On June 12, 2022 Gracell Biotechnologies Inc. ("Gracell" or the "Company",NASDAQ: GRCL), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, reported the updated clinical data from a multicenter study evaluating GC012F, the Company’s autologous CAR-T therapeutic candidate dual-targeting B-cell maturation antigen (BCMA) and CD19, for the treatment of relapsed/refractory multiple myeloma (RRMM). Gracell shared the data at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress (EHA2022 Congress), held from June 9-12 in Vienna, Austria (Press release, Gracell Biotechnologies, JUN 12, 2022, View Source [SID1234615914]).

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"The updated data of the final dataset of 29 treated patients underscore the deep responses achieved with GC012F, including a 100% MRD negativity rate in all patients treated," commented Dr. Martina Sersch, Chief Medical Officer of Gracell. "GC012F for the treatment of RRMM continues to demonstrate a favorable safety profile and a promising mDOR of 15.7 months in mostly high risk, heavily pretreated patients, including those with extramedullary disease and those who were previously exposed to PI, IMiDs and anti-CD38 agents. In addition, we presented at EHA (Free EHA Whitepaper) the first-in-human data of GC012F in B-NHL, a potential second indication. We look forward to continuing developing this lead asset and providing a new treatment option to the patients with high unmet needs."

Additionally, on June 10, Gracell presented the first clinical results of the first-in-human phase 1 investigator-initiated study (IIT) in China evaluating the safety and tolerability of GC012F in B-cell non-Hodgkin’s lymphoma patients, and longer-term follow-up results of a safety and efficacy study from an IIT evaluating allogeneic TruUCAR-T GC502 in patients with B-cell acute lymphoblastic leukemia. Gracell announced these data in a press release on May 12.

BCMA/CD19 Dual-Targeting FasTCAR-T GC012F for the Treatment of RRMM
From October 2019 to January 2022, 29 heavily pretreated RRMM patients were enrolled and treated in this single-arm, open label, multicenter IIT with a single infusion of GC012F at three dose levels: 1×105 cells/kg (DL1), 2×105 cells/kg (DL2), and 3×105 cells/kg (DL3). 90% (26/29) patients were high risk based on mSMART 3.0 criteria and patients had received a median of five prior lines of therapy.

At the data cutoff of June 8, 2022, the 29 patients had been evaluated for response with a median follow-up duration of 11 months, ranging from 4.9 to 34.5 months. Patients continue to be followed for deepening responses. The response rate at different dose levels was 100% (2/2) in DL1, 80% (8/10) in DL2, and 100% (17/17) in DL3. All patients 100% (29/29) achieved minimal residual disease (MRD) negativity. 75.9% (22/29) of all patients treated achieved MRD- sCR. Median duration of response (DOR) at data cut off was 15.7 months (95% CI: 7.6-33.1).

The safety profile of GC012F was consistent with previous findings with mostly low grade of cytokine release syndrome (CRS). 93% (27/29) of events were Grade 0-2 and 7% (2/29) of events were Grade 3. No Grade 4 or 5 CRS, or any Grade immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Patients continue to be monitored for safety and efficacy including best overall response (BOR) and DOR. Due to the COVID-19 related lockdowns at the lead site of the study in Shanghai, China, follow-up assessment visits of certain patients were delayed and Gracell is looking forward to providing further updates in future publications for DOR, ORR, and BOR in all treated patients.

In November 2021, GC012F was granted Orphan Drug Designation for the treatment of multiple myeloma by the U.S. Food and Drug Administration.

Details of the presentation are as follows:

Abstract title: Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting FasTCAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM)
Session title: Relapsed/refractory myeloma: BCMA-directed therapies
Presentation time: Sunday, June 12 from 11:30 AM – 12:45 PM CEST
Presentation location: Hall A2-A3
For more information about the EHA (Free EHA Whitepaper)2022 Hybrid Congress, visit www.ehaweb.org.

Clinical update conference call and webcast details
Monday, June 13, 2022 @ 8:00AM ET
Investor domestic dial-in: (833) 693-0545
Investor international dial-in: +1(661) 407-1586
Conference ID: 1820109
Live webcast link: View Source
A replay of the webcast will be available on ir.gracellbio.com shortly after the conclusion of the event for 90 days.

About GC012F
GC012F is a FasTCAR-enabled dual-targeting CAR-T product candidate that is currently being evaluated in IIT studies in China for the treatment of multiple myeloma and B-cell non-Hodgkin’s lymphoma. GC012F simultaneously targets CD19 and BCMA to drive fast, deep and durable responses, which can potentially improve efficacy and reduce relapse in multiple myeloma and B-NHL patients.

About FasTCAR
CAR-T cells manufactured on Gracell’s proprietary FasTCAR platform appear younger, less exhausted and show enhanced proliferation, persistence, bone marrow migration and tumor cell clearance activities as demonstrated in preclinical studies. With next-day manufacturing, FasTCAR is able to significantly improve cell production efficiency which may result in meaningful cost savings, and, together with fast release time, enables enhanced accessibility of cell therapies for cancer patients.

On June 12, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that it has released results from a Phase I study of the company’s novel Bcl-2-selective inhibitor lisaftoclax (APG-2575) in Chinese patients with relapsed/refractory non-Hodgkin lymphoma (r/r NHL) at the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress (EHA 2022) (Press release, Ascentage Pharma, JUN 12, 2022, View Source;ascentage-pharma-releases-encouraging-results-of-bcl-2-inhibitor-lisaftoclax-apg-2575-in-chinese-patients-with-relapsedrefractory-non-hodgkin-lymphoma-301566251.html [SID1234615913]).

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The EHA (Free EHA Whitepaper) Congress is the largest gathering of the hematology field in Europe. It showcases the most cutting-edge research and state-of-the-art innovative therapies, attracting over 10,000 clinical experts and researchers from more than 100 countries every year.

The data presented at this year’s EHA (Free EHA Whitepaper) Congress show that lisaftoclax was well tolerated at doses of up to 800 mg/day, without evidence of tumor lysis syndrome (TLS). In addition, lisaftoclax demonstrated preliminary efficacy in a range of relapsed/refractory hematologic malignancies, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and T-cell NHL, having achieved 4 complete responses (CRs) and 8 partial responses (PRs) in 32 efficacy evaluable patients.

In the 11 efficacy evaluable patients with CLL (all of whom were heavily pretreated and had failed prior therapies such as chemoimmunotherapies and Bruton’s tyrosine kinase [BTK] inhibitors, and the majority had at least 1 type of adverse prognostic factors such as 17p deletion/TP53 mutation), there were 8 efficacy evaluable patients in cohorts received 200 mg or higher doses, including 3 CRs and 4 PRs, thus demonstrating an ORR of 87.5%. In the 6 efficacy evaluable patients with MCL, the ORR was 33.3% (1 CR). In the 4 efficacy evaluable patients with MZL, the ORR was 50%. In the 3 efficacy evaluable patients with T-cell NHL, the ORR was 33.3%.

Lisaftoclax is a novel, orally administered small-molecule Bcl-2-selective inhibitor being developed by Ascentage Pharma to treat hematologic malignancies and solid tumors by selectively blocking the antiapoptotic protein Bcl-2 and hence restoring the normal apoptosis process in cancer cells. Lisaftoclax is the first Bcl-2 inhibitor developed and entering clinical development in China, and is also the second such agent entering pivotal trials globally. Lisaftoclax is being studied in multiple clinical studies encompassing a range of solid tumors and hematologic malignancies, and has shown high clinical potential.

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, commented, "Lisaftoclax is a key drug candidate in Ascentage Pharma’s apoptosis-targeted pipeline. It has shown favorable tolerability and efficacy in multiple clinical studies in patients with solid tumors and hematologic malignancies. The drug candidate’s therapeutic potential was further validated by the data released at EHA (Free EHA Whitepaper) 2022. We will press ahead with the clinical development of lisaftoclax in efforts to bring a much-needed new treatment option to patients."

Highlights of this abstract on lisaftoclax are as follows:

Preliminary Results of a Phase 1 Study of Novel Bcl-2 Inhibitor Lisaftoclax (APG-2575) in Chinese Patients (pts) with Relapsed or Refractory (r/r) Non-Hodgkin Lymphomas (NHLs)

Abstract: #P1106

Highlights:

This multicenter, single-agent, Phase I trial consists of a dose escalation and a dose expansion and is the first-in-human study of lisaftoclax in adults with R/R NHL in China. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of lisaftoclax in Chinese patients with R/R NHL.
Patients were dosed with lisaftoclax orally once daily in 28-day cycles. A daily ramp-up schedule was used in patients with CLL or NHL with medium/high-risk TLS.
As of January 1, 2022, 40 patients had been treated with lisaftoclax (dose range 20-800 mg), including 20 who remain in the trial. NHL subtypes included: 12 CLL, 9 follicular lymphoma (FL), 7 MCL, 4 MZL, 4 T-cell lymphoma, 2 diffuse large B-cell lymphoma, and 2 Waldenström macroglobulinemia.
With a median treatment duration of 4 cycles, 4 of 32 evaluable patients achieved CR and 8 achieved PR, resulting in an ORR of 37.5%. In the 11 evaluable patients with CLL, the ORR was 63.6%, the CR rate was 27.3%, and the PR rate was 36.4%. In patients with CLL treated at doses ≥ 200 mg, the ORR was 87.5%. In the 6 evaluable patients with MCL, 1 patient achieved CR and 1 achieved PR. In the 4 evaluable patients with MZL, 2 achieved PR. In the 3 evaluable patients with T-cell NHL, 1 achieved PR.
Lisaftoclax was generally well tolerated. Most treatment-emergent adverse events (TEAEs) were grade 1-2 (67.5%). Dose-limiting toxicity (DLT) and laboratory/clinical TLS were not observed in any of the dose cohorts, and there were no dose-reduction or discontinuation due to intolerance.
Conclusions:

Lisaftoclax showed promising antitumor activity and favorable responses in subtypes of NHL including CLL/SLL, MZL, MCL, T-cell NHL. In addition, lisaftoclax demonstrated a favorable safety profile, with no TLS or DLT observed during the dose ramp-up from 20 mg – 800 mg/day.

On June 12, 2022 IASO Biotherapeutics ("IASO Bio"), a clinical-stage biopharmaceutical company engaged in discovering, developing, and manufacturing innovative cell therapies and antibody products, and Innovent Biologics, Inc. ("Innovent," HKEX: 01801), reported that the updated data from phase 1/2 study of Equecabtagene Autoleucel (IASO Bio R&D code: CT103A, Innovent R&D code: IBI326), a fully-human anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed and/or refractory multiple myeloma (R/R MM), was presented in the form of an oral presentation at the 27th European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting in Vienna on June 9-12, 2022 (Press release, IASO Biotherapeutics, JUN 12, 2022, View Source [SID1234615912]).

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Presentation Title: Updated Phase 1/2 Data of the Safety and Efficacy of CT103A, Fully-Human BCMA-Directed CAR-T Cells in Relapsed/Refractory Multiple Myeloma
Session Title: Relapsed/refractory myeloma: BCMA-directed therapies
Abstract Code: EHA (Free EHA Whitepaper)-S187
Session date and Time: Sunday, June 12, 2022, at 11:30 AM – 12:45 PM CEST
Place: Vienna, Austria or online
Speaker: Chunrui Li, MD, Ph.D., from Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology

The updated data from the Phase 1/2 study with a longer duration of follow-up in more patients has showed durable and deepening efficacy, manageable safety and long-term in vivo persistence, indicating that Equecabtagene Autoleucel has the potential to be a breakthrough therapy for patients with R/R MM.

The updated data is from the 14 clinical sites involved in the Phase 1/2 clinical study of Equecabtagene Autoleucel (ChiCTR1800018137, NCT05066646) in the treatment of patients with R/R MM. As of the data cutoff date of January 21, 2022, 79 patients received recommended phase 2 dose（RP2D）of 1.0×106 CAR-T cells/kg with the median follow-up of nine months (range 1.2, 19.6) and median prior five lines of therapy(range 3,23). Among the 79 patients, 34.2% (27/79) had high-risk cytogenetic abnormalities, 34.2%（27/79）had extramedullary multiple myeloma (EMM), and 15.2%（12/79）had received prior CAR-T therapy.

Equecabtagene Autoleucel demonstrated a favorable and manageable safety profile: Among the 79 patients, 94.9% (75/79) experienced cytokine release syndrome (CRS). The majority experienced 1~2 CRS, and no patient experienced grade 3 CRS. The median time to CRS onset was six days after infusion, and the median duration of CRS was five days. Only two patients experienced immune effector cell-associated neurotoxicity syndrome (ICANS), including one patient who experienced grade 1 ICANS and one who experienced grade 2 ICANS. All patients with CRS or ICANS have recovered.

Equecabtagene Autoleucel showed favorable and durable efficacy: Among the 79 patients, the overall response rate (ORR) was 94.9% (75/79), with 89.9 (71/79) of those patients achieving very good partial response (VGPR) or deeper responses, and the complete response/stringent complete response (CR/sCR) rate was 68.4% (54/79). Equecabtagene Autoleucel also demonstrated favorable efficacy in 10 patients with EMM, achieving an ORR of 100% (10/10) and a CR/sCR rate of 90.0% (9/10). In all 79 patients, 92.4% (73/79) achieved minimal residual disease (MRD) negativity, all CR/sCR subjects achieved MRD negativity, and the median duration of MRD negativity was not reached.

Equecabtagene Autoleucel demonstrated favorable efficacy in patients who had received prior CAR-T therapy: Among the 12 patients who previously received CAR-T therapy, the ORR was 75.0% (9/12), with 41.7% (5/12) of those patients achieving CR/sCR.

Equecabtagene Autoleucel demonstrated robust expansion and prolonged persistence: The expansion of Equecabtagene Autoleucel in peripheral blood reached the peak at a median of 12 days, with a median Cmax of 92,000 copies/ug DNA. Equecabtagene Autoleucel was still detectable in 62.3% (38/61) and 53.3% (8/15) of the subjects who completed 6-months and 12-month follow-ups after infusion. Soluble BCMA in peripheral blood of patients rapidly declined after Equecabtagene Autoleucel infusion and persistently remained below the detectable limit.

Equecabtagene Autoleucel has low immunogenicity: 16.5% (13/79) of the subjects tested anti-drug antibody (ADA)-positive after Equecabtagene Autoleucel infusion. Among them，1.3% (1/79) tested ADA-positive before Equecabtagene Autoleucel infusion, and 2.5% (2/79) tested ADA-positive within three months.

"Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. In our previous studies, Equecabtagene Autoleucel has shown excellent efficacy and manageable safety profiles. Its CAR structure contains fully human single-chain fragment variables (scFvs) to bypass potential anti-CAR immunogenicity of the host while retaining antitumor activity. At the 27th EHA (Free EHA Whitepaper) conference, we updated the data on the efficacy and safety of Equecabtagene Autoleucel in R/R MM patients with longer median follow-up extended to 9.0 months, the CR/sCR deepened to 68.4%, compared with the CR/sCR of 58.2% with a median follow-up of 7.0 months, which were released at 63rd ASH (Free ASH Whitepaper) conference in 2021. The updated data showed long-lasting safety and deepening efficacy of Equecabtagene Autoleucel. We are glad that Equecabtagene Autoleucel also shows favorable efficacy on patients who have relapsed after receiving prior CAR-T therapy. This has meaningful clinical value and is worthy of further exploration in the clinic to potentially bring forth new hope to patients with R/R MM." Prof. Chunrui Li, MD, PhD, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology.

About Multiple Myeloma (MM)
Multiple Myeloma is a deadly blood cancer that often infiltrates the bone marrow causing anemia, kidney failure, immune problems, and bone fractures. For multiple myeloma patients, common first-line drug treatments include proteasome inhibitors, immunomodulatory drugs, and alkylating agents. While treatment may result in remission, most patients will inevitably enter the relapsed or refractory stage as there’s currently no cure. As a result, there is a significant unmet need for patients with relapsed/refractory multiple myeloma. In the United States, MM accounts for nearly 2% of new cancer cases and more than 2% of all cancer-related deaths. According to Frost & Sullivan, the number of new MM cases in the United States rose from 30,300 in 2016 to 32,300 in 2020 and is expected to increase to 37,800 by 2025. Additionally, the total number of patients diagnosed with MM increased from 132,200 in 2016 to 144,900 in 2020 and is expected to rise to 162,300 by 2025. In China, the number of new MM cases rose from 18,900 in 2016 to 21,100 in 2020 and is expected to increase to 24,500 by 2025. The total number of patients diagnosed with MM in China increased from 69,800 in 2016 to 113,800 in 2020 and is expected to rise to 182,200 by 2025.

About Equecabtagene Autoleucel
Equecabtagene Autoleucel is an innovative therapy co-developed by Innovent and IASO Bio, with a fully-human anti- BCMA CAR-T cell therapy which uses lentivirus as a gene vector to transfect autologous T cells. The CAR contains a fully-human scFv, CD8a hinge and transmembrane, and 4-1BB-mediated co-stimulation and CD3ζ activation domains. Based on rigorous screening and comprehensive in vivo and in vitro evaluation, Equecabtagene Autoleucel is proven to have potent and rapid anti-myeloma activity and outstanding safety, efficacy, and persistence results.

Equecabtagene Autoleucel was granted "Breakthrough Therapy Designation (BTD)" by the NMPA kn February 2021 and was granted "Orphan Drug Designation (ODD)"by the Office of Orphan Products Development (OOPD) of the U.S. Food and Drug Administration (FDA) in February 2022. The NMPA has accepted the New Drug Application for Equecabtagene Autoleucel for the Treatment of Relapsed and/or Refractory Multiple Myeloma in June 2022.

In addition to multiple myeloma, the NMPA has accepted the investigational new drug (IND) application of Equecabtagene Autoleucel for a new expanded indication of Neuromyelitis Optica Spectrum Disorder (NMOSD).

On June 12, 2022 Novartis reported long-term results from the ELIANA pivotal clinical trial of Kymriah (tisagenlecleucel), the first-ever approved CAR-T cell therapy, in children and young adult patients with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL), with a maximum survival follow-up of 5.9 years (Press release, Novartis, JUN 12, 2022, View Source [SID1234615909]). For the 79 patients treated with Kymriah in this study, the five-year overall survival (OS) rate was 55% (95% CI, 43-66), while the median event-free survival (EFS) for patients in remission within three months of infusion (n=65) was 43.8 months. These findings demonstrate the curative potential of Kymriah, the only CAR-T cell therapy available for these patients who previously had limited treatment options. These data were presented as an oral presentation during the 2022 European Hematology Association (EHA) (Free EHA Whitepaper) Hybrid Congress (Abstract #S112)1.

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"These data mark a moment of profound hope for children, young adults and their families with relapsed or refractory B-cell ALL, as relapse after five years is rare," said Stephan Grupp, MD, PhD, Section Chief of the Cellular Therapy and Transplant Section, and Inaugural Director of the Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy at Children’s Hospital of Philadelphia (CHOP). "Since the approval of Kymriah nearly five years ago, we have been able to offer a truly game-changing option to patients who previously faced a five-year survival rate of less than 10 percent."

This long-term follow up of ELIANA demonstrated the potential for Kymriah to transform cancer treatment in pediatric and young adult patients with r/r B-cell ALL, significantly improving outcomes with durable responses and a consistent safety profile in this patient population1:

Eighty-two percent of patients experienced remission (either complete remission [CR] or CR with incomplete hematologic recovery within three months after infusion) (95% CI, 72-90)
For patients in remission, the five-year relapse-free survival (RFS) rate was 44% (95% CI, 31-56) and the median RFS was 43 months
No new or unexpected adverse events were reported during long-term follow-up
"At Novartis, we strive for cures. With nearly six-year follow-up data in these pediatric and young adults treated for B-cell ALL, we have our strongest evidence yet that one-time treatment with Kymriah has curative potential," said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development. "These results strengthen our confidence in CAR-T cell therapies as a truly transformative and paradigm-shifting advance in cancer care, as well as our commitment to continue developing this technology with next-generation platforms."

Additional updates on the Novartis CAR-T program presented at the 2022 EHA (Free EHA Whitepaper) Congress include new data from more patients and longer follow-up from the first-in-human dose-escalation trials with YTB323 in adults with r/r diffuse large B-cell lymphoma and PHE885 in adults with r/r multiple myeloma, the first Novartis CAR-T cell therapies developed using the Novartis T-Charge platform2,3,4. Visit View Source to learn more about these data and our ongoing commitment to reimagining cancer care with CAR-T cell therapies.

About Kymriah
Kymriah is the first-ever FDA-approved CAR-T cell therapy. It is a one-time treatment designed to empower patients’ immune systems to fight their cancer. Kymriah is currently approved for the treatment of r/r pediatric and young adult (up to and including 25 years of age) acute lymphoblastic leukemia (ALL), r/r adult diffuse large B-cell lymphoma (DLBCL) and r/r adult follicular lymphoma1.

About the ELIANA Trial
ELIANA was the first pediatric global CAR-T cell therapy registration trial, examining patients in 25 centers in 11 countries across the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy, Norway and Spain. The trial was an open-label, multicenter, single-arm, global Phase II trial investigating the efficacy and safety of Kymriah in pediatric and young adult patients in r/r B-cell ALL who were primary refractory, chemorefractory, relapsed after, or were not eligible for allogeneic stem cell transplantation (SCT). The primary endpoint was overall remission rate (ORR), defined as best overall response of CR or CR with incomplete blood count recovery (CRi) within 3 months and maintained for ≥28 day. The secondary endpoints include CR/CRi with undetectable minimal residual disease (MRD), duration of remission, event-free survival, overall survival, cellular kinetics and safety5.

About T-Charge
T-Charge is a next-generation CAR-T platform, innovated at the Novartis Institutes for BioMedical Research (NIBR), that will serve as the foundation for various new investigational CAR-T cell therapies in the Novartis pipeline. By implementing the T-Charge platform, we aim to revolutionize CAR-T cell therapy with new products that have the potential to offer patients a higher likelihood of better and more durable responses, improved long-term outcomes and a reduced risk of severe adverse events. The T-Charge platform preserves T cell stemness (T cell ability to self-renew and mature), an important T cell characteristic closely tied to its therapeutic potential, which results in a product containing greater proliferative potential and fewer exhausted T cells. With T-Charge, CAR-T cell expansion occurs primarily within the patient’s body (in-vivo), eliminating the need for an extended culture time outside of the body (ex-vivo). The T-Charge platform, which implements important process efficiencies, will be rapid, compared with traditional CAR-T, and reliable, through simplified processes and streamlined quality control. Multiple CAR-T therapies, including YTB323 and PHE885, are being developed using the Novartis T-Charge platform.

About Novartis commitment to Oncology Cell Therapy
As part of the unique Novartis strategy to pursue four cancer treatment platforms – radioligand therapy, targeted therapy, immunotherapy and cell and gene therapy – we strive for cures through cell therapies in order to enable more patients to live cancer-free. We will continue to pioneer the science and invest in our manufacturing and supply chain process to further advance transformative innovation.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of the Novartis commitment to CAR-T cell therapy.

We have made strong progress in broadening our delivery of Kymriah, which is currently available for use in at least one indication in 30 countries and at more than 370 certified treatment centers, with clinical and real-world experience from administration to more than 6,900 patients. We continue to pioneer in cell therapy, leveraging our vast experience to develop next-generation CAR-T cell therapies. These therapies will utilize our new T-Charge platform being evaluated to expand across hematological malignancies and bring hope for a cure to patients with other cancer types.

On June 11, 2022 Daiichi Sankyo reported that Positive results from the global pivotal QuANTUM-First phase 3 trial of Daiichi Sankyo’s (TSE:5468) quizartinib combined with standard induction and consolidation chemotherapy and then continued as a single agent demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in adult patients aged 18-75 with newly diagnosed FLT3-ITD positive acute myeloid leukemia (AML) compared to standard chemotherapy alone (Press release, Daiichi Sankyo, JUN 11, 2022, View Source [SID1234615910]). The data were featured as part of the press program and presented during the Presidential Symposium (#S100) at the European Hematology Association (EHA) (Free EHA Whitepaper) (#EHA2022) Congress.

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AML is one of the most common leukemias in adults with an estimated five-year survival rate of approximately 30.5%.1,2 Of all newly diagnosed cases of AML, 25% carry the FLT3-ITD gene mutation, which is associated with particularly unfavorable prognosis including increased risk of relapse and shorter overall survival.3

Quizartinib combined with standard induction and consolidation chemotherapy and then continued as a single agent demonstrated a 22.4% reduction in the risk of death compared to standard chemotherapy alone (HR = 0.776 [95% CI: 0.615-0.979; 2-sided p=.0324]) in patients with newly diagnosed FLT3-ITD positive AML. After a median follow-up of 39.2 months, median OS was more than double at 31.9 months for patients receiving quizartinib (95% CI: 21.0-NE) compared to 15.1 months for patients receiving chemotherapy (95% CI: 13.2-26.2).

The safety of quizartinib combined with intensive chemotherapy and as continuation monotherapy in QuANTUM-First was generally manageable, with no new safety signals observed. Rates of grade 3 or higher treatment emergent adverse events (TEAEs) were similar for both study groups and the most common grade 3 or higher TEAEs occurring in ≥ 10% of patients were febrile neutropenia (43.4% quizartinib; 41.0% placebo), neutropenia (18% quizartinib; 8.6% placebo), hypokalemia (18.9% quizartinib; 16.4% placebo) and pneumonia (11.7% quizartinib; 12.7% placebo). Rates of TEAEs associated with fatal outcomes were 11.3% for quizartinib versus 9.7% for chemotherapy alone and were mainly due to infections.

QTcF > 500 ms occurred in 2.3% of patients receiving quizartinib and 0.8% of patients discontinued quizartinib due to QT prolongation. Ventricular arrhythmia events with quizartinib were uncommon. Two (0.8%) patients experienced cardiac arrest with recorded ventricular fibrillation on ECG (one with fatal outcome) both in the setting of severe hypokalemia.

"The QuANTUM-First results show that adding quizartinib to standard chemotherapy significantly improved overall survival in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia," said Harry P. Erba, MD, PhD, Instructor, Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke Cancer Institute. "There is great interest in the increased use of targeted therapies to improve outcomes for patients with AML, particularly those with the FLT3-ITD subtype, which is one of the most common, aggressive and difficult-to-treat."

"We are proud that another one of our medicines has demonstrated a significant survival advantage, as our goal is to leverage innovative science to change the way cancer is treated," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Adding targeted treatment with quizartinib, a potent and selective FLT3 inhibitor, to standard chemotherapy resulted in a doubling of median overall survival in patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia compared to standard chemotherapy alone. Based on these positive QuANTUM-First results, we have initiated global regulatory filings in order to bring quizartinib to patients as quickly as possible."

The OS improvement with quizartinib was also supported by a sensitivity analysis censoring for the effect of allogenic hematopoietic stem cell transplant (HSCT) (HR = 0.752; [95% CI: 0.562-1.008]).

Additional secondary and exploratory analyses provide further understanding and some supporting evidence for improved OS in patients receiving quizartinib combined with chemotherapy in the trial.

The primary event-free survival (EFS) analysis (with induction treatment failure (ITF) defined as not achieving complete remission (CR) by day 42 of the last induction cycle), did not show a statistically significant difference between the two study arms; two pre-specified sensitivity analyses on EFS (the first one defining ITF as not achieving CR by the end of induction; the second one defining ITF as having not achieved composite complete remission (CRc) by the end of induction) showed HR = 0.818 [95% CI: 0.669, 0.999] and HR = 0.729 [95% CI: 0.592-0.897], respectively.

The CRc rate was numerically higher for patients receiving quizartinib compared to chemotherapy alone (71.6% versus 64.9%), and rates of CR were similar for the two study arms (54.9% and 55.4%). The median duration of CR was 38.6 months for quizartinib (95% CI: 21.9-NE) and 12.4 months for chemotherapy (95% CI: 8.8-22.7).

The median relapse-free survival (RFS) for patients who achieved CR was 39.3 months for quizartinib and 13.6 months for placebo, representing a 38.7% relative risk reduction of relapse or death (HR = 0.613 [95% CI: 0.444-0.845]).

*A hierarchical testing procedure was used to test the primary endpoint OS, followed by EFS, CR and CRc. Formal statistical testing was stopped after EFS as its result was not statistically significant.
Data cut-off: August 13, 2021
Abbreviations: HR = Hazard ratio; NE = not estimable; OS = overall survival

About QuANTUM-First

QuANTUM-First is a randomized, double-blind, placebo-controlled global phase 3 study evaluating quizartinib in combination with standard induction and consolidation chemotherapy and then as continued single agent therapy in adult patients (aged 18-75) with newly diagnosed FLT3-ITD positive AML. Patients were randomized 1:1 into two treatment groups to receive quizartinib or placebo combined with anthracycline- and cytarabine-based regimens. Eligible patients, including those who underwent allogeneic HSCT, continued with single agent quizartinib or placebo for up to 36 cycles.

The primary study endpoint was OS. Secondary endpoints include EFS, post-induction rates of CR and CRc, and the percentage of patients who achieve CR or CRc with FLT3-ITD minimal residual disease negativity. Safety and pharmacokinetics, along with exploratory efficacy and biomarker endpoints, also were evaluated. QuANTUM-First enrolled 539 patients at 193 study sites across Asia, Europe, North America, Oceania and South America. For more information, visit ClinicalTrials.gov.

About Acute Myeloid Leukemia (AML)

More than 474,500 new cases of leukemia were reported globally in 2020 with more than 311,500 deaths.4 AML is one of the most common types of leukemia in adults, representing about one-third of all cases, and the average age of diagnosis is 68 years old.1 The five-year survival rate for AML is 30.5%, the lowest by far among the major leukemia subtypes, and is 9.4% for patients aged 65 and older.5,6,7 The conventional treatment for newly diagnosed AML is intensive induction and consolidation chemotherapy with HSCT for eligible patients.8 The introduction of new targeted therapies in recent years has added to the standard of care and improved outcomes for some patients with molecularly defined AML subtypes.9

About FLT3-ITD

FLT3 (FMS-like tyrosine kinase 3) is a tyrosine kinase receptor protein normally expressed by hematopoietic stem cells that plays an important role in cell development, promoting cell survival, growth and differentiation through various signaling pathways.3 Mutations of the FLT3 gene, which occur in approximately 30% of AML patients, can drive oncogenic signaling.3 FLT3-ITD (internal tandem duplication) is the most common type of FLT3 mutation in AML, occurring in about 25% of all newly diagnosed patients, and is associated with increased risk of relapse and shorter overall survival.3

About Quizartinib

Quizartinib is an oral, highly potent and selective type II FLT3 inhibitor currently in clinical development for the treatment of FLT3-ITD positive AML.3 In addition to QuANTUM-First, the quizartinib development program includes a phase 1/2 trial in pediatric and young adult patients with relapsed/refractory FLT3-ITD AML in Europe and North America. Several phase 1/2 combination studies with quizartinib are also underway at The University of Texas MD Anderson Cancer Center as part of a strategic research collaboration focused on accelerating development of Daiichi Sankyo pipeline therapies for AML.

Quizartinib has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of adult patients with newly diagnosed AML that is FLT3-ITD positive, in combination with standard cytarabine and anthracycline induction and cytarabine consolidation. Orphan Drug Designation has been granted to quizartinib for the treatment of AML in Europe, Japan and the U.S.

Quizartinib is currently approved for use in Japan under the brand name VANFLYTA for the treatment of adult patients with relapsed/refractory FLT3-ITD AML, as detected by an approved test. Quizartinib is an investigational medicine in all countries outside of Japan.