#ESMO20: Out to beat Tagrisso, J&J touts 100% ORR for EGFR bispecific/TKI combo — fueling a quick leap to PhIII
J&J’s one-two punch on EGFR-mutant non-small cell lung cancer has turned up some promising — although decidedly early — results, fueling the idea that there’s yet room to one up on third-generation tyrosine kinase inhibitors.
Twenty out of 20 advanced NSCLC patients had a response after taking a combination of an in-house TKI dubbed lazertinib and amivantamab, a bispecific antibody targeting both EGFR and cMET engineered on partner Genmab’s platform, J&J reported at ESMO. All were treatment-naïve, and none has seen their cancer progress at a median follow-up of seven months.
Armed with the Phase Ib data, J&J is taking the combo straight to Phase III , where it’s going head to head with AstraZeneca’s dominant TKI, Tagrisso, for previously untreated patients.
“So while it’s 20 patients and it’s quite early still, you can’t get better than a 100% response rate. You just can’t,” Mark Wildgust, the VP of global medical affairs, oncology at J&J’s Janssen subsidiary, told Endpoints News. “We know that osimertinib itself gets you in the mid-80% range for response rate, so it’s hard to say that amivantamab or lazertinib is better, I would never say that, but certainly as I was saying you can’t get better than 100%.”
While lazertinib binds to EGFR intracellularly like the other drugs in the class, amivantamab targets the receptor extracellularly, he explained. The bispecific is thus unaffected by co-mutations within binding pockets that can blunt the efficacy of TKIs, while also promoting macrophage driven antibody dependent trogocytosis and blocking other resistance pathways driven by MET amplifications.
At the same time, Wildgust noted that lazertinib stands out among TKIs with low rates of rash and diarrhea as well as low cardiac toxicity — a key reason J&J chose to license the drug from Korea’s Yuhan for $50 million upfront almost two years ago. In selecting a drug for the combo, overlapping toxicity was a key concern.
“We really wanted to find a third generation EGFR TKI that has a really good safety profile,” he said, “and we found that with lazertinib.”
The soon-to-begin Phase III MARIPOSA trial will have three arms, designed to suss out the contributions of each J&J drug in addition to pitting them against Tagriso: lazertinib alone, lazertinib plus amivantamab, and Tagrisso.
The frontline use of the combo regimen, though, is only one of three paths where the Janssen team is steering amivantamab.
In the Phase Ib CHRYSALIS study presented at ESMO, following the dose escalation portion investigators also enrolled a group of 45 patients who have relapsed after taking Tagrisso. There, the amivantamab/lazertinib combo results in a 36% ORR, with one complete response and 15 partial responses.
Notably, all were taking both amivantamab and lazertinib at their respective full doses.
“Today in fact there are no approved agents post a third generation EGFR TKI,” Wildgust said. “So today many patients are getting osimertinib, and really the next therapy for those patients afterwards is chemotherapy.”
The next step here will be a Phase II trial testing the combination in patients who have progressed after receiving both Tagrisso and chemotherapy.
The final play is pushing amivantamab as a monotherapy to treat patients with rare EGFR Exon 20 insertion mutations, an indication that’s earned the drug a breakthrough therapy designation.
Both amivantamab — which is designed with Genmab’s Duobody tech — and lazertinib are featured on J&J’s latest list of late-stage blockbuster candidates, although Wildgust hinted that pitching the two together remains the primary goal.