BH-30643, a novel macrocyclic OMNI-EGFR tyrosine kinase inhibitor (TKI), demonstrated encouraging antitumor activity in patients with EGFR C797S–positive non–small cell lung cancer (NSCLC), according to updated results from the ongoing phase 1/2 SOLARA trial (NCT06706076) presented at the IASLC 2026 World Conference on Lung Cancer (WCLC).1
What was the efficacy of BH-30643 in EGFR C797S–positive NSCLC?
Among 40 patients with EGFR C797S–positive resistance in the target population, BH-30643 produced responses in 18 patients for an ORR of 45% (95% CI, 29%-62%) and a DCR of 88% (n = 35/40). Responses were observed in patients with or without concurrent T790M. At a median follow-up of 6.9 months, 25 patients (63%) remained on therapy.
The target population had received a median of 2 prior lines of therapy (range, 1-12); 98% had received prior osimertinib (Tagrisso), 43% had received other prior EGFR-targeted therapy, and 53% had received prior chemotherapy and/or an antibody-drug conjugate. EGFR exon 19 deletions were present in 60% of patients along with L858R mutations in 38%, with concurrent T790M in 35% and other atypical mutations in 18%.
What was the safety profile of BH-30643?
Across the expansion dose levels of 40 mg, 50 mg, and 60 mg twice daily (n = 174), treatment-related adverse events (TRAEs) of any grade occurred in 89% of patients, with grade 3 or 4 TRAEs in 22%. The most common TRAE was bilirubin elevation (45%), which followed a “Gilbert’s-like,” predominantly unconjugated, and usually asymptomatic pattern attributed to UGT1A1 inhibition by BH-30643 and was reversible with dose modification or often tolerated without dose adjustment. Other common TRAEs included rash (43%), diarrhea (39%), dry skin (22%), and stomatitis (21%); EGFR wild-type–associated TRAEs were mostly grade 1.
Grade 3 or higher alanine aminotransferase and aspartate aminotransferase increases occurred in 7% and 5% of patients, respectively, with no cases meeting Hy’s law. Pneumonitis was rare (approximately 1%), and no clinically significant treatment-related cardiac effects or QTc prolongation were reported. Dose reduction (9%) and treatment discontinuation (3%) due to TRAEs were uncommon, and no grade 5 TRAEs occurred.
“C797S-driven resistance to third-generation EGFR inhibitors was first described over 10 years ago, yet patients whose tumors develop this mutation currently have no approved targeted treatment options. The responses observed with BH-30643 in this heavily pretreated population, together with encouraging early evidence of durability, support the potential of BH-30643 to directly target this resistance mechanism,” presenting study investigator Hidehito Horinouchi, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, stated in a press release regarding these data.2 “These results are particularly encouraging given the need for new precision treatment options that can extend the benefits of targeted therapy for patients with EGFR-mutant lung cancer.”
What is the SOLARA trial design?
SOLARA is a global phase 1/2 trial evaluating BH-30643 across more than 40 sites in 10 countries in North America and the Asia-Pacific region. The phase 1 portion includes a dose-escalation part using a Bayesian optimal interval design across 7 dose levels, followed by a dose-expansion part enrolling multiple molecularly defined subsets, including TKI-resistant and targeted therapy–naive cohorts.
The data presented at WCLC reflect a May 12, 2026, data cutoff, with efficacy follow-up through August 10, 2026. The C797S target population excluded patients with concurrent driver alterations or those who had previously received an EGFR TKI specifically targeting a known C797S mutation.
What is BH-30643, and what are the next steps?
BH-30643 is a macrocyclic, mutant-selective OMNI-EGFR TKI designed to address on-target resistance, with subnanomolar potency against classical, atypical, and resistance EGFR mutations; activity that is not compromised by EGFR C797S or T790M; sparing of wild-type EGFR; and central nervous system penetrance. Following progression on third-generation EGFR TKIs, treatment options are limited for patients with EGFR-mutant NSCLC, and approximately 10% to 15% develop secondary EGFR mutations such as C797S, for which no targeted therapies are approved.
The FDA granted BH-30643 fast track designation for C797S-positive NSCLC after a prior third-generation TKI.2 Expansion cohorts evaluating on-target resistance mutations, patients with no prior targeted therapy, and a chemotherapy combination are ongoing, and a global phase 2 study targeting C797S is planned for the first quarter of 2027.
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: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract MO12.02.
- 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. BlossomHill Therapeutics. September 15, 2026. Accessed September 16, 2026. https://tinyurl.com/2s3vb5e3
