Part 3: Moving Forward and Keeping Stem Cell Treatments Safe – MedShadow

Times up, said the Food and Drug Administration (FDA). A three-and-a-half-year grace period during which companies manufacturing and providing regenerative medicine procedures were instructed to get their operations in line with new, clarified rules announced in 2017, ended May 31, 2021. Those procedures had previously fallen into a gray area of regulation because they rely on harvesting live stem cells or related products rather than traditionally manufactured drugs to repair damaged tissues and organs. Starting June 1, the agency expects all such companies to be in compliance or risk a variety of enforcement actions from warning letters to pursuing criminal prosecution.

For many years, the regenerative medicine industry operated with limited FDA oversight. The field exploded in the 2010s, with nearly a thousand clinics popping up throughout the US. In 2017, the FDA announced stricter, clearer regulations for those treatments. Knowing that a multibillion-dollar industry already existed and wanting to support research and innovation in what most researchers believe is a promising field of medicine, the agency didnt penalize all clinics that werent following the rules. Instead, the FDA offered a grace period, during which companies could file regulatory paperwork and design trials in line with the agencys requirements.

Traditional clinical trials can take years and sometimes even decades to complete, so the FDA has offered several types of expedited approval pathways for therapies expected to provide valuable treatment to patients who have few options. In 2016, it created the Regenerative Medicine Advance Therapy Designation (RMAT) as a part of the 21st Century Cures Act. If the FDA grants the designation to a treatment, the researchers conducting its trials get special support from the agency that can streamline the approval process. The company may be permitted to submit real world data and patient registries in lieu of data from a standard clinical trial, in which some patients are randomized to receive a placebo, to be considered for approval.

But in June 2019, Ned Sharpless, the acting FDA commissioner, announced that the agency had received far fewer approval requests RMAT or otherwise than it had anticipated during the grace period. Were more than halfway through the enforcement discretion period, and the pace of progress of those offering these human cells, tissues and cellular and tissue-based products, including stem cell treatments, to come into compliance with the requirements has been slower than expected. Its possible some stakeholders have questions about the requirements or the length of the process, he said in a statement announcing the Tissue Reference Groups Rapid Inquiry Program (TRIP). Essentially, companies that were unsure which level of regulation their products required could have submitted a request to the Tissue Regerence Group, which would answer within three days, outlining the steps needed to meet the FDAs requirements for compliance. That program ended on March 31, 2021.

While the FDA offered to help companies willing to seek regulatory approval, the agency continued to penalize those companies it believes are conducting the riskiest procedures and making the boldest claims, which had fallen outside of even the previous, cloudier regulations.

For instance, Vibrant Health Care received a warning letter from the FDA in November 2020, after marketing umbilical-cord-derived stem cell treatments designed to boost the immune system and protect patients against COVID-19.

A banner on the companys homepage now reads: Vibrant Health Care does not offer any products or treatments that can mitigate, prevent, treat, diagnose or cure COVID-19. If you are experiencing COVID 19 symptoms, please contact your primary care physician or local hospital.

The letter also cited patient testimonials on the website that claimed that Vibrants treatments had cured their asthma overnight, for example, or led to other dramatic improvements. The testimonials page no longer includes references to specific treatments other than Botox. Instead, patients make broad statements like, Dr. Farrell has been keeping me functional for many years. She always finds some way to alleviate my pain.

An FDA spokesperson told MedShadow in an email, Clinics currently offering products outside of FDAs review process are taking advantage of patients and flouting federal statutes and FDA regulations. This ultimately puts at risk the very patients that these clinics claim to want to help, by either delaying treatment with legitimate and scientifically sound treatment options, or worse, posing harm to patients.

While some providers are working to get their products in line with FDA recommendations, others continue to claim that their products should not be subject to FDA review. Some companies may be toeing a fine line, registering clinical trials as a way to offer treatments to patients, but not designing those trials in ways that are likely to bring the therapies to market.

A search for stem cell and COVID on clinicaltrials.gov, a government website that lists clinical trial information, yields over 100 results. It could be a sign that researchers are working on new therapies and developing them through traditional clinical trial pathways sanctioned by the FDA. But, trials listed here are not always what they seem and the listings are subject to limited oversight. Thousands of trials registered on clinicaltrials.gov are not completed and the results never published. Its possible that some companies dont intend to send their results to the FDA for review and instead have set up sham trials for the appearance of legitimacy.

Leigh Turner, PhD, a bioethicist at the University of Minnesota published an analysis in 2017 that found 18 US-based clinical trials testing stem cells listed on clinicaltrials.gov required the patients to pay for their own treatments. In most clinical trials, patients are responsible for little to none of the cost of treatment or are paid a stipend and compensated for some travel costs to and from the medical facility. Moreover, Wired reported that patients paid $5,000 to $15,000 per treatment, a fact that was not disclosed in any of the clinicaltrials.gov listings themselves. None of the 18 studies were randomized or blinded, conditions usually required in studies intended for FDA review, because they minimize bias in results.

In 2019, Google banned advertisements for treatments that have no established biomedical or scientific basis. The companys announcement also stated, The new policy also includes treatments that are rooted in basic scientific findings and preliminary clinical experience, but currently have insufficient formal clinical testing to justify widespread clinical use. Some companies, Turner suggests in his article, may be using clinicaltrials.gov as an advertising tool to recruit patients willing to pay for the treatments, without conducting scientifically sound trials.

[Disclosure: The MedShadow Foundation advocated against the Right to Try Act.]

Even if you might benefit from an experimental drug, you might not be eligible for a trial. Maybe youre not the right age, youve been prescribed drugs in the past or have a comorbidity that interferes with the treatment being tested. Those conditions could cloud the data for scientists, even if the treatment is still helpful to you. For these situations, the FDA created the Expanded Access Pathway.

The expanded access pathway has been around for a long time. It tries to acknowledge that there may be circumstances where its justifiable to provide access to investigational new drugs outside of a clinical trial context, says Turner. But with the expanded access route, there is a fair degree of oversight.

The FDA evaluates each application for a patient who has exhausted other options to receive a drug through the expanded access pathway. According to a 2017 study, initiating the process requires paperwork that takes about 45 minutes to fill out. On average, the FDA issues a decision within four days. In emergency situations, it usually responds in less than 24 hours. The overwhelming majority of requests are approved, though about 11% require adjustments like a change in dosing or an informed consent form before approval.

The Right to Try Act allows patients, physicians and sponsors to bypass this FDA review. It really means that decision-making devolves onto patients, their physicians and a sponsor, says Turner. If everyone is being careful and cautious and doing everything they can to be compliant, it may be an approach that works in an acceptable fashion.

When Congress passed the Right to Try act in 2018, Matthew Feshbach, who had previously run a company that provided stem cell treatments in the Bahamas, saw an opportunity to return to the US and open Ambrose Cell Therapy, which now offers stem cell treatments for patients with a wide range of diseases who have exhausted conventional therapeutic options.

On the companys website, the tagline under the Ambrose Cell Therapy logo reads your right to try, and the site has a page dedicated to explaining the legislation. The company uses a system made by another company, Cytori Therapeutics, to process cells collected from a patients fat and reintroduce them into the patients body. The system has been tested for safety in nine Phase I and Phase II trials, but Ambrose is not currently pursuing any clinical trials of the treatment to bring it to market for specific diseases under FDA approval. Rather, the company is offering the stem cell treatment exclusively on a Right to Try basis. Feshbach says, There are very few large-scale clinical trials that have been done with adult stem cells. They usually dont make it past Phase II, primarily because of funding. Additionally, he says, he is not a big believer in randomized controlled trials, because in the real world, [treatments] dont work out the way they did in a trial.

He explains that there is a growing body of peer-reviewed literature to support the cells that Ambrose uses (and encourages patients to ask for such literature when searching for stem cell treatment options). The company is collecting data on patients and plans to publish a series of case reports.

Turner worries that the offering treatment in this context is never going to bring a safe and efficacious stem cell product to market. Its a way of sitting out there for years, [technically] complying with regulations.

Prices for different products and procedures arent readily available, and Feshbach declined to discuss the cost of care at Ambrose. A 2017 study showed that the average price quoted to a patient seeking stem cell injections for osteoarthritis in the knee is about $5,000. Its important to review all costs you can expect before beginning treatment, especially considering that, in most cases, insurance wont cover it.

During our conversation, Turner also mentions that there is a line in the Right to Try act that seemed to suggest that companies, like Ambrose Cell Therapy, couldnt profit solely from offering treatments on a Right to Try basis. He admitted that while it had caught his eye, he wasnt yet positive if he was interpreting the law accurately.

The Right to Try states that eligible investigational drugs must be in compliance with 312.6, 312.7 and 312.8 d (1). Of Title 21 Code of Federal Regulations. 312.8d states that, A sponsor may recover only the direct costs of making its investigational drug available.

To investigate, I reached out to a retired biotech executive who was involved with several expanded access requests, which are also required to conform to 312.8d, prior to the approval of the Right to Try act. She explains that her companies were only allowed to charge patients what it cost the company to make and send the treatments to a patients doctors, and that her companies never charged patients for anything.

I also emailed the FDA spokesperson, who responded, FDA does not review or approve requests for use under the Right to Try Act. FDAs role is limited to receipt and posting of certain information submitted under the Right to Try Act. Section 561B (C)(b) of the Right to Try Act (Public Law 115-176), Investigational Drugs For Use By Eligible Patients, describes the requirement to be in compliance with the applicable regulations set forth in section 312.8(d)(1) of the CFR [Code of Federal Regulations].

At this point, it seems clear to me that a company cant profit from selling its unapproved treatments to patients outside of clinical trials, but that its unlikely the rule would be enforced because as Turner put it, The FDA is not actively involved in scrutinizing any of this. The Right to Try law stops the agency from overseeing requests.

When I present this information to Feshbach, however, he explains that I am missing a key detail. The price of the treatment itself cannot exceed the companys cost of providing access to it, but the law does not address additional costs like having a doctor administer the treatment on-site.

While the cost of knee injections average $5,000, some stem cell treatments cost tens of thousands of dollars. In 2018, one company said it may even charge several hundreds of thousands to patients who requested their Right to Try a treatment that had demonstrated little efficacy even in the companys own trials. The company later announced it would offer the treatment to only a limited number of patients through expanded access, and that it would do so for free. One for-profit cancer treatment company currently offers Right to Try treatments alongside other options.

Some types of minimally manipulated regenerative medicine are still exempt from much FDA oversight, requiring only that their facilities keep up manufacturing standards that limit contamination. Even in these instances, there is a movement among some researchers to collect better data on patient outcomes, in hopes of better understanding who benefits from the treatments and when.

At the Center for Regenerative Orthopedic Medicine at the Feinstein Institutes for Medical Research, where Daniel Grande, PhD is the scientific director, he and others provide, for a fee, platelet-rich plasma and stem cell injections derived from a patients own bone marrow or fat, with techniques that fall under the FDAs lowest-risk tier and are thus not subject to the clinical trial process.

But he laments the lack of consistent data reporting in the field. He says you can do a literature search and find thousands of papers on a particular procedure only to realize theyre mostly individual case studies or lack a control group. We want to bring a standardization to the clinic, he says. For example, when Grande gives a patient a platelet-rich plasma treatment, he takes a sample of the blood and conducts a complete blood count, which analyzes the concentration of different cells and biomarkers in your blood to evaluate overall health and diagnose certain diseases. Next, he takes a sample of just the plasma. Both are stored in freezers for continued analysis. Then [I] follow these patients from zero to one year to see how they actually do, he adds.

Grande is not alone. His group has teamed up with several other institutions, including the Cedars-Sinai Medical Center, Northwell Health, Hospital for Special Surgery, Cleveland Clinic, Mayo Institute, Stanford University and the University of Colorado Denver, to form the Biological Alliance of Regenerative Medicine and Biorepository. He says its members have committed to measuring the same variables through treatment and sharing data in hopes of answering questions about who the treatments are most likely to help and how many stem cells are actually needed for best results. In the first year, their goal is to enroll 1,400 patients. Grande also hopes the effort may lead to insurance companies eventually reimbursing for the procedures.

Theres a movement underway nationally to better characterize these regenerative therapies in a way that everybody can either figure out whats going on [with them], Grande adds. Theres a call to action for trying to better characterize these things and to provide information to not only clinicians, but also [to] the public about what works and what doesnt, so that people can be informed.

Continued here:
Part 3: Moving Forward and Keeping Stem Cell Treatments Safe - MedShadow

Early Promise of AntiCLL-1 CAR T-Cell Therapy Reported in Pediatric AML – Cancer Network

Feasibility of chimeric antigen receptor (CAR) T-cell therapy targeting C-type lectin-like molecule-1 (CLL-1) for pediatric patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) was validated in a small patient cohort in a phase 1/2 trial (ChiCTR1900027684), results of which were presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

At an interim analysis, 10 of 11 patients completely responded to anti-CLL1based CAR-T cell therapy, with CLL-1positive AML blasts eliminated within 1 month. Six patients achieved complete remission with minimal residual disease (MRD) negativity, added lead investigator Hui Zhang, MD, PhD, an assistant professor at Shanghai Childrens Medical Center and director of Guangzhou Women and Childrens Medical Center at Chinas Guangzhou Medical University.

From all the research shown, we can say that anti-CLL1 based CAR T-cells is a safe therapeutic candidate with manageable CAR T-cellassociated toxicity for children with R/R AML, he said. It is highly effective in targeting CLL1-positive AML cells with superior overall response rate (ORR) relative to conventional/novel targeting compounds.

In this study, 11 pediatric R/R AML patients aged 2 to 16 years were infused between October 2019 and January 2021 with a second-generation CLL1 CAR-T created in Zhangs laboratory. Investigators administered a single dose of CLL1 or CLL1-CD33 dual CAR-T cells (target dose: 0.3-1 x 106/kg) following lymphodepleting conditioning with a cyclophosphamide/fludarabine combination.

Zhang said all 11 patients experienced CAR T-cell expansion in vivo during the first month. Five patients demonstrated persistence of T-cell expansion.

All patients experienced grade 1 to 3 cytokine release syndrome (CRS) but there were no lethal events, Zhang said. All patients experienced myelosuppression, which he said might be due to chemotherapy. Three patients experienced a grade 1/2 hepatic event. No patient experienced cardiac, renal, or gastrointestinal adverse events.

Investigators have suggested that CLL-1 is a promising target because it not expressed on normal hematopoietic stem cells (HSCs), but is expressed on 85% to 92% of AML blasts cells and leukemia stem cells.2 In a humanized mouse model, investigators demonstrated that CAR T-cell therapy specific for CLL-1 exhibit potent cytokine production and cytotoxicity against CLL-1-expressing AML cell lines without disrupting normal HSCs.

Investigators theorized that developing an anti-CLL1 CAR T therapy would help patients avoid the need for HSC transplant.

In 2020, Zhang published a case study of a 10-year-old girl who presented with an elevated peripheral blood blast percentage while undergoing maintenance treatment for a B-cell ALL relapse. Investigators developed a CAR containing a CLL1-specific single-chain variable fragment.3

The patient received lymphodepleting chemotherapy for 4 days before CAR T-cell transfer to enhance in vivo expansion of CAR T-cells. This was followed by a single dose anti-CLL1 CAR-T cells infusion. She experienced Grade 1 to CRS.

After completing CAR T-cell therapy, the patient achieved a complete response and was negative for MRD (<0.1%) on day 29. But the CLL1+ cells were not completely eliminated until 6 months after CAR T-cell therapy. The patient achieved a 10-month response using 1 dose of anti-CLL1 CAR-T monotherapy.

References

1. Zhang H, Bu C, Pen Z, et al. The efficacy and safety of anti-CLL1 based CAR-T cells in children with relapsed or refractory acute myeloid leukemia: A multicenter interim analysis. J Clin Oncol. 2021;39(suppl 15):10000. doi:10.1200/JCO.2021.39.15_suppl.10000

2. Tashiro H, Sauer T, Shum T, et al. Treatment of acute myeloid leukemia with T cells expressing chimeric antigen receptors directed to C-type lectin-like molecule 1. Mol Ther. 2017;25(9):2202-2213. doi:10.1016/j.ymthe.2017.05.024

3. Zhang H, Gan WT, Hao, WG, et al. Successful ant-CLL1 CAR T-cell therapy in secondary acute myeloid leukemia. Front Oncol. 2020;10:685. Doi:10.3389/fonc.2020.00685

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Early Promise of AntiCLL-1 CAR T-Cell Therapy Reported in Pediatric AML - Cancer Network

Innovative research refines the treatment of patients with advanced cancers and the use of immunotherapy – Network News, Press Releases – Hackensack…

June 4, 2021

John Theurer Cancer Center investigators report new findings at American Society of Clinical Oncology 2021 Annual Meeting

Researchers from Hackensack University Medical Centers John Theurer Cancer Center, a part of Georgetown Lombardi Comprehensive Cancer Center, are presenting data from 25 studies at the Annual Meeting of the American Society of Clinical Oncology, the largest gathering of cancer professionals in the country. This years meeting is being held virtually June 4-8, 2021. Abstracts of the studies can be viewed at abstracts.asco.org.

At John Theurer Cancer Center patients have access to the latest cancer treatments and technologies, including those being evaluated in clinical trials. People with all types and stages of cancer are treated by world-renown experts. The cancer center is especially well-known for its research that drives treatment guidelines, and expertise in the management of hematologic cancers, having pioneered more effective therapies for leukemia, lymphoma, and multiple myeloma. John Theurer Cancer Center was the first center in New Jersey to offer CAR T-cell therapy, a revolutionary immunotherapy for patients with select leukemias and lymphomas. The center is home to one of the nations largest bone marrow transplant programs, with more than 7,500 completed.

Many of the studies being presented at ASCO report on novel treatments for patients with recurrent or persistent multiple myeloma or non-Hodgkin lymphomas (including mantle cell lymphoma, an especially challenging type), as well as acute myeloid leukemia and chronic lymphocytic leukemia. John Theurer Cancer Center investigators are also leaders in the development of immunotherapy regimens, and several of the studies being presented at ASCO evaluated its effectiveness and side effects, including real-world data in unique patient populations. Other studies report provocative findings on targeted therapies and other treatments for kidney and bladder cancers, brain cancer, and other solid tumors. Data from the following studies by John Theurer Cancer Center researchers are being presented at ASCOs 2021 virtual meeting:

Blood Cancers and Stem Cell Transplantation

Developmental Therapeutics and Immunotherapy

Targeted Therapies and Tumor Biology

Central Nervous System Tumors

The COVID-19 pandemic challenged health care in ways we have never been challenged before. Despite the obstacles it presented, however, investigators at John Theurer Cancer Center continued to expand our understanding of cancer, refine its treatment, and develop innovative approaches to improve patient outcomes," asserted Andre Goy, M.D., M.S., chairman and executive director of John Theurer Cancer Center.

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Innovative research refines the treatment of patients with advanced cancers and the use of immunotherapy - Network News, Press Releases - Hackensack...

In Some Heavily Pretreated Patients with R/R MM Ide-Cel Continues to Show Deep and Durable Responses – Targeted Oncology

Long-term follow-up data from the KarMMa trial found that treatment with the chimeric antigen receptor (CAR) T-cell therapy, idecabtagene vicleucel (ide-cel; formerly bb2121; Abecma), continues to demonstrate improved survival among heavily pretreated patients with relapsed/refractory multiple myeloma, according to a presentation presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

The favorable benefit risk profile of ide-cel, regardless of the number of prior lines of therapy, supports its role as a treatment option for heavily pretreated relapse refractory multiple myeloma, Larry D. Anderson, MD, PhD, associate professor, UT Southwestern Medical Center, said during a presentation of the poster.

At the December 21, 2020, data cutoff, the median follow-up was 24.8 months (range, 1.7-33.6).

Overall response rate (ORR) was 73% in the overall population, including a 33% complete response rate (CRR; complete response [CR] or stringent complete response [sCR]), 20% with a very good partial response (VGPR), and 20% who had a partial response (PR). ORR rates were 50%, 69%, and 81%, respectively, across the 150, 300, and 450 million CAR T cell-dose arms, including CR/sCR rates of 25%, 29%, and 39%.

Of note, ORR did not vary by the number of prior lines of therapy received. For those who received 3 prior lines of therapy (n = 15), the ORR was 73%, including a CRR of 53% and VGPR of 20%, compared with an ORR of 73% in those who received 4 (n = 112) lines of therapy, including a CRR of 30%, VGPR of 23%, and PR of 20%.

Median duration of response (DOR) was 10.9 months (95% CI, 9.0-11.4), including 9.9 months for the 300 million CAR T cells-dose arm and 11.3 months for the 450 million CAR T cells-dose arm -dose arm. Median DOR was 21.5 months in patients who experienced a CR or sCR. Median DOR by response were 21.5 months (95% CI, 12.5 to not estimable [NE]) among those who experienced a CR, 10.4 months (95% CI, 5.1-12.2) for those with VGPR, and 4.5 months (95% CI, 2.9-6.7) in those with PRs.

Moreover, the rate of event-free 24-month DOR appeared to be similar in patients who received 3 or 4 or more lines of therapy. For those who received 3 lines of prior therapy, median DOR was 8.0 months (95% CI, 3.3-11.4), compared with 10.9 months (95% CI, 9.2-13.5) in those who received 4 or more lines of therapy.

Median progression-free survival (PFS) was 8.6 months (95% CI, 5.6-11.6) across all target doses, including 5.8 months for the 300 million CAR T cells-dose arm and 12.2 months for the 450 million CAR T cells-dose arm -dose arm. Similarly, median PFS was similar among those who previously received 3 lines of therapy, compared with 4 or more prior lines of therapy (8.6 months (95% CI, 2.9-12.1) vs 8.9 months (95% CI, 5.4-11.6)]

The median time to first response was 1 month (range, 0.5-8.8), with a median time to CR of 2.8 months (range, 1.0-15.8).

Median overall survival (OS) was 24.8 months (95% CI, 19.9-31.2), including a median OS of 22.0 months (95% CI, 10.-NE) in those who received 3 lines of prior therapy and 25.2 months (95% CI, 19.9-NE) in those who received 4 or more lines of prior therapy. Moreover, OS was 20 months or longer across several key high-risk subgroups, including those aged 65 or older (21.7 months; 95% CI, 17.1-31.2), those with extramedullary disease (20.2 months; 95% CI, 15.5-28.3), and those with triple refractory disease (21.7 months; 95% CI, 18.2-NE).

In regards to safety, cytokine release syndrome (CRS) and neurotoxicity were similar, regardless of prior lines of therapy received, and were mostly low grade. In total, 85% and 18% of the overall population experienced at least 1 CRS or neurotoxicity event, respectively.

The safety profile of ide-cel was consistent with long-term follow-up, with similar rates of infections and secondary primary malignancies, and no unexpected gene therapy related toxicities were observed. The most common grade 3 to 4 adverse events (AEs) in the overall population were neutropenia (89%), anemia (61%), thrombocytopenia (52%), leukopenia (39%), lymphopenia (27%), and infections (27%).

Long-term results from the KarMMA trial continue to demonstrate frequent, deep, and durable responses in heavily pretreated patients with [relapsed/refractory multiple myeloma], the study authors write in the poster. ORR, CRR, DOR, and PFS were consistent with previous reports and patients received similar benefit regardless of the number of prior lines of therapy.

In his presentation, Anderson presented data on long-term efficacy and safety following treatment with ide-cel in the pivotal phase 2 KarMMa trial (NCT03361748)-including overall data and by prior line of therapy that patients had received (3 vs 4), since the FDA label is requiring at least 4 prior lines, and this study only required 3, he added.

In total, 140 patients who had received at least 3 prior lines of therapy for multiple myeloma including an IMiD, a PI, and an anti-CD38 antibody and were refractory to their last treatment regimen, were enrolled in the study. However, only 128 patients received infusion with ide-cel.

Patients were treated with ide-cel across the target dose range of 150 (n = 4), 300 (n = 70), and 450 (n = 54) million CAR T cells.

ORR served as the primary end point of the study. Secondary end points included CRR, safety, DOR, PFS, OS, pharmacokinetics, minimal residual disease, quality of life, and health economics and outcomes research.

At baseline, the median patient age was 61 years (range, 33-78) and patients had a median of 6 years (range, 1-18) since their diagnosis. A majority of the patients were male (59%), had high tumor burden (51%), B-cell maturation antigen (BCMA) expression 50% at screening (85%), ECOG performance status of 1 (53%), and Revised International Staging System disease stage of II (70%). Thirty-five percent of patients had high-risk features.2

The median number of prior therapies was 6 (range, 3-16) and 94% had previously undergone at least 1 autologous hematopoietic stem cell transplant (94%). Eighty-eight percent of patients required bridging therapy. Eighty-nine percent of patients had double-refractory disease, 84% were triple-refractory, and 26% were penta-refractory.

Patients who had received 3 prior lines of therapy had similar baseline characteristics, compared with those who received 4 prior lines, including differences in extramedullary disease, high-risk cytogenetics, prior refractoriness, and time since the initial diagnosis to screening.

Patients with relapsed/refractory multiple myeloma previously exposed to immunomodulatory agents, protease inhibitors, and anti-CD38 antibodies have poor outcomes with subsequent therapy using previously approved regimens, with expected response rates in the 26% to 31% range, PFS in the 2- to 4-month range, and overall survival less than 9 months, Anderson explained.

However, the BCMA-directed CAR T-cell therapy previously demonstrated favorable tolerability with deep, durable responses in patients who were heavily pretreated with relapsed/refractory multiple myeloma.2 As a result, the FDA approved the agent for the treatment of adult patients with relapsed or refractory multiple myeloma after 4 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, representing the first BCMAdirected CAR T-cell therapy approved.3

The study authors noted that ide-cel is being explored in ongoing clinical trials, including the following:

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In Some Heavily Pretreated Patients with R/R MM Ide-Cel Continues to Show Deep and Durable Responses - Targeted Oncology

Mustang Bio to Host Key Opinion Leader Webinar on MB-106 CD20-Targeted CAR T for the Treatment of High-Risk B-Cell Non-Hodgkin Lymphomas and Chronic…

Webinar to be held Tuesday, June 15, 2021, at 1:00 p.m. ET

WORCESTER, Mass., June 07, 2021 (GLOBE NEWSWIRE) -- Mustang Bio, Inc. (Mustang) (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, today announced that it will host a key opinion leader (KOL) webinar on MB-106 CD20-targeted CAR T cell therapy, which is being developed for high-risk B-cell non-Hodgkin lymphomas (B-NHL) and chronic lymphocytic leukemia (CLL), on Tuesday, June 15, 2021, at 1:00 p.m. Eastern Time.

The webinar will feature a presentation by Mazyar Shadman, M.D., M.P.H., Associate Professor at the Fred Hutchinson Cancer Research Center (Fred Hutch), who will discuss interim results from the ongoing Phase 1/2 clinical trial investigating the safety and efficacy of MB-106 CD20-targeted CAR T for B-NHL and CLL. These data have been selected for an e-poster presentation at the European Hematology Association 2021 Virtual Congress (EHA2021), which is being held June 9-17. Dr. Shadman, along with colleague Brian Till, M.D., also an Associate Professor at Fred Hutch, will be available to answer questions following the formal presentations.

Mustangs management team will also provide more details on the planned MB-106 Phase 1/2 clinical trial to be conducted under Mustangs Investigational New Drug (IND) application. The Company recently announced that the U.S. Food and Drug Administration (FDA) accepted its IND to initiate a multicenter Phase 1/2 clinical trial investigating the safety, tolerability and efficacy of MB-106 for relapsed or refractory B-NHL and CLL.

To participate in the webinar, please register here.

About Dr. Shadman Mazyar Shadman, M.D., M.P.H., is an Associate Professor at the University of Washington (UW) and Fred Hutch. He is a hematologic malignancies expert who specializes in treating patients with lymphoma and CLL.

Dr. Shadman is involved in clinical trials using novel therapeutic agents, immunotherapy (CAR T cells), and stem cell transplant for treatment of lymphoid malignancies with a focus on CLL. He also studies the clinical outcomes of patients using institutional and collaborative retrospective cohort studies.

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Dr. Shadman received his M.D. from Tehran University in Iran. He finished an internal medicine internship and residency training at the Cleveland Clinic in Cleveland, Ohio. He completed his fellowship training in hematology and medical oncology at UW and Fred Hutch. Dr. Shadman also earned an M.P.H. degree from UW and was a fellow for the National Cancer Institutes cancer research training program at Fred Hutch, where he studied cancer epidemiology.

About Dr. Till Brian Till, M.D., is an Associate Professor in the Clinical Research Division of Fred Hutch and Department of Medicine at UW. His laboratory focuses on developing chimeric antigen receptor (CAR)-based immunotherapies for non-Hodgkin lymphoma and understanding why CAR T cell therapies work for some patients but not for others. He led the first published clinical trial testing CAR T cells as a treatment for lymphoma patients. Dr. Till also has a clinical practice treating patients with lymphoma and attends on the stem cell transplantation and immunotherapy services at the Seattle Cancer Care Alliance.

About Mustang Bio Mustang Bio, Inc. is a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR T therapies across multiple cancers, as well as a lentiviral gene therapy for X-linked severe combined immunodeficiency. Mustang is registered under the Securities Exchange Act of 1934, as amended, and files periodic reports with the U.S. Securities and Exchange Commission (SEC). Mustang was founded by Fortress Biotech, Inc. (NASDAQ: FBIO). For more information, visit http://www.mustangbio.com.

ForwardLooking Statements This press release may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. Such statements include, but are not limited to, any statements relating to our growth strategy and product development programs and any other statements that are not historical facts. Forward-looking statements are based on managements current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock value. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our growth strategy; our ability to obtain, perform under, and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; risks relating to the timing of starting and completing clinical trials; uncertainties relating to preclinical and clinical testing; our dependence on third-party suppliers; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law, and we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995.

Company Contacts: Jaclyn Jaffe and Bill Begien Mustang Bio, Inc. (781) 652-4500 ir@mustangbio.com

Investor Relations Contact: Daniel Ferry LifeSci Advisors, LLC (617) 430-7576 daniel@lifesciadvisors.com

Media Relations Contact: Tony Plohoros 6 Degrees (908) 591-2839 tplohoros@6degreespr.com

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Mustang Bio to Host Key Opinion Leader Webinar on MB-106 CD20-Targeted CAR T for the Treatment of High-Risk B-Cell Non-Hodgkin Lymphomas and Chronic...

Karen Hasty Named Among 2021 Super Women In Business by Memphis Business Journal – UTHSC News

Karen Hasty, PhD, a professor, researcher, and director of Basic Research in the Department of Orthopaedic Surgery and Biomedical Engineering/Campbell Clinic in the College of Medicine at the University of Tennessee Health Science Center, has been named among the 2021 Super Women in Business by the Memphis Business Journal. The annual list honors women business leaders for their career accomplishments and work in the Memphis community.

I am thrilled to receive this honor, said Dr. Hasty, who holds the George Thomas Wilhelm Endowed Professorship in Orthopaedic Surgery. It allows me to have a new platform to bring attention to many philanthropic projects, while continuing to encourage young women to consider medical careers in orthopaedic surgery or in academia.

Dr. Hastys philanthropic efforts include establishing a summer internship for undergraduate women called the Kappa Delta Foundation Orthopaedic Research Internship, which encourages them to consider orthopaedic surgery as a career option. It provides stipends, housing, and research funding for selected participants. She has also served as the medical chair for the West Tennessee Board of the Arthritis Foundation since 2017.

Because of her professional appointment, Dr. Hasty holds a dual position with UTHSC and the Memphis VA Medical Center, where she does basic science research. Studying arthritis for more than four decades, her current studies focus on exploring new therapies to interrupt the disease progression and stimulate repair of joint destruction. Dr. Hastys research efforts have been funded by the VA, the National Institutes of Health, the Department of Defense, and the Arthritis Foundation.

She is currently in a research collaboration with Revotek Co., Ltd., in the Memphis Institute of Regenerative Medicine (MIRM). The project titled, MIRM Project 3: Stem Cell-Enhanced Tissue Regeneration: Engineering of Vascularized Bone/Cartilage Graft from Adipose-Derived Stem Cells, will utilize Revoteks cell encapsulation technology of Biosynspheres and bioprinting for basic and translational research in stem cell regenerative medicine.

Dr. Hasty earned her Bachelor of Science degree in microbiology from the University of Tennessee, Knoxville and received her MS and PhD degrees in anatomy from UTHSC. She began working at the university in 1977, after a stint at Boston Childrens Hospital, where she studied hemoglobin A1c, a marker that determines long-term control of blood glucose in diabetes.

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Karen Hasty Named Among 2021 Super Women In Business by Memphis Business Journal - UTHSC News

High Overall Response Rates Achieved With Cirmtuzumab/Ibrutinib in MCL and CLL – Targeted Oncology

The combination of cirmtuzumab and ibrutinib (Imbruvica) achieved high overall response rates (ORR) in patients with mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) who were treated in a phase 1/2 study, according to findings from presented during the 2021 ASCO Annual Meeting.

The safety profile of the treatment regimen was also well tolerated, Hun Ju Lee, MD stated during the presentation.

The majority of the patients demonstrated a significant reduction in tumor sizes, lead study author Lee, assistant professor of medicine in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center said during the presentation.

ORR for patients with MCL was 83.3% and was 91.1% for patients with CLL. The complete response rates were 38.9% and 14.7% for the MCL and CLL arms, respectively. Ultimately, 94.4% of patients with MCL and 100% of patients with CLL elicited a clinical benefit from the cirtuzumab/ibrutinib regimen.

The median progression free survival in both cancers was not reached.

Because MCL and CLL are considered incurable, the study aimed to test the efficacy and safety profile of cirmtuzumab, which inhibits tumor promoting activity of onco-embryonic tyrosine kinase receptor ROR1 found in many solid and hematologic cancers, plus ibrutinib in patients with relapsed/refractory MCL or treatment nave or relapsed/refractory CLL.

The study was performed in 3 parts with separate arms. Part 1, for dose escalation; part 2, for dose expansion; and part 3, comparing cirmtuzumab plus ibrutinib with ibrutinib alone in CLL.

Overall, 26 patients with refractory MCL (median age 66.5, 15.4% women) and 34 patients with treatment nave or RR CLL (median age 68, 23.5% women) were enrolled in the study.

For part 1, 12 patients with MCL were enrolled, and 5 into part 2. The median number of prior regimens was 2, including patients relapsing after ibrutinib (n=4), autologous stem-cell transplantation (n=3), autologous stem cell transplantation/allogenic stem cell transplantation (1) and autologous stem cell transplantation /CAR-T (1). For patients with CLL, at least 74% were high risk, as determined by unmutated IGHV, del17p and/or del11q, in parts 1 and 2.

In part 1, cirmtuzumab was given intravenously 5 times every 2 weeks, and then every 4 weeks, at 2 to 16 mg. Three-hundred or 600 mg doses were also examined. Researchers assessed the safety profile of cirmtuzumab during the first 28 days, which was then followed by ibrutinib at approved doses for each indication. A treatment regimen of cirmtuzumab (600 mg) given intravenously 3 times every 2 weeks, and then every 4 weeks, in combination with ibrutinib starting day 0, was chosen as the recommended dosing for parts 2 and 3.

In summary, cirmtuzumab plus ibrutinib is a very well tolerated regimen, Lee noted.

Adverse events with 20% or greater incidence were recorded, including fatigue (n=11), diarrhea (n=9), contusion (n=7), dizziness (n=7) and nausea (n=7). The efficacy is robust in many of these pre-treated patients, [including] high response, rate durable response [and] encouraging PFS, demonstrating clinical benefit, he concluded.

Of note, the phase 2 study for CLL is completed, and is awaiting a long-term follow-up. Phase 2 for MCL is currently enrolling.

References

Lee HJ, Choi M, Siddiqi T, et al. Phase 1/2 study of cirmtuzumab and ibrutinib in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL).J Clin Oncol. 2021;39(suppl 15; abstr 7556).

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High Overall Response Rates Achieved With Cirmtuzumab/Ibrutinib in MCL and CLL - Targeted Oncology

Chao family gifts to UCI Health for cancer care top $50 million – UCI News

Orange, Calif., June 1, 2021 With its current gift, longtime UCI Health benefactor the Chao family has committed $50 million since 1995 to UCI Health toward advancing cancer care in Orange County and beyond. The familys latest gift will name the cancer center at the new UCI Medical Center in Irvine, expanding access to leading-edge cancer treatments and therapies, promising clinical trials, and world-class cancer care driven by the latest in precision medicine.

Few families have been as generous in support of their fellow residents of Orange County as the Chao family, said Chancellor Howard Gillman. This latest extraordinary gift is testament to their belief in the power of academic medicine to lead the fight against cancer and to provide the best and most up-to-date care to cancer patients.

The Chao Family Comprehensive Cancer Center and Ambulatory Care will be one of three medical facilities at the new $1.2 billion medical center adjacent to the UCI campus; the others are a 144-bed acute care hospital with an emergency department and the Center for Advanced Care. The cancer care center is strategically located at the new medical center campus in Irvine to allow patients to receive multidisciplinary care by interprofessional and integrative teams working together to apply the latest innovations from university-backed clinical research.

The Chao familys commitment to UCI and the fight against cancer has brought much-needed hope to patients and their families over the past 25 years, said Steve A.N. Goldstein, M.A., M.D., Ph.D., FAAP, UCI vice chancellor for health affairs. Their most recent gift extends the opportunity for cancer patients to receive lifesaving therapies and empowers the worlds top cancer clinician-scientists to advance cancer treatment through personalized healthcare. This is only possible at an academic health center committed to developing and applying advanced AI, machine-learning, genomics and therapeutics to clinical practice.

More than anyone else, the Chao familys generosity and dedication has changed the face of cancer care and research in Orange County, said Richard Van Etten, M.D., Ph.D., director of UCIs Chao Family Comprehensive Cancer Center in Orange, the only National Cancer Institute-designated comprehensive cancer center based in Orange County. The Chao familys investment allows UCI Health to treat the most complex cancers, and patients benefit from the power of the University of California Cancer Consortium.

Since their first gift to the university in 1995, three generations of Chaos have supported the growth of UCIs cancer program, including expanded clinical care and advanced research facilities and the creation last year of Orange Countys only adult hematopoietic stem cell/bone marrow transplant program. Today, UCIs Chao Family Comprehensive Cancer Center in Orange is one of only 51 NCI-designated centers across the U.S. those that meet the highest standards for an institutions commitment to and excellence in cancer research and clinical care.

Doing good in our community has always been very important to our family, said Allen Chao. We are proud to continue our partnership with UCI and to know that community members from all walks of life benefit from the lifesaving treatments offered here.

Its a value passed down to us from our matriarch and patriarch, Hsu Hwa Chao and Hsi Hsiung Chao, he said.

In 1999, Allen Chao developed stomach cancer. He sought the care of UCI Health gastroenterologistDr. Kenneth Chang, who helped to remove all signs of the disease. Chang, head of gastrointestinal oncology, also directs UCIs Chao Family Comprehensive Digestive Disease Center (CDDC), supported by the Chao family as part of its vision to expand access to cancer care.

The CDDC is a multidisciplinary center where gastroenterologists, hepatologists, oncologists, surgeons and other specialists work in concert to provide the best care for the most complex digestive diseases, including cancer of the colon, liver, stomach, esophagus and pancreas. Under Changs leadership and with the support of the Chao family, the CDDC has become a leader in innovation and clinical care, advancing research and clinical trials on the development of treatments for digestive cancers. Chang has pioneered the development of endoscopic ultrasound guided fine-needle aspiration and injection, techniques that have revolutionized the intervention and treatment of many gastrointestinal diseases and cancers.

The Chao family has expanded access to the most innovative treatments for those with cancer and those with gastrointestinal diseases, which are also highly prevalent among the Asian population, Chang said.

The Chao familys commitment is a key to extending access to UCI Health cancer care and clinical trials to residents across the region. The new cancer center and hospital are slated to begin construction later this year and open in late 2023 and 2025, respectively, according to UCI Health CEO Chad Lefteris.

We encourage others to do good in their community in whatever way they can, Chao said. Philanthropy can take many forms and is not limited to financial support.

I commend the Chao family for their naming gift to the Comprehensive Cancer Center and Ambulatory Care facility at the UCI Medical Center in Irvine, and we are grateful for UCIs continued partnership and contributions to maintaining the wellbeing of Irvine, said Irvine Mayor Farrah Khan. This new facility will provide the world-class cancer research and care that befits the unsurpassed quality of life for Irvine residents by providing additional healthcare options and new jobs for the community.

Orange Countys landmark cancer center

Established in 1989 as Orange Countys first cancer center, the UCI facility in Orange achieved its initial National Cancer Institute cancer center designation in 1994 and comprehensive designation in 1997. The familys landmark 1995 gift catalyzed the universitys efforts to earn this status.

The significance for Orange County was profound. A region with a population greater than that of 20 states now had an institution where people with advanced-stage or treatment-resistant diseases could receive world-class cancer care advanced by basic and translational research, including access to early-phase clinical trials involving the very latest therapies.

A strong research base, in particular, helps drive progress, Van Etten said. It is our mission to translate the findings of basic research into treatments that can benefit patients. Institutions lacking their own research base can follow and adopt advances developed elsewhere, but they cannot lead in the same way comprehensive cancer centers that integrate research with clinical care can.

The current gift furthers UCI efforts to expand cancer prevention and screening, address disparities and provide equitable access to specialty cancer care. For example, enrollment in potentially lifesaving clinical trials increased by more than 260 percent between 2015 and 2020.

UCIs advancements in cancer care are made possible thanks to the Chao familys friendship and support, and we are excited to be able to offer this level of care across Orange County, Lefteris said. In just the last five years, the UCI Chao Family Comprehensive Cancer Center in Orange and our community locations across Orange County have seen more than 400,000 patient visits.

David Liu is one of the people whose lives were saved by UCI Health cancer specialists supported by the Chao family. Diagnosed with stage 3 colon cancer a decade ago at a community hospital, the Orange County resident turned to the regions only academic health system for treatment.

This is a wonderful organization, and I was treated by many excellent doctors, nurses and other staff, said Liu, an engineer and part-time musician whose band supports fundraisers for several community groups. It really touches me that the Chao family has committed to a vision of a cancer center available for everybody.

About the UCI Health: UCI Healthis the clinical enterprise of the University of California, Irvine. Patients can access UCI Health at primary and specialty care offices across Orange County and at its main campus,UCI Medical Center in Orange, Calif. The 418-bed acute-care hospital, listed among Americas Best Hospitals byU.S. News & World Reportfor 20 consecutive years, provides tertiary and quaternary care, ambulatory and specialty medical clinics, as well as behavioral health and rehabilitation services. UCI Medical Center is home to Orange Countys onlyNational Cancer Institute-designated comprehensive cancer center,high-risk perinatal/neonatal programandAmerican College of Surgeons-verified Level I adult and Level II pediatric trauma centerandregional burn center. It is the primary teaching hospital for theUCI School of Medicine. UCI Health serves a region of nearly 4 million people in Orange County, western Riverside County and southeast Los Angeles County. Follow us onFacebookandTwitter.

About the University of California, Irvine: Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities and is ranked among the nations top 10 public universities by U.S. News & World Report. The campus has produced three Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. Its located in one of the worlds safest and most economically vibrant communities and is Orange Countys second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit http://www.uci.edu.

About UCIs Brilliant Future campaign:Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for UCI. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UCI seeks to reach new heights of excellence instudent success, health and wellness, research and more. Learn more by visitingbrilliantfuture.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu. Additional resources for journalists may be found at communications.uci.edu/for-journalists.

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Chao family gifts to UCI Health for cancer care top $50 million - UCI News

New Data on KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Versus Sunitinib in First-Line Treatment for Patients With Advanced Renal Cell…

KENILWORTH, N.J., & WOODCLIFF LAKE, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai Inc. today announced new investigational data from the pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial, which evaluated the combinations of KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, and LENVIMA plus everolimus versus sunitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC). Results from a new analysis evaluating health-related quality of life (HRQoL) based on patient-reported outcomes are being presented during an oral abstract session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #4502). Data from CLEAR/KEYTNOTE-581 were originally presented at the 2021 Genitourinary Cancers Symposium (ASCO GU) and published in the New England Journal of Medicine, and data from this trial are currently under review with the U.S. Food and Drug Administration (FDA).

This press release features multimedia. View the full release here: https://www.businesswire.com/news/home/20210607005121/en/

This new analysis expands our understanding of the results weve seen from the CLEAR/KEYNOTE-581 trial in the treatment of patients with advanced renal cell carcinoma, said Dr. Robert Motzer, Medical Oncologist, Kidney Cancer Section Head, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center. The additional data showed an improvement of specific health-related quality of life measures for patients who received KEYTRUDA plus LENVIMA compared with sunitinib, supporting the importance of this combination as a potential new first-line treatment option for patients.

We continue to see an increasing number of patients diagnosed with advanced renal cell carcinoma and remain committed to improving outcomes for those facing this difficult-to-treat disease, said Dr. Gregory Lubiniecki, Vice President, Oncology Clinical Research, Merck Research Laboratories. This new analysis builds on earlier findings from the CLEAR/KEYNOTE-581 trial and further supports the potential use of KEYTRUDA plus LENVIMA for the treatment of patients in the first-line setting.

This analysis addresses questions of interest to healthcare professionals who treat patients with advanced renal cell carcinoma and reinforces the KEYTRUDA plus LENVIMA combination as a possible new treatment option for patients with this disease, said Dr. Takashi Owa, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. These results reflect Eisai and Mercks shared commitment to relentlessly pursue thorough scientific investigations with the goal of improving cancer care.

Data From HealthRelated Quality of Life (HRQoL) Analysis From CLEAR/KEYNOTE-581

In an analysis of a secondary endpoint of HRQoL scores in the CLEAR/KEYNOTE-581 trial, KEYTRUDA plus LENVIMA and LENVIMA plus everolimus were evaluated to determine the impact on HRQoL compared to sunitinib in patients with advanced RCC. This was assessed based on patient-reported outcomes using three HRQoL and symptom measures: Functional Assessment of Cancer Therapy Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer Core 30 (EORTC QLQ-C30) and European Quality of Life Five-Dimensions 3-Level System (EuroQoL EQ-5D-3L). Unless otherwise noted, HRQoL analyses were based on data from randomized patients who received at least one dose of study treatment. No adjustments for multiple testing or estimation were used; p-values (two-sided) and confidence intervals (CI) are nominal and descriptive. Longitudinal change from baseline was assessed by mixed model analysis. Least squares mean differences (LSMD) and 95% CI were calculated from baseline. Time to deterioration (based on changes in HRQoL and disease-related symptom scores meaningful thresholds) was assessed using time to first deterioration (TTD), which is the number of weeks between randomization and the first deterioration event, and time until definitive deterioration (TUDD), which is the number of weeks between randomization and the earliest deterioration event with no subsequent recovery above the deterioration threshold or no subsequent HRQoL assessment data. All times to deterioration were calculated and compared using the Kaplan-Meier method, stratified log-rank tests and Cox models.

KEYTRUDA plus LENVIMA demonstrated similar changes from baseline at mean follow-up (Week 46) on 14 out of 18 HRQoL and disease-related symptom scores and better HRQoL and disease-related symptom scores for the following measures (LSMD [95% CI]): physical functioning (3.01 [0.48, 5.54]), fatigue (-2.80 [-5.52, -0.08]), dyspnea (-2.79 [-5.33, -0.25]) and constipation (-2.19 [-4.19, -0.18]), as measured by the QLQ-C30, versus sunitinib. LENVIMA plus everolimus demonstrated similar changes from baseline at mean follow-up (Week 46) on 14 out of 18 HRQoL and disease-related symptom scores and worse HRQoL and disease-related symptom scores in the following measures (LSMD [95% CI]): Global Health Score/QoL (-2.81 [-5.08, -0.54]), pain (2.80 [0.11, 5.49]), appetite loss (4.23 [1.34, 7.13]) and diarrhea (5.26 [2.61, 7.91]) compared to sunitinib.

KEYTRUDA plus LENVIMA demonstrated a similar TTD in 14 out of 18 HRQoL and disease-related symptom scores, and a delay in TTD for physical functioning, dyspnea, appetite loss, and EQ-5D visual analog scale compared to sunitinib. KEYTRUDA plus LENVIMA demonstrated a delay in TUDD in 16 out of 18 HRQoL and disease-related symptom scores and a similar TUDD for cognitive functioning and financial difficulties compared to sunitinib.

Dr. Motzer has provided consulting and advisory services for Merck and Eisai.

About CLEAR (Study 307)/KEYNOTE-581

The CLEAR/KEYNOTE-581 trial is a multicenter, randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT02811861) evaluating LENVIMA in combination with KEYTRUDA or in combination with everolimus versus sunitinib for the first-line treatment of patients with advanced RCC. The primary endpoint is progression-free survival, as assessed by independent review per RECIST v1.1. Secondary endpoints include overall survival, objective response rate, HRQoL and safety. A total of 1,069 patients were randomized (1:1:1) to receive:

Treatment continued until unacceptable toxicity or disease progression as determined by the investigator and confirmed by independent radiologic review committee using RECIST v1.1. Administration of KEYTRUDA plus LENVIMA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA was continued for a maximum of 24 months; however, treatment with LENVIMA could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every eight weeks.

About Renal Cell Carcinoma (RCC)

Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In the U.S., it is estimated there will be nearly 76,000 new cases of kidney cancer diagnosed and almost 14,000 deaths from the disease in 2021. Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCC. Renal cell carcinoma is about twice as common in men as in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Approximately 30% of patients with RCC will have metastatic disease at diagnosis, and as many as 40% will develop metastases after primary surgical treatment for localized RCC. Survival is highly dependent on the stage at diagnosis, and the five-year survival rate is 13% for patients with metastatic disease.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, and fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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New Data on KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Versus Sunitinib in First-Line Treatment for Patients With Advanced Renal Cell...

Sorrento and Researchers at Karolinska Institutet Have Signed a Research Collaboration Agreement on iPSC-Derived Dimeric – GlobeNewswire

SAN DIEGOandSTOCKHOLM, Sweden, June 04, 2021 (GLOBE NEWSWIRE) -- Sorrento Therapeutics, Inc. (Nasdaq: SRNE, "Sorrento")today announced that the Company has entered into an additional collaborative agreement with NextGenNK Competence Center-associated research groups at the Department of Medicine, Huddinge, KarolinskaInstitutet(KI) inStockholm, Sweden, aimed at producing novelcell-based therapeutics using natural killer (NK) cells derived from induced pluripotent stem cells (iPSCs). Sorrento and KI are collaborative partners in the Competence Center for the development of next-generation NK cell-based cancer immunotherapies (NextGenNK) coordinated by KI.

Under the agreement, Sorrento willprovide know-how in the core chimeric antigen receptor (CAR) and dimeric antigen receptor (DAR) technologies and support the collaborative effort to develop newCAR-NK andDAR-NK candidates, as well as fund the translational validation of the technologies. Multiple product candidates will be developed and tested in the initial phase of the planned work, with the goal that the candidate products will qualify for further human clinical trials.

The foundational Sorrento research assets critical to this program are novel proprietary CAR and DARconstructsidentified through Sorrentos proprietary G-MAB fully human antibody library and previously validated as determinants of cell-based therapy potency against hematologic and solid tumors.

It is a privilege to continue and extend ourcollaborative workwith the distinguished KI faculty. We are proud to contribute our technologiesto producenewoptimizedoff-the-shelf adoptive NK cell immunotherapies," said Dr.Henry Ji, Chairman and CEO of Sorrento. "Our partnership with KIcombines our know-how with the expertise of aworld-renownedinstitution in thefield ofNK cell therapy.Thesetypes ofpartnershipsareessential inadvancing medicine and bringingnew solutionstocancerpatients inneed.

KI scientists within NextGenNK will establishiPSC-derived NK-basedtherapeutic candidatesutilizing Sorrentos constructs and DAR technology. Work within KI has contributed to the development of methodologies that consistently generate robust and potent NK cell lineages following iPSC differentiation. Clinical trials of NK cell-based therapies for treatment of multiple myeloma led by researchers at KI have yielded promising preliminary results with long-lasting remissions. In a very cross-knit collaboration between Sorrento and KI, the team will aim to establish novel allogeneic, off-the-shelf, retargeted NK cell-based therapies.

Utilizing iPSCs enables mass production of off-the-shelf NK cell therapies that leverage Sorrentos existing manufacturing infrastructure and know-how. Sorrento expects these validated re-engineered NK cell-based therapeutic candidates could potentially become a new generation in off-the-shelf treatments for cancer and infectious diseases. Thecoreresearch will be performed atKarolinskaInstitutet withactiveinvolvement oftheSorrento R&Dteamin San Diego.

The present collaboration brings together key competence from Sorrento and KI in an important area of cancer immunotherapy research. Sorrentos intellectual contribution to the research at the Competence Center is a critical piece in enabling retargeted off-the-shelf NK cell products, said Evren Alici, Principal Investigator at KI.

This is an important step in further enabling academic and industrial partnerships in the mission of achieving common goals for advancement of novel cancer immunotherapies, said Hans-Gustaf Ljunggren, Director of the NextGenNK Competence Center.

About Sorrento Therapeutics, Inc.

Sorrento is a clinical stage, antibody-centric, biopharmaceutical company developing new therapies to treat cancers and COVID-19. Sorrento's multimodal, multipronged approach to fighting cancer is made possible by its extensive immuno-oncology platforms, including key assets such as fully human antibodies (G-MAB library), clinical stage immuno-cellular therapies (CAR-T, DAR-T), antibody-drug conjugates (ADCs), and clinical stage oncolytic virus (Seprehvir). Sorrento is also developing potential antiviral therapies and vaccines against coronaviruses, including COVIGUARD, COVI-AMG, COVISHIELD, Gene-MAb, COVI-MSC and COVIDROPS; and diagnostic test solutions, including COVITRACK, COVISTIX and COVITRACE.

Sorrento's commitment to life-enhancing therapies for patients is also demonstrated by our effort to advance a first-in-class (TRPV1 agonist) non-opioid pain management small molecule,resiniferatoxin(RTX), and SP-102 (10 mg, dexamethasone sodium phosphate viscous gel) (SEMDEXA), a novel, viscous gel formulation of a widely used corticosteroid for epidural injections to treat lumbosacral radicular pain, or sciatica, and to commercializeZTlido (lidocaine topical system) 1.8% for the treatment of post-herpetic neuralgia. RTX has completed a Phase IB trial for intractable pain associated with cancer and a Phase 1B trial in osteoarthritis patients. SEMDEXA is in a pivotal Phase 3 trial for the treatment of lumbosacral radicular pain, or sciatica.ZTlido was approved by the FDA on February 28, 2018.

For more information, visit http://www.sorrentotherapeutics.com.

About KarolinskaInstitutet

Karolinska Institutet is one of the worlds leading medical universities. Our vision is to advance knowledge about life and strive towards better health for all. Karolinska Institutet accounts for the single largest share of all academic medical research conducted in Sweden and offers the countrys broadest range of education in medicine and health sciences. The Nobel Assembly at Karolinska Institutet selects the Nobel laureates in Physiology or Medicine.

For more information about KarolinskaInstitutet, visit https://ki.se/en/research/research-at-karolinska-institutet.

For more information about NextGenNK, visit https://ki.se/en/research/nextgennk.

Forward-Looking Statements

This press release and any statements made for and during any presentation or meeting contain forward-looking statements related to Sorrento Therapeutics, Inc., under the safe harbor provisions of Section 21E of the Private Securities Litigation Reform Act of 1995 and subject to risks and uncertainties that could cause actual results to differ materially from those projected. Forward-looking statements include statements regarding Sorrentos and KIs to bring off-the-shelf NK cell-based cancer treatments to patients; Sorrentos and KIs ability to produce novel cell-based therapeutics using NK cells derived from iPSCs; Sorrentos and KIs ability to develop new CAR-NK and DAR-NK candidates and to validate such technologies; the expectation that the collaborative effort will result in the development and testing of multiple product candidates and that any such product candidates will qualify for human clinical trials; the ability of KI scientists to establish iPSC-derived NK-based therapeutic candidates utilizing Sorrentos constructs and DAR technology; the expectation that utilizing iPSCs will enable mass production of off-the-shelf NK cell therapies; the potential for Sorrento to be able to use its existing manufacturing infrastructure and know-how to mass produce any off-the-shelf NK cell therapies; the potential for re-engineered NK cell-based therapeutic candidates to become a new generation in off-the-shelf treatments for cancer and infectious diseases; and the therapeutic potential of iPSC-derived NK-based therapeutic candidates. Risks and uncertainties that could cause our actual results to differ materially and adversely from those expressed in our forward-looking statements, include, but are not limited to: risks related to Sorrento's and its subsidiaries, affiliates and partners technologies and prospects and collaborations with partners, including, but not limited to: risks related to seeking regulatory approvals; clinical development risks, including risks in the progress, timing, cost, and results of clinical trials and product development programs; risk of difficulties or delays in obtaining regulatory approvals; risks that clinical study results may not meet any or all endpoints of a clinical study and that any data generated from such studies may not support a regulatory submission or approval; risks that prior test, study and trial results may not be replicated in future studies and trials; risks of manufacturing and supplying drug product; risks related to leveraging the expertise of its employees, subsidiaries, affiliates and partners to assist Sorrento in the execution of its therapeutic antibody product candidate strategies; risks related to the global impact of COVID-19; and other risks that are described in Sorrento's most recent periodic reports filed with the Securities and Exchange Commission, including Sorrento's Annual Report on Form 10-K for the year ended December 31, 2020, and subsequent Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission, including the risk factors set forth in those filings. Investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release and we undertake no obligation to update any forward-looking statement in this press release except as required by law.

Media and Investor Relations Contact Alexis Nahama, DVM (SVP Corporate Development) Email: mediarelations@sorrentotherapeutics.com

Sorrento and the Sorrento logo are registered trademarks of Sorrento Therapeutics, Inc.

G-MAB, DAR-T, SOFUSA, COVIGUARD, COVI-AMG, COVISHIELD, Gene-MAb, COVIDROPS, COVI-MSC, COVITRACK, COVITRACE and COVISTIX are trademarks of Sorrento Therapeutics, Inc.

SEMDEXA is a trademark of Semnur Pharmaceuticals, Inc.

ZTlido is a registered trademark owned by Scilex Pharmaceuticals Inc.

All other trademarks are the property of their respective owners.

2021 Sorrento Therapeutics, Inc. All Rights Reserved.

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Sorrento and Researchers at Karolinska Institutet Have Signed a Research Collaboration Agreement on iPSC-Derived Dimeric - GlobeNewswire