AstraZeneca’s Tagrisso has taken firm hold of the EGFR market over the last few years, pushing aside drugs including AZ’s own older drug Iressa. But could a combination EGFR therapy approach be a viable alternative?
Combination therapy for EGFR
Adding Elevar Therapeutics’ rivoceranib (aka apatinib) to Iressa helped keep cancer at bay in previously untreated, EGFR-mutated non–small cell lung cancer (NSCLC) patients, data presented at the 2020 European Society for Medical Oncology Virtual Congress show. In a phase 3 trial called Active, patients in the apatinib arm went a median 13.7 months without their cancer worsening, compared with 10.2 months for Iressa alone.
Overall, 77.1% of patients responded to the apatinib combo versus 73.7% for Iressa, but that difference failed to reach statistical significance. Only one patient in the apatinib arm saw cancer cleared completely. The trial will continue to see if apatinib can help extend patients’ lives, considered the gold standard in oncology trials.
Apatinib works as a small-molecule, multi-targeted tyrosine kinase inhibitor (TKI) that selectively inhibits VEGFR2, while Iressa works as an epidermal growth factor receptor (EGFR) inhibitor, which interrupts signaling through the EGFR in target cells.
The idea is that combining the two pathways “may be a feasible therapeutic strategy for patients with EGFR-mutant NSCLC based on early preclinical studies that demonstrated the dual blockade’s efficacy delaying the emergence of resistant tumor,” according to the trial’s protocol.
But while apatinib might have helped stave off cancer progression, it also raised the rate of safety issues ranked grade 3 or higher. Those side effects impacted 84.1% of patients treated in the combination arm, versus just over two-thirds of patients in the placebo arm.
The most common issue flagged in the apatinib group was hypertension, with nearly half of patients being hit. Overall, “no unexpected safety signals were identified beyond the established safety profile of each single agent,” said Li Zhang, M.D., a professor of medical oncology and director of the Phase I Unit of Sun Yat-Sen University Cancer Centre (SYSUCC) as well as deputy director of lung cancer research at SYSUCC, who presented the data.
Elevar’s drug is approved in China in certain patients with advanced gastric cancer.
Should it gun for an approval in the U.S. in NSCLC cancer patients with EFGR mutations, it would be up against the likes of AstraZeneca’s EGFR drug Tagrisso, which has taken the market by storm since winning its own first-line approval; the drug racked up $2.02 in first-half 2020 sales.
Tagrisso, on its way to its own first-line approval, also beat out Iressa and Roche’s Tarceva by a winder margin than the apatinib combo did, stalling tumor progression for a median 18.9 months—though comparing results across trials can be problematic due to differences in study design and patient population.
Other companies are also looking at combo approaches, though—including Johnson & Johnson, which at ESMO unveiled phase 1b data for its TKI-bispecific antibody combo that hits the EGFR and MET pathways. The tandem shrank tumors in 20 first-line patients and curbed tumor growth in 60% of patients who had previously taken Tagrisso, and J&J has a first-line head-to-head showdown with the AZ med underway.