On March 15, 2022 GlaxoSmithKline (GSK) plc reported that it will present new findings in support of advancing treatment for certain gynaecologic cancers, including data evaluating Zejula (niraparib) and Jemperli (dostarlimab) at the upcoming Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer (Press release, GlaxoSmithKline, MAR 15, 2022, View Source [SID1234610112]). The meeting will take place in Phoenix, Arizona, and virtually from 18-21 March 2022. The presentations demonstrate GSK’s commitment to improving outcomes for patients with gynaecologic cancers through research programmes that identify and address high unmet patient needs.

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Hesham Abdullah, Global Head of Oncology Development, GSK said: "The data we’re presenting at SGO will provide the research community with deeper insights about Zejula and Jemperli. We will also share data that furthers our understanding of ovarian and endometrial cancers, and real-world data that sheds light on potential gaps in the care of patients with gynaecologic cancer that need to be addressed."

Exploring optimal use of PARP inhibition maintenance therapy in ovarian cancer

Research being presented at SGO reinforces the role of first-line maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors in helping to optimise treatment outcomes for patients living with advanced ovarian cancer. This data contributes to the understanding of niraparib in the maintenance treatment of ovarian cancer.

Key oral presentations include:

OVARIO (oral presentation, ID #39): an oral plenary presentation featuring an updated analysis from this phase II study evaluating niraparib in combination with bevacizumab as first-line maintenance therapy in patients with ovarian cancer following platinum-based chemotherapy and bevacizumab.
ROYAL (oral presentation, ID #28): an oral plenary presentation featuring a real-world evidence study examining the evolution of the ovarian cancer treatment paradigm in the US and Europe from 2017 to 2020. The findings may help us better understand the treatment paradigm of ovarian cancer and identify remaining unmet needs.
In addition, Zai Lab (a GSK partner) will present a late-breaking oral presentation of the phase III PRIME study (late-breaking oral presentation, ID #5), featuring data evaluating niraparib (independently manufactured by Zai Lab) in Chinese patients with newly diagnosed advanced ovarian cancer using an individualized starting dose.

As part of GSK’s ongoing commitment to the ovarian cancer community, additional real-world studies assessing unmet needs will also be presented, including a study evaluating trends in first-line maintenance treatment use in patients with newly diagnosed advanced ovarian cancer, a study evaluating outcomes in patients with recurrent ovarian cancer who received niraparib as second-line maintenance therapy, and a study that assessed trends in niraparib starting dose as first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer.

Zejula is a once-daily oral monotherapy maintenance treatment approved for women with first-line platinum-responsive (complete or partial response) advanced ovarian cancer regardless of biomarker status in the US and the European Union (EU).

Advancing standard of care treatment in endometrial cancer

Key dostarlimab presentations at SGO include:

GARNET trial subgroup (poster presentation, ID #210): a post-hoc analysis from the GARNET trial evaluating the antitumour activity and safety of dostarlimab therapy in patients with endometrial cancer by age subgroups. This analysis will provide insights on outcomes in an older endometrial cancer patient population, potentially helping to inform treatment decisions.
Dostarlimab indirect treatment comparison (poster presentation, ID #216): an analysis comparing the clinical effectiveness of dostarlimab with doxorubicin in the treatment of advanced or recurrent endometrial cancer, which may help further contextualize how dostarlimab fits in the recurrent or advanced dMMR endometrial cancer treatment landscape.
The GARNET trial was the basis for the US and EU regulatory approvals of Jemperli, a programmed cell death receptor-1 (PD-1) blocking antibody.

Jemperli is the first anti-PD-1 monotherapy approved for endometrial cancer in the EU and received a conditional approval in April 2021 for the treatment of women with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer who have progressed on or following prior treatment with a platinum-containing regimen. The treatment also received accelerated approval based on tumour response rate and durability of response in the US for adult patients with dMMR recurrent or advanced endometrial cancer, as determined by an FDA-approved test, who have progressed on or following prior treatment with a platinum-containing regimen. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Full list of GSK’s presentations at SGO for niraparib and ovarian cancer:

Abstract Name

Presenter

Presentation Details

Evolution of the Ovarian Cancer Treatment Paradigm, Including Maintenance Treatment, in the US and Europe: A Real-World Chart Review Analysis (2017–2020)

K. Moore

Oral Presentation, ID #28

OVARIO, A Phase II Study of Niraparib + Bevacizumab in Advanced Ovarian Cancer Following Front-Line Platinum-Based Chemotherapy with Bevacizumab: Updated Analysis

M. Hardesty

Oral Presentation, ID #39

Poly (adenosine diphosphate [ADP]-ribose) Polymerase Inhibitor First-Line Maintenance Among Patients with Newly Diagnosed Advanced Ovarian Cancer in a Real-World Database

J. Liu

Poster Presentation, ID #351

Real-World Clinical Outcomes with Poly (adenosine diphosphate [ADP]-ribose) Polymerase Inhibitors as Second-Line Maintenance Therapy in Patients with Recurrent Ovarian Cancer in the United States

U. Matulonis

Poster Presentation, ID #353

Starting Dose of Niraparib as First-Line Maintenance Among Patients with Newly Diagnosed Advanced Ovarian Cancer in a Real-World Database

J. Liu

Poster Presentation, ID #352

Full list of GSK’s presentations at SGO for dostarlimab and endometrial cancer:

Abstract Name

Presenter

Presentation Details

Antitumor Activity and Safety of Dostarlimab Therapy in Patients with Endometrial Cancer by Age Subgroups: A Post-hoc Analysis from the GARNET Trial

A. Oaknin

Poster Presentation, ID #210

The Comparative Clinical Effectiveness of Dostarlimab Versus Doxorubicin in the Treatment of Advanced/Recurrent Endometrial Cancer

C. Mathews

Poster Presentation, ID #216

Patient Characteristics and Treatment Patterns in Patients With Advanced or Recurrent Endometrial Cancer in Europe: A Real-World Study

Q. Shen

Poster Presentation, ID #348

About ovarian cancer

Ovarian cancer is the 8th most common cancer in women worldwide.[1] Despite high response rates to platinum-based chemotherapy in the front-line setting, approximately 85% of patients will experience disease recurrence.[2] Once the disease recurs, it is rarely curable, with decreasing time intervals to each subsequent recurrence.

About endometrial cancer

Endometrial cancer is found in the inner lining of the uterus, known as the endometrium. It is the most common gynaecologic cancer in the US and second most common gynaecologic cancer globally [3]. Approximately 15-20% of women with endometrial cancer will be diagnosed with advanced disease at the time of diagnosis. [4]

Indications and Important US Safety Information for ZEJULA (niraparib)

ZEJULA is indicated:

for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.
for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.
for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:
a deleterious or suspected deleterious BRCA mutation, or
genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy.

Select patients for therapy based on an FDA-approved companion diagnostic for ZEJULA.
Important Safety Information

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including some fatal cases, was reported in 15 patients (0.8%) out of 1785 patients treated with ZEJULA monotherapy in clinical trials. The duration of therapy in patients who developed secondary MDS/cancer therapy-related AML varied from 0.5 months to 4.9 years. These patients had received prior chemotherapy with platinum agents and/or other DNA-damaging agents including radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Hematologic adverse reactions (thrombocytopenia, anemia, neutropenia, and/or pancytopenia) have been reported in patients receiving ZEJULA. The overall incidence of Grade ≥3 thrombocytopenia, anemia and neutropenia were reported, respectively, in 39%, 31%, and 21% of patients receiving ZEJULA in PRIMA; 29%, 25%, and 20% of patients receiving ZEJULA in NOVA; and 28%, 27%, and 13% of patients receiving ZEJULA in QUADRA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 4%, 2%, and 2% of patients in PRIMA; 3%, 1%, and 2% of patients in NOVA; and 4%, 2%, and 1% of patients in QUADRA. In patients who were administered a starting dose of ZEJULA based on baseline weight or platelet count in PRIMA, Grade ≥3 thrombocytopenia, anemia and neutropenia were reported, respectively, in 22%, 23%, and 15% of patients receiving ZEJULA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 3%, 3%, and 2% of patients. Do not start ZEJULA until patients have recovered from hematological toxicity caused by prior chemotherapy (≤Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months, and periodically thereafter. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations.

Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 6% of patients receiving ZEJULA vs 1% of patients receiving placebo in PRIMA, with no reported discontinuations. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in NOVA, with discontinuation occurring in <1% of patients. Grade 3-4 hypertension occurred in 5% of ZEJULA-treated patients in QUADRA, with discontinuation occurring in <0.2% of patients. Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year, and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Manage hypertension with antihypertensive medications and adjustment of the ZEJULA dose, if necessary.

Posterior reversible encephalopathy syndrome (PRES) occurred in 0.1% of 2,165 patients treated with ZEJULA in clinical trials and has also been described in postmarketing reports. Monitor all patients for signs and symptoms of PRES, which include seizure, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. Diagnosis requires confirmation by brain imaging. If suspected, promptly discontinue ZEJULA and administer appropriate treatment. The safety of reinitiating ZEJULA is unknown.

Embryo-Fetal Toxicity and Lactation: Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months after receiving their final dose of ZEJULA. Because of the potential for serious adverse reactions from ZEJULA in breastfed infants, advise lactating women not to breastfeed during treatment with ZEJULA and for 1 month after receiving the final dose.

Allergic reactions to FD&C Yellow No. 5 (tartrazine): ZEJULA capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

First-line Maintenance Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of all patients who received ZEJULA in PRIMA were thrombocytopenia (66%), anemia (64%), nausea (57%), fatigue (51%), neutropenia (42%), constipation (40%), musculoskeletal pain (39%), leukopenia (28%), headache (26%), insomnia (25%), vomiting (22%), dyspnea (22%), decreased appetite (19%), dizziness (19%), cough (18%), hypertension (18%), AST/ALT elevation (14%), and acute kidney injury (12%).

Common lab abnormalities (Grades 1-4) in ≥25% of all patients who received ZEJULA in PRIMA included: decreased hemoglobin (87%), decreased platelets (74%), decreased leukocytes (71%), increased glucose (66%), decreased neutrophils (66%), decreased lymphocytes (51%), increased alkaline phosphatase (46%), increased creatinine (40%), decreased magnesium (36%), increased AST (35%) and increased ALT (29%).

Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients who received ZEJULA in NOVA were nausea (74%), thrombocytopenia (61%), fatigue/asthenia (57%), anemia (50%), constipation (40%), vomiting (34%), neutropenia (30%), insomnia (27%), headache (26%), decreased appetite (25%), nasopharyngitis (23%), rash (21%), hypertension (20%), dyspnea (20%), mucositis/stomatitis (20%), dizziness (18%), back pain (18%), dyspepsia (18%), leukopenia (17%), cough (16%), urinary tract infection (13%), anxiety (11%), dry mouth (10%), AST/ALT elevation (10%), dysgeusia (10%), palpitations (10%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients who received ZEJULA in NOVA included: decrease in hemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%).

Treatment of Advanced HRD+ Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients who received ZEJULA in QUADRA were nausea (67%), fatigue (56%), thrombocytopenia (52%), anemia (51%), vomiting (44%), constipation (36%), abdominal pain (34%), musculoskeletal pain (29%), decreased appetite (27%), dyspnea (22%), insomnia (21%), neutropenia (20%), headache (19%), diarrhea (17%), acute kidney injury (17%), urinary tract infection (15%), hypertension (14%), cough (13%), dizziness (11%), AST/ALT elevation (11%), blood alkaline phosphatase increased (11%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients who received ZEJULA in QUADRA included: decreased hemoglobin (83%), increased glucose (66%), decreased platelets (60%), decreased lymphocytes (57%), decreased leukocytes (53%), decreased magnesium (46%), increased alkaline phosphatase (40%), increased gamma glutamyl transferase (40%), increased creatinine (36%), decreased sodium (34%), decreased neutrophils (34%), increased aspartate aminotransferase (29%), and decreased albumin (27%).

Please see full Prescribing Information

Indications and Important US Safety Information for JEMPERLI (dostarlimab-gxly)

JEMPERLI is indicated for the treatment of adult patients with mismatch repair deficient (dMMR) recurrent or advanced:

endometrial cancer (EC), as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen, or
solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.
These indications are approved under accelerated approval based on tumor response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Important Safety Information

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which can be severe or fatal, can occur in any organ system or tissue and can occur at any time during or after treatment with a PD-1/PD-L1–blocking antibody, including JEMPERLI.
Monitor closely for signs and symptoms of immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function tests at baseline and periodically during treatment. For suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Based on the severity of the adverse reaction, withhold or permanently discontinue JEMPERLI. In general, if JEMPERLI requires interruption or discontinuation, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) until improvement to ≤Grade 1. Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroids.
Immune-Mediated Pneumonitis

JEMPERLI can cause immune-mediated pneumonitis, which can be fatal. In patients treated with other PD-1/PD-L1–blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Pneumonitis occurred in 1.4% (7/515) of patients, including Grade 2 (1.2%) and Grade 3 (0.2%) pneumonitis.
Immune-Mediated Colitis

Colitis occurred in 1.4% (7/515) of patients, including Grade 2 (0.8%) and Grade 3 (0.6%) adverse reactions. Cytomegalovirus infection/reactivation have occurred in patients with corticosteroid-refractory immune-mediated colitis. In such cases, consider repeating infectious workup to exclude alternative etiologies.
Immune-Mediated Hepatitis

JEMPERLI can cause immune-mediated hepatitis, which can be fatal. Grade 3 hepatitis occurred in 0.2% (1/515) of patients.
Immune-Mediated Endocrinopathies

Adrenal Insufficiency
Adrenal insufficiency occurred in 1.4% (7/515) of patients, including Grade 2 (0.8%) and Grade 3 (0.6%). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity.
Hypophysitis
JEMPERLI can cause immune-mediated hypophysitis. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity.
Thyroid Disorders
Thyroiditis occurred in 0.4% (2/515) of patients; both were Grade 2. Hypothyroidism occurred in 7.2% (37/515) of patients, all of which were Grade 2. Hyperthyroidism occurred in 1.9% (10/515) of patients, including Grade 2 (1.7%) and Grade 3 (0.2%). Initiate hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity.
Type 1 Diabetes Mellitus, Which Can Present with Diabetic Ketoacidosis
JEMPERLI can cause type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue JEMPERLI depending on severity.
Immune-Mediated Nephritis with Renal Dysfunction

JEMPERLI can cause immune-mediated nephritis, which can be fatal. Nephritis occurred in 0.4% (2/515) of patients; both were Grade 2.
Immune-Mediated Dermatologic Adverse Reactions

JEMPERLI can cause immune-mediated rash or dermatitis. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), have occurred with PD-1/PD-L1–blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes. Withhold or permanently discontinue JEMPERLI depending on severity.
Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred in <1% of the 515 patients treated with JEMPERLI or were reported with the use of other PD-1/PD-L1–blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.
Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy
Cardiac/Vascular: Myocarditis, pericarditis, vasculitis
Ocular: Uveitis, iritis, other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur
Gastrointestinal: Pancreatitis, including increases in serum amylase and lipase levels, gastritis, duodenitis
Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica
Endocrine: Hypoparathyroidism
Other (Hematologic/Immune): Autoimmune hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection
Infusion-Related Reactions

Severe or life-threatening infusion-related reactions have been reported with PD-1/PD-L1–blocking antibodies. Severe infusion-related reactions (Grade 3) occurred in 0.2% (1/515) of patients receiving JEMPERLI. Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue JEMPERLI based on severity of reaction.
Complications of Allogeneic HSCT

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after treatment with a PD-1/PD-L1–blocking antibody, which may occur despite intervening therapy. Monitor patients closely for transplant-related complications and intervene promptly.
Embryo-Fetal Toxicity and Lactation

Based on its mechanism of action, JEMPERLI can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with JEMPERLI and for 4 months after their last dose. Because of the potential for serious adverse reactions from JEMPERLI in a breastfed child, advise women not to breastfeed during treatment with JEMPERLI and for 4 months after their last dose.
Common Adverse Reactions

The most common adverse reactions (≥20%) in patients with dMMR EC were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased sodium, decreased leukocytes, decreased albumin, increased creatinine, increased alkaline phosphatase, and increased alanine aminotransferase.

Please see full Prescribing Information

GSK in Oncology

GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, cell therapy, tumour cell targeting therapies and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, antibody-drug conjugates and cell therapy, either alone or in combination.

On March 15, 2022 Shanghai Junshi Biosciences Co., Ltd. ("Junshi Biosciences", HKEX: 1877; SSE: 688180) and Coherus BioSciences, Inc. ("Coherus", Nasdaq: CHRS), reported the presentation of positive results and biomarker analyses from the pivotal study "CHOICE-01" (clinicaltrials.gov identifier# NCT03856411), a randomized, double-blind, placebo-controlled Phase 3 clinical trial evaluating toripalimab plus chemotherapy as first-line treatment of advanced squamous or non-squamous non-small cell lung cancer ("NSCLC") (Press release, Coherus Biosciences, MAR 15, 2022, View Source [SID1234610111]). The final progression-free survival ("PFS") analysis confirms the finding of the previous interim PFS analysis, demonstrating a statistically significant and clinically meaningful improvement in PFS per RECIST v1.1 compared to chemotherapy alone. The study also demonstrated an improvement in overall survival ("OS") in a prespecified interim OS analysis. These results will be summarized later today during the ASCO (Free ASCO Whitepaper) Plenary Series, in an oral presentation by Professor Jie Wang, MD, PhD, from the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College. The abstract is now available on the ASCO (Free ASCO Whitepaper) website.

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"We are excited about the consistently strong clinical evidence that toripalimab has displayed across multiple tumor types," said Dr. Patricia Keegan, Chief Medical Officer at Junshi Biosciences. "The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided superior PFS and OS compared to chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as first-line therapy for advanced NSCLC patients without EGFR/ALK mutations."

"In the CHOICE-01 study in patients with non-small cell lung cancer, toripalimab has once again demonstrated the potential to delay disease progression and help patients live longer," said Theresa LaVallee, PhD, Chief Development Officer at Coherus. "The study investigators also reported interesting biomarker data with toripalimab plus chemotherapy having activity independent of PD-L1 expression as well as a statistically significant overall survival advantage in NSCLC patients who have alterations in the focal adhesion-PI3K-AKT signaling pathway, a finding which may inform the design of future toripalimab clinical trials."

About CHOICE-01
A total of 465 treatment-naïve advanced NSCLC patients without EGFR/ALK mutations were randomized (2:1): 309 to toripalimab plus chemotherapy (the "toripalimab arm") and 156 to placebo plus chemotherapy (the "placebo arm"). The primary endpoint was PFS assessed by the investigator. Secondary endpoints included PFS assessed by a blinded independent review committee ("BIRC"), OS and safety. Patients from the placebo arm were actively crossed over to toripalimab treatment upon disease progression.

As of October 31, 2021:

At the final analysis, a significant improvement in PFS was detected in the toripalimab arm over the placebo arm (hazard ratio ("HR")=0.49; 95% confidence interval ("CI"): 0.39-0.61, P<0.0001) with median PFS of 8.4 vs. 5.6 months. The 1-year PFS rates for the toripalimab and placebo arms were 36.7% and 17.2%, respectively.
PFS as assessed by BIRC was also significantly longer in the toripalimab arm.
A prespecified interim analysis demonstrated a statistically significant improvement in overall survival for the toripalimab arm over the placebo arm (median OS not reached vs. 17.1 months, HR = 0.69 (95% CI: 0.52-0.92)).
The PFS benefits were observed in patients treated with toripalimab plus chemotherapy across key subgroups, including histologic subtype and tumor PD-L1 expression.
Genomic analysis revealed a PFS benefit associated with high tumor mutation burden and with genetic alterations in the focal adhesion-PI3K-AKT and IL-7 pathways in patients treated with toripalimab plus chemotherapy.
The addition of toripalimab to standard first-line chemotherapy in patients with advanced NSCLC showed a manageable safety profile with no new safety signals observed. The incidence of Grade ≥3 adverse events (AEs) was 78.6% in the toripalimab arm vs. 82.1% in the placebo arm. AEs leading to discontinuation of toripalimab or placebo were 14.3% vs. 3.2%, respectively.
Junshi Biosciences and Coherus are evaluating potential registration avenues for toripalimab in combination with chemotherapy for the first-line treatment of advanced non-small cell lung cancer in the United States. In China, the supplemental New Drug Application for this indication was accepted in December 2021 by the National Medical Products Administration ("NMPA").

About Toripalimab
Toripalimab is an anti-PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 promote the immune system’s ability to attack and kill tumor cells.

More than thirty company-sponsored toripalimab clinical studies covering more than fifteen indications have been conducted globally by Junshi Biosciences, including in China, the United States, Southeast Asia, and European countries. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney and skin.
In China, toripalimab was the first domestic anti-PD-1 monoclonal antibody approved for marketing (approved in China as TUOYI). Currently, there are four approved indications for toripalimab in China:

unresectable or metastatic melanoma after failure of standard systemic therapy;
recurrent or metastatic nasopharyngeal carcinoma ("NPC") after failure of at least two lines of prior systemic therapy;
locally advanced or metastatic urothelial carcinoma that failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy;
in combination with cisplatin and gemcitabine as the first-line treatment for patients with locally recurrent or metastatic NPC.
The first three indications have been included in the National Reimbursement Drug List ("NRDL") (2021 Edition). Toripalimab is the only anti-PD-1 monoclonal antibody included in the NRDL for melanoma and NPC.

In addition, two supplemental New Drug Applications ("NDAs") for toripalimab are currently under review by the National Medical Products Administration ("NMPA") in China:

in combination with chemotherapy as the first-line treatment of patients with advanced or metastatic ESCC.
in combination with chemotherapy as the first-line treatment of patients with advanced or metastatic NSCLC without EGFR or ALK mutations.
In the United States, the FDA has granted priority review for the toripalimab biologics license application ("BLA") for the treatment of recurrent or metastatic NPC, an aggressive head and neck tumor which has no FDA-approved immuno-oncology treatment options. The FDA has assigned a Prescription Drug User Fee Act ("PDUFA") target action date for April 2022 for the toripalimab BLA. The FDA granted Breakthrough Therapy designation for toripalimab in combination with chemotherapy for the first-line treatment of recurrent or metastatic NPC in 2021 as well as for toripalimab monotherapy in the second or third-line treatment of recurrent or metastatic NPC in 2020. Additionally, the FDA has granted Fast Track designation for toripalimab for the treatment of mucosal melanoma and orphan drug designation for the treatment of esophageal cancer, NPC, mucosal melanoma and soft tissue sarcoma. In 2021, Coherus in-licensed rights to develop and commercialize toripalimab in the United States and Canada. Coherus and Junshi Biosciences plan to file additional toripalimab BLAs with the FDA over the next three years for multiple other cancer types.

On March 15, 2022 Enochian BioSciences, a company focused on gene modified cellular and immune therapies for infectious diseases and cancer, reported that has issued an exclusive sub-license of one of its proprietary technologies that could improve the effectiveness of a potential cure for HIV with an anti-HIV CAR-T therapy that Caring Cross is studying in a clinical trial (Press release, Enochian BioSciences, MAR 15, 2022, View Source [SID1234610110]). Caring Cross is an innovative non-profit that partners with others, including for-profit companies, to increase access to new technologies and medicines under a collaborative value sharing model. Caring Cross and Enochian BioSciences entered into a profit-sharing agreement as part of the sub-license.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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The CAR-T approach being studied in humans was shown to cure HIV infection in an animal model that was published in the prestigious scientific journal, Science Translational Medicine View Source). Based on those and other key data, Caring Cross received approval from the US Food and Drug Administration to advance to clinical studies that are being conducted by researchers from the University of California, San Francisco and the University of California, Davis with funding from the California Institute of Regenerative Medicine. More details of the trial can be found at clinicaltrials.gov with the identifier NCT04648046.

"We are very excited that our clinical trial has now begun. Combining innovative technologies could significantly increase the effectiveness of our therapy in the future and therefore improve its access and affordability said Dr. Boro Dropulic, the Executive Director of Caring Cross. "The technology acquired from Enochian BioSciences is an innovative strategy that could enhance the selection of the anti-HIV CAR-T cells, potentially increasing effectiveness, lowering cost and side effects, and increasing access to those in need. If it is shown to work in laboratory and animal evaluations, we would hope to pursue additional clinical studies combining our CAR-T therapy with Enochian BioSciences’ technology."

Dr. Mark Dybul, CEO of Enochian BioSciences, said: "Our Co-Founder and Inventor, Dr. Serhat Gumrukçu, has presented data at scientific meetings showing that our proprietary approach substantially increased the selection of different cell types, including in an animal model. We have seen similar results in the laboratory with T-cells, the key to CAR-T therapy. Therefore, we are enthusiastic that the exclusive sub-license issued to Caring Cross will prove to be effective, offering hope to many people living with HIV. While these studies proceed, we continue to pursue several other novel approaches to potentially cure HIV." View Source

On March 15, 2022 Shattuck Labs, Inc. (Shattuck) (NASDAQ: STTK), a clinical-stage biotechnology company pioneering the development of bi-functional fusion proteins as a new class of biologic medicine for the treatment of patients with cancer and autoimmune disease, reported financial results for the fourth quarter and full year ended December 31, 2021 and provided recent business highlights (Press release, Shattuck Labs, MAR 15, 2022, View Source [SID1234610109]).

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"We took a very important step in 2021 toward validating the Agonist Redirected Checkpoint (ARC) platform as a new class of biologic medicine, through sharing initial clinical data from our SL-172154 and SL-279252 programs at the 36th annual meeting of the Society for the Immunotherapy of Cancer (SITC) (Free SITC Whitepaper). The observation of initial anti-tumor activity and dose-dependent activation of CD40 and OX40 are differentiating features of ARCs that bode well for the next stage of clinical development," said Taylor Schreiber, M.D., Ph.D., and Chief Executive Officer of Shattuck. "With SL-172154, we are pleased with the safety profile, evidence of target saturation, and potent dose-dependent CD40 activation, which prompted our combination strategy aimed to demonstrate significant anti-tumor activity. Based on the clinical data to date and evolving development landscape, we believe SL-172154 could emerge as both a first-in-class and best-in-class CD47 inhibitor and CD40 agonist."

Fourth Quarter 2021 Recent Business Highlights and Other Recent Developments

ARC Clinical-Stage and Preclinical Pipeline

SL-172154 (SIRPα-Fc-CD40L)

Announced Initial Data from SL-172154 Phase 1 Dose-Escalation Clinical Trial in Platinum-Resistant Ovarian Cancer Demonstrating Favorable Safety Profile, High Target Occupancy, and Unique Pharmacodynamic Activity at the 36th Annual SITC (Free SITC Whitepaper) Meeting: The Phase 1 trial is an open-label, multi-center, dose-escalation trial to evaluate the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamic effects of SL-172154 administered intravenously in patients with platinum-resistant ovarian cancer. Data reported at the 36th Annual SITC (Free SITC Whitepaper) Meeting was in 15 evaluable patients, across four dose levels on two schedules: schedule 1 (day 1, 8, 15, 29, then every two weeks) at 0.1 and 0.3 mg/kg and schedule 2 (weekly) at 0.3, 1.0, and 3.0 mg/kg. SL-172154 was well tolerated through 3.0 mg/kg, and no dose-limiting toxicities were observed. Preferential binding to CD47 on leukocytes, compared to red blood cells, was observed and exceeded 80% of CD47 expressing leukocytes in most patients at doses of 1.0 and 3.0 mg/kg. Dose-dependent CD40 receptor occupancy was also observed, which approached 100% of CD40 expressing cells at the 3.0 mg/kg dose level and correlated with multiple signs of CD40 activation. Specifically, dose-dependent margination of CD40 expressing B cells and monocytes was observed following each infusion, and large increases in multiple serum cytokines, including IL-12, were also reported. Shattuck is continuing dose escalation to 10.0 mg/kg.
Combination Trial with SL-172154 with Liposomal Doxorubicin Expected to Begin in 2022: A Phase 1B trial of SL-172154 in combination with liposomal doxorubicin to evaluate safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamics in patients with advanced, platinum-resistant ovarian cancer is expected to begin enrollment in 2022. Initial combination data from the trial are expected in the first half of 2023. Additional combination trials with SL-172154 in ovarian cancer and novel agents are currently being planned.
Initiated Phase 1A/B Clinical Trial in AML and HR-MDS with SL-172154: Shattuck is conducting a Phase 1A/B clinical trial evaluating the safety, tolerability, pharmacokinetics, anti-tumor activity, and pharmacodynamic effects of SL-172154, as both monotherapy and in combination. In acute myeloid leukemia (AML), Shattuck plans to evaluate SL-172154 in combination with both azacitidine and venetoclax. In both HR-MDS and TP53 mutant AML, Shattuck plans to evaluate SL-172154 in combination with azacitidine. Initial data from the trial are expected in the first half of 2023.
Closed Enrollment of Intratumorally Administered SL-172154 Phase 1 Clinical Trial in Squamous Cell Carcinoma of the Head and Neck or Skin to Focus on Intravenous Administration Strategy: Based on the totality of the safety and biomarker data collected to date in our ongoing Phase 1A clinical trial in ovarian cancer patients, we have decided to focus development of SL-172154 as an intravenously administered product candidate. As of February 24, 2022, Shattuck has closed enrollment of the Phase 1 clinical trial for SL-172154 in patients with squamous cell carcinoma of the head and neck (HNSCC) or skin (CSCC) to further focus all development of SL-172154 as an intravenously administered product candidate. Shattuck did not observe dose-limiting toxicities and did not reach a maximum tolerated dose in this trial. Data from the trial are expected in the first half of 2022. Shattuck may continue further development of HNSCC and/or CSCC in an intravenous administration trial of SL-172154 following selection of a recommended Phase 2 dose in Shattuck’s ovarian cancer trial.
SL-279252 (PD1-Fc-OX40L)

Announced Initial Data from Ongoing SL-279252 Phase 1 Dose-Escalation Clinical Trial in Advanced Solid Tumors Demonstrating Evidence of Anti-Tumor Activity and Dose-Dependent Pharmacodynamic Activity at the 36th Annual SITC (Free SITC Whitepaper) Meeting: The Phase 1 trial is an open-label, multi-center, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, anti-tumor activity and pharmacodynamic effects of SL-279252 in patients with advanced solid tumors and lymphoma. SL-279252 was well tolerated across a dose-range of 0.0001 mg/kg through 6.0 mg/kg, and dose-dependent margination of CD4+OX40+ T cells was the primary pharmacodynamic effect observed and had not plateaued through the 6.0 mg/kg dose level. Monotherapy anti-tumor activity was observed at doses of 1.0 mg/kg and higher, including a confirmed partial response in a PD-1 and CTLA-4 inhibitor experienced ocular melanoma patient who remained on therapy for over 12 months. Shattuck continues to dose patients, primarily selecting for patients with PD-L1 expressing tumors, at 12.0 mg/kg and plans to continue dose escalation to 24.0 mg/kg, to fully characterize pharmacokinetic, pharmacodynamic, and anti-tumor activity. Additional dose-escalation data from the trial are expected in the second half of 2022.
Preclinical

Presented Continued Preclinical Development of SL-9258 at the TIGIT Therapies Digital Summit in December 2021: Preclinical data for SL-9258 (TIGIT-Fc-LIGHT), a dual TIGIT inhibitor and HVEM/LTβR agonist, were presented at the TIGIT Therapies Summit in December 2021. These data, from studies in a mouse model, provided preclinical evidence for anti-tumor activity of the murine equivalent of SL-9258 in PD-1 acquired resistant tumors and increased tumor rejection in comparison to TIGIT blocking antibodies.
Upcoming Events

American Association for Cancer Research Annual Meeting (AACR) (Free AACR Whitepaper), April 8-13
Poster presentation on the preclinical development of SL-9258
Poster presentation on the preclinical development of GADLEN compounds
Shattuck plans to attend the following investor conferences. Details of the presentations and webcasts will be announced prior to the events.
21st Annual Needham Healthcare Conference, April 11-14
8th Annual Berenberg Conference USA 2022, May 23-25
Fourth Quarter 2021 Financial Results

Cash Position: As of December 31, 2021, cash, cash equivalents and short-term investments were $268.8 million, as compared to $335.4 million as of December 31, 2020.
Collaboration Revenue: Revenue for the fourth quarter of 2021, was $30.1 million, as compared to $1.3 million for the fourth quarter of 2020. Revenue for the year ended December 31, 2021 was $30.0 million, as compared to $9.9 million for the year ended December 31, 2020. The increase in revenue was due to the recognition of all remaining deferred revenue related to the Collaboration Agreement with Takeda Pharmaceuticals in the fourth quarter of 2021.
Research and Development (R&D) Expenses: R&D expenses were $16.2 million for the fourth quarter of 2021, as compared to $9.8 million for the fourth quarter of 2020. R&D expenses for the year ended December 31, 2021 were $56.6 million, as compared to $37.5 million for the year ended December 31, 2020. This increase was primarily due to clinical development, personnel-related costs, and laboratory capabilities.
General and Administrative (G&A) Expenses: G&A expenses were $4.6 million for the fourth quarter of 2021, as compared to $3.6 million for the fourth quarter of 2020. General and administrative expenses for the year ended December 31, 2021 were $18.7 million, as compared to $9.4 million for the year ended December 31, 2020. This increase was primarily due to personnel-related costs to support the operational expansion and costs associated with being a public company.
Net Income/Loss: Net income was $7.8 million for the fourth quarter of 2021, or $0.19 per basic share and $0.18 per diluted share, as compared to a net loss of $12.0 million for the fourth quarter of 2020, or $0.31 per basic and diluted share. Net loss for the year ended December 31, 2021 was $45.0 million, or $1.07 per basic and diluted share, as compared to $36.6 million, or $2.36 per basic and diluted share, for the year ended December 31, 2020.
2022 Financial Guidance

Shattuck believes its cash, cash equivalents and short-term investments will be sufficient to fund its operations into the second half of 2024, which is beyond results from its Phase 1 clinical trials of SL-172154 and SL-279252. This cash runway guidance is based on the Company’s current operational plans and excludes any additional funding that may be received or business development or additional clinical development activities that may be undertaken.

About SL-172154
SL-172154 (SIRPα-Fc-CD40L) is an investigational ARC fusion protein designed to simultaneously inhibit the CD47/SIRPα checkpoint interaction and activate the CD40 costimulatory receptor to bolster an anti-tumor immune response in patients with advanced cancer. Two Phase 1 clinical trials are ongoing, the first for patients with advanced and platinum-resistant ovarian cancer (NCT04406623) and the second for patients with AML and HR-MDS (NCT05275439).

About SL-279252

SL-279252 (PD1-Fc-OX40L) is an investigational ARC fusion protein designed to simultaneously inhibit the PD-1/PD-L1 interaction and activate the OX40 receptor in patients with advanced cancers. A Phase 1 trial in patients with solid tumors and lymphoma is ongoing (NCT03894618).

On March 15, 2022 IDEAYA Biosciences, Inc. (Nasdaq:IDYA), a synthetic lethality focused precision medicine oncology company committed to the discovery and development of targeted therapeutics, reported financial results for the year ended December 31, 2021 (Press release, Ideaya Biosciences, MAR 15, 2022, View Source [SID1234610108]).

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"We are encouraged by the early clinical activity and the tolerability profile in our clinical-stage programs, including our Phase 1 MAT2A inhibitor, IDE397, in MTAP-deletion patients, and our Phase 2 PKC inhibitor, darovasertib, in MUM and other GNAQ/11 patients. As these data mature, we are evaluating multiple expansion opportunities for these clinical programs, including various combination therapies. We are also aggressively advancing our preclinical programs toward the clinic – including our potential first-in-class PARG inhibitor, IDE161, for which are targeting an IND in Q4 2022, and our potential first-in-class Pol Theta helicase inhibitor, for which we are collaborating with GSK with IND-enabling studies in H1 2022," said Yujiro S. Hata, Chief Executive Officer and President of IDEAYA Biosciences.

Program Updates
Key highlights for IDEAYA’s pipeline programs include:

IDE397 (MAT2A)
IDEAYA is evaluating IDE397, a potent and selective small molecule inhibitor targeting methionine adenosyltransferase 2a (MAT2A), in patients having solid tumors with methylthioadenosine phosphorylase (MTAP) deletion, a patient population estimated to represent approximately 15% of solid tumors. IDEAYA is leading early clinical development of IDE397. Subject to exercise of its option, GlaxoSmithKline (GSK) will lead later stage global clinical development. Highlights:

Actively enrolling patients into Cohort 6 of the Phase 1 clinical trial IDE397-001 (NCT04794699)
Patients are being identified by next generation sequencing (NGS) or by MTAP immunohistochemistry (IHC) assay with confirmatory NGS
Evaluating IDE397 in patients with MTAP deletion across multiple solid tumor types, including non-small cell lung cancer, pancreatic cancer, thymic cancer, adenoid cystic carcinoma, esophagogastric cancer and bladder cancer
IDE397 has been generally well tolerated, with no observed drug-related serious adverse events, no observed dose limiting toxicities and without observing the maximum tolerated dose through Cohort 5
Observed dose-proportional pharmacokinetic exposures across dose ranges of Cohort 1 through Cohort 5 of the Phase 1 dose escalation; achieved active exposure targets established from preclinical models at doses of Cohort 4 and Cohort 5
Observed exposure-dependent pharmacodynamic modulation of S-adenosyl methionine (SAM) in evaluable plasma samples across dose ranges of Cohort 1 through Cohort 5
Observed exposure-dependent pharmacodynamic modulation of symmetric dimethyl arginine (SDMA) in evaluable tumor biopsies from Cohort 4 and Cohort 5
Observed preliminary signals of clinical activity in MTAP-deletion patients in early dose escalation cohorts, including pharmacodynamic modulation and tumor shrinkage
Submitted a clinical protocol amendment to the FDA to support monotherapy cohort expansion in NSCLC, esophagogastric cancer, as well as one or more basket cohorts, and to support potential combinations, including taxane and other combination agents
Targeting IDE397 monotherapy cohort expansion and initiation of combination cohorts mid-year 2022, with an aggregate of 150 or more patients across expansion cohorts; the timing of the monotherapy expansion cohorts and combination cohorts may be influenced by the timing of when a MTD is observed
Targeting delivery of IDE397 option data package to GSK mid-year 2022, subject to initiation of expansion cohorts or establishing the MTD; the option data package will trigger an evaluation period for GSK to make an opt-in decision; subject to GSK election to opt-in and HSR clearance, the company is entitled to receive a $50 million opt-in payment from GSK, ongoing development costs will be shared as 80% GSK / 20% IDEAYA, and IDEAYA is entitled to potential development and regulatory milestones aggregate up to $465 million; upon commercialization, IDEAYA is entitled to 50% of U.S. net profits and tiered royalties on global non-U.S. net sales ranging from high single digit to sub-teen double digit percentages, as well as certain commercial milestones of up to $475 million
Demonstrated robust preclinical PK / PD in in vivo models, with sustained target inhibition and biological impact, as evidenced for example, by modulation of alterations to pre-mRNA splicing profile
Observed preclinical in vivo efficacy of IDE397 in combination with standard of care agents, including with taxanes showing enhanced TGI in pancreatic cancer PDX models, and with novel combination agents; evaluating additional IDE397 combination strategies
PARG
IDEAYA is advancing preclinical research for an inhibitor of poly (ADP-ribose) glycohydrolase (PARG) in patients having tumors with a defined biomarker based on genetic mutations and/or molecular signature. PARG is a novel target in the same clinically validated biological pathway as poly (ADP-ribose) polymerase (PARP). IDEAYA owns or controls all commercial rights in its PARG program. Highlights:

Ongoing IND-enabling studies for IDE161, a potential first-in-class PARG inhibitor development candidate for patients having tumors with homologous recombination deficiencies (HRD), including BRCA1 and BRCA2, and potentially other genetic alterations
Targeting IND for IDE161 in the fourth quarter of 2022
Exercised option for an exclusive worldwide license from Cancer Research Technology Ltd., also known as Cancer Research UK (CRUK), and University of Manchester; following the option exercise, IDEAYA holds an exclusive worldwide license to patent rights covering a broad class of PARG inhibitors
Demonstrated preclinical in vivo efficacy as monotherapy, including dose-dependent efficacy with tumor regression or stasis in ovarian, gastric and breast cancer CDX models, and tumor regressions in multiple breast cancer PDX models with defined genetic and subtyping profiles
Observed in vivo efficacy with enhanced TGI or tumor regressions relative to niraparib, a PARPi, in multiple CDX models, including in a niraparib-resistant CDX model, as well as in niraparib resistant breast cancer PDX models
Showed pharmacological inhibition of PARG in a panel of homologous recombination deficient cell lines and in CDX and PDX models; study data reported at AACR (Free AACR Whitepaper) 2021
Pol Theta
IDEAYA’s DNA Polymerase Theta, (Pol Theta) program targets tumors with BRCA or other homologous recombination deficiency, or HRD, mutations. IDEAYA and GSK are collaborating on ongoing preclinical research, including small molecules and protein degraders, and GSK will lead clinical development for the Pol Theta program. Highlights:

Demonstrated in vivo efficacy with tumor regression in BRCA2 -/- xenograft model with IDEAYA Pol Theta Helicase inhibitor in combination with niraparib, a GSK PARP inhibitor
Targeting IND-enabling studies for a Pol Theta helicase inhibitor in the first half of 2022 in collaboration with GSK
Potential for up to $20 million in aggregate milestone payments from GSK for advancing a Pol Theta Helicase inhibitor from preclinical to early Phase 1 clinical
Werner Helicase
IDEAYA is advancing preclinical research for an inhibitor targeting Werner Helicase for tumors with high microsatellite instability (MSI). IDEAYA and GSK are collaborating on ongoing preclinical research, and GSK will lead clinical development for the Werner Helicase program. Highlights:

Observed dose-dependent cellular viability effect and dose-dependent cellular PD response in multiple endogenous MSI high cell lines
Demonstrated efficacy and PD response in relevant MSI high in vivo models
Targeting selection of a Werner Helicase development candidate in 2023
Potential for up to $20 million in aggregate milestone payments from GlaxoSmithKline for advancing a Werner Helicase inhibitor from preclinical to early Phase 1 clinical
Other Synthetic Lethality Pipeline Programs
IDEAYA is advancing additional preclinical research programs to identify small molecule inhibitors for an MTAP-synthetic lethality target, as well as for multiple potential first-in-class synthetic lethality programs for patients with solid tumors characterized by proprietary biomarkers or gene signatures.

Darovasertib (IDE196)
IDEAYA continues to execute on its clinical trial strategy to evaluate darovasertib (IDE196), a potent and selective PKC inhibitor.

IDEAYA is evaluating darovasertib in combination with crizotinib, a cMET inhibitor, in metastatic uveal melanoma (MUM). The company is also clinically evaluating darovasertib as a combination with crizotinib in GNAQ/11 mutant skin melanoma in an ongoing arm of the current clinical trial, and in adjuvant primary uveal melanoma (UM) as monotherapy through an investigator sponsor clinical trial (IST). IDEAYA is also evaluating other potential darovasertib expansion opportunities, including in cMET driven tumors and in KRAS-mutation tumors.

Darovasertib / Crizotinib Combination Therapy
IDEAYA is continuing patient enrollment into the darovasertib / crizotinib combination arm of the Phase 1/2 clinical trial under clinical trial collaboration and supply agreements with Pfizer. Highlights:

As of March 1, 2022, the company has enrolled 53 MUM patients into the darovasertib/crizotinib combination arm, and is continuing patient enrollment in the dose expansion cohort of this combination arm
IDEAYA presented darovasertib and crizotinib clinical combination data in December 2021. As of data and analyses cutoff on November 25, 2021, twenty-two heavily pre-treated MUM patients (91% with prior therapies, and 59% with 2 or more prior therapies) had enrolled in the darovasertib and crizotinib combination arm at the expansion dose, with sixteen evaluable patients who had received one or more tumor scans and six patients who were awaiting their 1st tumor scan. Thirteen patients had received two or more tumor scans for evaluation of potential response. The reported preliminary data, based on an unlocked database, showed robust clinical activity with manageable side effect profile:
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 investigator or central review; and no patients have 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 is awaiting follow-on tumor scan
Observed side effect profile in MUM patients (n=22) showed a low rate of drug-related serious adverse events (SAE’s) and predominantly Grade 1 or 2 drug-related adverse events; eighteen patients experienced a drug-related AE, of which six patients observed Grade 3, and no patients observed Grade 4 or Grade 5
These data provide clinical proof-of-concept for the darovasertib and crizotinib synthetic lethal combination treatment, and are consistent with the company’s translational research discovery that Phase 1 clinical response to darovasertib monotherapy associated with low cMET activity, as measured by gene signature score
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 potential registration-enabling trial design to evaluate darovasertib and crizotinib combination in MUM in mid-2022. The timing of the clinical data and FDA regulatory guidance may be influenced by data maturity, including observation of median duration of response (DOR) or median progression free survival (mPFS).
Expanded relationship with Pfizer under a clinical collaboration and supply agreement to support clinical evaluation of darovasertib and crizotinib combination in a potential registration-enabling clinical trial in MUM, subject to FDA feedback and guidance
Associated cMET expression and activation to observed clinical response based on a retrospective analysis of human clinical biopsies from the Novartis darovasertib Phase 1 clinical trial, supporting cMET expression / activation as potential combination agent
Observed preclinical synergies between darovasertib and crizotinib in relevant cellular models under conditions simulating a tumor microenvironment in the liver, the site of approximately 90% of uveal melanoma metastases; study data reported at AACR (Free AACR Whitepaper) 2021
Darovasertib Monotherapy
IDEAYA has completed enrollment into its ongoing Phase 1/2 clinical trial evaluating darovasertib as monotherapy in MUM patients.

IDEAYA is planning to initiate an Investigator Sponsored Trial, with St. Vincent’s Hospital Sydney Limited to evaluate IDE196 as monotherapy in a neo-adjuvant / adjuvant setting in (non-metastatic) uveal melanoma (UM) patients. Data from this clinical trial may offer proof of concept on its hypothesis that earlier treatment of UM patients with IDE196, prior to tumor metastasis, may lead to improved patient outcomes.

Darovasertib – Other Potential Indications
IDEAYA is evaluating the potential for darovasertib in other oncology indications, including in cMET-driven tumors and in KRAS-mutation tumors. The company is also evaluating darovasertib for potential treatment of GNAQ mutation-mediated rare diseases, including Sturge-Weber Syndrome (SWS) and Port Wine Stains (PWS), neurocutaneous disorders characterized by capillary malformations and associated with mutations in GNAQ. Highlights:

Expanded its relationship with Pfizer under a clinical collaboration and supply agreement for clinical evaluation of darovasertib and crizotinib combination therapy in cMET-driven tumors, such as NSCLC or HCC, subject to preclinical validation studies
Evaluating darovasertib in combination with a KRAS inhibitor in preclinical studies in KRAS-driven solid tumors
General

IDEAYA continues to monitor Covid-19 and its potential impact on clinical trials and timing of clinical data results. Initiation of clinical trial sites, patient enrollment and ongoing monitoring of enrolled patients, including obtaining patient computed tomography (CT) scans, may be impacted for IDEAYA clinical trials evaluating IDE397 and darovasertib; the specific impacts are currently uncertain.

Corporate Updates

IDEAYA’s net losses were $49.8 million and $34.5 million for the years ended December 31, 2021 and December 31, 2020, respectively. As of December 31, 2021, the company had an accumulated deficit of $176.7 million.

As of December 31, 2021, IDEAYA had cash, cash equivalents and marketable securities of $368.1 million. IDEAYA believes that its cash, cash equivalents and marketable securities will be sufficient to fund its planned operations into 2025. These funds will support the company’s efforts through potential achievement of multiple preclinical and clinical milestones across multiple programs.

Our updated corporate presentation is available on our website, at our Investor Relations page: View Source

Financial Results

As of December 31, 2021, IDEAYA had cash, cash equivalents and short-term and long-term marketable securities totaling $368.1 million. This compared to cash, cash equivalents and short-term and long-term marketable securities of $283.6 million at December 31, 2020. The increase was primarily due to $86.0 million in net proceeds received from issuance of common stock in an underwritten public offering on July 12, 2021 and $57.3 million in net proceeds under the ATM Program received through December 31, 2021, offset by cash used in operations and purchases of property and equipment.

Collaboration revenue for the three months ended December 31, 2021 totaled $3.0 million compared to $10.6 million for the same period in 2020. Collaboration revenue was recognized for the performance obligations satisfied through December 31, 2021 under the GSK Collaboration Agreement.

Research and development (R&D) expenses for the three months ended December 31, 2021 totaled $16.1 million compared to $12.1 million for the same period in 2020. The increase was primarily due to higher personnel-related expenses, laboratory supplies expenses and consulting fees.

General and administrative (G&A) expenses for the three months ended December 31, 2021 totaled $5.2 million compared to $3.8 million for the same period in 2020. The increase was primarily due to higher personnel-related expenses, software expenses and consulting fees.

The net loss for the three months ended December 31, 2021 was $18.2 million compared to $5.1 million for the same period in 2020. Total stock compensation expense for the three months ended December 31, 2021 was $2.1 million compared to $1.0 million for the same period in 2020.

The net loss for the year ended December 31, 2021 was $49.8 million compared to $34.5 million for the same period in 2020. Total stock compensation expense for the year ended December 31, 2021 was $8.2 million compared to $3.6 million for the same period in 2020.