Targeted treatments like AstraZeneca’s Tagrisso have proved useful in treating EGFR-mutated lung cancer, but patients often develop resistance to the drugs over time. Johnson & Johnson’s Janssen is working on a combination approach to help these patients—and the first data, presented Sunday at the virtual meeting of the European Society for Medical Oncology, look promising.
The combo includes lazertinib, a tyrosine kinase inhibitor (TKI) like Tagrisso (osimertinib) that Janssen licensed from South Korea’s Yuhan in 2018, and amivantamab, a bispecific antibody that hits the EGFR and MET pathways. The phase 1b data come from 91 patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbored either of two mutations, which together make up 85% to 90% of all EGFR mutations in this type of cancer.
The treatment beat back cancer in 20 newly diagnosed, never-before-treated patients, shrinking tumors in all of them. And in 45 patients whose disease had worsened despite taking Tagrisso, J&J’s treatment curbed tumor growth in 60% of them and shrank tumors in 36% of them. One patient had a complete response, meaning the drug eliminated all signs of cancer.
“To see 60% of patients having clinical benefit is really good,” said Mark Wildgust, Ph.D., vice president of global medical affairs, oncology, at Janssen’s R&D unit. He added that there are no approved treatments for patients who relapse on Tagrisso, which is the standard of care in first-line metastatic EGFR-mutated lung cancer.
As for the 100% response rate in newly diagnosed patients, Janssen is excited but appropriately cautious. With a median seven months of treatment, none of the 20 patients has seen their disease worsen.
“We know that that osimertinib itself has a response rate in the 88% range. It’s hard to say this is better than osimertinib but certainly, numerically, you can’t get any better than 100%,” Wildgust said. “We know that the median progression-free survival for osimertinib is about 18 months, so the fact that at seven months we’ve not seen anyone progress, that is very, very encouraging.”
The safety data were encouraging, too: The majority of treatment-related side effects were mild, with a “low incidence” of severe side effects including rash (4%) and low levels of albumin, a protein made in the liver (2%). It’s important for lazertinib to show it’s even safer than its EGFR-targeting peers because of Janssen’s plan to combine it with amivantamab.
“When we look at many other EGFR TKIs, they have off-target toxicities, like rash and diarrhea,” Wildgust said. “We don’t believe that you could combine other EGFR TKIs with amivantamab. We just don’t think they have a clean enough profile,” he added.
With the lazertinib combo, investigators tested escalating doses of both drugs in 26 patients, arriving at a recommended dose for phase 2 studies that is equivalent to the full dose of each drug if it were given as a single agent. This dose is being tested in a phase 2 study of patients whose cancer got worse after treatment with chemotherapy and Tagrisso, as well as in a randomized phase 3 study that will pit the lazertinib/amivantamab head-to-head against Tagrisso in untreated patients with advanced NSCLC.
J&J isn’t the only company taking a combination approach to EGFR-mutated lung cancers. In May, Eli Lilly snagged FDA approval for its anti-VEGF antibody Cyramza to treat NSCLC patients alongside EGFR med Tarceva, based on phase 3 data showing the combo outshone Tarceva alone. But for now, Tagrisso is the drug to beat.
J&J thinks its combo might have some tricks up its sleeve, though. Preclinical data suggest lazertinib is better at penetrating the central nervous system than AZ’s drug—important for a patient group whose cancer often spreads to the brain. Another advantage could be the more complete targeting of EGFR; while lazertinib and other TKIs hit the receptor from inside the cell, antibodies like amivantamab attack it from outside the cell, so they aren’t vulnerable to resistance-causing mutations.
Finally, blocking MET as well as EGFR is a plus: “We know one of the mechanisms by which EGFR drives lung cancer progression is through MET. So the idea of targeting in this dual fashion of EGFR and MET together really has the potential not only to target primary driver mutation but also to target one of the major pathways of resistance,” Wildgust said.