On December 1, 2020 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported that the U.S. Food and Drug Administration (FDA) has approved Gavreto (pralsetinib) for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic rearranged during transfection (RET)-mutant medullary thyroid cancer (MTC) who require systemic therapy, or with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) (Press release, Genentech, DEC 1, 2020, View Source [SID1234572052]). These indications were approved under the FDA’s accelerated approval program based on data from the Phase I/II ARROW study. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

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"We are proud to partner with Blueprint Medicines to bring this important new option to people with certain types of RET-altered thyroid cancer," said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. "Gavreto is now approved across multiple RET-altered tumor types, underscoring our commitment to advancing personalized healthcare with treatments that target the underlying biology of each person’s cancer."

Approximately 10-20% of people with papillary thyroid cancer (the most common type of thyroid cancer) have RET fusion-positive tumors, and roughly 90% of people with advanced MTC (a rare form of thyroid cancer) carry RET mutations. Biomarker testing for RET fusions and mutations can help identify people who are eligible for treatment with Gavreto.

The approvals are based on results from the Phase I/II ARROW study, which demonstrated durable clinical activity in people with or without prior therapy and regardless of RET alteration genotypes. Treatment with Gavreto led to an overall response rate (ORR) of 60% (95% CI: 46%, 73%) in 55 people with RET-mutant metastatic MTC previously treated with cabozantinib and/or vandetanib, and the median duration of response (DoR) was not reached (95% CI: 15.1 months, not estimable). In 29 people with RET-mutant advanced MTC who were cabozantinib and vandetanib treatment-naïve, the ORR was 66% (95% CI: 46%, 82%), and the median DoR was not reached (95% CI: not estimable, not estimable). In nine people with RET fusion-positive metastatic thyroid cancer, Gavreto demonstrated an ORR of 89% (95% CI: 52%, 100%), and the median DoR was not reached (95% CI: not estimable, not estimable). In ARROW trial patients across RET-altered tumor types, the most common adverse reactions (≥25%) were constipation, increased blood pressure (hypertension), fatigue, musculoskeletal pain and diarrhea.

The FDA reviewed and approved the application under its Real-Time Oncology Review (RTOR) pilot program, which aims to explore a more efficient review process to ensure safe and effective treatments are available to patients as early as possible. In September, the FDA also granted accelerated approval to Gavreto for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. In addition, the FDA granted Breakthrough Therapy Designation to Gavreto for the treatment of RET mutation-positive MTC that requires systemic treatment and for which there are no acceptable alternative treatments and for RET fusion-positive NSCLC that has progressed following platinum-based chemotherapy.

Gavreto is a once-daily, oral precision therapy designed to selectively target RET alterations, including fusions and mutations. Gavreto is jointly commercialized by Genentech and Blueprint Medicines in the United States. For those who qualify, Blueprint Medicines offers patient assistance programs for people prescribed Gavreto by their doctor through YourBlueprint. Please visit www.yourblueprint.com or contact 1-888-BLUPRNT for more information.

About the ARROW study

ARROW (NCT03037385) is a Phase I/II, open-label, first-in-human study designed to evaluate the safety, tolerability and efficacy of Gavreto, administered orally in people with rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer (MTC), RET fusion-positive thyroid cancers and other RET-altered solid tumors. The trial consists of two parts: a dose escalation portion, which is complete, and an expansion portion in people treated with 400 mg of Gavreto, once-daily. ARROW is being conducted at multiple sites across the United States, European Union and Asia.

About RET-altered cancers

RET gene alterations, such as fusions and mutations, are key disease drivers in many types of cancer, including NSCLC and several types of thyroid cancers. Approximately 10-20% of people with papillary thyroid cancer (the most common type of thyroid cancer) have RET fusion-positive tumors, and roughly 90% of people with advanced MTC (a rare form of thyroid cancer) carry RET mutations. In NSCLC, RET fusions represent approximately 1-2% of patients. Oncogenic RET fusions also are observed at low frequencies in cholangiocarcinoma, colorectal, neuroendocrine, ovarian, pancreatic and thymus cancers.

About Gavreto

Gavreto is a once-daily, oral precision therapy designed to selectively target RET alterations, including fusions and mutations, regardless of the tissue of origin. Preclinical data have shown that Gavreto inhibits primary RET fusions and mutations that cause cancer in subsets of patients, as well as secondary RET mutations predicted to drive resistance to treatment. Blueprint Medicines and Genentech are co-developing Gavreto for the treatment of patients with various types of RET-altered cancers.

Gavreto U.S. Indications

Gavreto (pralsetinib) is indicated for the treatment of:

Adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.
Adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy.
Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate)
These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

Interstitial Lung Disease (ILD)/Pneumonitis occurred in 10% of patients who received Gavreto, including 2.7% with Grade 3/4, and 0.5% with fatal reactions. Monitor for pulmonary symptoms indicative of interstitial lung disease (ILD)/pneumonitis. Withhold Gavreto and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue Gavreto based on severity of confirmed ILD.

Hypertension occurred in 29% of patients, including Grade 3 hypertension in 14% of patients. Overall, 7% had their dose interrupted and 3.2% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Gavreto in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Gavreto. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Gavreto based on the severity.

Hepatotoxicity: Serious hepatic adverse reactions occurred in 2.1% of patients treated with Gavreto. Increased aspartate aminotransferase (AST) occurred in 69% of patients, including Grade 3/4 in 5% and increased alanine aminotransferase (ALT) occurred in 46% of patients, including Grade 3/4 in 6%. The median time to first onset for increased AST was 15 days (range: 5 days to 1.5 years) and increased ALT was 22 days (range: 7 days to 1.7 years). Monitor AST and ALT prior to initiating Gavreto, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue Gavreto based on severity.

Grade ≥ 3 hemorrhagic events occurred in 2.5% of patients treated with Gavreto including one patient with a fatal hemorrhagic event. Permanently discontinue Gavreto in patients with severe or life-threatening hemorrhage.

Tumor Lysis Syndrome (TLS): Cases of TLS have been reported in patients with medullary thyroid carcinoma receiving Gavreto. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, Gavreto has the potential to adversely affect wound healing. Withhold Gavreto for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Gavreto after resolution of wound healing complications has not been established.

Based on findings from animal studies and its mechanism of action, Gavreto can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Gavreto and for 2 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Gavreto and for 1 week after the final dose. Advise women not to breastfeed during treatment with Gavreto and for 1 week after the final dose.

Common adverse reactions (≥25%) were constipation, hypertension, fatigue, musculoskeletal pain and diarrhea. Common Grade 3/4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased calcium (corrected), decreased sodium, increased AST, increased ALT, decreased platelets and increased alkaline phosphatase.

Avoid coadministration of Gavreto with strong CYP3A inhibitors or combined P-gp and strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the Gavreto dose. Avoid coadministration of Gavreto with strong CYP3A inducers. If coadministration cannot be avoided, increase the Gavreto dose.

Please click here to see the full Prescribing Information for Gavreto.

Blueprint Medicines, Gavreto, YourBlueprint and associated logos are trademarks of Blueprint Medicines Corporation.

On December 1, 2020 A cancer-killing virus that City of Hope scientists developed could one day improve the immune system’s ability to eradicate tumors in colon cancer patients, reported a new study in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) (Press release, City of Hope, DEC 1, 2020, View Source [SID1234572051]).

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The preclinical research is a first step to showing that City of Hope’s oncolytic virus CF33 can target hard-to-treat tumors that "handcuff" the immune system and keep T cells from activating the immune system to kill cancer cells. More specifically, the researchers demonstrated in mouse models that CF33 appears to increase PD-L1 expression in tumor cells and causes them to die in a way that stimulates an influx of activated immune cells.

"CF33 is a safe, innovative virus City of Hope developed that can become a game changer because of how potent it is and because of its ability to recruit and activate immune cells," said Susanne Warner, M.D., a surgical oncologist at City of Hope and senior author of the study. "Our oncolytic virus trains the immune system to target a specific cancer cell. Preclinical models show that a combination treatment of oncolytic virus CF33 with anti-PD-L1 checkpoint inhibition leads to lasting anti-tumor immunity, meaning if a similar cancer cell ever tries to regrow, the immune system will be ready and waiting to shut it down."

Colorectal cancer is the third leading cause of cancer-related deaths in the United States and is expected to cause 53,200 deaths in 2020, according to the American Cancer Society. City of Hope researchers are excited about the potential of CF33 to enhance colon cancer treatment and point out that CF33 has been effective preclinically against a wide variety of cancers.

Yuman Fong, M.D., the Sangiacomo Family Chair in Surgical Oncology at City of Hope, and his team created oncolytic virus CF33 and expect to open a clinical trial to test the safety of this treatment in human patients in 2021. This treatment addresses a problem in cancer: Most solid tumors do not respond to checkpoint inhibitors because the "uncloaked tumor cell" still isn’t recognized by the immune system, Fong said.

"CF33 selectively infects, replicates in and kills cancer cells. This study demonstrates that a designer virus we created to infect a wide variety of cancers can make tumor cells very recognizable to the immune system," Fong said. He, Warner and other City of Hope physician-scientists are working on turning "cold tumors" resistant to treatment into "hot tumors" that can be killed by a well-trained immune system.

The U.S. Food and Drug Administration has approved only one oncolytic virus thus far: T-VEC, which is a local immunotherapy treatment that kills melanoma cells.

To confirm their hypothesis, City of Hope scientists tested four groups: control with no treatment, anti-PD-L1 alone, CF33 alone, and a combination of CF33 and anti-PD-L1. Results indicated that a combined treatment of City of Hope’s oncolytic virus and anti-PD-L1 appeared to be most effective. It also increased CD8+ T cells, which are immune cells that remember previous diseases and are trained to kill them if they are reintroduced later. In other words, the models developed anti-tumor immunity. This means that animals cured of their cancer were effectively immune to future tumor growth.

Fong and colleagues have demonstrated CF33’s anti-tumor immune efficacy against triple-negative breast cancer cell lines, in brain tumor cells, in liver cancer models, and in pancreatic, prostate, ovarian, lung and head and neck cancer. Moreover, a recent City of Hope-led study found that CF33 could be combined with chimeric antigen receptor (CAR) T cell therapy to target and eliminate solid tumors that are otherwise difficult to treat with CAR T therapy alone. City of Hope has licensed CF33 to Imugene Limited, a company developing novel therapies that activate the immune system against cancer.

Notably, the CF33 virus may be tracked by non-invasive PET scanning. "If we can perfect the technique, we can give someone a viral injection and watch it work – see where it goes and identify cancer cells that we didn’t even know existed," Warner said. "Doctors would have real-time data and know if we should give a patient a higher dose or where to direct the treatment based on tumors that have not yet been killed."

What Warner describes is a developing field called theranostic precision medicine, meaning doctors are able to give patients therapies and concurrently diagnose them to provide the most appropriate treatment for that patient. It is one of many precision medicine approaches City of Hope is developing and offering to patients.

The next step for the current study is to test the innovative CF33 virus platform in different solid tumor models.

This research was supported by the American Cancer Society Mentored Research Scholar Grant (MRSG-16-047-01-MPC) and through the generosity of the Natalie and David Roberts Family.

On December 1, 2020 Cellaria Inc (Wakefield, MA, USA) and the Spring Lab, Northeastern University, reported the successful receipt of a National Institutes of Health (NIH) R01 grant to extend and advance the application of innovative new photomedicine-based therapies for hard-to-treat cancers (Press release, Cellaria, DEC 1, 2020, View Source [SID1234572050]). The grant highlights the close working relationship of the two organizations and will provide $3.2M funding to develop precision therapeutics closely tailored to the requirements of specific patient populations. Cellaria’s contribution to the partnership is next generation, patient-derived, customized cell models that boost the effectiveness of in vitro studies, helping researchers to identify where the technology can have the most impact. Dr Bryan Spring, Assistant Professor of Biomedical Physics credits Cellaria with a vital role in accelerating his research.

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"We’ve demonstrated proof of concept and seen significant interest from clinicians," said Dr Spring. "However, we initially targeted just a single ovarian cancer biomarker. To capture the heterogeneity of the disease and efficiently study multiple biomarkers we needed to upgrade our cell models. Developing new models in-house would have taken years and instead we chose to work with Cellaria. This has really accelerated progress by providing rapid access to rigorously characterized cell models for specific molecular subtypes and patient populations."

Dr Spring’s research focuses on the use of antibody-photosensitizer conjugates to make cancer cells susceptible to light-induced destruction, targeting microscopic cancer cell deposits left behind by conventional therapies. Primary areas of application are pancreatic and ovarian cancer. With these cancers, cells left behind by surgery and other conventional therapies can metastasize in the peritoneal cavity and abdomen, attacking other organs and increasing the severity of the disease. The new NIH research grant is entitled "Multiplexed and dynamically targeted photoimmunotherapy of heterogeneous, chemoresistant micrometastases guided by online in vivo optical imaging of cell-surface biomarkers."

Cellaria provides cell models, complete with comprehensive omics data, that help the researchers to determine which biomarkers are most actionable when it comes to targeting drug resistant cells and applying the photomedicine. These cell models robustly represent the full heterogeneity of the cancers, which is essential for the development of precision therapies. Dr Spring has been using Powder, a high grade serous ovarian cancer cell model developed from the carcinoma of a 65 – 69 Caucasian, stage IV patient. New models for pancreatic cancer have recently been added to the Cellaria portfolio. All have a robustly authenticated lineage and are provided with protocols to maintain specific biomarker expression. Cellaria’s unrivalled expertise in cell line growth, stabilization and characterization underpin the company’s ability to supply customised models that enable researchers to identify the specific biomarkers of most relevance to their work.

"Cellaria have all the -omics in place and are highly responsive in terms of refining models to our requirements," said Dr Spring. "The Cellaria team are experts in their field and great to work with. The bottom line is that via this collaboration we get to concentrate on our science, rather than the tools we need to support it, which is just as we prefer it."

On December 1, 2020 Calidi Biotherapeutics, Inc., a clinical-stage biotechnology company at the forefront of oncolytic virus-based immunotherapies for cancer, reported that it has been granted a new patent from the European Patent Office (EPO) (Press release, Calidi Biotherapeutics, DEC 1, 2020, View Source [SID1234572049]). European Patent Number 3209382, "Combination Immunotherapy Approach for Treatment of Cancer," secures Calidi’s proprietary technology platform, Supernova 1 (SNV1), composed of the oncolytic agent, CAL1 vaccinia virus, loaded into allogeneic, adipose-derived mesenchymal stem cells (AD-MSC).

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"We’re very excited to be granted this European Patent to protect our innovative immunotherapy product and combination approach abroad," said Allan J. Camaisa, CEO and Chairman of Calidi Biotherapeutics. "This new patent provides considerable opportunity for the expansion of Calidi’s years of research into the profound oncolytic potential of SNV1."

Pre-clinical data has shown Calidi’s SVN1 product to shield the viral payload of CAL1 vaccinia virus from the patient’s immune system, supporting efficient delivery to tumor sites and effectively potentiating oncolytic viruses.

"Our talented, seasoned team of doctors and scientists have exerted years of intensive research and groundbreaking work to produce Calidi’s SVN1 technology," said Boris Minev, MD, President, Medical and Scientific Affairs at Calidi Biotherapeutics. "This patent represents the culmination of their impressive expertise, dedication, and passion."

As of the EP Grant Date, November 25, 2020, the European Patent covers Calidi’s combination immunotherapy approach and SNV1 product in 37 contracting European countries. Earlier in the year, the patent was also granted in Canada, Russia, Singapore, Australia, and New Zealand.

On December 1, 2020 BostonGene Corporation, a biomedical software company committed to defining optimal precision medicine-based therapies for cancer patients, reported that two abstracts were selected for poster presentations at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, BostonGene, DEC 1, 2020, View Source [SID1234572048]). The all-virtual event will be held from December 5 – 8, 2020.

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Details of the presentations are below:

Title: Integration and Iteration: Using Advanced, High-Content Imaging and Single-Cell Gene Expression Analysis to Uncover Unique Aspects of Follicular Lymphoma Biology
Session: 621: Lymphoma—Genetic/Epigenetic Biology: Poster I
Abstract Number: 1106
Date and Time: Saturday, December 5, 2020: 10:00 AM – 6:30 PM ET
Presenter: Andrea J. Radtke, PhD, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)

Follicular lymphoma is an indolent B-cell lymphoma with remarkable heterogeneity in disease progression and trajectory; therefore, determining the cell intrinsic and extrinsic factors underlying this clinical heterogeneity is necessary to impact patient clinical outcomes. Using a multi-omics approach, including whole exome sequencing (WES) and bulk RNA-seq integrated with single-cell analyses such as scRNA-seq and multiparameter imaging, notable patient-specific cellular interactions and expression patterns were identified that may drive cancer patient survival. This integrated approach provides insights into both tumor biology and disease trajectory, which can ultimately benefit therapeutic strategies in follicular lymphoma.

Research conducted with the National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Diseases (NIAID), both part of the National Institutes of Health (NIH).

Title: High Dimensional Tissue-based Spatial Analysis of the Tumor Microenvironment of Follicular Lymphoma Reveals Unique Immune Niches inside Malignant Follicles
Session: 622
Abstract Number: 1117
Date and Time: Saturday, December 5, 2020: 10:00 AM – 6:30 PM ET
Presenter: Jose C. Villasboas, MD, Mayo Clinic

Cells of the immune system play an important role in modulating the trajectory of lymphomas; therefore, understanding the composition and spatial distribution of immune cells within the tumor microenvironment (TME) is critical to improve clinical outcomes for patients. Analysis of a follicular lymphoma tumor section that used Co-Detection by Indexing (CODEX) multiplex immunofluorescence image processing identified unique cell subsets and specific spatial distribution of immune cells. These insights into the complex immune cell composition and architecture of the TME add to the prognostic value of the TME as a therapeutic target in follicular lymphoma.

Research conducted with Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Mayo Clinic, Memorial Sloan Kettering Cancer Center, Université Claude Bernard Lyon and the University of Iowa.

In addition to the poster presentations, the abstracts have been published online in the November supplemental issue of "Blood".