Read Time: 5 minutes
Takeaways:
- RAS oncoproteins, once considered undruggable, are now being successfully targeted by new drugs like daraxonrasib, showing dramatically improved survival in pancreatic cancer patients.
- Personalized pancreatic cancer vaccines may help stop the disease from returning by training the immune system to recognize and attack tumor cells—but this development is in very early stages.
Impact: Both KRAS inhibitors and an anti-recurrence vaccine represent substantial, but early, progress against pancreatic cancer.
Two developments in pancreatic cancer therapies have attracted the attention of the cancer community—and show promise for a new era of medicine in one of the most difficult to treat cancers.
At the American Society of Clinical Oncology Annual Meeting, the results of a pancreatic cancer clinical trial led to a standing ovation from thousands of physician-scientists. The Phase 3 trial nearly doubled survival time in patients with metastatic pancreatic cancer.
Targeting KRAS: Drugging the Undruggable
Huntsman Cancer Institute at the University of Utah (the U) is one of only 60 sites who offered the trial (RASolute 302) both in the United States and worldwide. The trial evaluated the groundbreaking drug daraxonrasib, developed by Revolution Medicines.
Daraxonrasib is an oral therapy that targets and inhibits mutant RAS, a gene that can drive cancer when altered. In pancreatic cancer, ongoing trials suggest it could be particularly effective in targeting KRAS, a type of RAS mutation that was once considered to be undruggable.
“KRAS is a driver of 90% of pancreatic cancer cases, and we are now targeting a protein that we couldn’t target before research made this possible,” says Vaia Florou, MD, MS, Huntsman Cancer Institute oncologist, associate professor of internal medicine at the U, and principal investigator on the daraxonrasib trial. “Therapies like this one will definitely be practice-changing for physicians. Five years from now, I think we may be treating pancreatic cancer in a totally different way.”
The results of the trial are a remarkable achievement for a disease with a 5-year survival rate of less than 10% for metastatic disease—one of the lowest amongst all cancers. The 5-year survival rate of all pancreatic cancers is 13%.
Florou hopes that the introduction of KRAS inhibitors will change long-term outcomes for pancreatic cancer patients. The disease is often diagnosed late, as symptoms don’t always appear in early stages. By the time of diagnosis, the disease has often metastasized, or spread beyond the pancreas. This makes surgical removal of the pancreas less effective.
“KRAS is a driver of 90% of pancreatic cancer cases, and we are now targeting a protein that we couldn’t target before research made this possible.”
Vaia Florou, MD
Florou says KRAS inhibitors could be a game changer for offering treatment beyond surgery and chemotherapy. She emphasized that these drugs still have side effects. Targeted therapies also can stop working over time as the cancer can adapt to the treatment.
But she remains optimistic about the therapy’s future use in oncology, especially at Huntsman Cancer Institute. Many patients travel far from rural and frontier areas to receive specialized care in Salt Lake City. Taking KRAS inhibitors as a pill could reduce the need to travel for infusions.
Huntsman Cancer Institute is involved in several ongoing clinical trials evaluating the use of daraxonrasib and other KRAS inhibitors as primary, first-line treatment in metastatic disease, in combination with chemotherapy, and after surgery in earlier-stage disease.
The Food and Drug Administration (FDA) also recently announced that Revolution Medicines could initiate an expanded access treatment protocol, allowing daraxonrasib to be used by more patients outside of clinical trials.
“For patients with pancreatic cancer, KRAS-targeted therapy may be an option worth talking about with their care team,” says Florou. “I believe this will lead to more treatment combinations down the line, and hopefully we can keep improving them for our patients. I want to thank every patient who participated.”
A Vaccine Against Cancer’s Return
The results of another pioneering treatment were discussed earlier at the annual meeting of the American Association for Cancer Research (AACR), another major conference for cancer researchers. At AACR, a team led by Vinod Balachandran, MD, from Memorial Sloan Kettering, an NCI-designated Comprehensive Cancer Center in New York City, presented the results of a clinical trial evaluating the efficacy of a pancreatic cancer vaccine in a small number of patients.
Conan Kinsey, MD, PhD, oncologist at Huntsman Cancer Institute and assistant professor of internal medicine at the U, says not to think about this vaccine as a traditional immunization.
“The frustrating thing for us as pancreatic cancer doctors is that pancreatic cancer very commonly comes back after surgery. It recurs,” says Kinsey. “What these researchers were trying to do is understand whether this vaccination could stop the disease from coming back again in patients who have already been treated. It’s not about preventing the disease from happening in the first place.”
This Phase 1 trial, which is the earliest step in determining the safety of new therapies, enrolled just 16 people. These pancreatic cancer patients had already had surgery to remove the cancer, as well as immunotherapy and chemotherapy.
Researchers developed the personalized vaccine by sequencing the DNA of each patient’s unique tumor. The vaccine is designed to activate immune cells to attack the cancerous cells.
“We desperately need new therapies for patients with pancreatic cancers. We're at the cusp of turning the tide in favor of patients."
Conan Kinsey, MD, PhD
Of the 16 patients enrolled in the trial, half of them responded positively to the vaccine. Seven of these patients were still alive six years after surgery. For the patients who did not respond to the vaccine, survival rates were lower. Only two of this cohort had no recurrence of the disease.
“A lot of us are very excited about this, as about 85% of patients will have a recurrence of pancreatic cancer within five years,” says Kinsey. “I think the other part that’s interesting is that, so far, we have not been able to figure out how to get the immune system to attack pancreatic cancer. This particular study may show an avenue as to how this could happen.”
Kinsey cautions that this is an early and small study. There is a chance that the experiment will not pan out as it moves through the clinical trial process toward getting approval from the FDA.
Still, between the revolution in KRAS inhibitors and the possibility of an anti-recurrence vaccine, Kinsey is hopeful about the future of pancreatic cancer treatment.
“There’s a lot of excitement over these new developments because we desperately need new therapies for patients with pancreatic cancers,” says Kinsey. “We're at the cusp of turning the tide in favor of patients. The more research that occurs, the more therapies we can bring to bear for this terrible disease.”
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