMANN FOR THE NEW YORK TIMES

Christopher Nelson of New Jersey could barely eat or walk when he began a drug trial. Soon, he was out enjoying meals with his family. / COURTESY OF THE NELSON FAMILY

Elmer Bucksbaum with his great-grandson Manu and daughter Sharon Lovitz in 2008. After a drug trial, his tumors seemed to disappear. / GEOFFREY LOVITZ