On December 8, 2020 Amgen (NASDAQ: AMGN) reported that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for its investigational KRASG12C inhibitor, sotorasib, for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with KRAS G12C mutation, as determined by an FDA-approved test, following at least one prior systemic therapy (Press release, Amgen, DEC 8, 2020, View Source [SID1234572464]).

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"For more than 40 years, scientists have been trying to target KRAS. Today’s news is a welcome update for the many non-small cell lung cancer patients with the KRAS G12C mutation, who currently have no targeted therapies," said Bonnie J. Addario, cofounder and board chair of the GO2 Foundation for Lung Cancer. "We are pleased that the FDA and Amgen recognize the unmet need for these patients and are working to make new treatment options available as quickly as possible."

KRAS G12C is the most common KRAS mutation in NSCLC.1,2 In the U.S., about 13% of patients with NSCLC adenocarcinoma harbor the KRAS G12C mutation3 and each year approximately 25,000 new patients in the U.S. are diagnosed with KRAS G12C-mutated NSCLC.4 Unmet need remains high and options are limited for NSCLC patients with the KRAS G12C mutation that have failed first-line treatment. The outcomes with current therapies are suboptimal with response rates of approximately 9-18% and a median progression-free survival of approximately 4 months for second-line NSCLC.5,6,7

Amgen has taken on one of the toughest challenges of the last 40 years in cancer research8 by developing sotorasib. Sotorasib was the first KRASG12C inhibitor to enter the clinic and is being studied in the broadest clinical program exploring 10 combinations with global sites spanning across 4 continents. In just over two years, the sotorasib clinical program has also established the deepest clinical data set with more than 600 patients studied across 13 tumor types.

"Breakthrough Therapy designation and Real-Time Oncology Review bring Amgen closer to potentially providing a targeted therapy to patients with a KRAS G12C mutation and establishing sotorasib as the foundational therapy in KRAS G12C-driven cancers," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "We are pleased to receive these regulatory designations and plan to submit a new drug application by end of year as we rapidly work to get sotorasib to the patients who need it."

A Breakthrough Therapy designation is designed to expedite the development and regulatory review of medicines that may demonstrate substantial improvement on a clinically significant endpoint over available medicines.9 The Real-Time Oncology Review (RTOR) pilot program aims to explore a more efficient review process that ensures safe and effective treatments are made available to patients as early as possible.10

The designation and RTOR are supported by positive Phase 2 results in patients with advanced NSCLC from the CodeBreaK 100 clinical study, whose cancer had progressed despite prior treatment with chemotherapy and/or immunotherapy. In the study, treatment with sotorasib provided durable anticancer activity with a positive benefit-risk profile.11

About CodeBreaK
The CodeBreaK clinical development program for Amgen’s investigational drug sotorasib is designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers. As the most advanced KRAS G12C clinical development program, CodeBreaK has enrolled more than 600 patients across 13 tumor types since its inception.

CodeBreaK 100, the Phase 1 and 2, first-in-human, open-label multicenter study, enrolled patients with KRAS G12C-mutant solid tumors. Eligible patients must have received a prior line of systemic anticancer therapy, consistent with their tumor type and stage of disease. The primary endpoint for the Phase 2 study was centrally assessed objective response rate. The Phase 2 trial in NSCLC enrolled 126 patients, 123 of whom had centrally evaluable lesions by RECIST at baseline. The Phase 2 trial in colorectal cancer (CRC) is fully enrolled and topline results are expected in 2021.

A global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in patients with KRAS G12C-mutated NSCLC (CodeBreaK 200) is currently recruiting. Amgen also has several Phase 1b combination studies across various advanced solid tumors (CodeBreaK 101) open for enrollment.

For information, please visit www.codebreaktrials.com.

About Amgen Oncology
Amgen Oncology is searching for and finding answers to incredibly complex questions that will advance care and improve lives for cancer patients and their families. Our research drives us to understand the disease in the context of the patient’s life – not just their cancer journey – so they can take control of their lives.

For the last four decades, we have been dedicated to discovering the firsts that matter in oncology and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen continues to advance the largest pipeline in the Company’s history, moving with great speed to advance those innovations for the patients who need them.

At Amgen, we are driven by our commitment to transform the lives of cancer patients and keep them at the center of everything we do.

To learn more about Amgen’s innovative pipeline with diverse modalities and genetically validated targets, please visit AmgenOncology.com. For more information, follow us on www.twitter.com/amgenoncology.

On December 8, 2020 Natera,Inc. (NASDAQ: NTRA), a pioneer and global leader in cell-free DNA testing, reported it will present new data on its personalized and tumor-informed circulating tumor DNA (ctDNA) assay, Signatera, at the 2020 virtual San Antonio Breast Cancer Symposium (SABCS) taking place December 8-11, 2020 (Press release, Natera, DEC 8, 2020, View Source [SID1234572463]).

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Natera will present two posters: one from the I-SPY2 Trial describing Signatera’s performance as a predictive biomarker for response to neoadjuvant immunotherapy, and the other from the Beyond BRCA study describing Natera’s plasma-based whole exome analysis as a tool for tracking clonal evolution and discovering new treatment resistance mutations.

Details about the presentations are as follows:

Poster #PD9-02 | Spotlight Poster Discussion
Presenter: Mark Jesus M. Magbanua, Ph.D.
Date: Dec 10, 2020 | 3:30 PM to 4:45 PM CT

Personalized ctDNA as a predictive biomarker in high-risk early stage breast cancer treated with neoadjuvant chemotherapy (NAC), with or without pembrolizumab

A study from the prospective, randomized I-SPY2 Trial exploring the predictive value of personalized ctDNA analysis, performed by Natera, in patients with early-stage breast cancer undergoing either standard NAC or NAC in combination with the immune checkpoint inhibitor pembrolizumab. Early clearance of ctDNA (three weeks after initiation of treatment) is significantly associated with achieving pathological complete response, and may serve as an early surrogate marker for response to therapy. Persistent presence of ctDNA after completion of NAC, but prior to surgery, is strongly correlated with poor disease-free survival.

"Just last week, the I-SPY investigators published a paper in Annals of Oncology validating Signatera’s performance in neoadjuvant treatment monitoring for patients with early-stage breast cancer," said Angel Rodriguez, M.D., Medical Director at Natera. "This new study presented at SABCS follows a different cohort of I-SPY2 patients who received NAC in combination with immunotherapy. The results from this new cohort further validate the initial finding that Signatera can be a powerful tool for neoadjuvant treatment response monitoring, regardless of the type of therapy, and can complement existing tools, such as pathology and imaging, to optimize decisions around the escalation or de-escalation of treatment."

Poster #PD10-12 | Spotlight Poster Discussion
Presenter: Joshua J. Gruber, M.D., Ph.D.
Date: Dec 11, 2020 | 1:00 PM to 2:15 PM CT

Genomic analysis from the Talazoparib Beyond BRCA clinical trial: homologous recombination deficiency (HRD) scores, loss-of-heterozygosity and mutations in non-BRCA 1/2 mutant tumors

A poster on the genomic characterization of treatment response and resistance to the PARP1 inhibitor, talazoparib, in non-BRCA 1/2 mutant tumors with mutations in other HRD-associated genes. Plasma-based whole exome sequencing of ctDNA, performed by Natera, provides a comprehensive view of tumor evolution over the course of treatment, wherein responders and nonresponders show distinct patterns, leading to the identification of novel mutations responsible for acquired resistance to talazoparib treatment.

"Drug resistance remains a significant challenge in the management of breast cancer," said Joshua J. Gruber, M.D., Ph.D., medical oncologist at Stanford University Medical Center and the lead author of the Beyond BRCA study. "The ability to non-invasively characterize the molecular evolution of tumors during treatment using ctDNA can guide further investigation of treatment resistance."

About Signatera
Signatera is a custom-built circulating tumor DNA (ctDNA) test for treatment monitoring and molecular residual disease (MRD) assessment in patients previously diagnosed with cancer. The test is available for clinical and research use, and in 2019, it was granted Breakthrough Device Designation by the FDA. The Signatera test is personalized and tumor-informed, providing each individual with a customized blood test tailored to fit the unique signature of clonal mutations found in that individual’s tumor. This maximizes accuracy for detecting the presence or absence of residual disease in a blood sample, even at levels down to a single tumor molecule in a tube of blood. Unlike a standard liquid biopsy, Signatera is not intended to match patients with any particular therapy; rather, it is intended to detect and quantify how much cancer is left in the body, to detect recurrence earlier and to help optimize treatment decisions. Signatera test performance has been clinically validated in multiple cancer types including colorectal, non-small cell lung, breast, and bladder cancers. Signatera has been developed and its performance characteristics determined by Natera, the CLIA-certified laboratory performing the test. The test has not been cleared or approved by the US Food and Drug Administration (FDA). CAP accredited, ISO 13485 certified, and CLIA certified.

On December 8, 2020 Caris Life Sciences, a leading innovator in molecular science and artificial intelligence focused on fulfilling the promise of precision medicine, reported positive results from validation studies of MI FOLFOXai, the company’s Artificial Intelligence (AI)-based predictor intended to gauge a metastatic colorectal cancer (mCRC) patient’s likelihood of benefit from first-line treatment FOLFOX followed by FOLFIRI versus FOLFIRI followed by FOLFOX, both standard of care options (Press release, Caris Life Sciences, DEC 8, 2020, View Source [SID1234572462]). The studies demonstrated that the overall survival (OS) of patients treated in a manner consistent with the FOLFOXai prediction was 17 months longer than the OS of patients treated counter to the prediction. FOLFOXai is the first clinically validated machine-learning powered molecular predictor of chemotherapy efficacy in patients with mCRC. The results were published in Clinical Cancer Research December 8, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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"The clinical application of these findings could have a major impact on how FOLFOX and FOLFIRI are sequenced, both options are recognized standard of care in metastatic disease, for patients," said Heinz-Josef Lenz, M.D., FACP, Associate Director Clinical Science and Co-director of the Center for Cancer Drug Development at USC Norris Comprehensive Cancer Center. "Using this AI predictor, we saw a 71% difference in OS in patients treated with FOLFOX-FOLFIRI in whom we predicted would benefit from FOLFOX-FOLFIRI chemotherapy compared to those predicted to benefit from FOLFIRI-FOLFOX."

Across two independent validation studies, researchers determined a significant difference in OS based on the FOLFOXai-predicted increased benefit or decreased benefit with FOLFOX-FOLFIRI chemotherapy in combination with bevacizumab. A study using real-world evidence demonstrated a median OS of 42 months in patients expected to see an increased benefit compared to 24.5 months in patients expected to see a decreased benefit (Hazard Ratio [HR]=0.466, 95% Confidence Interval [CI]: 0.325-0.670, p<0.0001). Additionally, patients predicted to have a decreased benefit from FOLFOX-FOLFIRI chemotherapy had significantly better outcomes when treated with FOLFIRI-FOLFOX than those predicted to have an increased benefit and vice versa (HR=2.631, 95% CI: 1.041-6.649, p=0.034). Analysis of samples from the TRIBE2 randomized phase-3 study which compared standard chemotherapy with FOLFOX followed by FOLFIRI to the FOLFOXIRI combination, confirmed the ability of FOLFOXai to predict OS for both study arms.

"These studies validate the potential role of FOLFOXai to improve overall survival in patients with metastatic colorectal cancer who receive first-line standard of care options in the optimal order," said Alan P. Venook, M.D., FASCO, The Madden Family Distinguished Professor of Medical Oncology and Translational Research and Shorenstein Associate Director, Program Development, UCSF Helen Diller Family Comprehensive Cancer Center.

In addition to mCRC, exploratory analyses also found that FOLFOXai predicted a treatment benefit from oxaliplatin-containing regimens in patients with advanced esophageal/gastro-esophageal junction cancers (EC/GEJC) and pancreatic ductal adenocarcinoma (PDAC). These analyses demonstrated FOLFOXai was predictive of OS, with a median OS difference of 10.1 months in the increased benefit cohort compared to decreased benefit (21.4 months versus 11.3 months; HR=0.478, CI: 0.289 – 0.792, p=0.003) but not the nab-paclitaxel/gemcitabine cohort (median OS of 10.8 months for increased benefit versus 9.8 months for decreased benefit; HR=0.958, CI: 0.658 – 1.395, p=0.823). Similarly, data from 104 patients with advanced EC/GEJC demonstrated that FOLFOXai was predictive of efficacy of oxaliplatin containing regimens also in this clinical setting (median OS for increased benefit: 14 months versus 8.9 months for decreased benefit; HR=0.437, CI: 0.250 – 0.763, p=0.003).

"The results of these analyses demonstrate that precision medicine powered by AI has the potential to change how clinicians approach treatment for metastatic colorectal cancer and other cancers, given the selection of initial therapy has implications for improved treatment outcomes and disease progression," said W. Michael Korn, M.D., Chief Medical Officer at Caris Life Sciences. "Based on the results of this study, FOLFOXai should be considered as part of the initial therapeutic decision-making process in the clinical setting."

"Cancer is a complex genetic disease that results from perturbations in cell’s signaling pathways that make it virtually impossible for humans to interpret. Application of AI to truly comprehensive genomic profiling and outcome data of these systems has allowed us to make clinically impactful insights and improve patient care. Using our database of over 215,000 profiles and outcomes, we have begun to deconvolute the drivers of therapy resistance and tailor treatment strategies to each individual patient. This is one of many benefits patients receive automatically when they get profiled by Caris, as this is additional clinical insight from an already covered diagnostic test," said David Spetzler, M.S., MBA, Ph.D., President and Chief Scientific Officer at Caris Life Sciences.

"Application of AI to molecular data sets involves overcoming some significant computational challenges. The molecular data generated by MI Profile provides hundreds of thousands of data points per patient that had to be analyzed to derive a robust and generalizable set of features and algorithms," said Jim Abraham, Ph.D., Chief Data Officer at Caris Life Sciences. "We were able to deploy 318 different machine learning algorithms to solve these problems and validate the results in blinded, well controlled studies, and this is the first of many AI signatures to come."

Colorectal cancer is the third most common cancer globally, with more than 1.8 million patients diagnosed with the disease each year i. As many as 25% of colorectal cancer patients will present with Stage IV – or metastatic – disease, where the cancer has spread to other parts of the body, making the choice of treatment critical to the patient’s prognosis.

On December 8, 2020 Precigen, Inc. (Nasdaq: PGEN), a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported that the Company will host a virtual event on Tuesday, December 15, 2020 at 11:00 AM ET to provide an update on the latest progress for its clinical pipeline (Press release, Precigen, DEC 8, 2020, View Source [SID1234572461]).

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The event will showcase data from several of the Company’s most advanced clinical programs, such as PRGN-3005 UltraCAR-T, PRGN-3006 UltraCAR-T and AG019 ActoBioticsTM. Precigen executives and key opinion leaders will participate in the event, including:

Helen Sabzevari, PhD, President and CEO of Precigen
Pieter Rottiers, PhD, CEO of Precigen ActoBio
Mary L. (Nora) Disis, MD, faculty member at the University of Washington and Fred Hutchinson Cancer Research Center and one of the lead investigators for the PRGN-3005 clinical study
Kevan Herold, MD, Professor of Immunobiology and of Medicine (Endocrinology) at Yale School of Medicine and one of the lead investigators for the AG019 clinical study
Participants may register and access the live webcast through Precigen’s investor relations website in the Press & Events section. An archived recording will be posted to the investor relations website following the event.

On December 8, 2020 Applied BioMath (www.appliedbiomath.com), the industry-leader in applying systems pharmacology and mechanistic modeling, simulation, and analysis to de-risk drug research and development, reported a collaboration with Antengene Corporation for the development of a systems pharmacology modeling in immuno-oncology (Press release, Applied BioMath, DEC 8, 2020, View Source [SID1234572460]). Applied BioMath will develop a systems pharmacology model for a PDL1/41BB bispecific antibody, ATG-101, in immuno-oncology indications. The model will be used to predict clinical starting and efficacious doses for first-in-human studies. "Antengene Corporation is dedicated to developing first-in-class and/or best-in-class therapies in oncology," said Dirk Hoenemann, M.D., VP, Head of Medical Affairs for Asia Pacific Region (APAC) and Early Clinical Development. "We decided to collaborate with Applied BioMath in an effort to provide ourselves the highest likelihood possible of predicting accurate starting and efficacious doses which is a critical part of our first-in-human studies."

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Applied BioMath employs a rigorous fit-for-purpose model development process which quantitatively integrates knowledge about therapeutics with an understanding of its mechanism of action in the context of human disease mechanisms. Their approach employs proprietary algorithms and software that were designed specifically for systems pharmacology model development, simulation, and analysis. "Predicting starting and efficacious doses for first-in-human studies is non-trivial for complex therapeutics such as Antengene’s bispecific therapeutic," said Dr. John Burke, Ph.D., Co-Founder, President, and CEO of Applied BioMath. "We have developed algorithms and tools specifically for this purpose that have a proven track record of predicting such doses. We look forward to collaborating with Antengene to support them in this project."