Black Diamond Therapeutics and Ideaya Biosciences are mulling over registrational trials for their lead assets after receiving encouraging phase 2 data in lung and eye cancers, respectively.
For Black Diamond, the company’s fourth-generation EGFR inhibitor BDTX-1535 reported interim phase 2 data showing a preliminary 36% objective response rate in 22 evaluable patients with previously treated non-small cell lung cancer with non-classical driver mutations or with acquired C797S resistance mutations.
Among 19 patients expressing known resistance mutations to AstraZeneca’s Tagrisso, eight patients (42%) responded, while an additional nine patients (47%) had stable disease, according to Black Diamond. All results came from a 200 mg daily dose, which has been selected for further development.
Data on the duration of the responses were limited. With a data cut on Aug. 17 following an average follow-up of 4.7 months, 14 of the 19 patients (74%) remained on treatment. The patient with the longest follow-up, who had tried two prior lines of therapies and developed a C797S mutation, had progressive disease at around 10 months, according to a Black Diamond presentation.
In terms of safety, as of June 15 among 20 patients who took the 200 mg dose, the most common treatment-related adverse events were rash, experienced by 70% of individuals, and diarrhea, which happened in 35% of patients. Four patients had their dose reduced and one discontinued. No cases of liver enzyme elevation or irregular heartbeats, known as QTc prolongation, were recorded, according to the company.
The study is still enrolling patients. But with the early phase 2 data, Black Diamond expects to hear back from the FDA on a potential registrational trial design in the first quarter of 2025 during which time the company also expects to disclose initial results from another trial cohort among newly diagnosed patients with non-classical EGFR driver mutations.
In a statement facilitated by Black Diamond, Danny Nguyen, M.D., from City of Hope, said BDTX-1535’s phase 2 data “look quite promising,” noting that “[p]atients with recurrent EGFRm NSCLC have few treatment options, with chemotherapy delivering limited benefit and significant toxicity.”
Compared with Black Diamond, Ideaya has a clearer idea of its registrational trial design for its darovasertib in the rare eye cancer uveal melanoma following a meeting with the FDA.
For the potential first-in-class protein kinase C inhibitor, Ideaya plans to initiate a phase 3 trial in neoadjuvant uveal melanoma. As the company noted in a release, no FDA-approved therapeutics currently exist for premetastatic uveal melanoma, which has an annual incidence of roughly 12,000 patients in North America, Europe and Australia.
Based on feedback from the FDA, the phase 3 trial will use eye preservation rate and time to vision loss as primary endpoints for two cohorts of enucleation and brachytherapy patients, respectively. No detriment to event-free survival (EFS) will serve as a secondary endpoint. By Ideaya’s estimate, an initial readout with mature EFS data will require about two years of follow-up.
The trial will enroll patients with a high risk of metastatic disease, but Ideaya said there may be an opportunity for a broad indication covering lower-risk patients.
The trial protocol has yet to be finalized. Ideaya is still discussing with the FDA the prospect of using objective response rate as a surrogate and composite endpoint to support an accelerated approval.
Ideaya is pushing darovasertib into phase 3 testing as a neoadjuvant treatment based on combined results from a company-sponsored phase 2 trial and an investigator-initiated study. Among 31 enucleation and 18 plaque brachytherapy premetastatic uveal melanoma patients who received neoadjuvant darovasertib, 24 (49%) achieved at least 30% ocular tumor shrinkage. Among the enucleation patients, 61% had eye preservation.
Seemingly trying to provide support for its surrogate endpoint proposal, Ideaya said a 20% or greater tumor reduction correlates with eye preservation and vision benefit, according to a company presentation.
As for tolerability, Ideaya recorded one treatment discontinuation caused by a drug-related adverse event among 38 patients in its own trial. Serious adverse events happened in two (5.3%) patients.
Besides the neoadjuvant setting, Ideaya already has a registrational study for darovasertib in combination with Pfizer’s Xalkori in metastatic uveal melanoma focusing on those with HLA-A2-negative disease.