EGFR–cMET bispecific antibody shows efficacy in NSCLC patients with high unmet needs
medwireNews: Preliminary findings for a first-in-human study of JNJ-372 – a bispecific IgG antibody targeting both the EGFR and cMET receptors – have been reported at the 2019 ASCO Annual Meeting in Chicago, Illinois, USA.
Presenting author Eric Haura, from Moffitt Cancer Center in Tampa, Florida, USA, reported that the agent was tested in 142 patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations after preclinical analysis in multiple models of EGFR- and cMet-mediated tyrosine kinase inhibitor (TKI) resistance.
The data from these early studies was “consistent” with the proposed antitumor mechanisms of signalling inhibition, receptor degradation, and antibody-dependent cellular cytotoxicity, he explained.
Of note, 63% of participants were female, 70% were Asian, and all but one patient had a good ECOG performance status. The group had all progressed after receiving a median of three lines of standard of care treatment, including a median of two lines of EGFR–TKI therapy.
The majority (92%) of patients had a primary EGFR mutation, most commonly exon 19 deletion (46%) or exon 21 L858R (26%). The EGFR TKI resistance mutations T790M and C797S were present in 37% and 21% of patients, respectively, while 8% had cMet amplification of at least six copies.
JNJ-372 was given intravenously once weekly in the first 28-day cycle and every 2 weeks thereafter, at doses of 140 mg, 350 mg, 700 mg, 1050 mg, and 1400 mg.
Grade 3 or more severe treatment-emergent adverse events (AEs) were reported in 35% of the group; treatment-related AEs occurred at this severity in 9%, with 4% of patients requiring a dose reduction and 4% discontinuing treatment.
Infusion-related reactions affected 88 patients, the majority of which were grade 1–2, most commonly chills, dyspnea, nausea, and flushing that were reported on first infusion. Serious AEs were “rare,” the presenter said, with 14 events reported in 12 patients, and there were no grade 5 events.
Efficacy results indicated that there was evidence of tumor response at doses of 700–1400 mg including a partial response in 30% of patients. These included patients with the primary mutations of exon 21 L858R, exon 19 deletion, exon 20 insertion, exon 20 T790M, and exon 18 G719A, as well as those with a secondary T790M or C797S mutation, or cMet amplification.
Of the 58 patients who had progression after treatment with the third generation EGFR–TKI osimertinib, 28% had a partial response, including eight patients with a C797S mutation, three with cMet amplification, and five with no known EGFR or cMet resistance mutation.
Median duration of treatment in the osimertinib-treated group was 3 months and 39% of patients are still receiving treatment, Eric Haura said.
In addition, 30% of the 27 patients with an exon 20 insertion EGFR mutation had a partial response, including one patient who also had cMet amplification. This outcome was seen in patients treated with the 1050 mg or 1400 mg doses and he emphasized that the data suggested “even patients who are not achieving partial response are nonetheless receiving durable benefit of the agent.”
Eric Haura summarized that “JNJ-372 activity was observed across diverse EGFR-mutated NSCLC, including those with unmet need” and had a “manageable safety profile consistent with EGFR inhibition.”
He said that the 1050 mg and 1400 mg doses will now be further explored in phase II studies, with recruitment focusing on patients with osimertinib resistance and a high unmet need.
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