Home Colorectal Cancer Three Drugs Top Two for BRAF+ Metastatic Colorectal Cancer

Three Drugs Top Two for BRAF+ Metastatic Colorectal Cancer

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Adding a second targeted agent to chemotherapy significantly increased progression-free survival (PFS) in BRAF-mutant metastatic colorectal cancer (mCRC), a multicenter randomized trial showed.

Median PFS increased from 2.0 months with irinotecan and cetuximab (Erbitux) to 4.2 months with the same two drugs plus the BRAF inhibitor vemurafenib (Zelboraf). Overall survival (OS) improved numerically from 5.9 months with two drugs to 9.6 months with the addition of vemurafenib.

Objective response rate (ORR) and disease control rate (DCR) were three to four times higher with the three-drug combination, Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and co-authors reported in the Journal of Clinical Oncology.

“This supports the finding that the combination of BRAF and EGFR inhibition can provide clinical benefit in a setting where the activity of either BRAF or EGFR inhibition alone is minimal,” the authors said of their findings. “Indeed, in the control arm, the median PFS of 2 months corresponded with the first restaging and no patients demonstrated any regression in ct [circulating tumor] DNA with the control therapy, reiterating the need for novel approaches for this population.”

“While the OS demonstrated improvement with the vemurafenib combination, this was not statistically significant and was impacted by crossover to the experimental regimen at the time of progression on the control arm. The activity of the crossover arm was consistent with the experimental arm, suggesting that prior irinotecan and cetuximab exposure did not meaningfully preclude benefit from the VIC [vemurafenib-irinotecan-cetuximab] regimen.”

The findings contrasted with what Kopetz reported earlier this year from a trial pairing cetuximab with the BRAF inhibitor encorafenib (Braftovi) plus or minus the MEK inhibitor binimetinib (Mektovi). Results with the two chemotherapy-free regimens showed that adding the MEK inhibitor did not improve OS in metastatic BRAF-mutant CRC beyond the 9.3-month median observed with the BRAF/EGFR-inhibitor doublet. Both arms outperformed the irinotecan-cetuximab doublet, which led to median OS of 5.9 months.

In the current study (Southwest Oncology Group S1406), investigators tested the hypothesis that combined BRAF/EGFR inhibition would improve outcomes in BRAF-mutant mCRC. Objective responses rarely occur in that setting with vemurafenib alone, Kopetz and coauthors noted. However, vemurafenib blockade of BRAFV600E leads to upregulation of EGFR and increased signaling activity that can be disrupted by cetuximab.

The study included 106 patients with previously treated, BRAFV600Emutant mCRC. About 40% of the patients had prior exposure to irinotecan and half had prior adjuvant chemotherapy. The patients received irinotecan and cetuximab with or without concomitant vemurafenib, and the primary endpoint was PFS.

The 2.2-month improvement in median PFS with the triplet represented a 50% reduction in the hazard ratio (HR) for disease progression or death (95% CI 0.32-0.76, P=0.001). The addition of vemurafenib was associated with more than a fourfold increase in ORR (17% vs 4%), and DCR more than tripled from 21% with irinotecan and cetuximab to 65% with the three-drug combination.

Although median OS increased by 63%, the difference did not achieve statistical significance (HR 0.77, 95% CI 0.50-1.18).

Analysis of ctDNA showed that BRAFV600E variant allele frequency decreased in 87% of patients randomized to vemurafenib versus none of the patients who received the irinotecan-cetuximab doublet (P<0.001).

Grade 3/4 adverse events occurred more often with the triplet regimen, including neutropenia (30% vs 7%), anemia (13% vs 0%), and nausea (19% vs 2%). The authors reported that 11 (22%) patients in the vemurafenib arm discontinued treatment as compared with four (8%) in the control group.

“The VIC regimen is notable for the addition of irinotecan in the treatment, in contrast to other strategies only using targeted therapies,” the authors noted. “Preclinical data have demonstrated the ability of irinotecan to increase the depth of response and induce apoptosis in the models. This is consistent with low response rates seen in prior studies of vemurafenib and cetuximab and suggests strategies to combine optimal BRAF and EGFR targeting with irinotecan.”

“Our ctDNA results do suggest differences between this regimen and alternate BRAFV600E-targeting strategies. In contrast to prior reports of acquired KRAS and NRAS mutations at the time of progression on regimens with targeted therapy alone, this study found only one acquired KRAS, and no NRAS mutations, and low rates of other identifiable genomic mechanisms of resistance.”

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

The study was supported by the National Cancer Institute in collaboration with the Southwest Oncology Group, the Hope Foundation for Cancer Research, Guardant Health, and Genentech.

Kopetz disclosed relationships with MolecularMatch, Navire, Lutris, Roche, Genentech, EMD Serono, Merck, Karyopharm, Amal Therapeutics, Symphogen, Holy Stone, Biocartis, Amgen, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, Sanofi, Guardant Health, and Array BioPharma.

https://www.medpagetoday.com/hematologyoncology/coloncancer/90478

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