Advanced Colorectal Cancer Treatment Targets KRAS Gene With Drug Combo

Two photos of Anthony and Arianna Robles

Since being diagnosed with stage 4 colorectal cancer, Anthony Robles is grateful for every moment he spends with his daughter, Arianna.

  • MSK investigators led a recent trial that examined a new two-drug combination for patients with advanced colorectal cancer caused by a gene mutation called KRAS-G12C.
  • Research in the lab is focused on how to make these targeted drugs even more effective.

Anthony Robles, a 53-year-old accountant and single father from the Bronx, values every moment he’s able to spend with his 9-year-old daughter, Arianna. Their time together is especially precious because in February 2022, Anthony was diagnosed with stage 4 colorectal cancer. Since he joined a clinical trial at Memorial Sloan Kettering Cancer Center (MSK) in September, his tumors have shrunk by almost 40%.

Anthony has been receiving a combination of two drugs to target the KRAS gene mutation that fuels the growth of his colorectal cancer tumors. The drugs are cetuximab (Erbitux®) and adagrasib (KrazatiTM). His medical oncologist, Rona Yaeger, MD, is leading the clinical trial.

“Given the fact that we caught my diagnosis at stage 4, I’m appreciative of all that I’m still able to do,” says Anthony, who recently took Arianna to see the Rockettes at the annual Radio City Christmas Spectacular. “Most of the time, I don’t even feel like I’m sick.”

Results of a New Drug Combination Treatment for People With Advanced Colorectal Cancer

Dr. Yaeger was lead author of a paper published in The New England Journal of Medicine (NEJM) on December 21, 2022, that reported the first clinical findings from the cetuximab and adagrasib drug combination given to Anthony. Based on those results, on the same day the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for this drug combination. The NEJM paper reported:

  • All 76 patients in the study had a specific mutation in the KRAS (pronounced “kay-rass”) gene called G12C.
  • 32 patients received both drugs, and, among 28 evaluated for efficacy, more than 46% had a response, which means their tumors shrunk at least 30%. All patients had their tumor stop growing or get smaller with this combination.
  • 44 patients received adagrasib alone, and, among 43 evaluated for efficacy, about 19% responded.
  • Everyone in the trial had previously received other treatments for their colorectal cancer that had stopped working.

“Based on the findings from this study, we’ve already started a phase 3 trial,” Dr. Yaeger says. “I’ve had people coming to me from all over to receive this treatment.” Until very recently, adagrasib was considered experimental and was not approved for any patients outside of clinical trials. It received accelerated approval from the FDA on December 12, 2022, but only for lung cancer.

Based on the findings from this study, we've already started a phase 3 trial.
Rona Yaeger medical oncologist

The NEJM study, a multicenter, phase 1B/phase 2 trial, was primarily designed to evaluate the safety of this therapy. The most commonly reported side effects of the drug combination were fatigue, gastrointestinal issues, and acne. Anthony has experienced them, too, but says overall he is feeling good.

How Scientists Are Able To Target the KRAS Gene in Colorectal Cancer

Mutations in the KRAS gene — one of the first cancer genes ever identified — are most commonly found in colorectal cancer, pancreatic cancer, and lung cancer. But despite four decades of research, scientists could not figure out how to block its activity. They called the KRAS mutation “undruggable.” But finally, a drug called sotorasib (Lumakras™) — a drug similar to adagrasib — was proven effective for a subset of people with lung cancer found to have the KRAS-G12C mutation. The FDA granted accelerated approval to sotorasib in May 2021.

Much of the early research on blocking KRAS was done by MSK researchers Neal Rosen, MD, PhD, and Piro Lito, MD, PhD. They helped determine how drugs were able to bind to the KRAS protein and trap it in an inactive state, which in turn prevented the protein from triggering the growth of cancer cells.

Developing KRAS-targeting drugs for treating colorectal cancer has been more difficult than it has been for lung cancer. For several years, Dr. Yaeger has worked with molecular biologist Sandra Misale, PhD, a senior research scientist in Dr. Rosen’s lab, which is part of the Molecular Pharmacology Program in the Sloan Kettering Institute. They have been studying how to make these drugs more effective, often by combining drugs that take aim at two different genetic targets at the same time. This double-barreled approach inspired the current treatment: combining adagrasib with cetuximab, an older drug that blocks another cancer-causing protein called EGFR.

How the Colorectal Drug Treatment Is Administered

Anthony takes adagrasib as pills at home twice a day. He receives cetuximab, which is given as an infusion, every two weeks at MSK’s Rockefeller Outpatient Pavilion in midtown Manhattan.

“I’m usually there seven or eight hours — it’s a long day,” he says. That’s because in addition to getting the infusion, the trial requires him to have extra tests, such as blood tests and EKGs. “I try to make the most of my time there,” he adds. “I always talk to other patients while I’m waiting. I take inspiration from them and from sharing what we’re going through.”

How MSK Is Trying To Prevent Drug Resistance Commonly Developed in Patients

In another recent paper published December 15, 2022, in Cancer Discovery, Drs. Yaeger and Misale reported more details on how resistance to the combination of adagrasib and cetuximab develops in colorectal cancer. Their research used animal models and cell cultures. They also analyzed samples collected from many of the patients who participated in the clinical trial published in NEJM.

“Everyone knows that when you use targeted drugs, patients almost always develop secondary resistance,” Dr. Misale says. “We started studying this even before the treatment had been given to patients.”

Their research revealed several ways that resistance can develop. One of the most common is that the gene for KRAS-G12C becomes amplified, causing it to produce more of the protein than the drug is able to block. “Based on these findings, we have ideas for potential future approaches,” Dr. Misale says.

Tumor Genetic Testing at MSK Leads to Targeted Therapies

When Anthony was diagnosed with colorectal cancer at a local hospital in the Bronx after months of rectal bleeding, it had already spread to his liver and bones. He and his mother discussed his treatment, and he decided to go to MSK. He first saw medical oncologist Nitya Raj, MD, who treated him with chemotherapy.

He also received a biopsy and analysis with MSK-IMPACT®, a test that looks for genetic changes in tumors that can help match patients with targeted therapies. The test revealed that Anthony’s tumor had the KRAS-G12C mutation. Only about 3% of colorectal cancers have this mutation. After learning he had the mutation, he was introduced to Dr. Yaeger, who told him about the experimental treatment. He is participating in an extension of the earlier clinical trial.

The Multiple Treatments Needed for Anthony’s Late-Stage Colorectal Cancer

In addition to receiving the new drug combination, radiation oncologists Adam Schmitt, MD, and Paul Romesser, MD, used radiation therapy to destroy a tumor in Anthony’s spine that was causing pain in his legs. In June, gastrointestinal surgeon Alice Wei, MD, performed an emergency procedure to repair a perforation in his large intestine.

Dr. Yaeger doesn’t know how long the treatment will work for Anthony. All of the patients in the first trial eventually developed resistance to the drug combination. But Drs. Yaeger and Misale are actively working to find new approaches that could target this resistance.

Meanwhile, Anthony is grateful for any time that he can have with Arianna. “If I can squeeze out five or six more years, I aim to make them the best five or six years of my life,” he says.

He also expresses profound appreciation for his care team at MSK, especially clinical trial nurse practitioner Jenna Sinopoli. “Jenna has been a huge source of support for me,” he says. “But everyone at MSK has been so wonderful and so nice. You can tell they really care.”

The NEJM study was supported by Mirati Therapeutics Inc., and National Institutes of Health (NIH) Cancer Center Core Grant P30 CA 008748 to MSK.

The Cancer Discovery paper was funded by NIH grants R01 CA233736, U54 OD020355, P30 CA008748, and CTSA UL1TR00457. Researchers also received support from a Cancer Research Institute Irvington Fellowship supported by the Cancer Research Institute and a Kristina M. Day Young Investigator Award from Conquer Cancer, the ASCO Foundation.

Dr. Yaeger has relationships with or financial interests in Medscape, Mirati Therapeutics, and PER Events LLC.