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No Survival Benefit for Upfront VEGF Inhibitors in Metastatic CRC

Real-world data did not always show the promising results that were seen in clinical trials when researchers looked at outcomes with targeted therapies for metastatic colorectal cancer.

Reviewing electronic records of 9134 patients from across the United States, investigators found improved overall survival when epithelial growth factor receptor (EGFR) inhibitors were added to chemotherapy (regardless of chemotherapy backbone) in patients with RAS wild-type tumors; this finding is in line with trial results.  

However, the team found no survival benefit when vascular endothelial growth factor (VEGF) inhibitors were added to first-line chemotherapy, in contrast to results from clinical trials.

This was despite the fact that VEGF inhibitors were used in in 55.6% of the subjects, far more than the 7.8% who received EGFR inhibitors.

The review was published online January 19 in JAMA Network Open.

“We were somewhat surprised by” the discrepancies, lead investigator Siran Koroukian, PhD, a professor of population and quantitative health sciences at Case Western Reserve University in Cleveland, Ohio, told Medscape Medical News.

The findings highlight the well-known phenomenon of treatment outcomes in real-world patients falling short of those in clinical trials, which tend to enroll  relatively younger and healthier patients, Koroukian said.

“A lot is made about real world data, and there’s something to be said for that,” medical oncologist Alan Venook, MD, an expert on CRC at the University of California San Francisco who wasn’t involved with this research, told Medscape Medical News when asked for comment.

However, he had his doubts about this particular study.

For one, the investigation didn’t take into account how patients were treated in the second and later lines of therapy, which probably has a greater impact on overall survival. The study also didn’t address several factors that influence outcomes, including right vs left-sided disease; metastasis limited to operable liver lesions; and newer advances, he pointed out.

Even so, the absence of survival benefit with VGEF inhibitors is “probably believable” given their lackluster performance in metastatic CRC trials, said Venook. He noted that many European countries don’t even cover the VGEF inhibitor bevacizumab (Avastin) for this indication.

“The truth is that neither of these drug classes [ie, VGEF and EGFR inhibitors] are a panacea,” Venook commented. “When they came on board 20 years ago, we thought they were going to change the face of colorectal cancer, [but] they didn’t,” he said.

Most Common Regimen Had Worst Survival

In fact, the team found that the most common first-line treatment regimen in the study — FOLFOX chemotherapy plus a VEGF inhibitor — had worse overall survival in patients with RAS wild-type tumors than other options, including FOLFOX + an EGFR inhibitor and FOLFOX alone.

The finding didn’t surprise Venook, who said he’s been wondering for years “who in the world made the decision” that FOLFOX + bevacizumab should be the default first-line option for metastatic CRC, which he estimated is used in more than two thirds of patients.

“It’s probably the least impactful” option, he said, and “it makes no sense” that it’s often the first choice. Venook said that he is working on a paper to get to the bottom of this situation for the upcoming 40th anniversary edition of the Journal of Clinical Oncology.

In his own practice, he usually uses FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) for first-line metastatic CRC, which he said “the field has evolved to” in recent years, and he does so without any targeted therapy add-ons.

Study Details

For this study, Koroukian and colleagues reviewed data on patients who were undergoing first-line treatment for newly diagnosed metastatic CRC. They were treated at 800 sites, 94% of which were community oncology practices, from January 2013 through March 2020. The median age at diagnosis was 62 years; just over half the subjects were men, and 62.3% were White.

“Unexpectedly,” the investigators noted, Black patients had higher odds of receiving targeted therapies than White patients.

RAS wild-type EGFR patients did better than others, with survival curves starting to separate at about 5 months and staying separated through 90 months (7½ years). At 30 months, for instance, about 50% of EGFR-treated patients were alive vs 40% of patients without EGFR inhibition (adjusted hazard ratio (aHR), 0.85). Curves separated for RAS-mutated patients as well, but the finding wasn’t statistically significant (P = 0.30).

Survival curves did not separate with VEGF inhibition vs no targeted therapy for both RAS wild-type (aHR, 1.00) and RAS-mutant tumors (aHR, 1.01).

In addition to efficacy concerns, Venook noted that there are toxicity concerns with the targeted agents. EGFR inhibitors “cause a horrible acne rash in many patients that they don’t like,” and VEGF inhibitors carry a considerable risk of bleeding, heart attacks, and other issues, he said.

These considerations might be at least partly behind why over a third of the patients in the study also weren’t treated with targeted agents, particularly patients older than age 80 years and those with poor performance scores, he suggested.

The work was funded by the American Cancer Society and others. Koroukian and co-authors and Venook report no relevant financial relationships. 

JAMA Open Network. Published online January 19, 2023. Full text

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]

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