BARCELONA, SPAIN – First-line treatment with Johnson and Johnson's anti-EGFR therapies Rybrevant (amivantamab) and Lazcluze (lazertinib) in locally advanced or metastatic non-small cell lung cancer patients harboring certain EGFR alterations significantly reduced MET amplifications and EGFR resistance alterations compared to AstraZeneca's tyrosine kinase inhibitor Tagrisso (osimertinib).
In a presentation at the European Society for Medical Oncology Congress on Saturday, Benjamin Besse, a professor of medical oncology at Paris-Saclay University, shared data from a next-generation sequencing analysis of circulating tumor DNA from patients in J&J's Phase III MARIPOSA trial, in which researchers compared the activity of Rybrevant and Lazcluze as a first- and second-line combination treatment against Lazcluze monotherapy or Tagrisso monotherapy in patients with EGFR exon 19 deletions or exon 21 L858R substitutions.
The MARIPOSA trial demonstrated that the Rybrevant-Lazcluze combo significantly improved progression-free survival compared to Tagrisso, and in August, the US Food and Drug Administration approved the regimen, making it the first front-line combination regimen for advanced EGFR-mutant NSCLC that does not include a chemotherapy agent.
Rybrevant is a bispecific EGFR-MET antibody with immune cell-directing activity that is designed to target EGFR- and MET-based resistance mechanisms. Using Guardant Health's Guardant360 NGS panel, the researchers conducted ctDNA analysis before patients received treatment in the study and when they discontinued treatment. Based on this analysis, they aimed to characterize mechanisms of resistance in patients on first-line Rybrevant-Lazcluze compared to Tagrisso.
In MARIPOSA, 177 patients in the Tagrisso arm and 214 patients in the Rybrevant-Lazcluze arm were still receiving treatment at the time of data analysis. "This is important because it means that, here, we report early signals in the patients that were the first progressers on these drugs," he said.
The analysis revealed that 13.6 percent of patients in the Tagrisso arm had MET amplifications after discontinuing treatment compared to 4.4 percent of patients on Rybrevant-Lazcluze, representing a threefold reduction in MET amplification in ctDNA in the combination arm. The difference was even greater for secondary EGFR resistance mutations, including C797S, L718X, and G724X. Among patients on Tagrisso, 7.9 percent had EGFR resistance mutations in ctDNA, and 0.9 percent of patients on Rybrevant-Lazcluze had them.
"This data provides strong evidence that [Rybrevant] works not only through MET inhibition but also through a double blockade of EGFR inside the cell with [Lazcluze] and outside the cell with [Rybrevant]," Besse said.
The researchers also looked for mechanisms of resistance unrelated to EGFR and MET, finding that Rybrevant-Lazcluze did not significantly increase other molecular escape pathways compared to Tagrisso. However, Besse acknowledged that there was a numerical increase in HER2 amplifications and cell cycle amplifications in the Rybrevant-Lazcluze arm. Although no clear resistance mechanisms were identified in 61 percent of Tagrisso-treated patients and 68 percent of patients on Rybrevant-Lazcluze, an overview of known resistance mutations revealed that Tagrisso produced a more heterogenous mutational landscape.
"Interestingly, the rate of TP53/RB1 loss typically related to small cell lung cancer transformation was 2.9 percent in the [Tagrisso] arm and 0.9 percent in the [Rybrevant-Lazcluze] arm," Besse said.
The liquid biopsy results identified patients with complex resistance, defined as the presence of at least two resistance mechanisms, in 42.6 percent of those in the Tagrisso arm and 27.8 percent of patients in the Rybrevant-Lazcluze arm. At the beginning of treatment, roughly the same proportion, around 80 percent, of patients in each arm had EGFR exon 19 and exon 21 L858R driver mutations in ctDNA. At the end of treatment, the driver mutations were still present in 72.1 percent of Tagrisso-treated patients, but among patients on Rybrevant-Lazcluze, only 53 percent still had circulating mutant exon 19 and exon 21 DNA.
Besse concluded that Rybrevant-Lazcluze treatment significantly reduces the incidence of MET amplification and EGFR resistance alterations compared to Tagrisso, while there were no significant differences for MET- and EGFR-independent resistance mechanisms.
In a discussion of the study, Jurgen Wolf, an oncologist at the University Hospital of Cologne, compared the use of targeted therapies in cancer to the mythological battle of Heracles and the Hydra, a nine-headed serpent. In the story, every time Heracles chopped off one of the Hydra's heads, two more grew in its place.
Similarly, he said, with each targeted therapy, the cancer finds new ways to evade it. "Even if we suppress the MET and EGFR receptor associated mechanisms with the MARIPOSA combination more effectively, leading to a longer duration of response, the outgrowth of different resistant clones is unavoidable," he said. "This means with sequential targeted therapies, you're always running behind the outgrowth of new resistant clones, and most probably, this is a reason why we will never cure lung cancer with targeted therapies alone."
However, Wolf pointed out that Heracles eventually vanquished the Hydra by burning off the stumps with the severed heads. "From the oncologist's point of view, he introduced a new treatment modality," Wolf said, and as a tool to enable that approach, end-of-treatment liquid biopsies can help doctors to understand the development of resistance and optimize both initial and sequential therapies.
David Gandara, a clinical professor in the translational and clinical research program at the University of Hawaii Cancer Center and chief medical officer of the International Society of Liquid Biopsy, said the identification of resistance mechanisms to Rybrevant-Lazcluze within the study was "incredibly important" and supersedes the study itself. "It may be that this is really paradigm-changing compared to resistance mechanisms for [tyrosine kinase inhibitors alone]."
Gandara suggested that a similar study could be conducted using the GuardantINFINITY assay, which tracks changes in DNA methylation, to look for epigenetic resistance mechanisms. "If you found, for example, that there is a high level of DNA methylation change consistent with resistance, it might have therapeutic implications," Gandara said, adding that it would also be a significant scientific finding because it would mean that the Rybrevant combo had fundamentally changed the way that cancer cells develop resistance.
A J&J spokesperson said, "These [MARIPOSA] data support the concept that the combination of Rybrevant and Lazcluze is changing the underlying biology of EGFR-mutated NSCLC, which leads to the sustained clinical benefit seen with this combination," and the company will continue to evaluate the mechanisms of resistance in ongoing research "to better understand their impact on patient benefits and refine future treatment strategies."