On May 29, 2020 NRG Oncology reported that Results of the phase III clinical trial NRG-GY004 indicated that the addition of the investigational agent cediranib to olaparib and standard platinum-based chemotherapy did not improve progression-free survival (PFS) outcomes for women with platinum-sensitive ovarian cancer;, however, activity between the treatments were similar in patients (Press release, NRG Oncology, MAY 29, 2020, https://www.nrgoncology.org/Home/News/Post/combined-cediranib-and-olaparib-presents-similar-activity-to-standard-of-care-treatment-for-platinum-sensitive-ovarian-cancer [SID1234558772]). These results were recently presented at the virtual Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

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NRG-GY004 was designed to expand upon the findings of a phase II trial that indicated a combination of cediranib and olaparib improved PFS outcomes compared to olaparib alone for women with platinum-sensitive, high-grade serous/endometrioid ovarian cancer, regardless if they had a BRCA mutation. On NRG-GY004, women were randomly assigned to one of three treatment regimens. Participants randomly assigned to the first treatment arm received the standard of care chemotherapy chemotherapy with either carboplatin and paclitaxel, carboplatin and gemcitabine, or carboplatin and pegylated lipsomal doxorubicin. The participants on the experimental treatment arms either received olaparib at 300mg twice a day or olaparib at 200mg twice a day with cediranib at 30mg twice a day. The primary endpoint of this study was to assess PFS of cediranib and olaparib treatment compared to chemotherapy for women with platinum-sensitive ovarian cancer.

Between March 2016 and June 2018, 565 patients had enrolled in NRG-GY004 and, of those patients, 528 initiated treatment: 23.7% of the patients had a germline BRCA mutation. At a median follow-up of 29.1 months, the hazard ratio for PFS was 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail) for the combination of cediranib and olaparib compared to chemotherapy treatment. The hazard ratio for PFS was 1.20 (95% CI 0.93-1.54) for olaparib alone compared to chemotherapy treatment. Median PFS for patients was 10.3 months for the standard of care chemotherapy, 8.2 months for olaparib alone, and 10.4 months for patients receiving combination cediranib and olaparib. In a predefined biomarker subset analysis of women with a germline BRCA mutation, the PFS hazard ratio was 0.55 (95% CI 0.73-1.30) for combined cediranib and olaparib compared to chemotherapy and 0.63 (95% CI 0.37-1.07) for olaparib alone versus the standard chemotherapy. In women without a germline BRCA mutation, the PFS hazard ratio was 0.97 (95% CI 0.73-1.30) for combined cediranib and olaparib compared to chemotherapy and 1.41 (1.07-1.86) for olaparib alone versus standard chemotherapy.

"This is the first Phase 3 trial comparing a completely oral non platinum-based therapy regimen to standard of care platinum-based chemotherapy in platinum-sensitive ovarian cancer. While the combination of cediranib and olaparib was not found to improve PFS compared to standard of care chemotherapy, the findings of this study suggest that non-platinum based alternatives have potential in this setting, especially in appropriate biomarker subgroups such as patients with BRCA mutations," stated Joyce Liu, MD, MPH, of the Dana-Farber Cancer Institute and the lead author of the NRG-GY004 abstract.

There were no overall survival differences between the treatment arms. Patients who received cediranib and olaparib in addition to the standard of care did experience a higher frequency of grade 3 or higher gastrointestinal, hypertension, and fatigue adverse events.

This study was supported by the National Cancer Institute grants U10CA180822 (NRG Oncology SDMC), U10CA180868 (NRG Oncology Operations), U24CA180803 (IROC), U24CA196067 (NRG Specimen Bank). , NRG-GY004 was sponsored by National Cancer Institute (NCI), part of the National Institutes of Health. AstraZeneca provided cediranib and olaparib to support the study through a Collaborative Research and Development Agreement with NCI. Olaparib is jointly developed and commercialized by AstraZeneca and Merck & Co. (Merck: known as MSD outside the US and Canada).

Citation

Liu JF, Brady MF, Matulonis UA, Miller A, Kohn EC, Swisher E, Tew WP, Cloven NG, Muller C, Bender D, Moore RG, Michelin D, Waggoner SE, Geller MA, Fujiwara K, D’ Andre SD,Carney M, Secord AA, Moxley KM, Bookman MA. A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Recurrent Platinum Sensitive Ovarian Cancer. Abstract presented at the virtual Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper).

On May 29, 2020 Caris Life Sciences, a leading innovator in molecular science focused on fulfilling the promise of precision medicine, reported that it will present results from a study today that characterize KRAS mutations in patients with non-small cell lung cancer (NSCLC) (Press release, Caris Life Sciences, MAY 29, 2020, View Source [SID1234558771]). In this study, the molecular profiles of more than 17,000 patients with NSCLC were evaluated using the Caris Molecular Intelligence platform, which were then classified based on specific types of KRAS mutations using a 592-gene DNA sequencing panel. The study found that KRAS mutations are relatively common in NSCLC and that differences between KRAS mutation subtypes warrant further investigation in how they could guide treatment decisions, including the use of targeted and immuno-oncology drugs.

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Across 17,113 NSCLC patients, KRAS mutations were present in 27% of samples (n=4,706), with KRAS G12C being the most common variant and present in 40% of samples that exhibited a mutation. KRAS G12C was associated with the highest rate of PD-L1 expression. The rate of high tumor mutational burden (TMB) (>10 mutations/MB) was significantly different across KRAS mutation subtypes and was most frequently seen in KRAS G13X (68.3%) and least frequently in G12D (43.2%). KRAS mutations were more commonly seen in adenocarcinoma versus squamous subtype (37.2% vs. 4.4%)

The full results will be presented today during a poster session (Abstract 9544/Poster 310) as part of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 (ASCO20) Virtual Scientific Program. The poster is titled, "Characterization of KRAS mutations (mt) in non-small cell lung cancer (NSCLC)."

In a second study, the molecular profiles of a large cohort of KRAS wild-type (WT) pancreatic tumors were evaluated using DNA sequencing and whole transcriptome sequencing (WTS), which were then classified based on specific types of KRAS mutations using a 592-gene DNA sequencing panel. The study looked to assess the prevalence of alterations that could represent targets for personalized treatment. Researchers found that the use of WTS, in combination with DNA sequencing, identified activated molecular pathways in the majority of KRAS WT tumors, and that these tumors are significantly more enriched with targetable alterations (e.g., BRAF, ALK, ROS1, NRG1, MSI-H) compared to KRAS mutant tumors. These findings suggest a potential benefit of using targeted therapies to treat patients with KRAS WT tumors.

"While KRAS mutations in pancreatic cancer are found in the majority of cases, we used comprehensive molecular profiling to generate crucial information on mutations and transcriptional programs found in KRAS wild-type pancreatic cancer that provide additional opportunities for therapeutic intervention in this cancer type that has a low survival rate and few treatment options," said Philip A. Philip, M.D., Ph.D., FRCP., lead investigator of the study and an oncologist with Barbara Ann Karmanos Cancer Institute at Wayne State University, a member of the Caris Precision Oncology Alliance.

The full results will be presented today during a poster session (Abstract 4629/Poster 237). The poster is titled, "Alterations in targetable molecular pathways are enriched in KRAS wild-type (WT) pancreatic cancer (PC)."

"Our data at ASCO (Free ASCO Whitepaper)20 continue to reinforce the power of molecular profiling and precision medicine technologies in changing the face of cancer treatment," said W. Michael Korn, M.D., Chief Medical Officer at Caris Life Sciences. "The combination of Next-Generation DNA Sequencing and whole transcriptome sequencing is giving clinicians new insights and clearer direction in how they approach non-small cell lung cancer and pancreatic cancer, two particularly difficult-to-treat cancers."

Additional Presentations Provide Key Insight Into The Genetic Profile of Cancer
Caris will present additional data from studies highlighting the distinct molecular landscapes of patients across several cancer types, including mesothelioma and gastroesophageal cancers. Better understanding of a tumor’s genomic landscape and distribution of immune biomarkers has the potential to enable the development of new, novel therapies and can help physicians prescribe the optimal treatment to each patient.

A study, "Genomic Landscape and Immune Phenotype of Malignant Pleural Mesothelioma" (Abstract 9056/Poster 249), found that the majority of mesothelioma tumors harbor at least one alteration in key cellular pathways, with homologous recombination (HR) pathway mutations the most common.
"Molecular correlates of PD-L1 expression in patients (pts) with gastroesophageal (GE) cancers" (Abstract 4558/Poster 166) is the largest study to investigate the distinct molecular landscape of patients with different PD-L1 expression levels in GE cancers. These data can be used by oncologists to bring the right treatment to the right patient and by researchers to develop new combination immunotherapy regiments in GE cancers.
"As we continue to learn more about the molecular landscape of cancer, it is important to study all cancers, including those that are more uncommon and those that have an established treatment paradigm," said Chadi Nabhan, M.D., MBA, FACP, Chairman of the Caris Precision Oncology Alliance. "At Caris, our goal is to work with leading institutions to bring precision medicine to all people living with a cancer diagnosis, so that each patient can receive the best possible therapy for their own distinct cancer."

About the Caris Precision Oncology Alliance
A collaborative and growing network of leading cancer centers that demonstrate a commitment to precision medicine. The Alliance currently comprises 38 academic, hospital and community-based cancer institutions, including 12 NCI-designated Comprehensive Cancer Centers and now includes over 2,200 physicians, spanning more than 440 locations, who provide services for over 350,000 people with cancer each year.

On May 29, 2020 Gracell Biotechnologies Co., Ltd. ("Gracell"), a clinical-stage immune cell and gene therapy company, reported that two presentations were accepted at the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program (Press release, Gracell Biotechnologies, MAY 29, 2020, View Source [SID1234558770]).

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Both presentations can be found in the Development Therapeutics – Immunotherapy session, central on Gracell’s TruUCAR GC027 in relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) patients and EnhancedCAR GC008t in patients with advanced mesothelin-positive solid tumors.

"We are delighted to report on both TruUCAR GC027 in T-ALL and EnhancedCAR GC008t in solid tumors" said Dr. Martina Sersch, CMO of Gracell. "and glad to share safety and preliminary efficacy data on two of our exciting new CAR-T platform therapies with the scientific community at the ASCO (Free ASCO Whitepaper) annual meeting." Dr. William CAO, CEO of Gracell, added "Thanks to our highly efficient gene editing capability, CAR-T cells with PD-1 gene edited are generated to have enhanced capability of tumor control in inhibitory tumor microenvironment. We believe this strategy will improve CAR-T/TCR-T’s potency against solid tumors. Gracell carried out this strategy as early as 2017, upon our foundation. With two years’ preclinical and clinical investigations, we are very glad to see it showing first encouraging results in an effort to enhance CAR-T cells to combat solid tumors".

Session type: poster discussion
Abstract Title: Safety and efficacy results of GC027: The first-in-human, universal CAR-T cell therapy for adult relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL)
Abstract ID: 3013
Link: View Source

Session type: poster
Abstract Title: Phase I study of CRISPR-engineered CAR-T cells with PD-1 inactivation in treating mesothelin-positive solid tumors
Abstract ID: 3038
Link: View Source

About TruUCAR

TruUCAR is Gracell’s proprietary and patented platform technology, with selected genes being edited to avoid GvHD and immune rejection without using strong immunosuppressive drugs. In addition to T-ALL antigen, the platform technology can also be implemented for other targets of hematological malignancies.

About GC027

GC027 is an investigational, off-the-shelf CAR-T cell therapy, redirected to CD7 for the treatment of T cell malignancies. GC027 was manufactured from T cells of human leukocyte antigen (HLA) unmatched healthy donors using TruUCAR technology, which is expected to improve efficacy and reduce production time, available for off-the-shelf use in a timely manner.

About EnhancedCAR

EnhancedCAR is Gracell’s proprietary and patented platform technology, with selected genes edited to enhance immune cell performance in terms of killing efficiency, in vivo persistence, including selected PD-1 and TCR mediations. The technology can be implemented to many other targets with high editing precision and efficiency.

About GC008t

GC008t is an investigational, autologous CAR-T cell therapy, redirected to mesothelin with PD-1 disruption for the treatment of mesothelin-positive solid tumors. With PD-1 knocking out, GC008t is expected improve persistence and clinical efficacy.

About T-ALL

T – Lymphoblastic Leukemia (T-ALL) is an aggressive form of acute lymphoblastic leukemia, with a diffuse invasion of bone marrow and peripheral blood. In 2015, T-ALL affected around 876,000 people globally and resulted in 110,000 deaths worldwide. T-ALL compromises about 15%-20% of all children and adult acute lymphoblastic leukemia[1]. Current standard of care therapies for T-ALL are chemotherapy and stem cell transplantation. 40-50% of patients will experience relapse within two years following front line therapy with limited treatment options available[2][3]. Treatment of relapsed and refractory T-ALL remains a high unmet medical need.

About Mesothelin-positive Solid Tumors

Mesothelin, a cell surface antigen, has high expression to a broad spectrum of solid tumors while express low levels on normal cells. Mesothelin is believed as a good target for multiple solid tumors. The GC008t study enrolled patients with advanced solid tumors, including pancreatic cancer, ovarian cancer, and colorectal cancer, of which clinical outcome of standard of care remains poor.

On May 29, 2020 COTA, Inc., a healthcare technology company that uses real-world data (RWD) to bring clarity to cancer care, is pleased to announce its involvement and participation in two industry leading conferences – the 2020 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Scientific Program taking place May 29-31 and the DIA 2020 Virtual Global Annual Meeting to be held June 14-18 (Press release, COTA, MAY 29, 2020, View Source [SID1234558769]). Collectively, the involvement at these two premier events further underscores the importance of RWD’s role in clinical research and oncology care delivery.

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"As real-world data continues to play an increasing role in clinical research with expanding regulatory applications, COTA is proud to be a leader in the space, and share our expertise and findings at two of the industry’s most important meetings," said Mike Doyle, President and CEO of COTA. "Not only are we working to provide clinically relevant insights that might otherwise remain hidden, but we are doing so by collaborating with industry experts, including Friends Of Cancer Research. This work is more important than ever during these unprecedented times, and we look forward to sharing our findings with conference attendees."

ASCO 2020 Areas of Study and Abstracts

The company is proud to announce that five abstracts have been accepted at ASCO (Free ASCO Whitepaper)’s 2020 annual meeting. The key areas of study include the following:

Characterization of African-American patients with multiple myeloma including time to 1st line therapy and 1st stem cell transplant.
Two abstracts as part of the Friends of Cancer Research RWE collaboration in oncology (Pilot 2.0)
Heterogeneity in the timing of IO uptake among patients with advanced non-small cell lung cancer
An analysis of patients with advanced non-small cell lung cancer to highlight the ability of RWD to generate evidence on patients that are routinely excluded from clinical trials.
Molecular markers of an NCCN-IPI prognostic model and its predictive power in a RWD cohort of patients with diffuse large b-cell lymphoma.
A literature review on techniques for the assessment of real-world progression and response to treatment in patients with multiple myeloma.
COTA has partnered with leading organizations, life science companies, hospitals, and cancer centers to produce these important findings. Links to the full abstracts and additional author information can be found below:

1. Incorporating molecular markers in standard prognostic models for DLBCL patients using real-world data.

2. Disparities in clinical characteristics and treatment of multiple myeloma in African American patients.

3. Trends in immunotherapy use in patients with advanced non-small cell lung cancer (aNSCLC) patients: Analysis of real-world data.

4. Overall survival (OS) in advanced non-small cell lung cancer (aNSCLC) patients treated with frontline chemotherapy or immunotherapy by comorbidity: A real-world data (RWD) collaboration.

5. Assessing real-world clinical response in patients with multiple myeloma (MM): A survey of the literature.

Industry Thought Leaders to Share Expertise at DIA 2020

In addition to its involvement in ASCO (Free ASCO Whitepaper)20, the Company will also be participating in DIA 2020, leading panel discussions with industry experts and thought leaders.

#301 SL: Combining Multiple Real World Data Sources to Maximize Value, will be held Wednesday, June 17, 2020 at 8:00 am. The discussion, led by COTA’s Chief Medical Officer, C.K. Wang, M.D., will discuss the approach and complexities to working with different real world datasets.
Panelists include Kim Van Naarden Braun, Associate Director, Translational Epidemiology, Informatics and Predictive Science, Bristol-Myers Squibb Company; Jennifer Christian, Vice President, Clinical Evidence and Epidemiology, IQVIA; and Jeremy Rassen, President and Chief Science Officer, Aetion.
#509 OD: ON DEMAND – Faster, Better, Cheaper: The Changing Role of Real World Data in Drug Development, will be available on demand for conference attendees. The session will explore how clinical trials will evolve in the era of big data from key regulatory leaders and real-world data experts. The discussion will be moderated by COTA’s Vice President of Life Sciences, Viraj Narayanan, MBA.
Panelists include Sean Khozin, Global Head of Data Strategy, Janssen Research & Development, LLC; Kimberly Wilson, Senior Director, Translational Epidemiology, Bristol-Myers Squibb Company; and Christopher Boone, Vice President, Global Head, Health Economics and Outcomes Research, Abbvie.
"As the value of real-world data becomes more accepted and its use more widely adopted, we are looking forward to speaking with industry leaders with invaluable insights on the topic," said CK Wang, M.D., COTA’s Chief Medical Officer. "With expertise spanning from a past Associate Director of the FDA, to an epidemiologist with over 20 years of healthcare research experience, as well as a pharmacoepidemiologist with 25 years of academic and industry experience, these will be fruitful discussions that can help push the industry forward as it expands its use of RWD."

On May 29, 2020 Tolero Pharmaceuticals, Inc., a clinical-stage company focused on developing novel therapeutics for hematological and oncological diseases, reported data from the first clinical studies evaluating the oral investigational agents TP-1287, a cyclin-dependent kinase 9 (CDK9) inhibitor, and TP-3654, a PIM kinase inhibitor, in patients with advanced solid tumors (Press release, Tolero Pharmaceuticals, MAY 29, 2020, View Source [SID1234558768]). These results were presented in poster presentations at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Annual Meeting, being held May 29-31, 2020.

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Preliminary findings from a Phase 1, first-in-human, dose escalation study of TP-1287 showed clinical activity and a tolerable safety profile as a monotherapy in patients with heavily pretreated, relapsed and refractory solid tumors. In the study, 44% (n=12 of 27) of evaluable patients remained on treatment for more than four cycles. Additionally, 48% (n=13 of 27) of evaluable patients experienced a best response of stable disease, and one patient experienced a partial response. TP-1287 administered at a dose of 8 mg twice daily showed proof of mechanism by reducing levels of phosphorylated RNA polymerase II, a downstream target of CDK9.1

The most frequently observed Grade 3 adverse events in this study included diarrhea, anemia and pain. Pending the results from the dose escalation portion of the Phase 1 trial, the study will advance into a Phase 2 expansion in patients with metastatic castrate-resistant prostate cancer to evaluate clinical activity in this setting.1

Initial findings from a separate Phase 1, first-in-human, dose escalation study of TP-3654 presented at ASCO (Free ASCO Whitepaper) showed clinical activity and tolerability as a monotherapy in patients with heavily pretreated, relapsed and resistant solid tumors. Data from the study indicated that one-third of response-evaluable patients (33%, n=3 of 9) experienced stable disease for more than 16 weeks. Additionally, two-thirds of response-evaluable patients (67%, n=6 of 9) experienced a best response of stable disease. This study also found that patients administered TP-3654 had a reduction of BAD phosphorylation, a pro-survival downstream effector of PIM kinase activation. Further downstream biomarker data evaluating the impact of TP-3654 on the PIM kinase pathway are pending analyses.2

TP-3654 was tolerated up to doses of 1440 mg once daily with no dose-limiting toxicities observed. The dose escalation portion of the study is continuing with a twice daily dosing schedule to determine the maximum tolerated dose and recommended dose for a Phase 2 study.2

"We are pleased to share these clinical data on TP-1287 and TP-3654 at ASCO (Free ASCO Whitepaper), to support proof of mechanism for each investigational compound. These initial findings are representative of the continued advancement of our investigational pipeline of innovative cancer therapeutics," said David J. Bearss, Ph.D., Chief Executive Officer, Tolero Pharmaceuticals, and Chief Scientific Officer and Global Head of Research, Global Oncology. "We are continuing to progress these clinical programs as we build our understanding of the potential of TP-1287 and TP-3654 in various tumor types."

Below are the details for the presentations:

Abstract Title

Details

Author

A Phase I, First-in-human, Open-label, Dose escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP 1287 Administered Daily to Patients with Advanced Solid Tumors

Abstract# 3611

May 29, 2020

8 a.m. ET

Poster Presentation

Ben George, M.D., Medical College of Wisconsin

A Phase I, First-in-Human, Open-Label, Dose Escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-3654 Administered Daily for 28 Days to Patients with Advanced Solid Tumors

Abstract# 3586

May 29, 2020

8 a.m. ET

Poster Presentation

Ignacio Garrido-Laguna, M.D., Huntsman Cancer Institute

About TP-1287

TP-1287 is an investigational oral cyclin-dependent kinase 9 (CDK9) inhibitor under evaluation in a Phase 1 study in patients with advanced solid tumors (NCT03604783). TP-1287 has shown favorable oral bioavailability in preclinical models.

About TP-3654

TP-3654 is an investigational second-generation selective PIM kinase inhibitor under evaluation in a Phase 1 study in patients with myelofibrosis (NCT04176198), led by Boston Biomedical, Inc., as well as a Phase 1 study in patients with advanced solid tumors (NCT03715504), led by Tolero Pharmaceuticals, Inc.

About CDK9 Inhibition and MCL-1

MCL-1 is a member of the apoptosis-regulating BCL-2 family of proteins.3 In normal function, it is essential for early embryonic development and for the survival of multiple cell lineages, including lymphocytes and hematopoietic stem cells.4 MCL-1 inhibits apoptosis and sustains the survival of leukemic blasts, which may lead to relapse or resistance to treatment.3,5 The expression of MCL-1 in leukemic blasts is regulated by cyclin-dependent kinase 9 (CDK9).6,7 Because of the short half-life of MCL-1 (2-4 hours), the effects of targeting upstream pathways are expected to reduce MCL-1 levels rapidly.6 Inhibition of CDK9 has been shown to block MCL-1 transcription, resulting in the rapid downregulation of MCL-1 protein, thus restoring the normal apoptotic regulation.3

About PIM Kinase

PIM kinases are major effectors of JAK/STAT proliferative signaling downstream of multiple growth factors and cytokines.8 PIM is overexpressed in cancers and it may enhance the ability of fibroblasts to differentiate into myofibroblasts.8