September 24, 2026
The investigational macrocyclic EGFR TKI BH-30643 generated antitumor activity in patients with EGFR C797S–positive non–small cell lung cancer (NSCLC) who experienced disease progression on previous EGFR TKIs, including in those with or without concurrent T790M, according to updated data from the phase 1/2 SOLARA trial (NCT06706076) presented at the International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer.¹
Among patients in the C797S target population (n = 40), the objective response rate was 45% (95% CI, 29%-62%), and the disease control rate was 88%. Responses included confirmed partial responses and unconfirmed partial responses. At a median follow-up of 6.9 months, 63% of patients remained on therapy.
“Expansion cohorts are ongoing [and] studying on-target resistance mutations, targeted therapy naive cohorts, [and] chemotherapy combination,” Hidehito Horinouchi, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, said in the presentation. “[A] global phase 2 study targeting C797S planned for A1 2027.”
Why is C797S a resistance target for BH-30643 in EGFR-mutant NSCLC?
C797S is among the secondary EGFR mutations that arise in approximately 10% to 15% of patients on third-generation EGFR TKIs, and no targeted therapy is approved for this resistance pattern. Following progression, most patients receive chemotherapy-based combinations, which can be difficult to tolerate. No macrocyclic EGFR TKI has been approved, although macrocyclic agents are established in ALK– and ROS1-driven disease.
BH-30643 is a mutant-selective macrocyclic EGFR TKI engineered to keep its activity in the presence of C797S or T790M. By binding the kinase in its active conformation, it inhibits classical, atypical, and resistance EGFR variants at subnanomolar concentrations while largely sparing wild-type EGFR. The agent also reaches high plasma exposures and crosses into the central nervous system. The FDA has granted BH-30643 fast track designation for patients with EGFR C797S–positive NSCLC previously treated with a third-generation TKI.1,2 Early dose-escalation and backfill data from SOLARA were reported at the 2026 ASCO Annual Meeting.³
How was the phase 1/2 SOLARA trial of BH-30643 designed?
SOLARA is a global, 2-part phase 1/2 trial of BH-30643 enrolling at more than 40 sites spanning 10 countries across North America and the Asia-Pacific region.¹ Escalation used a Bayesian optimal interval design across 7 dose levels, with additional backfill patients enrolled at doses showing potential activity. The expansion portion is enrolling molecularly defined cohorts, including those with TKI resistance and those who have not received targeted therapy. Expansion dose levels include 40 mg, 50 mg, or 60 mg twice daily.
Patients from both parts were pooled into the C797S target population, which left out anyone with a concurrent driver alteration or previous exposure to an EGFR TKI designed against C797S. In this population, the median age was 64 years (range, 38-82), 65% were Asian, and 53% had a history of brain metastases. Patients had received a median of 2 prior lines of therapy (range, 1-12), which included osimertinib (Tagrisso) in 98% of patients, another EGFR-targeted agent in 43%, and chemotherapy and/or an antibody-drug conjugate in 53%. The underlying driver was an EGFR exon 19 deletion in 60% of patients and L858R in 38%; T790M co-occurred in 35% of patients, and 18% of patients carried other atypical mutations.
The data cutoff date was May 12, 2026, with efficacy follow-up through August 10, 2026. The efficacy analysis excluded 14 patients who enrolled after the cutoff and 1 patient who stopped treatment because of an adverse effect (AE) on day 6.
What is the safety profile of BH-30643 in EGFR-mutant NSCLC?
Toxicity with BH-30643 was mostly low grade: among patients who received the 40-mg, 50-mg, or 60-mg twice-daily expansion doses (n = 174), grade 3/4 treatment-related AEs (TRAEs) occurred in 22%, and none were grade 5. TRAEs of any grade were reported in 89% of patients over a median exposure of 3 months. TRAEs led to dose reductions for 9% of patients and resulted in discontinuation in 3% of patients.
Bilirubin elevation was the most frequent TRAE (45%), followed by rash (43%), diarrhea (39%), dry skin (22%), stomatitis (21%), increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (17% each), fatigue (14%), nausea (11%), and paronychia (11%). Wild-type EGFR–related toxicities were largely grade 1, including grade 1 rash in 34% of patients and grade 1 diarrhea in 35%.
Investigators attributed the bilirubin rise to UGT1A1 inhibition by BH-30643, which produced a pattern resembling Gilbert syndrome: typically asymptomatic, mainly unconjugated, and dependent on drug exposure. The elevation was grade 3/4 in 7% of patients and was reversible with dose modification or often tolerated without it. Grade 3 or higher ALT and AST increases were seen in 7% and 5% of patients, respectively, and no case met Hy’s law criteria. Pneumonitis occurred in approximately 1% of patients, and no clinically significant treatment-related cardiac toxicity or QTc prolongation was observed.
What are the next steps for BH-30643 in EGFR C797S–positive NSCLC?
BH-30643 is set to advance into a global phase 2 study focused on C797S-positive disease, planned for the first quarter of 2027. Enrollment to SOLARA continues, with expansion cohorts in patients with on-target resistance mutations and in targeted therapy–naive patients, plus a dose-escalation cohort combining BH-30643 with chemotherapy.
References
- Horinouchi H, Li M, Gupta D, et al. Anti-tumor activity of BH-30643, a novel macrocyclic EGFR TKI, in patients with secondary EGFR resistance mutations. Presented at: International Association for the Study of Lung Cancer 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, Republic of Korea. Abstract MO12.02.
- BlossomHill Therapeutics. BlossomHill Therapeutics presents updated data from ongoing phase 1/2 SOLARA trial demonstrating encouraging anti-tumor activity of OMNI-EGFR inhibitor BH-30643 in EGFR C797S-positive NSCLC at IASLC 2026 World Conference on Lung Cancer. News release. September 15, 2026. Accessed September 23, 2026. https://www.globenewswire.com/news-release/2026/09/15/3361888/0/en/blossomhill-therapeutics-presents-updated-data-from-ongoing-phase-1-2-solara-trial-demonstrating-encouraging-anti-tumor-activity-of-omni-egfr-inhibitor-bh-30643-in-egfr-c797s-posit.html
- Le X, et al. First-in-human trial of BH-30643, a novel macrocyclic, non-covalent, mutant-selective OMNI-EGFR inhibitor, in EGFR-mutant (EGFRm) NSCLC. J Clin Oncol. 2026;44(suppl 16):3014. doi:10.1200/JCO.2026.44.16_suppl.3014
