Orphan Drug Designation Update: IDEAYA Biosciences inc Darovasertib and Crizotinib Synthetic Lethal Combination Expansion Dose in Heavily Pre-Treated Metastatic Uveal Melanoma (MUM)

* Press Release Update May 12, 2022 – IDE196 Darovasertib and crizotinib combination Orphan Drug Designation by FDA

Darovasertib has been identified as an Orphan Drug Designation by the U.S. FDA, entitling IDEAYA to certain tax credits, exemption from user fees, and potential statutory marketing exclusivity.

-  Targeting a clinical data update for darovasertib and crizotinib combination and FDA regulatory guidance for a potential registration-enabling trial design in mid-2022

SOUTH SAN FRANCISCO, Calif., May 2, 2022 /PRNewswire/ – IDEAYA Biosciences, Inc. (NASDAQ: IDYA), a synthetic lethality focused precision medicine oncology company committed to the discovery and development of targeted therapeutics, announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to darovasertib, a potential first-in-class protein kinase C (PKC) inhibitor, for the treatment of uveal melanoma.

IDEAYA is currently evaluating the synthetic lethal combination of darovasertib, a PKC inhibitor, and crizotinib, a cMET inhibitor, in patients with metastatic uveal melanoma (MUM) and in patients with GNAQ or GNA11 mutant solid tumors, in an ongoing Phase 1/2 clinical trial (NCT03947385) pursuant to a clinical trial collaboration and supply agreement with Pfizer. 

“We are excited to advance darovasertib towards a potential registration-enabling trial in metastatic uveal melanoma, and the orphan-drug designation is an important step towards our goal to bring this novel therapy to patients,” said Matthew Maurer, M.D., Vice President, Head of Clinical Oncology and Medical Affairs, at IDEAYA Biosciences.

Orphan-drug designation (ODD) is granted by the FDA to a drug or biologic intended to treat a rare disease or condition, which generally includes a disease or condition that affects fewer than 200,000 individuals in the U.S.   Under the ODD, IDEAYA may be entitled to certain tax credits, exemption from user fees, and seven years of statutory marketing exclusivity, subject to FDA approval of a marketing application for darovasertib as a designated orphan-drug product. 

As of May 1, 2022, Darovasertib has been evaluated in over 200 patients, including 74 patients in combination with crizotinib. The company is targeting a clinical data update for darovasertib and crizotinib combination in mid-2022, including tolerability and clinical efficacy.   IDEAYA is also planning to seek FDA regulatory guidance for a potential registration-enabling trial design to evaluate the darovasertib and crizotinib combination in MUM in mid-2022.  IDEAYA is preclinically evaluating potential expansion opportunities for darovasertib in other oncology indications, including in additional cMET-driven tumors, such as hepatocellular carcinoma and non-small cell lung cancer, and in KRAS G12C non-small cell lung cancer.

Heavily Pre-Treated Metastatic Uveal Melanoma (mUM): Synthetic Lethal Combination Expansion Dose of Darovasertib and Crizotinib

Key Statistics for the IDE196 study

• 100% Disease Control Rate (DCR): 16 of 16 evaluable patients with >1 post-baseline scan showed tumor shrinkage as determined by target lesion size reduction;

• 31% Overall Response Rate (ORR): 4 of 13 patients with > 2 post-baseline scans had a confirmed partial response (PR) as determined by RECIST 1.1 based on an investigator or central review, and no patients had come off-treatment prior to the 2nd scan.

• 46% of patients (6 of 13) with > 2 post-baseline scans observed >30% tumor reduction, including one patient with an unconfirmed PR as determined by RECIST 1.1 who is awaiting a follow-on tumor scan.

• The historical overall response rate (ORR) in metastatic uveal melanoma has generally been reported with an ORR of approximately 0 to 5%, including pembrolizumab and tebentafusp (each ~5%); MEK inhibitor selumetinib in combination with dacarbazine (3%); and cMET inhibitor cabozantinib monotherapy (~0%).

• A manageable side effect profile was observed with the darovasertib and crizotinib combination at the Phase 2 expansion dose, with predominantly Grade 1 or 2 drug-related adverse events.I"™m excited to talk to you today about Darovasertib (IDE196). And some of the data that’s recently been presented, so, most recently, the data that was presented was looking at IDE196 in combination with Crizotinib. There was some pretty exciting data that showed in the initial cohort of patients of 16 patients. All patients had some level of shrinkage of their target lesions, which is really exciting for a tumor type that we’ve just had such a difficult time trying to determine effective therapies metastatic uveal melanoma patients.

What is Tebentafusp?

Tebentafusp is an ImmTAC molecule that targets a portion of the HLA-A*02:01-presented melanocyte lineage-specific antigen gp100280-288 (other names: Melanocyte protein Pmel17, melanoma-associated ME20 antigen, ME20-M, [UniProtKB-P40967]). The target, gp100, was first identified as melanoma-associated by isolating melanoma-specific cytotoxic T cells that recognized HLA-presented gp100 fragments. Following RNA expression analysis, it was discovered that gp100 is expressed substantially in melanomas, weakly in normal melanocytes, and barely in non-melanocyte cells [89,90]. The gp100 fragment targeted by tebentafusp, gp100280-288, exhibits a strong affinity for the HLA-A*02:01 subtype. The HLA-A*02:01-gp100280-288 peptide complex is thus an appealing target for anti-melanoma therapy [89,90], but one drawback is that only around half of Caucasian people are HLA-A*02:01 positive. According to the manufacturer’s indications, tebentafusp is ineffective in HLA-A*02:01-negative patients.

T cell-mediated death of gp100+/HLA-A*02:01+ cell lines was corroborated by the preclinical findings with the tebentafusp group. These findings reveal that when CD8+ T cells are treated with gp100+ cancer cell lines plus tebentafusp, they exhibit lytic activity and cytokine production (cytokine release syndrome) not seen in the absence of tebentafusp. Furthermore, only gp100-positive and HLA-A*02:01-positive cancer cell lines exhibit lytic activity. Further in vitro research revealed that antitumor action is not limited to CD8+ T cells, and that in the presence of tebentafusp, CD4+ T cells are also driven to lyse gp100+ cancer cell types. Furthermore, T cells activated by tebentafusp release significant quantities of tumor necrosis factor (TNF), interferon (IFN), and IL-2. TNF and IFN are potent pro-inflammatory chemicals that promote cancer cell death by recruiting and activating lymphocytes and triggering dendritic cell maturation. Furthermore, in vitro investigations have revealed that in the tebentafusp group it promotes “epitope spreading,” in which tumour-associated antigens released by apoptotic tumor cells are collected and presented by dendritic cells, which then engage T lymphocytes to lyse more melanoma cells.

The preclinical findings paint a picture of the MoA of tebentafusp. Tebentafusp stimulates the development of an immunological synapse between a T cell and a tumor cell, resulting in tumor lysis. Regardless of the specificity of their native TCR, T cells are stimulated in a polyclonal way. On a broader level, the engaged T cells release a variety of pro-inflammatory cytokines, while the surrounding dendritic cells gather up tumor-associated antigens from dead cells and deliver them to lymphocytes. Both of these processes may help to boost the immune response to tumors.

Is Tebentafusp FDA approved?

There are currently no FDA-approved medicines for metastatic uveal melanoma or GNAQ/GNA11 solid tumors, indicating that there is a significant unmet medical need. Pembrolizumab and tebentafusp (both 5%), MEK inhibitor selumetinib in conjunction with dacarbazine (3%), and cMET inhibitor cabozantinib monotherapy (0%).

Investigator’s Opening Statement on Synthetic Lethal Combination Expansion Dose of Darovasertib and Crizotinib

If you remember, the way IDE196 works is that it’s a PKC inhibitor for patients with mUM, 90 to 90.5% of patients have a GNAQ/GNA11 mutation. This PKC inhibition is just downstream of this activation pathway. This has been tested in combination with Crizotinib, which is a MET inhibitor. The exciting data shows a hundred percent C-shrinkage on the initial imaging and then also shows that in this initial subset of patients treated that have had greater than or equal to two post-baseline scans, the response rate of 31% is still very exciting. This patient population that’s had very limited treatment options. But will this help with overall progression-free survival? Sure, I think the most common questions about this study are about the types of patients that were enrolled and can be enrolled in the IDE196 study in general. These have been pretty heavily pretreated patients that have received several prior lines of therapy.

Patients Treated for Metastatic Uveal Melanoma Reported Side Effects and Disease Progression

Although patients can be treatment-naive with metastatic uveal melanoma or have received any number of prior lines of therapy. So that’s one question that gets asked. The other is just tolerability, and overall survival. The data that’s been presented has shown that a number of toxicities have been seen with this combination treatment. GI toxicity, including nausea and diarrhea, rash, and lower extremity edema. In general, though, these have been grade 1 or 2 toxicities, so we’ve been able to help patients manage these most common adverse reactions. And so, in general, it’s been a pretty well-tolerated regimen, although we are in frequent communication with patients if they have any of these side effects to try to help them manage them.

So, I think the data is really exciting because metastatic uveal melanoma has been a patient population where we just haven’t had great systemic therapy treatment options. So to have this data for these patients treated is very encouraging for the future implications. Now we’re enrolling more patients just to be able to further see that signal and continue to develop this compound for this patient population.

This study, ID196, is now known as Darovasertib. This drug has actually been in development for a number of years. And this has been an exciting development to be able to look at it at tolerable doses in combination with Crizotinib and then also with Binimetinib. And so, at this point, more patients are being enrolled for these 2 combinations to be able to look at, which means more patients are able to further benefit.

This study is also enrolling patients that have GNAQ or 11 mutations across other tumor types. And so, this has been an option for patients with other tumor types, including cutaneous melanoma. And so that’s also been something exciting to participate in, and we look forward to it.

Overall Survival Benefit with Darovasertib and Crizotinib in Metastatic Uveal Melanoma Patients

Sure. I think there’s a lot of enthusiasm and drug development for metastatic uveal melanoma patients (mUM) in the metastatic setting that we haven’t had. Obviously, we’re all awaiting potential FDA proof of Tebentafusp, a bispecific gp100 peptide HLA directed CD3 T cell engager. And that’s going to be a big milestone in the field. If it’s approved, it’ll be the first agent that receives FDA approval based on the median overall survival benefit compared to the standard of care.

Now, the challenge there is obviously the response rate is less than 10%, and there’s only about 50% of patients with metastatic uveal melanoma. They are eligible for that treatment based on their HLA a 02 01 status. And so that’s why it’s so important to continue clinical trials and looking at treatment options for patients and developing other molecules to be able to have first-line treatments for those patients that are HLA-A2 negative and have other options, even for the patients that will be eligible for tebentafusp group. So, I think there’s a lot of encouragement in the field and a lot of excitement for these patients.

Opportunities for Darovasertib Expansion

IDEAYA is also looking at other indications as potential expansion opportunities, such as GNAQ/11 mutant skin melanoma, which is being evaluated in an ongoing arm, and adjuvant uveal melanoma (UM), which the company expects to start through an investigator sponsor clinical trial (IST) in the first half of 2022. The company is also conducting exploratory testing of the PKC-cMET synthetic lethal hypothesis in other tumor contexts with MET-amplification and high MET expression, such as hepatocellular carcinoma (HCC).

What is Darovasertib?

Darovasertib (IDE196) is a tiny chemical that has the potential to be the first-in-class inhibitor of PKC. According to a clinical study collaboration and medication supply agreement with Pfizer, IDEAYA is evaluating the synthetic lethal combination of darovasertib and crizotinib, a small-molecule cMET inhibitor. The firms have committed to funding the recruitment of about 40 patients in mUM’s ongoing Phase 1/2 clinical combo arm.

Darovasertib and Crizotinib in Combination Clinical Data Update on Metastatic Uveal Melanoma Patients

Twenty-two (22) heavily pre-treated mUM patients had enrolled in the darovasertib and crizotinib combination arm at the expansion dose at the time of the data and analysis cutoff on November 25, 2021, with sixteen (16) evaluable patients who had received one or more tumor scans and six patients who were awaiting their first tumor scan. Thirteen (13) patients have had at least two tumor scans to assess potential responses. The information provided is preliminary and comes from an unlocked database. The clinical trials darovasertib and crizotinib combo arm is still enrolling participants. In the expansion dose cohort of a Phase 1/2 clinical trial assessing darovasertib and crizotinib synthetic lethal combination in metastatic uveal melanoma (MUM) patients, the business saw good clinical activity.

Preliminary intermediate data on Synthetic Lethal Combination Expansion Dose of Darovasertib and Crizotinib

16 of 16 evaluable patients with a post-baseline scan showed tumor shrinkage as evaluated by target lesion size reduction, resulting in a 100% Disease Control Rate (DCR). 4 of 13 patients with 2 post-baseline scans showed a confirmed partial response (PR) as evaluated by RECIST 1.1 based on an investigator or central review, and no patients were taken off treatment prior to the second scan. One patient with an unconfirmed PR as indicated by RECIST 1.1 is awaiting a follow-up tumor scan. 46 percent of patients (6 of 13) with > 2 post-baseline scans saw a 30 percent tumor decrease, including one patient with an unconfirmed PR as defined by RECIST 1.1. These findings provide clinical proof of concept for the synthetic lethal combo therapy of darovasertib and crizotinib. These findings support the company’s translational research finding that reduced cMETactivity, as evaluated by gene signature score, was related to Phase 1 clinical response to darovasertib monotherapy. But will this help with disease progression?

Darovasertib and Crizotinib Combination Study: Data Update (2021)

At the time of the data and analysis cutoff on November 25, 2021, twenty-two (22) heavily pre-treated mUM patients (91 percent with prior therapies, and 59 percent with 2 or more prior therapies) had enrolled in the darovasertib and crizotinib combination arm at the expansion dose, with sixteen (16) evaluable patients who had received one or more tumor scans, and six (6) patients who were awaiting their first tumor scan. Thirteen (13) patients have had two or more tumor scans to assess potential responses. The data presented is preliminary and is based on an unlocked database. The study of the Darovasertib and Crizotinib combo arm is still enrolling patients. In the expansion dose cohort of a Phase 1/2 trial assessing darovasertib and crizotinib synthetic lethal combination in metastatic uveal melanoma (MUM), the business saw good clinical results.

The preliminary interim data set comprises the following items:

100% Disease Control Rate (DCR): 16 of 16 evaluable patients with at least one post-baseline scan showed tumor shrinkage as measured by target lesion size decrease.

Overall Response Rate (ORR): 31 percent: 4 of 13 patients with more than two post-baseline scans showed a confirmed partial response (PR) as judged by RECIST 1.1 based on investigator or central review; and no patients were taken off therapy prior to the second scan.

46 percent of patients (6 of 13) with more than two post-baseline scans had tumor reduction of more than 30%, including one patient with an unconfirmed PR as indicated by RECIST 1.1 who is awaiting a follow-up tumor scan.

These findings provide clinical proof-of-concept for the synthetic lethal combo therapy of darovasertib and crizotinib. These findings support the company’s translational study finding that Phase 1 clinical response to darovasertib monotherapy was related to decreased cMETactivity as evaluated by gene signature score.

In disease progression mUM patients (n=22), the darovasertib and crizotinib combination therapy had a manageable side effect profile, with a low occurrence of drug-related serious adverse events (SAEs); mostly grade 1 or 2 drug-related adverse events. A drug-related AE occurred in eighteen (18) patients, with six (6) patients experiencing Grade 3 and no patients experiencing grade 4 or grade 5 adverse events.

Future Milestones for Tebentafusp in Metastatic Uveal Melanoma

To facilitate possible registrational investigations, IDEAYA has chosen a darovasertib and crizotinib combo expansion dose. The company intends to seek regulatory approval for a potential darovasertib and crizotinib combination registrational approach in the first part of 2022. In addition, IDEAYA plans to provide additional clinical results for the darovasertib and crizotinib combination, including median progression free overall survival (mPFS) in mUM patients, in the first half of 2022.

Opportunities for Darovasertib Expansion

IDEAYA is also looking at other indications as potential expansion opportunities, such as GNAQ/11 mutant skin melanoma, which is being evaluated in an ongoing arm of the current clinical trial, and adjuvant uveal melanoma (UM), which the company expects to start through an investigator-sponsored clinical trial (IST) in the first half of 2022. The company is also conducting exploratory testing of the PKC-cMET synthetic lethal hypothesis in other tumor contexts with MET-amplification and high MET expression, such as hepatocellular carcinoma (HCC).

Does Tebentafusp Help with Median Overall Survival in Metastatic Uveal Melanoma?

The FDA approved tebentafusp (Kimmtrak, Immunocore Limited), a bispecific gp100 peptide HLA directed CD3 T cell engager, for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma, on January 25, 2022. IMCgp100-202 (NCT03070392), a randomized, open-label, multicenter trial of 378 patients with metastatic uveal melanoma, was used to assess efficacy. Patients have to be HLA-A*02:01 genotype positive as determined by a central assay. Patients were excluded if they had previously received systemic or localized liver-directed treatment. Prior to metastatic disease, surgical resection was permitted. Patients with clinically severe heart illness or untreated symptomatic brain metastases were excluded.

How are Patients with Metastatic Uveal Melanoma Assigned in this Trial?

Treated patients were randomly assigned (2:1) to receive tebentafusp (N=252) or the investigator’s choice of pembrolizumab, ipilimumab, or dacarbazine (N=126). Tebentafusp was given weekly through intravenous infusion at 20 mcg on day one, 30 mcg on day eight, 68 mcg on day fifteen, and every week afterwards until disease progression or unacceptable toxicity. Overall survival benefit was the primary efficacy outcome measure (OS). Investigator-assessed progression-free survival (PFS) using RECIST 1.1 was another efficacy endpoint. The median OS for patients treated with tebentafusp-tebn was 21.7 months (95 percent CI: 18.6, 28.6), compared to 16 months (95 percent CI: 9.7, 18.4) in the investigator’s choice arm (HR=0.51, 95 percent CI: 0.37, 0.71, p0.0001). PFS for those taking tebentafusp-tebn was 3.3 months (95 percent CI: 3, 5) and 2.9 months (95 percent CI: 2.8, 3) in the investigator’s choice of pembrolizumab, ipilimumab, or dacarbazine arm (HR=0.73, 95 percent CI: 0.58, 0.94, p=0.0139). Cytokine release syndrome, rash, pyrexia, pruritus, exhaustion, nausea, chills, abdominal discomfort, edema, hypotension, dry skin, headache, and vomiting were the most prevalent side effects (30%). The most prevalent laboratory abnormalities (50 percent) were lower lymphocyte count, higher creatinine, higher glucose, higher aspartate aminotransferase, higher alanine aminotransferase, lower hemoglobin, and lower phosphate.

Author Credit and Affiliations Meredith McKean, MD, MPH

Dr. McKean joined Tennessee Oncology’s Sarah Cannon Research Institute in 2018 as the director of melanoma and skin cancer research. Dr. McKean is in charge of metastatic uveal melanoma and other skin cancer experimental therapeutic trials.

Dr. McKean earned her bachelor’s degree at Iowa State University, her master’s degree in public health at the University of Iowa, and her medical degree at the University of Iowa. She finished her residency in hematology-oncology at the University of Texas MD Anderson Cancer Center before joining Sarah Cannon. Dr. McKean was awarded the ASCO Conquer Cancer Foundation Young Investigator Award in 2017. She holds board certifications in both internal medicine and medical oncology.

In this video, she speaks about IDEAYA Reports Clinical Data from Phase 2 Expansion Dose of Darovasertib and Crizotinib Synthetic Lethal Combination in Heavily Pre-Treated Metastatic Uveal Melanoma.

What Company is Behind The IDEAYA Clinical Trial?

IDEAYA is a precision medicine cancer firm focused on synthetic lethality that is dedicated to the discovery and development of targeted therapies for patient populations selected through molecular diagnostics. IDEAYA’s methodology combines capabilities for identifying and testing translational biomarkers with drug discovery in order to identify patient categories most likely to benefit from its tailored medicines. IDEAYA is focusing its research and drug discovery efforts on synthetic lethality, which is a new class of precision medicine targets and median overall survival.

About IDEAYA Biosciences, Inc.

IDEAYA Biosciences, Inc., a precision medicine oncology company focused on the discovery and development of targeted therapeutics, has provided a clinical data update for the Phase 1/2 clinical trial evaluating the synthetic lethal combination of darovasertib and crizotinib in patients with metastatic uveal melanoma (mUM)

 

References

Sarah Cannon Research Institute – Sarah Cannon Research Institute Leadership and Physician Experts. Sarah Cannon Research Institute, 2022

IDEAYA Biosciences, Inc. – IDEAYA and Pfizer Expand Clinical Trial Collaboration and Supply Agreements for Evaluation of Darovasertib and Crizotinib Combination in Metastatic Uveal Melanoma and Additional cMET-Driven Tumors. CISION PR Newswire, May 14, 2022

IDEAYA Biosciences, Inc. – IDEAYA Reports Clinical Data from Phase II Trial Expansion Dose of Darovasertib and Crizotinib Synthetic Lethal Combination in Heavily Pre-Treated Metastatic Uveal Melanoma. IDEAYA Biosciences News, December 7, 2021

NIH – National Library of Medicine – Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma – NIH – PMC6679206 – July 11, 2019