FDA批准Revolution Medicines的daraxonrasib（Rasonque）用于经治转移性胰腺腺癌，Bloomberg发布长篇特写报道

Jay Williams, a former movie studio executive, was diagnosed with pancreatic cancer in 2023 when he was just 55. Despite surgery to remove a tumor and multiple rounds of chemotherapy, the disease progressed, eventually spreading to his liver. Toward the start of this year, his doctor bluntly told him he was starting to run out of treatment options.

But in early July, Williams qualified for special access to a powerful new drug from Revolution Medicines Inc. Within days after he started taking daraxonrasib, his energy started to come back and he was able to go on early morning walks with his wife for the first time in years. Blood tests suggest his tumors have begun to shrink, and side effects such as a skin rash have been much easier to tolerate than chemo. “It’s been life-changing,” says Williams, who lives in Santa Clarita, California.

Revolution Medicines’ pill, which secured US regulatory approval today, is the first in a wave of targeted drugs that could reshape treatment for pancreatic cancer, long one of the hardest types of cancer to treat. In a final-stage trial whose results were first announced in April, the drug almost doubled the typical survival time for advanced patients whose cancer had stopped responding to chemo, to 13.2 months. When the results were presented at a big oncology conference in Chicago in May, attendees responded with a standing ovation.

New drugs are badly needed. More than 67,000 Americans are diagnosed with pancreatic cancer each year, but only about 13% of patients survive longer than five years. Growing deep inside the body, the disease often doesn’t cause obvious symptoms until it’s advanced. Chemotherapy typically works only for a few months once the cancer has spread widely.

Pharmaceutical companies had few good new approaches for treating pancreatic cancer until recently. (Chemotherapy typically works only for a few months once the cancer has spread widely.) Now drugmaker interest is “just escalating exponentially,” says Eileen O’Reilly, an oncologist at Memorial Sloan Kettering Cancer Center in New York City and a top investigator on the big daraxonrasib trial. With all the promising drugs in testing, she predicts that a few years from now, newly diagnosed patients will likely have a choice of several regimens to treat their pancreatic cancer.

Since the start of last year, drug companies have announced 24 final-stage trials of pancreatic cancer treatments — more than in the entire preceding five-year period, according to a Bloomberg Businessweek analysis of a government database. The global market for branded pancreatic cancer medicines could soar to about $12 billion in 2035, from less than $500 million today, according to estimates from Bloomberg Intelligence. Daraxonrasib alone could ultimately reach more than $9 billion in annual sales, say pharma industry analysts surveyed by Bloomberg.

Behind the deluge are advances in drug-design technology that are for the first time allowing scientists to target the crucial molecular drivers behind the disease. Most cases of pancreatic cancer — as well as many other types — are caused by a gene mutation that’s proven almost impossible to target with traditional pharmaceutical technology. The gene, called KRAS, governs the production of a protein that regulates cell growth. When the gene is mutated, the protein can get stuck in the “on” position, allowing cells to grow uncontrollably. Daraxonrasib, which will be sold under the brand name Rasonque, works using a newfangled “molecular glue” mechanism that cements the bad protein to another healthy protein to inactivate it. It wasn’t clear such an approach would be safe and practical until Revolution Medicines showed it could work. “What is exciting is we now have a targeted therapy that applies to the majority of pancreatic cancer patients,” says Vincent Chung, a medical oncologist at City of Hope medical center in Duarte, California, who treats Williams.

“This is probably one of the greatest unmet needs in oncology,” says Incyte Corp. Chief Executive Officer Bill Meury, whose company in April started a final-stage trial of a drug that could be used to treat about 40% of pancreatic cancer patients with a particular type of KRAS mutation. The same month, Astellas Pharma Inc. dosed the first pancreatic cancer patient in a final-stage trial of its drug setidegrasib targeting the same subset of patients. Meanwhile, Erasca Inc. is planning final-stage trials next year for its daraxonrasib-style drug ERAS-0015, a compound it says is more potent than Revolution Medicines’ pill. A dark horse in the race is Immuneering Corp., whose drug blocks a related protein called MEK that promotes the growth of tumors.

So far, Revolution Medicines is in the lead. Even before the Food and Drug Administration had completed its review of daraxonrasib for previously treated pancreatic cancer, the drugmaker provided the treatment at no cost to more than 2,000 US patients, including Williams, through a special expanded-access program for people who didn’t qualify for ongoing trials. The company has begun additional final-stage trials that could expand use of the drug to patients with earlier stages of pancreatic cancer as well as advanced lung cancer. “We are launch-ready. This is something we have been preparing for for a long time. Our engines are revving,” says Revolution Medicines CEO Mark Goldsmith. Until recently, he says, “pretty much everyone viewed pancreatic cancer as a place drugs go to die.”

Revolution Medicines reportedly drew takeover interest from several large pharma players early this year, before its shares surged when positive results from the latest daraxonrasib trial were first announced. With a current market capitalization of around $45 billion, the Redwood City, California-based company’s valuation is too rich for all but a handful of potential buyers, especially factoring in the type of lofty premium that’s typical in biotech takeovers.

Revolution Medicines, founded in 2014, has retained most rights to daraxonrasib and several other drugs in its portfolio that target RAS (of which KRAS is a subset), outside of certain Asian markets, meaning it will also get to keep the sales revenue as the medicines are approved. In late 2023, when some investors were still skeptical about daraxonrasib’s potential, the company did an unusual all-stock transaction to buy a struggling biotech company called EQRx Inc., to gain access to its $1.1 billion pile of cash. That money helped it complete costly Phase III trials on its own, Goldsmith says.

Unlike some targeted cancer drugs that work for only a narrow subset of patients, daraxonrasib is effective against all forms of the RAS protein. That gives it potential to treat the vast majority of pancreatic cancer cases, as well as other tumors such as lung cancer, another disease often linked to the mutated gene. Because patients eventually develop resistance to the drug, researchers are racing to find combination treatments that have longer-lasting effects.

In July, Revolution Medicines released data from an early trial showing that combining daraxonrasib with zoldonrasib, another targeted pill it developed, shrunk tumors in half of patients, better than daraxonrasib can do alone. A final-stage trial of this combo has been initiated. In June, Tango Therapeutics Inc. reported that tumors shrank in 11 of 12 pancreatic cancer patients who received daraxonrasib in combination with its own drug vopimetostat, which targets a different growth-promoting gene present in a subset of pancreatic cancer patients. Tango says it’s planning a final-stage trial.

Williams, the former film executive, knows daraxonrasib is unlikely to be a cure for him. But he’s optimistic the drug could buy him enough time for even more effective regimens to be developed. “They are making so much progress now in pancreatic cancer,” he says. “Who knows what can happen in the next 12 months to 18 months?”