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More Help on the Way for Lung Cancers With Exon 20 Mutations?

<ѻý class="mpt-content-deck">— Early trials of DZD9008 demonstrated responses in over a third of patients
MedpageToday

An oral EGFR/HER2 inhibitor led to high levels of disease control in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, data from two ongoing phase I studies showed.

In the WU-KONG1 and WU-KONG2 trials, the confirmed objective response rate (ORR) among the 56 evaluable patients was 37.5% with DZD9008, and the disease control rate (DCR) reached 85.7%, reported Pasi Jänne, MD, PhD, of Dana-Farber Cancer Institute in Boston, at the virtual World Conference on Lung Cancer (WCLC).

The investigational drug demonstrated "encouraging antitumor activity" in heavily pretreated NSCLCs of various EGFR exon 20 mutation subtypes, said Jänne, and was well tolerated with a manageable safety profile.

At different DZD9008 dose levels across three expansion cohorts in the studies, the respective ORRs and DCRs were:

  • 200 mg: 45.5% and 81.8%
  • 300 mg: 41.9% and 90.3%
  • 400 mg: 22.2% and 77.8%

"EGFR exon 20 mutations represent a rare subset of EGFR-mutant lung cancer," said Jänne, with the tumors accounting for roughly 2-3% of all NSCLCs. DZD9008 is a selective, covalent EGFR inhibitor, being developed in NSCLCs with EGFR or HER2 mutations, Jänne explained.

The only FDA approved therapy specifically for tumors with exon 20 insertions is amivantamab (Rybrevant), a bispecific antibody, but no EGFR tyrosine kinase inhibitors (TKIs) have been approved for this subset of patients.

Patients with "these mutations represent an important unmet need," said WCLC-designated discussant Federico Cappuzzo, MD, of Istituto Nazionale Tumori Regina Elena in Rome. "Patients are generally not sensitive to first- or second-generation EGFR TKIs, less sensitive to immunotherapy, and also more recent agents. For example, poziotinib showed modest activity with significant toxicity."

In the current study, responses were seen among patients treated with prior amivantamab and in those with brain metastases at baseline -- which Cappuzzo called "promising" -- though ORRs were higher in those without brain lesions (22.7% vs 51.6%, respectively).

At data cutoff, the longest treatment duration stretched beyond 17 months. Median duration of response and progression-free survival had not been reached.

In the safety analysis, all patients experienced some form of adverse event (AE). Across all dose levels (50 mg to 400 mg), grade ≥3 drug-related AEs occurred in 33.3%, and drug-related dose reductions and discontinuations occurred in 15.7% and 5.9%, respectively. Grade ≥3 AEs increased from 12.5% at the 200-mg daily dose to 70.0% at the 4o0-mg dose. AE-related dose reductions, interruptions, and discontinuations were highest at the higher dose.

The two studies included a total of 102 previously treated NSCLC patients with EGFR or HER2 mutations treated with DZD9008 daily at different dose levels. The expansion cohorts required exon 20 mutations, and patients needed to have adequate organ function. WU-KONG1 was conducted in the U.S., Australia, South Korea, and Taiwan; while WU-KONG2 was conducted exclusively in China.

Responses were seen in patients with "near loop" exon 20 insertion mutations (n=20; ORR 47.5%, DCR 90.0%) and in those with far loop mutations (n=11; ORR 36.4%, DCR 81.8%), though none were seen in the five patients with "not distinguishable" exon 20 mutations (DCR 80.0%).

Across the two studies, patients had a median age of 59 years, 56% were women, 16.7% were white, and 83.3% were Asian. Median prior lines of therapy was 3 (range 1-10), with prior treatments including chemotherapy in 91%, TKIs in 46%, and checkpoint inhibitors in about a third. At baseline, 43% had brain metastases (stable lesions were required), with 61% of these patients having undergone radiotherapy.

In the efficacy evaluable group, a dose escalation cohort included 18 patients (50 mg to 400 mg) and the expansion cohort included 38 patients (200 mg, 300 mg, and 400 mg). Four patients had received prior amivantamab. A food effects analysis showed no differences in pharmacokinetics with high-fat foods, or in white versus Asian patients.

  • author['full_name']

    Ian Ingram is Managing Editor at ѻý and helps cover oncology for the site.

Disclosures

Jänne reported relationships (including consulting, advisory boards, research funding, or stock) with AbbVie, ACEA Biosciences, Accutar Biotech, Allorion, Araxes Pharmaceuticals, Astellas, AstraZeneca, Bayer Pharmaceuticals, Biocartis, Boehringer Ingelheim, Chugai Pharmaceuticals, Daiichi Sankyo, Eisai, Eli Lilly, Gatekeeper Pharmaceuticals, Genentech/Roche, Ignyta, LabCorp, LOXO Oncology, Mirati Therapeutics, Novartis, Pfizer, PUMA, Revolution Medicines, SFJ Pharmaceuticals, Silicon Therapeutics, Takeda Oncology, and Transcenta.

Cappuzzo reported advisory board ties with Roche, Amgen, AstraZeneca, Bristol Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Merck Sharp & Dohme, Novartis, and Sanofi.

Primary Source

World Conference on Lung Cancer

Jänne P, et al "Phase 1 studies of DZD9008, an oral, selective EGFR/HER2 inhibitor in advanced NSCLC with EGFR exon 20 insertion mutation" WCLC 2021; Abstract OA15.02.