BDTX-1535 Goes after Osimertinib Resistance

Preclinical data on BDTX-1535 (Black Diamond Therapeutics) suggest this investigational tyrosine kinase inhibitor (TKI) may address an unmet need in EGFR-mutant non–small cell lung cancer (NSCLC) by mitigating resistance to osimertinib (Tagrisso; AstraZeneca), the current standard of care.

Osimertinib, a third-generation drug, targets the chief resistance mutation, T790M, that arises in response to older TKIs. It's also much more effective against central nervous system (CNS) metastases. “However, as it's moved to first-line in terms of treatment choice, new resistance pathways have inevitably begun to emerge,” said Matthew Lucas, PhD, of Cambridge, MA–based Black Diamond. “These are quite heterogeneous, but some seem to still be through EGFR-dependent mechanisms, which is what we hope to pursue therapeutically.”

BDTX-1535 is “optimized against a broad spectrum of EGFR mutations,” Lucas said—not only C797S, acquired after osimertinib, but uncommon variants as well, including G719X and S768I. The drug also has “what we call a Goldilocks wild-type selectivity profile,” he added, “in that it retains activity against amplified wild-type EGFR—another acquired resistance pathway—but spares the target expressed in normal tissue.”

At the virtual International Conference on Molecular Targets and Cancer Therapeutics, held October 7–10, Lucas reported that in mice with NSCLC harboring C797S, BDTX-1535 “induced dose-dependent tumor shrinkage. At the higher dose used, we saw complete regression without loss of body weight.” Those given a clinically relevant dose of osimertinib, however, “looked similar to our control group of untreated mice.”

“Resistance to first-line osimertinib is a major challenge, so these data, although preclinical, are quite exciting,” said Zofia Piotrowska, MD, of Massachusetts General Hospital Cancer Center in Boston, who was not affiliated with the research. BDTX-1535′s fine-tuned selectivity should limit on-target toxicity, resulting in a better safety profile than earlier agents, she added. For instance, afatinib (Gilotrif; Boehringer Ingelheim), the only approved treatment for patients with uncommon EGFR mutations, “has quite a few side effects, so a new option would be welcome.”

Importantly, BDTX-1535 can cross the blood–brain barrier and could potentially treat CNS metastases in NSCLC, Lucas noted. This rationale is supported by preclinical findings in glioblastoma, where EGFR mutations also occur, but for which there are no approved targeted therapies. Prior to being studied in NSCLC, BDTX-1535 already looked “highly efficacious” in EGFR-mutant glioblastoma cell lines and mouse models, he said. Not only were the different variants potently suppressed, but “we also saw consistent, high levels of tumor regression and improved survival.”

CNS metastases in patients receiving osimertinib are “a real problem—osimertinib itself is relatively brain-penetrant compared with older drugs, so we don't have much else to offer once CNS progression develops,” Piotrowska explained. “It's not just parenchymal lesions, but leptomeningeal disease that's particularly challenging. If the CNS activity of BDTX-1535 bears out in patients, it would certainly help fill the gap in available treatments.”

Piotrowska did point out that C797S and other secondary EGFR mutations are infrequent, occurring in less than 10% of patients. “Among all who progress on osimertinib, a large fraction don't have an identified resistance mechanism and may not benefit from BDTX-1535,” she said.

Whether BDTX-1535′s broad activity extends to EGFR exon 20 insertions “would also be interesting to see,” Piotrowska added. This category, intrinsically resistant to early-generation TKIs, has been difficult to drug, likely “because the insertions push, rather than pull, the protein into an active conformation, causing steric hindrance.” With two recent approvals, however—amivantamab-vmjw (Rybrevant; Janssen) and mobocertinib (Exkivity; Takeda)—the therapeutic landscape is evolving.

Other contenders against osimertinib-resistant NSCLC include BLU-945 (Blueprint Medicines), for which the phase I/II SYMPHONY trial is now under way. Meanwhile, BDTX-1535 “is in IND-enabling studies,” Lucas said, “and we expect to file in the first half of 2022.” –Alissa Poh