Overcoming Obstacles to Targeted Therapy in Colon Cancer

When Mia Balko, 48, started experiencing an ongoing cough in early 2019, her primary care doctor treated her with medication for acid reflux disease, but the cough persisted. Then she noticed that her abdomen was becoming increasingly distended and firm, and she asked to see a gastroenterologist.

Balko, who lives in Waco, Texas, was shocked when she later learned that the cough had been triggered by stage 4 colon cancer. The disease had spread to her abdomen and caused fluid retention, which in turn pressed on her lungs. Balko initially received two different chemotherapy regimens over the course of a year, but despite each treatment, the disease continued to grow.

The cancer tested positive for a specific gene mutation known as KRAS G12C, which made Balko eligible to participate in a clinical trial at The University of Texas MD Anderson Cancer Center in Houston for a new targeted therapy known as AMG 510 (sotorasib). She started taking eight pills daily that contained a small molecule equipped to bind to a region of the KRAS G12C protein. Initially the only side effect was headaches, but once she started taking the medication before bed, the headaches disappeared. After nearly a year on the new targeted treatment, her scans showed that the cancer was stable.

“My quality of life improved when I switched to the targeted therapy,” Balko says. “I had a lot more stamina to work and do activities I enjoy.”

Although a recent scan showed a new lesion on her liver, she is grateful she can continue taking AMG 510 as she adds a new chemotherapy treatment to her regimen to address the growth.

For years, the only main targeted therapy available to patients with colorectal cancer was a medication that blocked the function of a protein called epidermal growth factor receptor (EGFR), but this treatment was not effective for patients with the KRAS mutation, which is present in approximately 40% of colorectal cancers. Now researchers are uncovering new treatments that are improving outcomes for people with colorectal cancer who have this mutation and other genetic aberrations, including the BRAF mutation and HER2 amplification.

“Compared (with) other forms of cancer, results of targeted therapy agents have not been as impressive in colorectal cancer, but we have learned from many negative trials,” explains Dr. Afsaneh Barzi, a gastrointestinal medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, California. “With the new clinical trials, we are right on the cusp of seeing significant changes in outcomes for this population of patients.”

Colorectal cancer is the third-leading cause of cancer deaths in the United States, and Barzi notes it is critical for patients to receive molecular testing at diagnosis to identify potential genetic targets. “Sometimes doctors wait to do this testing until patients have failed on standard therapy, but this is too late,” she says. “We need this information early on to identify potential clinical trials.”

For patients who do not have the KRAS mutation, which is known as KRAS wild-type, EGFR inhibitors combined with chemotherapy can slow progression of the disease, but more recent studies have shown that there is one more element to consider for these patients: the cancer’s location.

“When scientists analyzed the study results, they discovered that EGFR inhibition with first-line chemotherapy only worked with people who had left-sided colon cancers,” says Dr. Alfred Neugut, co-director of the Cancer Prevention Center at New York Presbyterian Hospital and Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center. For right-sided tumors, the better option for first-line treatment is chemotherapy plus Avastin (bevacizumab).

New Strategies for Treating BRAF and HER2 Cancers

The BRAF mutation — which occurs in approximately 10% of colorectal cancers — is another biomarker that has historically been difficult to target in patients with colorectal cancer, but researchers have started to uncover new ways to improve outcomes for this population.

“More than a decade ago, we recognized that this group of patients was not responding to traditional therapies, so initially we tried targeting the BRAF mutation,” notes Dr. Scott Kopetz, a professor in the department of gastrointestinal medical oncology at MD Anderson. “This strategy had worked in patients with melanoma, but we found that this was not the case for people with colorectal cancer.”

Researchers discovered that when they used a drug to block a receptor on BRAF-mutated cells, the cells increased EGFR signaling to compensate and continue cancer growth. Then Kopetz launched clinical trials in which patients received either one or two BRAF inhibitors in addition to an EGFR inhibitor, and this was more successful. In April 2020, the Food and Drug Administration (FDA) approved Braftovi (encorafenib), a BRAF inhibitor, in combination with Erbitux (cetuximab), an EGFR inhibitor, for patients with metastatic colon cancer. Findings from the recent BEACON CRC study showed that these combinations increased overall survival by more than four months. The most common side effects included diarrhea, acne and nausea.

Now researchers are exploring benefits of adding chemotherapy to this regimen or combining BRAF inhibitors with immunotherapy. Mary DeForest, 59, recently enrolled in a clinical trial for a combination of Braftovi and Erbitux plus the immunotherapy drug Opdivo (nivolumab) to treat stage 4 colon cancer, and she has been impressed by the results. After four months on the combination, the tumor in her liver has shrunk 75% and the cancer in her colon decreased 25%. “I feel so good that I don’t think about having cancer anymore,” DeForest, from Bay City, Texas, says.

Another promising target in colorectal cancer is the HER2 amplification, which means the cancer has too many copies of the HER2 gene. The amplification occurs in approximately 3% to 5% of colorectal cancers, and clinical trials combining two HER2-targeted therapies have shown that this strategy can have impressive results, according to Dr. James Cleary, a senior physician at Dana-Farber Cancer Institute in Boston.

One of Cleary’s patients has been taking a combination of Herceptin (trastuzumab) and Tykerb (lapatinib) for four years with an excellent quality of life, and now there is a second option for her if the cancer starts to grow.

Enhertu (trastuzumab deruxtecan) is an antibody-drug conjugate that binds to cells with the HER2 amplification and then delivers a toxin into these cancer cells. Results of a recent study showed that, among patients with the highest levels of HER2 expression, the response rate to this drug was 45% and the median progression-free survival (the time from treatment to disease progression or worsening) was seven months.

Immunotherapy for Colon Cancer

Genomic testing of cancer cells can reveal not only the presence of KRAS, BRAF and HER2 alterations but also the level of microsatellite instability (MSI). People who are MSI-high are deficient in the mismatch repair (MMR) proteins that find mistakes in DNA. These MSI high cancers accumulate DNA mutations that are felt to make tumors more recognizable, which is good news now that immunotherapy is an option for treatment.

“Immunotherapy uses the body’s own immune system to fight off cancers, and tumors with more mutations are easier to identify as invaders,” Cleary says. “The challenge is that only about 3% to 4% of people with metastatic colon cancer are MSI-high, so not many patients can benefit from immunotherapy at this point.”

Rodnell Workman, 47, was among the patients with stage 4 colon cancer who were eligible for immunotherapy. His symptoms began in 2016, when he felt as though he had the flu and later discovered that his appendix had ruptured. The surgical team identified abnormalities on his appendix and a colonoscopy showed that he had a large mass in his colon. Biomarker testing revealed that he had Lynch syndrome, an inherited condition associated with high levels of MSI and increased cancer risk. The doctors prescribed chemotherapy to shrink the tumor before removing it surgically, and they also recommended three months of the immunotherapy Keytruda (pembrolizumab) to ensure that the cancer was eradicated.

“I had no side effects from the immunotherapy and I’ve had clean scans ever since,” says Workman, who lives in New Jersey.

Although Workman received immunotherapy after chemotherapy, in June 2020 the FDA approved Keytruda as a first-line treatment for patients with colorectal cancer that is MSI-high, MMR deficient or unresectable. Researchers also have started to investigate whether immunotherapy in combination with Stivarga (regorafenib), which inhibits growth of blood vessels needed for tumor growth, could benefit the many patients with tumors that are not MSI-high.

Promising Targets on the Horizon

Although oncologists have more targeted therapy options for patients with colorectal cancer than in the past, the treatments are still limited to a somewhat small percentage of patients who have certain mutations, says Dr. Suneel Kamath, a medical oncologist who specializes in the treatment of gastrointestinal cancers at Cleveland Clinic in Ohio. “The biggest area of need is finding more mutations and developing drugs to target them,” he says.

For example, fibroblast growth factor receptor (FGFR) mutations in bile duct and bladder cancer have also been found in colon cancer. Clinical trials are underway to test whether Pemazyre (pemigatinib), an FGFR inhibitor that targets this mutation, blocks tumor growth in people with metastatic colon cancer.

Moreover, mutations in the RAS gene family have been known to be bad actors for decades — associated with more aggressive behavior in many tumor types — and were considered “undruggable” until recently.

Cleary said he hopes to see more studies that explore repurposing targeted treatments for other forms of cancer to help people with colorectal cancer. As part of one study, Cleary and his Dana-Farber colleague Dr. Harsh Singh treated two patients with colon cancer who tested positive for gene translocations seen in lung cancer: ROS1 and ALK. They prescribed targeted therapies that have been effective in lung cancer, and the results were encouraging. The treatment was beneficial for seven months for the patient with the ALK translocation, and the patient with the ROS1 translocation continues to do well after more than a year of targeted treatment.

“To me, this was very exciting,” Cleary says. “Seeing (patients with colorectal cancer) with these rare genomic alterations benefit from nontraditional therapies gives me hope that additional targetable alterations can be found and exploited, and, hopefully, this is just the beginning.”

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