Promising KRAS Inhibitor Offers Hope for Pancreatic Cancer Patients

Patients with advanced pancreatic cancer are receiving new hope through a drug currently undergoing clinical trials, including at Penn Medicine’s Abramson Cancer Center. Irene Blair, a 59-year-old grandmother from Newark, Delaware, was given a prognosis of six to eight months to live in June after her cancer progressed to stage 4. The drug, known as daraxonrasib, belongs to a groundbreaking class of medications designed to target KRAS mutations, which are prevalent in this aggressive form of cancer.

The survival rate for pancreatic cancer is alarmingly low, with only 13% of patients alive five years after diagnosis, marking it as the cancer with the highest mortality rate. While daraxonrasib is not a cure, initial results from clinical trials suggest it may significantly extend survival times. This latest development comes at a critical time, especially following former Nebraska Senator Ben Sasse‘s recent announcement of his own stage 4 pancreatic cancer diagnosis, in which he candidly stated he is “gonna die.”

Clinical Trials and Results

Accelerated by promising early results, the U.S. federal government has expedited the review timeline for daraxonrasib, produced by Revolution Medicines, Inc.. In a phase 1 trial involving 38 patients, the drug reportedly doubled survival durations for half of the participants, increasing the median survival time from approximately seven months to 15.6 months compared to standard chemotherapy.

Mark O’Hara, Blair’s oncologist and a leader in multiple clinical trials for KRAS inhibitors at Penn, expressed optimism, stating, “In pancreatic cancer, for too long, we haven’t had effective therapies beyond just chemotherapy.” After starting the phase 3 trial in July, Blair experienced a dramatic improvement; her cancer-related pain subsided within three weeks, and follow-up scans in October showed her tumors were either stable or decreasing. By December 2023, her cancer had not progressed, a significant difference compared to her previous chemotherapy treatment.

Targeting KRAS Mutations

The quest to target the KRAS protein, often described as a “gas pedal” for cancer growth, has been ongoing since its discovery in 1982. Mutated KRAS proteins drive uncontrolled cell proliferation and are found in about 25% of all human cancers, predominantly in aggressive forms such as pancreatic, lung, and colon cancers. The breakthrough came in 2021 when the first KRAS inhibitors were approved by the FDA for lung cancer. Daraxonrasib is one of the first KRAS inhibitors being tested specifically for pancreatic cancer, where nearly 90% of cases involve these mutations.

As a “pan-RAS inhibitor,” daraxonrasib not only targets KRAS but also inhibits two related proteins, HRAS and NRAS, which contribute to cancer growth when mutated. In the same phase 1 trial, over 90% of the 83 participants experienced stalled cancer progression during treatment, and approximately 30% saw their tumors shrink. The drug is taken in the form of three pills daily at home, with the most common side effect being a facial rash experienced by 91% of patients.

Other side effects include diarrhea, nausea, vomiting, and mouth sores; however, O’Hara noted these symptoms are generally manageable with medications, allowing patients to maintain a better quality of life compared to traditional chemotherapy.

Blair, now eager to make the most of her time, has expressed a desire to travel and reconnect with family. Reflecting on her situation, she shared, “You just wonder, ‘Will I be here next year?’” As researchers continue to explore and develop treatments targeting KRAS mutations, patients like Blair remain hopeful for advancements that could change the landscape of pancreatic cancer treatment.