On April 23, 2023 IDEAYA Biosciences, Inc. (Nasdaq: IDYA), a precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported further interim results from its Phase 2 clinical trial evaluating darovasertib and crizotinib combination in metastatic uveal melanoma (MUM) patients (ClinicalTrials.gov Identifier: NCT03947385) (Press release, Ideaya Biosciences, APR 23, 2023, View Source [SID1234630400]).
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"The observed efficacy in first-line metastatic uveal melanoma patients – including confirmed ORR of 45% and median PFS of ~ 7 months – is clinically significant and represents a potential paradigm shift for treating MUM patients. The interim data for the darovasertib and crizotinib combination treatment in MUM suggests a compelling clinical efficacy and tolerability profile," said Dr. Meredith McKean, M.D., MPH, Director, Melanoma and Skin Cancer Research at Sarah Cannon Research Institute.
"These clinical data, considered with the FDA’s guidance from our recent Type C meeting, provides IDEAYA with a registrational trial design in first-line HLA-A2 negative MUM patients which includes a path to potential accelerated approval based on median PFS as the primary endpoint," said Dr. Darrin Beaupre, M.D., Ph.D., Chief Medical Officer, IDEAYA Biosciences.
There are currently no FDA approved therapies for MUM patients with HLA-A2*02:01 (HLA-A2) negative serotype. Current therapies for MUM have relatively low confirmed overall response rates and short median progression free survival (PFS), highlighting the high unmet medical need. The historical overall response rate (ORR) in MUM clinical trials has generally been reported with a confirmed ORR ranging from approximately 0% to 5%. The historical median PFS in MUM clinical trials has been reported ranging from approximately 2 to 3 months.
Darovasertib (IDE196) is a small molecule, potential first-in-class protein kinase C (PKC) inhibitor. IDEAYA is evaluating the synthetic lethal combination of darovasertib and crizotinib, a small molecule cMET inhibitor, in MUM pursuant to a clinical trial collaboration and drug supply agreement with Pfizer.
Clinical Data Update – Darovasertib and Crizotinib Combination in MUM
The company observed encouraging clinical activity in the Phase 2 clinical trial evaluating the darovasertib and crizotinib combination in first-line and any-line MUM patients. The reported Phase 2 clinical data are based on twenty (20) evaluable first-line and sixty-three (63) evaluable any-line patients enrolled in the darovasertib and crizotinib combination study at the expansion dose of 300 mg twice-a-day darovasertib and 200 mg twice-a-day crizotinib as of September 22, 2022. Reported data are preliminary and based on investigator review from an unlocked database as of the data analyses cutoff date of March 8, 2023. Enrollment in the darovasertib and crizotinib combination expansion dose cohort of the Phase 2 clinical trial is ongoing.
In the twenty (20) evaluable first-line MUM patients in the expansion cohort, the investigator-reviewed data by RECIST 1.1 include:
45% confirmed Overall Response Rate (ORR) in First-Line MUM: 9 of 20 evaluable patients had a confirmed partial response (PR)
90% Disease Control Rate (DCR) in First-Line MUM: 18 of 20 evaluable patients showed disease control, including 9 confirmed PRs, 1 unconfirmed PR and 8 stable disease
~7 months median Progression Free Survival (PFS) in First-Line MUM
In the sixty-three (63) evaluable any-line MUM patients at the expansion dose, the investigator-reviewed data by RECIST 1.1 include:
30% confirmed Overall Response Rate (ORR) in Any-Line MUM: 19 of 63 evaluable patients had a confirmed partial response (PR); the Any-Line MUM patients were heavily pre-treated, with 63% of patients having received 1 or more prior lines of treatment and 43% of patients having received 2 or more prior lines of treatment in the metastatic setting
87% Disease Control Rate (DCR) in Any-Line MUM: 55 of 63 evaluable patients showed disease control, including 19 confirmed PRs, 4 unconfirmed PRs and 32 stable disease
~7 months median Progression Free Survival (PFS) in Any-Line MUM
Observed median PFS increased versus median PFS of ~5 months previously reported in September 2022 with thirty-five (35) evaluable Any-Line MUM patients
There were twenty (20) evaluable hepatic-only MUM patients, including first-line and pre-treated patients with only hepatic metastases, for whom the investigator-reviewed data by RECIST 1.1 include:
35% confirmed Overall Response Rate (ORR) in Hepatic-Only MUM: 7 of 20 evaluable patients had a confirmed partial response (PR)
100% Disease Control Rate (DCR) in Hepatic-Only MUM: 20 of 20 evaluable patients showed disease control, including 7 confirmed PRs, 1 unconfirmed PR and 12 stable disease
~11 months median Progression Free Survival (PFS) in Hepatic-Only MUM
These data demonstrate robust clinical efficacy of the darovasertib and crizotinib combination in first-line and any-line MUM patients.
The darovasertib and crizotinib combination has a manageable adverse event profile in MUM patients (n=68), with a low rate of drug-related serious adverse events (SAEs). Patients reported predominantly Grade 1 or 2 drug-related adverse events (AEs): 31% of patients reported at least one Grade 3 AE; no patients observed a Grade 4 AE; and one patient observed a Grade 5 AE. Four (6%) patients discontinued treatment with either darovasertib or crizotinib due to a drug-related adverse event.
FDA Guidance in Type C Meeting Supports Initiation of Potential Registrational Trial
IDEAYA is targeting to initiate a potential registration-enabling Phase 2/3 clinical trial in Q2 2023 in first-line HLA-A2 negative MUM patients. The Phase 2/3 clinical trial design incorporates guidance and feedback from the FDA following a recent Type C meeting.
The protocol includes an integrated Phase 2/3 open-label study-in-study design in first-line MUM patients with an HLA-A*02:01 negative serotype. The clinical trial design employs a Phase 2 portion with median PFS as a primary endpoint for potential accelerated approval. Patients enrolled in Phase 2 will continue on treatment within the same clinical trial and will be considered together with additional enrolled patients to evaluate OS in support of a potential Phase 3 registrational trial.
In the Phase 2 portion of the clinical trial, approximately 230 patients will be randomized on a 2:1 basis for treatment with the darovasertib and crizotinib combination in the treatment arm or investigators choice in the control arm, selected from a combination of ipilimumab (ipi) and nivolumab (nivo), PD1-targeted monotherapy or DTIC. The treatment arm of the Phase 2 portion includes a nested study to confirm the move forward combination dose for the integrated Phase 2/3 clinical trial – including cohorts at the Phase 2 expansion doses of (i) darovasertib 300 mg BID + crizotinib 200 mg BID and (ii) darovasertib 200 mg BID + crizotinib 200 mg BID. Under the nested study design, patients enrolled in the cohort at the move forward dose will be included within the Phase 2/3 registrational clinical trial. The Phase 2 portion of the clinical trial contemplates an efficacy and safety data set of approximately 200 patients randomized 2:1 with the treatment arm at the move forward dose to support a potential accelerated approval based on median PFS by blinded independent central review (BICR) as a primary endpoint.
Patients enrolled in Phase 2 at the selected dose would continue on treatment and be included in the Phase 3 study analysis, supplemented by enrollment of approximately 120 additional patients into the Phase 3 portion of the clinical trial with 2:1 randomization on the same basis as the Phase 2 portion. Efficacy data from the Phase 3 could support potential approval using median OS as a primary endpoint.
Clinical Data Update – Darovasertib in (Neo)Adjuvant Primary UM
The company observed further evidence of encouraging clinical activity for darovasertib as neoadjuvant therapy in primary uveal melanoma (UM), including responses in primary ocular tumor lesions. Data was reported from an ongoing investigator sponsored trial (IST) evaluating darovasertib in (neo)adjuvant uveal melanoma, from compassionate use protocol(s) and from the company’s Phase 1/2 clinical trial evaluating darovasertib as monotherapy and in combination with crizotinib. Best ocular tumor response is reported based on maximal percentage reduction in measured apical height or longest basal diameter.
Collectively, these data further substantiate clinical proof of concept (PoC) for the use of darovasertib in the (neo)adjuvant uveal melanoma setting:
Ocular tumor shrinkage by investigator review in 9 of 9 (100%) UM (n=6) or MUM (n=3) patients treated as monotherapy or in combination with crizotinib, including a neoadjuvant UM patient treated with darovasertib with a partial response at 1 month, and a second neoadjuvant UM patient treated with the darovasertib and crizotinib combination with ~80% ocular tumor shrinkage at 4 months who was spared enucleation, as described below.
A UM patient who was already blind in one eye from vascular disease developed a large uveal melanoma lesion in his other eye and sought neoadjuvant treatment with a goal to avoid enucleation and potentially preserve vision in the affected eye to prevent blindness. This patient, who remains on therapy, was treated with darovasertib and crizotinib combination under a compassionate use protocol. The preliminary clinical data showed:
observed ~80% ocular tumor shrinkage after 4 months of treatment and remains on therapy
avoided enucleation of the affected eye, which we believe to be a first reported case of systemic neoadjuvant therapy resulting in eye preservation
prompt responsiveness to treatment, including progressive tumor shrinkage, as determined by investigator measurement of tumor apical height, over each month of treatment, including approximately 30% ocular tumor shrinkage after 1 month, with ocular lesion size reduced to approach threshold for plaque brachytherapy, and further ocular tumor shrinkage to ~50% after 2 months, ~70% after 3 months and ~80% after 4 months of treatment
improved vision following course of treatment and treatment of a severe cataract: pretreatment vision score was 6/120, where 6/60 is legally blind; post-treatment vision score was 6/5, reflecting a greater than 20-fold improvement and resulting in better than normal vision. Vision scoring was based on AU meter measurement system: 6/6 m = 20/20 ft (normal vision).
"These additional clinical data underscore the potential for darovasertib as a (neo)adjuvant approach for the treatment of uveal melanoma patients. If clinically validated, this approach could significantly improve current primary treatment paradigms, which typically include radiotherapies and/or enucleation of the eye," said Prof. Anthony Joshua, MBBS Ph.D. FRACP, Head of the Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent’s Hospital/Garvan Medical Research Institute, Sydney, Australia.
IDEAYA is initiating a company-sponsored clinical trial to evaluate darovasertib as monotherapy in (neo)adjuvant uveal melanoma and is evaluating potential near-term clinical neoadjuvant endpoints such as organ preservation (avoiding enucleation) for large ocular tumors and reduction in radiation dose and/or vision preservation for small or medium ocular tumors.
IDEAYA is also supporting St. Vincent’s Hospital Sydney Limited, which has initiated an ongoing IST captioned as "Neoadjuvant / Adjuvant trial of Darovasertib in Ocular Melanoma" (NADOM) (NCT05187884), to evaluate darovasertib monotherapy in a neoadjuvant and adjuvant setting in primary UM patients.
Addressable Patient Population in MUM and UM
The potentially addressable patient population for metastatic uveal melanoma is estimated to include approximately 4,500 patients across U.S. and Europe, based on estimated annual incidence, and approximately 14,000 patients in total prevalence in the US and Europe. (Neo)Adjuvant UM represents a significant expansion opportunity for darovasertib – with a potential annual incidence of approximately 8,700 patients aggregate in U.S. and Europe, and approximately 100,000 patients in total prevalence in the U.S. and Europe.
IDEAYA owns or controls all commercial rights in darovasertib, including in MUM and in UM, subject to certain economic obligations pursuant to the Novartis exclusive, worldwide license.
IDEAYA Investor Webcast and Conference Call
IDEAYA will host an investor webcast and conference tomorrow morning, Monday, April 24, 2023 at 8:00 am Eastern Time (ET), to present the further darovasertib and crizotinib Phase 2 clinical efficacy and tolerability data in metastatic uveal melanoma, and the potential registrational clinical trial design based on guidance and feedback from the recent FDA Type C meeting. The company will also provide a clinical data update for darovasertib in neoadjuvant uveal melanoma.
Presenters at the investor webcast and conference call will include Dr. Meredith McKean, M.D., MPH, Director, Melanoma and Skin Cancer Research at Sarah Cannon Research Institute, Prof. Anthony Joshua, MBBS Ph.D. FRACP, Head of the Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent’s Hospital/Garvan Medical Research Institute, Sydney, Australia, and Prof. Mark Shackleton, MBBS, Ph.D., FRACP, Professor of Oncology, Monash University, Director of Oncology, Alfred Health, Chair, Melanoma and Skin Cancer Trials, Melbourne, Australia, each of whom are key opinion leaders and clinical investigators. Yujiro S. Hata, Chief Executive Officer of IDEAYA Biosciences, and Darrin Beaupre, M.D., Ph.D., Chief Medical Officer of IDEAYA Biosciences, will also present.
IDEAYA’s darovasertib investor webcast presentation, as well as an updated corporate presentation, which incorporates the updated darovasertib clinical data as well as IDE397, IDE161 and Werner Helicase program updates from AACR (Free AACR Whitepaper) 2023, will be available on the company’s website, at its Investor Relations portal (View Source) in advance of the investor webcast presentation at approximately 6:00 am ET.
Corporate Updates
IDEAYA had cash, cash equivalents and marketable securities of approximately $373 million as of December 31, 2022, which it currently projects will be sufficient to fund its planned operations into 2026.