On January 18, 2024 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a biopharmaceutical company focused on discovering, developing, and commercializing important new medicines to improve the lives of people with cancer, reported the presentation of new long-term results from the INTRIGUE Phase 3 clinical study comparing QINLOCK (ripretinib) versus sunitinib in patients with advanced gastrointestinal stromal tumor (GIST) previously treated with imatinib (Press release, Deciphera Pharmaceuticals, JAN 18, 2024, View Source [SID1234639326]).

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The presentation titled "Overall survival and long-term safety with ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: final analyses from INTRIGUE" will be presented by John Zalcberg, M.D., Ph.D., Cancer Research Program, Monash University School of Public Health and Preventive Medicine and Department of Medical Oncology, Alfred Health, Melbourne, Victoria, Australia at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium and will be available on the Company’s website at www.deciphera.com/presentations-publications.

"These long-term clinical results demonstrate that the overall survival rate was similar for both QINLOCK and sunitinib, and that treatment with QINLOCK continued to show a favorable safety profile compared to treatment with sunitinib," said Dr. Zalcberg. "In addition, the data show that patient outcomes in the third-line setting are comparable for patients that were treated with either QINLOCK or sunitinib in the second line."

"The final results from INTRIGUE demonstrate the strong clinical activity of QINLOCK in the broader second-line GIST patient population," said Matthew L. Sherman, M.D., Chief Medical Officer of Deciphera. "Importantly, these results also indicate that third line treatment is not adversely impacted by treatment with QINLOCK in the second line and that QINLOCK continues to show a favorable safety profile compared to sunitinib."

Results of INTRIGUE Study Long-Term Follow-Up

In INTRIGUE, 453 patients in the all-patient intent-to-treat population (AP-ITT) with second-line GIST were randomized 1:1 to receive QINLOCK 150 mg once daily (n=226) or sunitinib 50 mg once daily (4 weeks on/2 weeks off) (n=227) of which 444 patients received treatment.

In the primary analysis of the AP-ITT population based on a data cut of September 1, 2021, while the primary endpoint was not achieved, QINLOCK demonstrated similar efficacy with a median progression-free survival (PFS) of 8.0 months versus 8.3 months for sunitinib (hazard ratio [HR] 1.05, nominal p=0.72). There were fewer patients with Grade 3/4 drug-related treatment emergent adverse events (TEAE) with QINLOCK (26.5%) compared with sunitinib (55.2%). Based on the primary results from the INTRIGUE study, QINLOCK was included in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for GIST (version 1.2023) as a preferred second-line regimen for patients with advanced GIST who are intolerant to sunitinib.

The final analysis includes 18 months of additional follow up after the primary analysis based on a data cut of March 15, 2023. Key highlights from the final results presented include the following:

Overall Survival (OS)

There were 211 OS events (46.6%) in the AP-ITT population with median duration of follow-up in the QINLOCK and sunitinib arms of 35.1 months and 34.1 months, respectively.
Median OS in the AP-ITT population was similar with QINLOCK (35.5 months) versus sunitinib (31.5 months) (HR 0.86; 95% CI, 0.65 to 1.13; nominal p= 0.275).
Safety and Tolerability

Among the 444 patients treated, 9.0% of patients remained on treatment at the time of data cutoff including 12.6% of 223 patients treated with QINLOCK and 5.4% of 221 patients treated with sunitinib.
The long-term safety profile of QINLOCK was consistent with the primary analysis.
Fewer patients had Grade 3/4 drug-related TEAEs with QINLOCK (27.4%) versus sunitinib (57.9%).
Dose interruptions and reductions as well as treatment discontinuations due to TEAEs were lower with QINLOCK versus sunitinib. Fewer patients discontinued treatment due to any TEAE for QINLOCK (4.9%) versus sunitinib (9.0%).
The most common TEAEs in the QINLOCK arm were alopecia, fatigue, and myalgia. The most common TEAEs in patients treated with sunitinib were palmar-plantar erythrodysesthesia syndrome, diarrhea, and hypertension.
Exploratory Analysis: Efficacy of Next-Line Therapy

Median PFS on the next line of therapy after protocol treatment was similar for QINLOCK (7.7 months) versus sunitinib (7.4 months) in the AP-ITT population (HR 1.03; 95% CI, 0.78 to 1.35).
Following study treatment discontinuation, the most common third-line therapy was sunitinib for patients in the QINLOCK arm (59.7%) and regorafenib for patients in the sunitinib arm (42.7%).
Patients in the QINLOCK arm who received third-line sunitinib had a median PFS on next line of therapy of 8.5 months compared with 6.3 months for patients in the sunitinib arm who received third-line regorafenib (HR 0.90; 95% CI, 0.66 to 1.24).
Details of the poster presentation are as follows:

Title: Overall survival and long-term safety with ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: final analyses from INTRIGUE
Author: John Zalcberg, M.D., Ph.D., Monash University School of Public Health and Preventive Medicine
Session: A: Cancers of the Esophagus and Stomach and Other GI Cancers
Abstract #: 748
Date and Time: Thursday January 18, 2024 11:45 AM – 1:15 PM PT

In January 2024, Nature Medicine published the results of the exploratory ctDNA analysis from INTRIGUE showing substantial clinical benefit of QINLOCK compared to sunitinib in second-line GIST patients with mutations in KIT exon 11 and 17/18 only. Patients with mutations in KIT exon 11 and 17/18 had improved progression-free survival, objective response rate, and overall survival with QINLOCK versus sunitinib.

Based on the results of this prespecified exploratory objective in INTRIGUE, the Company is enrolling the INSIGHT pivotal Phase 3 clinical study of QINLOCK in second-line GIST patients with mutations in KIT exon 11 and 17/18 only.

About the INSIGHT Study

The INSIGHT Phase 3 clinical study is a randomized, global, multicenter, open-label study to evaluate the efficacy and safety of QINLOCK compared to sunitinib in patients with GIST previously treated with imatinib with mutations in KIT exon 11 and 17/18 (excluding patients with mutations in KIT exons 9, 13, or 14). In the study, 54 patients will be randomized 2:1 to either QINLOCK 150 mg once daily or sunitinib 50 mg once daily for four weeks followed by two weeks without sunitinib. The primary endpoint is PFS as determined by independent radiologic review using modified RECIST 1.1 criteria. Secondary endpoints include ORR as determined by independent radiologic review using modified RECIST 1.1 criteria and OS.

About the INTRIGUE Study

The INTRIGUE Phase 3 clinical study is a randomized, global, multicenter, open-label study to evaluate the efficacy and safety of QINLOCK compared to sunitinib in patients with GIST previously treated with imatinib. In the study, 453 patients were randomized 1:1 to either QINLOCK 150 mg once daily or sunitinib 50 mg once daily for four weeks followed by two weeks without sunitinib. As previously reported, the study did not achieve the primary efficacy endpoint of PFS as determined by independent radiologic review using modified RECIST 1.1 criteria. The statistical analysis plan included a hierarchical testing sequence that included testing in patients with a KIT exon 11 primary mutation and then in the AP-ITT population. In patients with a KIT exon 11 primary mutation (n=327), QINLOCK demonstrated a median PFS of 8.3 months compared to 7.0 months for the sunitinib arm (HR 0.88, p=0.360). Although not formally tested due to the rules of the hierarchical testing sequence, in the AP-ITT population QINLOCK demonstrated a median PFS of 8.0 months compared to 8.3 months for the sunitinib arm (HR 1.05, nominal p=0.72). QINLOCK was generally well tolerated. Fewer patients in the QINLOCK arm experienced Grade 3/4 treatment-emergent adverse events compared to sunitinib (41.3% vs. 65.6%). Similarly, there were fewer patients with Grade 3/4 drug-related TEAEs with QINLOCK (26.5%) compared with sunitinib (55.2%).

On January 18, 2024 Golden Biotechnology Corp. (TPEX 4132) ("GoldenBiotech", GBC), an advanced biopharmaceutical drug development company, reported the findings of its Phase II clinical trial investigating Antroquinonol (HOCENA) in combination with the standard of care (SOC): nab-paclitaxel + gemcitabine, as first-line treatment for metastatic pancreatic cancer (Press release, Golden Biotechnology, JAN 18, 2024, View Source [SID1234639341]). The trial showed a positive median overall survival (mOS) of 14.1 months, which is a substantial increase compared to 8.5 months mOS observed in the standard of care Phase III clinical study (nab-paclitaxel + gemcitabine). Notably, when compared to current first-line treatment options for this very difficult to treat cancer, there was a highly significant survival advantage of patients treated with oral Antroquinonol in combination with SOC. Metastatic Pancreatic Cancer remains a devastating disease with very low survival rate and significant unmet medical needs in terms of treatment options.

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The ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium 2024 Committee has selected Golden Biotech’s Phase 2 Study, titled "A Phase I/II study of Antroquinonol in combination with Nab-Paclitaxel and Gemcitabine for patients with metastatic pancreatic cancer," for poster presentation. This multinational study, registered under NIH Clinical Trial Registration Number NCT03310632, employed a single-arm, open-label design with participating sites in the United States, South Korea, and Taiwan.

The study revealed clinically meaningful responses in subjects treated with Antroquinonol in combination with the standard of care. The treatment demonstrated significantly longer overall survival (median OS) and OS rates at both 6 and 12 months when compared to the standard of care Phase III study. The OS figures were 14.1, 8.5, and 6.7 months for (Antroquinonol + nab-paclitaxel + gemcitabine), (nab-paclitaxel + gemcitabine), and gemcitabine alone, respectively. The corresponding OS rates at 6 months were 85.5%, 67%, and 55%, while the rates at 12 months were 62.2%, 35%, and 22%.

In addition, Antroquinonol in combination with the standard of care surpassed the efficacy of another chemotherapy regimen, FOLFIRINOX, in terms of median OS and OS rates (Antroquinonol + standard of care vs FOLFIRINOX: OS= 14.1 vs 11.1 months; OS rate at 6 months=85.5% vs 76%; OS rate at 12 months=62.2% vs 48%). The trial results also showed an mPFS of 5.3 months and a 6-month PFS rate of 41.7% for Antroquinonol in combination with the standard of care drugs.

The American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Committee have defined Clinically Meaningful Goals for clinical trials in Pancreas, Breast, Lung, and Colorectal Cancers. For Pancreatic Cancer patients eligible for treatment with Gemcitabine or Gemcitabine/Nab-paclitaxel, the current baseline median overall survival is estimated to range from 8 to 9 months. It is considered "clinically meaningful" if the minimum improvement over current overall survival is between 3 to 4 months.

Golden Biotech’s Antroquinonol has gained recognition for its groundbreaking work in the field of cancer treatment. It has been granted Orphan Drug Designation (ODD) by the FDA for the treatment of Pancreatic Cancer, Acute Myeloid Leukemia (AML), and Hepatocellular Carcinoma (liver cancer), as well as ODD by the EMA for Pancreatic Cancer. These acknowledgments underscore the potential of Antroquinonol in addressing the high-unmet medical needs associated with these challenging diseases.

When compared to gemcitabine and other existing first-line therapies for metastatic pancreatic cancer, Antroquinonol in combination with the standard of care exhibited a significant survival advantage. Additionally, hematological adverse events (AEs) induced by nab-paclitaxel and gemcitabine, such as neutropenia, thrombocytopenia, anemia, and leukopenia, were substantially improved across all grade levels. No additional safety concerns were observed during the study. By combining nab-paclitaxel and gemcitabine with Antroquinonol, the incidence of hematological side effects also decreased across all grades.

The results of this clinical trial may be a potential game changer for metastatic pancreatic cancer. Antroquinonol in combination with the standard of care may provide patients with significantly improved median overall survival and reduced hematological side-effects. Providing new hope for patients everywhere, for this very difficult to treat cancer.

On January 17, 2024 Xenetic Biosciences, Inc. (NASDAQ:XBIO) ("Xenetic" or the "Company"), a biopharmaceutical company focused on advancing innovative immune-oncology technologies addressing hard to treat cancers, reported that it has entered into a Research Funding Agreement and a Material Transfer Agreement with the University of Virginia ("UVA") to advance the development of its systemic DNase program (Press release, Xenetic Biosciences, JAN 17, 2024, View Source [SID1234639294]).

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Xenetic’s DNase-based oncology platform is designed to target neutrophil extracellular traps ("NETs"), which are weblike structures composed of extracellular chromatin coated with histones and other proteins. NETs are expelled by activated neutrophils, in response to microbial or pro-inflammatory challenges. However, excessive production or reduced clearance of NETs can lead to aggravated inflammatory and autoimmune pathologies, as well as creation and support of pro-tumorigenic niches in the case of cancer growth and metastasis, thereby potentially limiting response to therapy.

Under the terms of the UVA agreements, in addition to advancing Xenetic’s existing intellectual property, Xenetic has an option to acquire an exclusive license to any new intellectual property arising from the DNase research program. Allan Tsung, MD, member of the Company’s Scientific Advisory Board and Chair of the Department of Surgery at the UVA School of Medicine, will oversee the research conducted under the agreement. As a surgical oncologist and scientist, Dr. Tsung is internationally recognized for leading substantial research on the role of NETs in tumor growth, metastasis, and resistance to existing cancer therapies. Xenetic is working toward its planned first-in-human study to evaluate DNase combined with immune checkpoint inhibitors or chemotherapy.

"We believe the data generated by our research and development collaborations are key to fully unlocking the potential of our DNase technology and importantly, providing translational insights as we drive a clinical path for our lead solid tumor indications. These agreements provide a significant addition to our development capabilities and resources and we believe it bolsters our opportunity to accelerate development timelines," commented Jeffrey Eisenberg, Chief Executive Officer of Xenetic. "Additionally, we are pleased to deepen our work with Dr. Tsung who has provided a valuable perspective to our team and significant insight for our DNase platform."

"I am looking forward to further exploring the potential of the DNase platform and working with Xenetic to advance the program’s development. We share a goal of evaluating the potential addition of DNase to available treatment options in areas of significant unmet need," added Dr. Tsung.

On January 17, 2024 Partner Therapeutics, Inc. (PTx) reported the publication of a comprehensive review by Mora et al. in the International Journal of Cancer which summarizes the efficacy and safety of anti-GD2 monoclonal antibodies (mAbs) (dinutuximab, dinutuximab beta, and naxitamab) in children with high-risk neuroblastoma when given in combination with Leukine (sargramostim; glycosylated, yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]), recombinant human granulocyte colony-stimulating factor (G-CSF) or no cytokine (Press release, Partner Therapeutics, JAN 17, 2024, View Source [SID1234639296]).

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The review provides a succinct summary of the mechanistic rationale and clinical data supporting the use of Leukine in combination with anti-GD2 mAbs. It also describes why the authors believe it is suboptimal to replace with Leukine with G-CSF in this regimen for mechanistic reasons.

Leukine has been studied extensively in combination with dinutuximab and naxitamab leading to improved patient outcomes. As a result, all clinical trials supporting the FDA-approval of dinutuximab and naxitamab included Leukine and both products are labeled for use in combination with GM-CSF.

"The pleiotropic effects of Leukine contribute to its important role as an immunomodulatory adjuvant in combination with anti-GD2 mAbs," noted Jaume Mora, M.D., Ph.D., Scientific Director of Oncology and Hematology at Sant Joan de Déu Barcelona Children’s Hospital and lead author of the publication. "GM-CSF stimulates neutrophils and macrophages leading to increased cellular phagocytosis and increased ADCC. Further, GM-CSF increases major histocompatibility complex (MHC) class II expression which enhances tumor antigen presentation on dendritic cells that can mediate T cell antitumor effects. For all of these mechanistic reasons, Leukine is a critical component of anti-GD2 therapy." The figure below from the publication depicts these mechanisms.

ABOUT LEUKINE
LEUKINE (sargramostim) is a glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in yeast. The product is commercially available in the United States and accessible through a named patient program operated by Tanner Pharma Group outside of the United States.

LEUKINE is indicated:

To shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death following induction chemotherapy in adult patients 55 years and older with acute myeloid leukemia (AML).
For the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients.
For the acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation in adult and pediatric patients 2 years of age and older.
For the acceleration of myeloid reconstitution following allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older.
For treatment of delayed neutrophil recovery or graft failure after autologous or allogeneic bone marrow transplantation in adult and pediatric patients 2 years of age and older.
To increase survival in adult and pediatric patients from birth to 17 years of age acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome [H-ARS]).
Important Safety Information for Leukine (sargramostim)

Contraindications

Do not administer LEUKINE to patients with a history of serious allergic reaction, including anaphylaxis, to human granulocyte-macrophage colony-stimulating factor, sargramostim, yeast-derived products, or any other component of LEUKINE.

Warnings and Precautions

Serious hypersensitivity reactions, including anaphylactic reactions, have been reported with LEUKINE. If a serious allergic or anaphylactic reaction occurs, immediately discontinue LEUKINE therapy, and institute medical management. Discontinue LEUKINE permanently for patients with serious allergic reactions.
LEUKINE can cause infusion-related reactions that may be characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia. Observe closely during infusion, particularly in patients with preexisting lung disease; dose adjustment or discontinuation may be needed.
LEUKINE should not be administered simultaneously with or within 24 hours preceding cytotoxic chemotherapy or radiotherapy or within 24 hours following chemotherapy.
Edema, capillary leak syndrome, and pleural or pericardial effusions have been reported in patients after LEUKINE administration. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates, or congestive heart failure. Such patients should be monitored.
Supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a history of cardiac arrhythmia. Use LEUKINE with caution in patients with preexisting cardiac disease.
If absolute neutrophil count (ANC) > 20,000 cells/mm3 or if white blood cell (WBC) counts > 50,000/mm3, LEUKINE administration should be interrupted, or the dose reduced by half. Monitor complete blood counts (CBC) with differential twice per week.
Discontinue LEUKINE therapy if tumor progression, particularly in myeloid malignancies, is detected during LEUKINE treatment.
Treatment with LEUKINE may induce neutralizing anti-drug antibodies. Use LEUKINE for the shortest duration needed.
Avoid administration of solutions containing benzyl alcohol (including LEUKINE for injection reconstituted with Bacteriostatic Water for Injection, USP [0.9 % benzyl alcohol]) to neonates and low birth weight infants.

Drug Interactions

Avoid the concomitant use of LEUKINE and products that induce myeloproliferation. Monitor for clinical and laboratory signs of excess myeloproliferative effects.
Adverse Reactions
Adverse events occurring in >10% of patients receiving LEUKINE in controlled clinical trials and reported at a higher frequency than in placebo patients are:

In recipients of autologous bone marrow transplantation (BMT)–asthenia, malaise, diarrhea, rash, peripheral edema, urinary tract disorder
In recipients of allogeneic BMT–abdominal pain, chills, chest pain, diarrhea, nausea, vomiting, hematemesis, dysphagia, GI hemorrhage, pruritus, bone pain, arthralgia, eye hemorrhage, hypertension, tachycardia, bilirubinemia, hyperglycemia, increased creatinine, hypomagnesemia, edema, pharyngitis, epistaxis, dyspnea, insomnia, anxiety, high glucose, low albumin
In patients with AML–fever, weight loss, nausea, vomiting, anorexia, skin reactions, metabolic laboratory abnormalities, edema

On January 17, 2024 Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company leveraging PLK1 inhibition to develop novel therapies across a range of cancers, reported that the findings of the Phase 1b portion of the Phase 1b/2 study for the second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC) disclosed by Cardiff Oncology in August 2023 have been published in the peer-reviewed journal Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, Cardiff Oncology, JAN 17, 2024, View Source [SID1234639297]).

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The publication underscores the safety profile of onvansertib when combined with the standard-of-care (SoC) chemotherapy+bevacizumab. The results show that the combination has a lasting response, indicating its tolerability and efficacy in treating mCRC patients whose tumors harbor various KRAS mutations.

Onvansertib is a highly specific Polo-like kinase 1 (PLK1) inhibitor that has shown tolerability as a single agent and in combination with multiple chemotherapies in various solid tumors. Additional data from the full Phase 1b/2 study for the second-line treatment of patients with KRAS-mutated mCRC will be presented at the upcoming American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2024. These compelling insights, along with the agreement from the US FDA, led to Cardiff Oncology’s decision to initiate a first-line trial (CRDF-004) in RAS-mutated mCRC.

"Our groundbreaking Phase 1b study targeted the KRAS-mutated mCRC patient population that has limited effective treatment options, and for whom there has been no new targeted therapy approved in decades. The Phase 1b study revealed the safety and enhanced efficacy of integrating onvansertib, an oral PLK1 inhibitor, with SoC FOLFIRI+bevacizumab in KRAS-mutated second-line mCRC patients," said Dr. Fairooz Kabbinavar MD, FACP, Chief Medical Officer of Cardiff Oncology and one of the article’s lead authors. "Our study showed an improved objective response rate and median progression-free survival compared to historical controls. Encouragingly, the FOLFIRI+bevacizumab+onvansertib combination demonstrated efficacy across multiple KRAS mutations. Our upcoming presentation at AACR (Free AACR Whitepaper) will showcase the full Phase 1b/2 data from all 68 patients in the study. The data from this Phase 1b/2 study serves as the foundation for our CRDF-004 first-line study in RAS-mutated mCRC, which is now open for enrollment at multiple centers."