Conference Coverage

Antibodies may have role in ‘TKI world’ of EGFR-mutant NSCLC



– While tyrosine kinase inhibitors (TKIs) have long dominated treatment approaches for EGFR-driven advanced non-small cell lung cancer, a few newer antibodies are showing early promise as potential new strategies to use after progression, recent reports show.

Both JNJ-372, an EGFR and MET bispecific antibody, and U3-1402, a HER3-directed antibody-drug conjugate (ADC), demonstrated manageable safety profiles and preliminary antitumor activity in phase 1 study results presented here at the annual meeting of the American Society of Clinical Oncology.

“There is definitely a role to play for antibodies in the TKI world,” said Jessica Ruth Bauman, MD, of Fox Chase Cancer Center, Philadelphia, Pa., a discussant on both abstracts.

These two antibodies harness new mechanisms of action that are not specific to a resistance mechanism, which may lead to broad applicability, according to Dr. Bauman.

“Mechanisms of acquired resistance have been the Achilles heel of EGFR TKI treatment,” she said.

The JNJ-372 bispecific antibody has preclinical data consistent with several proposed mechanisms of action, including inhibition of EGFR and cMet signaling, receptor degradation, and antibody-dependent cellular cytotoxicity, said investigator Eric B. Haura, MD, of H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla.

In the phase 1 study, which included patients with diverse EGFR mutations, 32 out of 108 patients (30%) had a best response of partial response (PR) after treatment with JNJ-372, Dr. Haura reported in an oral abstract presentation.

Responses were seen in patients with mutations that represent areas of high unmet need, including those with EGFR C797S-mediated or cMet-mediated resistance to the third-generation TKI osimertinib, and those with TKI-naïve EGFR exon 20 insertions, he emphasized in his presentation.

The safety profile was “manageable” and consistent with EGFR inhibition, he said, with a low (9%) rate of grade 3 or greater toxicities and frequent infusion-related reactions, mostly after the first dose.

Enrollment of patients with high unmet need is ongoing, according to Dr. Haura.

U3-1402, the antibody-drug conjugate that may have a place in the TKI world, consists of a fully human HER3-targeted antibody linked to a topoisomerase I inhibitor payload.

“Targeting HER3 with U3-1402 may be a practical approach to treat EGFR-mutant NSCLC with diverse mechanisms of resistance to EGFR TKIs,” said investigator Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, Boston, Mass.

That’s because mechanisms of resistance to TKIs in EGFR-mutant NSCLC are turning out to be so diverse, that trying to combat each individual resistance mechanism is likely “impractical,” Dr. Jänne said.

Targeting HER3, the perhaps lesser-known of the four members of the EGFR tyrosine kinase family, may address multiple resistance mechanisms, and 57% to 67% of EGFR-mutant NSCLCs have at least some level of HER3 expression, according to the presenter.

In the phase 1 study data reported at the meeting, the response rate following U3-1402 treatment was about 31%, or 5 out of 16 patients, including 4 confirmed partial responses. Most treatment-emergent adverse events were grade 1 or 2, and only one patient discontinued due to an adverse event, according to Dr. Jänne, who said the study is ongoing.

Taken together, findings for U3-1402 and JNJ-372 show that there may be room for other approaches beyond TKIs to address the need for new therapies to overcome resistance, Dr. Bauman said in her commentary on these studies.

“Additional research will enable us to determine who will benefit from these compounds, what biomarkers are predictive, and novel combinations to consider,” she added.

Dr. Bauman reported a consulting or advisory role with Pfizer. Dr. Haura provided disclosures related to Bristol-Myers Squibb; Janssen Oncology, Boehringer Ingelheim, FORMA Therapeutics, Ignyta, Janssen, Lilly, and Ventana, plus a patent pending on technology related to kinase inhibitor sensitivity biomarkers. Dr. Jänne reported disclosures related to Gatekeeper Pharmaceuticals, Loxo, Araxes Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Lilly, and others.

SOURCE: Haura EB, et al. ASCO 2019. Abstract 9009, Jänne PA, et al. ASCO 2019. Abstract 9010.

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