BDTX-1535 Strives to Overcome Intrinsic and Acquired EGFR Mutations in NSCLC and GBM

Alexander I. Spira, MD, PhD, FACP

Patients with non–small cell lung cancer (NSCLC) harboring acquired EGFR mutations, such as C797S and intrinsic mutations in EGFR represent underserved populations where additional targeted therapies are needed. Additionally, as there are no FDA-approved targeted therapies for the rare cancer glioblastoma multiforme (GBM),¹ which is characterized by the presence of extracellular domain alterations in EGFR, investigators hope that the brain penetrant, irreversible EGFR inhibitor BDTX-1535 will be able to target EGFR mutations and fill unmet needs in NSCLC and GBM, according to Alexander I. Spira, MD, PhD, FACP.

“The whole idea with these fourth-generation inhibitors is to target newer mutations. We need to get drugs that target C797S and have central nervous system [CNS] penetration,” Spira, codirector of Virginia Cancer Specialists (VCS) Research Institute in Fairfax, Virginia, director of the Thoracic and Phase 1 Program, and clinical assistant professor at Johns Hopkins in Baltimore, Maryland, said in an interview with OncologyLive^®. “BDTX-1535 targets uncommon mutations, as well as the C797S mutation, and it specifically binds in the presence of C797S, which osimertinib does not do…[It is], is a new fourth-generation tyrosine kinase inhibitor [TKI] designed to work in EGFR mutations [and] has CNS penetration so it’s also being studied in EGFR-mutant GBM, which is a rare diagnosis but does happen, and there’s no good active drugs for that.”

C797S is the most common tertiary EGFR mutation in NSCLC, accounting for 10% to 26% of cases of resistance to second-line osimertinib (Tagrisso) and 7% of cases of resistance to first-line osimertinib.² A phase 1 study (NCT05256290) is currently enrolling patients with NSCLC or GBM in dose-expansion cohorts following the completion of dose escalation cohorts. Early efficacy data from the NSCLC group of patients have been presented, as have safety data from both the NSCLC and GBM cohorts.³

“There’s [not much] new for EGFR mutations in this space right now. There are a few [agents] that have been studied, but [BDTX-1535] is a very exciting prospect and will hopefully lead to larger studies,” Spira noted.

Early Data Show Preliminary Efficacy, Tolerability

Preliminary dose escalation results presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, which took place from October 11 to 15, 2023, in Boston, Massachusetts, demonstrated that BDTX-1535 was well tolerated up to a dose of 300 mg daily with dose modifications proportionate to drug exposure. Additionally, patients with NSCLC, intrinsic driver mutations, and acquired C797S mutations who were heavily pretreated experienced confirmed radiographic responses per RECIST 1.1 criteria.⁴

“We’ve seen some preliminary evidence of activity and we’ve gotten to some effective doses in the current clinical studies,” Spira said.

The maximum tolerated dose was determined to be 300 mg daily and the dose escalation portion of the study consisted of a daily oral dose of BDTX-1535 given at 15-, 25-, 50-, 100-, 200- and 400 mg in a 21-day cycle. Patients included in the dose escalation phase (n = 54) had recurrent GBM with EGFR alterations (n = 27) or advanced/metastatic NSCLC (n = 27); those with NSCLC had either an acquired resistance C797S EGFR mutation or intrinsic driver EGFR mutation following prior EGFR TKI therapy. Patients with known resistance mechanisms such as exon 20 insertions were not included in the study.⁴

All patients were included in the dose escalation safety analysis, and dose-limiting toxicities were observed in patients who received 300 mg (n = 1) or 400 mg (n = 5) of BDTX-1535 daily and included diarrhea, rash, anorexia, fatigue, and stomatitis. These events were all among the most common grade 3 adverse effects (AEs) reported in addition to decreased appetite. Additionally, there were no grade 4 AEs reported and no grade 3 events occurred at the 100 mg dose level. Dose reductions occurred in 1 patient treated at the 200 mg level and 5 patients at 300-mg level.⁴

Among those with NSCLC and eligible EGFR mutations (n = 21), 7 patients remain on treatment. Among response-evaluable patients (n = 15), 5 experienced a partial response, 9 achieved stable disease, and 1 had progressive disease, which investigators noted included 2 patients who were treated at a starting dose under 100 mg (both achieved stable disease).⁴

Investigators noted that the patients with NSCLC included in the study represented the real complex EGFR mutation landscape that occurs following frontline therapy with osimertinib; 7 patients had intrinsic driver mutations, 5 had intrinsic driver and classical driver mutations, 12 had classical driver and C797S acquired resistance mutations, and 3 patients had all 3 types of mutations.

Patients in the GBM group were a median age of 58.7 years (range, 41-85); received a median of 2 prior lines of therapy (range, 1-4); had previously received temozolomide (100%), anti-angiogenic or checkpoint inhibitor therapy (41%), and chemotherapy (26%); and had Karnofsky performance scores of 90 (17%), 80 (50%), 70 (21%), or 60 (13%).⁴

In the NSCLC group, patients were a median age of 64 years (range, 46-81) and had an ECOG performance status of 0 (26%) or 1 (74%). Patients had received a median of 2 (range, 1-9) prior lines of therapy including an EGFR-directed TKI (100%), chemotherapy (70%), anti-angiogenic or checkpoint inhibitor (41%), and HER3 antibody-drug conjugate (7%). The most common EGFR-directed TKI received was osimertinib (85%).

Enrollment Criteria

All patients enrolled in the dose expansion cohorts will be at least 18 years of age with measurable disease, and a life expectancy of at least 3 months. The dose expansion portion includes a BDTX-1535 monotherapy cohort of patients comprised of those with advanced/metastatic NSCLC and an acquired EGFR resistance mutation such as C797S occurring following treatment with a third-generation EGFR inhibitor in the first-line setting; advanced/metastatic NSCLC with an intrinsic EGFR resistance mutation such as L858R occurring after standard-of-care therapy with an EGFR inhibitor; or recurrent GBM with confirmed EGFR alterations with or without amplifications (FIGURE).³

Additionally, a second expansion cohort is enrolling patients with newly diagnosed GBM harboring EGFR mutations, postsurgical resection, and radiation therapy, with temozolomide to receive combination therapy with BDTX-1535 and temozolomide.

“Right now, there’s no active fourth-generation drug. We have amivantamab-vmjw [Rybrevant], patritumab deruxtecan [HER3-DXd], and other drugs coming out, but for patients who develop these C797S mutations, that’s a huge area of unmet need and that’s what the real focus of this [trial] is going to be. In the area of atypical mutations, we have 1 drug, afatinib [Gilotrif], but we’d like to find something a little bit better than that,” Spira noted.

Both expansion cohorts are currently enrolling patients and investigators noted that data from the GBM cohort in the dose escalation portion of the trial will be presented at a future scientific meeting.⁴

“The idea with the dose expansion is we’re going to be looking at C797S, we may be looking at atypical mutations [as well], those are going to be the big focus in NSCLC. We also hope that we further evaluate brain tumors, and that’s a huge area of unmet need. The focus is going to remain [primarily] on lung cancer for quite some time,” Spira concluded.

References

1. Johnson ML, Henry JT, Spira AI, et al. A phase 1 study to assess BDTX-1535, an oral EGFR inhibitor, in patients with glioblastoma or non–small-cell lung cancer. J Clin Oncol. 2023;41(suppl 16):TPS9156. doi:10.1200/JCO.2023.41.16_suppl.TPS9156
2. Li Y, Mao T, Wang J, et al. Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer. Cell Commun Signal. 2023;21(1):71. doi:10.1186/s12964-023-01082-8
3. Study of BDTX-1535 in patients with glioblastoma or non-small cell lung cancer with EGFR mutations. ClinicalTrials.gov. Updated October 25, 2023. Accessed December 4, 2023. bit.ly/46Qo7qw
4. Yu H, Johnson M, Henry JT, et al. A phase 1 study to assess BDTX-1535, an oral 4th generation EGFR inhibitor, in patients with non-small cell lung cancer and glioblastoma: preliminary dose escalation results. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 11-15, 2023; Boston, Massachusetts. bit.ly/47GH9Ay