BLU-945 Plus Osimertinib Has Favorable Tolerability, Warrants Further Development in EGFR+ NSCLC

Yasir Y Elamin, MD

BLU-945 alone or in combination with osimertinib (Tagrisso) demonstrated early signals of clinical activity and was well tolerated in heavily pretreated patients with EGFR-mutant non–small cell lung cancer (NSCLC), according to initial findings from the dose-escalation portion of the phase 1/2 SYMPHONY trial (NCT04862780).¹

Data presented at the 2023 ASCO Annual Meeting showed that single-agent BLU-945 was generally well tolerated with most treatment-related toxicities low grade. Twelve patients experienced dose-limiting toxicities (DLTs) spanning 400 mg to 600 mg total daily doses. The combination of BLU-945 and osimertinib also had favorable tolerability, with limited EGFR wild-type adverse effects (AEs). DLTs occurred in 3 patients at the twice-daily 100-mg dose and once-daily 300-mg and 400-mg doses of BLU-945. These patients experienced grade 3 acute respiratory failure, grade 4 pneumonitis, and grade 3 dermatitis acneiform, respectively.

The combination had clinical activity following disease progression on osimertinib. The regimen produced 4 confirmed partial responses (PRs). Tumor shrinkage was seen in 51% of patients with molecularly heterogeneous, osimertinib-refractory, late-line disease who were given the combination at a daily dose level of 300 mg or above.²

BLU-945 monotherapy also displayed antitumor activity and produced 2 confirmed PRs.¹ However, responses to BLU-945 monotherapy were not durable due to genomic heterogeneity. Most patients with tumor shrinkage went on to achieve stable disease.

Moreover, BLU-945 monotherapy reduced EGFR T790M and C797X mutant allele ctDNA levels in a dose-dependent manner by day 15 of the first treatment cycle.¹ Similarly, BLU-945 plus osimertinib showed dose-dependent reduction of EGFR T790M and C797S mutant allele levels at this time point, confirming the on-target potency of BLU-945.

“We have seen evidence of clinical activity based on radiological responses and responses at the plasma level as well,” said lead study author Yasir Y Elamin, MD, in a poster presentation of the data. Elamin is an assistant professor of Thoracic/Head & Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer.

The development of on- and/or off-target resistance to third-generation TKIs is a common occurrence for patients with EGFR-mutant NSCLC, and investigators believe that the optimization of current agents targeting EGFR could improve outcomes due to the lack of tumor heterogeneity in the frontline setting.

“One strategy is combining EGFR TKIs,” Elamin explained during the presentation. “...That has been tested with compounds like osimertinib and gefitinib [Iressa], but EGFR wild-type–related toxicities may be a limiting factor for the utility of these regimens.”

Accordingly, there remains an unmet need for safer, selective, and more clinically active regimens for this difficult-to-treat population. The novel, highly-selective EGFR inhibitor BLU-945 was identified as a viable combination partner for osimertinib due to its ability to spare EGFR wild-type while displaying substantial nanomolar potency against both EGFR-activating mutations and acquired C797X and T790Mresistance mutations.

At the 2023 ASCO Annual Meeting, investigators presented updated results from part 1 of the SYMPHONY study. The dose-escalation portion of the study was composed of 2 parts: a BLU-945 monotherapy arm (part 1A) and a BLU-945 plus osimertinib combination arm (part 1B).

The first-in-human study enrolled patients 18 years of age or older with metastatic EGFR-mutant NSCLC who had been previously treated with 1 or more EGFR TKIs with activity against T790M. Patients were also included if they had no other oncogenic tumor drivers and an ECOG performance status of 0 or 1. In part B, patients were required to have experienced disease progression with osimertinib as their last prior therapy.

In part 1A, patients were given a 25-mg starting dose of BLU-945 once a day beginning in May 2021, which could be increased to 600 mg. Dose escalation in part 1A utilized a Bayesian Optimal Interval (BOIN) trial design. In part 1B, a once daily 200 to 400 mg dose of BLU-945 was administered along with 80 mg of osimertinib starting in June 2022. A twice-daily dosing schedule was also evaluated in both arms, with 100 mg to 300 mg of BLU-945 administered in part 1A and 100 mg to 200 mg of BLU-945 in part 1B.

The primary end points were identification of the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D), and to assess safety.

A total of 167 patients were enrolled in the dose-escalation study, including 55 patients in the combination arm and 112 in the monotherapy arm. The median age of patients was 63 years (range, 34-84) in part 1A and 62 years (range 28-87) in part 1B. Most patients in both arms were younger than 65 years of age (part 1A, 56.3%; part 1B, 58.2%) and female (66.1%; 61.8%).

Central nervous system metastases were present at baseline in 38.4% of patients in part 1A, and 30.9% of those in part 1B. Patients in part 1A received a median number of 3.5 prior lines of therapy (range, 1-13) and those in part 1B had a median of 2 prior lines (range, 1-7). Additional EGFR mutations and/or detectable genetic alterations were present in 94% of patients in part 1A and 89% of patients in part 1B.

Safety analysis revealed that any-grade treatment-related AEs (TRAEs) were reported by 76.8% of patients who received BLU-945 monotherapy, with 33% of patients experiencing a grade 3 or greater TRAE. Common EGFR-related TRAEs included rash (9.8%), diarrhea (6.3%), dry skin (3.6%) and paronychia (1.8%). Other TRAEs occurring in 25% or more of patients were increased alanine aminotransferase (any-grade, 36.6%; grade ≥3, 22.3%), increased aspartate aminotransferase (33%; 10.7%), nausea (33.9%; 2.7%), headache (27.7%; 0%), and vomiting (26.8%; >1%).

With the combination, any-grade TRAEs were seen in 94.5% of patients, 10.9% of which were grade 3 or higher. EGFR-related TRAEs of any-grade in this arm included diarrhea (29.1%), dry skin (16.4%), dermatitis acneiform (14.5%) and paronychia (10.9%). These were all grade 1 or 2 events and occurred in less than 10% of patients; 1 patient had grade 3 or higher dermatitis acneiform. Any-grade TRAEs occurring in more than 10% of patients included headache (34.5%), nausea (34.5%), fatigue (21.8%), decreased appetite (12.7%) and vomiting (10.9%).There was 1 incident of grade 3 or higher fatigue. No treatment-related deaths occurred, although 3.6% of patients discontinued treatment due to a TRAE.

Pharmacokinetic data indicated that the combination’s exposure was comparable to data observed with BLU-945 monotherapy as well as prior data with single-agent osimertinib.

Importantly, both the RP2D and MTD of BLU-945 have not yet been determined. Based on the favorable safety profile seen with the combination, dose-escalation in part 1B is ongoing.^1,2

“[These] phase 1 data support BLU-945 plus osimertinib as a differentiated, fully oral, novel combination for the treatment of EGFR-mutant NSCLC, warranting further clinical development,” Elamin and colleagues concluded in their poster on the data.

Editor’s Note: Dr Elamin reported serving as a consultant or in an advisory role for AstraZeneca, Bristol-Myers Squibb/Medarex, Lilly, Sanofi, Spectrum Pharmaceuticals, Takeda, and Turning Point Therapeutics. He reports receiving institutional research funding from AstraZeneca, Blueprint Medicines, Elevation Oncology, Forward, Lilly, Precision Therapeutics, Spectrum Pharmaceuticals, Takeda, and Turning Point Therapeutics. He also received monetary support for travel and accommodations from Lilly.

References

1. Elamin Y, Nagasaka M, Shum E, et al. BLU-945 monotherapy and in combination with osimertinib (OSI) in previously treated patients with advanced EGFR-mutant (EGFRm) NSCLC in the phase 1/2 SYMPHONY study. J Clin Oncol. 2023;41(suppl 16):9011. doi:10.1200/JCO.2023.41.16_suppl.9011
2. Blueprint Medicines highlights clinical progress across precision oncology pipeline at 2023 ASCO Annual Meeting. Blueprint Medicines. June 3, 2023. Accessed July 6, 2023. https://www.prnewswire.com/news-releases/blueprint-medicines-highlights-clinical-progress-across-precision-oncology-pipeline-at-2023-asco-annual-meeting-301841730.html