Targeted Fusions Effective for Higher Response Rates and Longer PFS

Significantly higher response rates and a longer progression-free survival (PFS) were observed when targeting fusions compared with non-fusions, according to a study published in Cancer. 

When regarding both presented cohorts, these results suggest that targeting fusions is important for both hematologic and solid malignancies when they are present.

“I think with the findings we have about how important the fusions are and the better response rates, a lot of the drug development going forward needs to focus on making drugs for fusions, to target fusions,” Mina Nikanjam, MD, PhD, lead author and Assistant Clinical Professor at the University of California San Diego, suggested.

In the first cohort of 6,189 patients across 28 single-agent drugs approved by the FDA for specific genomic alteration, the median response rate was 68% vs 50% for fusions vs non-fusion matches (odds ratio [OR], 1.67; P< .0001). Additionally, solid tumor therapies had an OR of 2.07 (P< .0001) and hematologic therapies had an OR of 3.35 (P < .0001) for fusion versus non-fusion targets. 

A group of 2,455 patients from the University of California at San Diego were analyzed in the second cohort, and patients matched to fusions were found to have a longer median PFS (11.6 months; 95% CI, 4.0-35.4 months) compared with those unmatched to fusions (4.9 months; 95% CI, 3.5-8.8 months) (P= 0.34). Patients with fusions matched to other alterations present in the tumor had a median PFS that was indistinguishable from that of those patients with fusions who were treated with unmatched therapy (4 months vs 5 months; P = .75). 

Of the 28 drugs used in the FDA cohort, 11 were approved for fusion targets and 16 were approved for non-fusion targets. Imatinib had 2 separate FDA-approved indications; one for targeting the BCR-ABL fusion in CML and the other for targeting KIT, a non-fusion for gastrointestinal stromal tumor. The fusions included ALK, ROS1, NTRK, PML-RARA, and BCR-ABL.Non-fusion targets included EGFR, BRAF, KIT, BRCA, HER2, FLT3, IDH1, andIDH2. 

There were 79 patients in whom fusions were treated in the University cohort. Of those patients, 25 received a therapy matched to a gene fusion, 12 received a therapy matched to another alteration, and 42 received unmatched treatment. Forty-three percent of the 79 had fusions that were predicted to result in oncogenic tyrosine kinase activity.

According to researchers, fusions are present in a wide variety of solid tumors in addition to hematologic malignancies and many fusions lead to a state of oncogenic addiction, which makes them ideal for anticancer therapeutics.

“I think what these findings really show is you need to use fusions as your primary focus. That needs to be something that you have to target with your matched therapy,” Nikanjam said in regard to patient care.

Though this study does suggest that fusions are important targets, additional studies are needed to confirm that optimized therapy may require targeting fusions, even in the presence of other alterations. 

Currently, the majority of targeted therapies are antibodies that impact extracellular and cell surface proteins or small molecule inhibitors that also can suppress protein pathways inside the cell, according to researchers. Fusions though are increasingly being pursued as oncology therapeutic targets.

References:

Nikanjam M, Okamura R, Barkauskas DA, Kurzrock R. Targeting fusions for improved outcomes in oncology treatment. Cancer. doi:10.1002/cncr.32649