Pancreatic cancer has been, for decades, an untouchable tumor. The most lethal. Untreatable. With a five-year survival rate below 10% and an extremely limited therapeutic arsenal, the diagnosis of this tumor, almost always at very advanced stages, almost always presented a devastating outlook, with no way out. But the tide has begun to turn: the disease remains extremely aggressive and deadly, but a new targeted therapy has just achieved unprecedented success by achieving survival of up to 13 months in patients with metastases, double that of conventional chemotherapy. These findings, presented this weekend in Chicago during the plenary session of the American Society of Clinical Oncology (ASCO) congress, open a new era in the approach to one of the most devastating tumors.
Read more The Spanish team takes a mass bath in the first training session before the World Cup
The drug is called daraxonrasib and has achieved what some scientists already saw as unattainable: attacking the mutated KRAS gene, responsible for the aggressive growth of this and other tumors. “We haven’t had a study with such good results in years. This is the first step of a tsunami that is to come: the era of KRAS inhibitors is going to change the landscape in pancreatic cancer,” predicts Teresa Macarulla, head of Medical Oncology at the Hospital Clínic of Barcelona and an expert in this type of tumor. The research has not yet been published in a peer-reviewed scientific journal.
Scientists have known for decades that this mutated gene was one of the fundamental drivers for the development of pancreatic cancer because it produces a protein that, like a switch, when turned on, stimulates cells to reproduce uncontrollably. “RAS is a family of proteins [and KRAS is one member of that clan] involved in cell growth. It is one of the major targets in pancreatic cancer. Attempts have always been made to attack this pathway, but no way was found,” admits Berta Laquente, an oncologist specializing in these tumors at the Catalan Institute of Oncology (ICO).
Daraxonrasib is a panRAS inhibitor. That is, it blocks the activity of any altered form of the RAS gene. The drug, an oral medication taken once a day, acts like a molecular glue that attaches to a kind of pocket in the mutated protein and also to another molecule in the cell, forming a kind of clamp between them that blocks the activity of the mutated gene. “It prevents it from transmitting its message, which is to stimulate the cell to produce more,” explains Macarulla.
The potential of this drug is overwhelming and much of the scientific community has its eye on it. In fact, this drug is also part of the controversial therapeutic triad with which Spanish researcher Mariano Barbacid announced he had cured pancreatic cancer in mice. His research, surrounded by controversy due to excessive media expectations — it was even presented on television as “a miracle” and went viral on social media as “the cure for cancer” before being tested in humans — was withdrawn by the scientific journal where it was published (PNAS) after it was found that Barbacid had not declared a “relevant conflict of interest”: he and two colleagues owned part of the company Vega Oncotargets, a company founded to commercially exploit the results of that triple therapy.
Macarulla emphasizes the difference between Barbacid’s study and the one presented at ASCO: “Barbacid’s research was in mice and used this drug in combination with others. There are no patient data for that triple therapy. In contrast, the research presented in the ASCO plenary shows benefit in humans. It reduces the risk of death by 60%.”
The clinical trial presented at the ASCO congress tested the potential of this targeted therapy versus chemotherapy in second-line treatment. They selected a group of 500 patients with metastatic pancreatic cancer who had already undergone first-line chemotherapy treatment and had failed, and divided them into two arms: one received daraxonrasib and the other conventional chemotherapy. Among those who received the innovative treatment, the median overall survival doubled: 13 months versus six with traditional chemotherapy. “These results open the door to treating patients differently and give us hope,” explains the oncologist from Clínic. There are no Spanish signatories in this study, but the Barcelona hospital participated by recruiting patients for this research and is already preparing additional studies with these treatments starting this summer.
Read more Who are the Catholics today? The Spain that Leo XIV will find
For Laquente, the data are “good news,” but she urges caution. It is not a curative treatment. “We had many years without such potentially disruptive advances and the magnitude of the benefit of this drug is unusual, but we cannot talk about a cure. What this research does do is mark the beginning of a new stage of targeted therapies in pancreatic cancer,” she maintains.
“The RAS revolution”
The results of the clinical trial presented at the ASCO congress are still pending publication in a peer-reviewed scientific journal, but the fact that it was placed in one of the plenary sessions of this congress, the main conference within the most important global oncology event, is already a boost to the research and its transformative potential in cancer care. “We are seeing unprecedented survival and efficacy in second-line treatment. The RAS revolution is already here,” said Rachna Shroff, head of Oncohematology at the University of Arizona Cancer Center, in an ASCO statement. Experts say it will change clinical practice in the short term, at least in second-line treatment, and estimate that it will be available in the United States by the end of summer. It will take a little longer in the European Union.
In a statement from Revolution Medicine, the company that developed the drug, Brian Wolpin, director of the Hale Family Pancreatic Cancer Research Center at the Dana-Farber Cancer Institute and principal investigator of the trial, said in April that the drug represents “a clear and very significant advance for patients with pancreatic cancer who have experienced progression after prior treatment.” “I foresee it transforming clinical practice and improving care for patients with previously treated metastatic pancreatic cancer,” he says. The drug would also have potential against RAS mutations present in lung and colon cancer.
Macarulla highlights that the drug can serve the vast majority of pancreatic tumors, because 95% have some mutation in the KRAS gene. The oncologist puts it in context with other research she herself was part of: in 2019, for example, at another ASCO congress, she presented results of another targeted therapy, olaparib, for a subgroup of pancreatic tumors. It was a key finding, the first time positive results were achieved with a targeted therapy, but it only served 7% of patients, those with a mutation in the BRCA genes, which are responsible for activating proteins that help repair DNA. This time, with daraxonrasib, the pool of patients eligible for this therapy is broader.
“Almost everything had failed in pancreatic cancer and this is a new weapon to fight the tumor. A new era is opening,” she reflects. For now, the findings are limited to second-line treatment, but Macarulla says trials are already being prepared to explore the potential of this and other KRAS inhibitors earlier, in first-line treatment, and there are also preliminary studies, she explains, encouraging testing this drug in combination with some chemotherapies to maximize its effects.
The therapeutic revolution with KRAS inhibitors is already underway and daraxonrasib is presumed to be just the first chapter. Now, for example, it is administered while it works and stops tumor growth, but why does it work and when does it stop working? Is the impact the same in all patients? Who benefits the most? Will it generate resistance? Laquente assures that the fine print of the study will have to be examined and research in this line must continue: “This has just begun.”
Read more Ten things that Selectividad graders advise to do (or avoid) in the PAU exams