On April 10, 2021 Elevation Oncology, a clinical stage biopharmaceutical company focused on the development of precision medicines for patients with genomically defined cancers, reported the presentation by its collaborators in the Marc Ladanyi lab at Memorial Sloan Kettering (MSK) of further preclinical data on the specific inhibition of NRG1 fusion-induced tumorigenesis and signaling by seribantumab, a HER3 monoclonal antibody, at the American Association of Cancer Research Virtual Annual Meeting 2021 (Press release, Elevation Oncology, APR 10, 2021, View Source [SID1234577841]). These data (Odintsov et al., 2021) in patient-derived xenograft (PDX) models of NRG1 fusion-positive pancreatic and cholangiocarcinoma build on earlier studies generated in lung and ovarian NRG1 fusion PDX models, recently published in Clinical Cancer Research, and further support the mechanistic rationale for the Phase 2 CRESTONE study for patients with solid tumors of any origin harboring an NRG1 gene fusion. The CRESTONE study is currently enrolling at sites across the United States.

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"Here we observed that NRG1 fusions activated HER3 and downstream signaling mediators such as AKT in a pancreatic cell line," said Igor Odintsov, MD, Research Fellow at MSK and lead author of the poster presentation. "Treatment with seribantumab was able to inhibit phosphorylation of the activated HER3 and AKT in the same cell line, and subsequent treatment of an APP-NRG1 fusion-positive pancreatic PDX model with seribantumab robustly inhibited tumor growth at clinically achievable doses."

Regressions were observed in all mice treated with 10 mg/kg BIW seribantumab, equivalent to a clinical dose of 2.6 g seribantumab in humans by allometric scaling. As in prior analysis in lung and ovarian NRG1 fusion PDX models, the pan-ERBB inhibitor afatinib was used as an active control in this pancreatic PDX model. No regression was observed in pancreatic PDX tumors treated with afatinib at 5 mg/kg QD.

NRG1 fusions have been identified in a variety of solid tumors, including lung, pancreatic, gallbladder, breast, ovarian, colorectal, neuroendocrine, cholangiocarcinomas, and sarcomas. Current data suggest that NRG1 fusions are predominantly mutually exclusive with other known driver alterations and are therefore considered to be the primary driver of the tumor’s growth and proliferation.

"The rarity of competing oncogenic drivers in tumors driven by an NRG1 fusion presents a strong biological rationale for use of a targeted anti-HER3 monotherapy approach across tumor types. This approach is reflected in the design of our Phase 2 CRESTONE study as a tumor-agnostic study of monotherapy seribantumab with pre-defined exclusion of patients whose tumors harbor multiple actionable driver alterations," said Shawn M. Leland, PharmD, RPh, Founder and Chief Executive Officer of Elevation Oncology. "In rare instances when multiple actionable driver alterations are identified in the same tumor, we believe there may be a similar biological rationale for addressing each driver alteration through combinations of agents targeted to each individual alteration, rather than the traditional combinations with chemotherapy. We are excited to report early results from preclinical exploration of this hypothesis, and look forward to continued investigation of new treatment paradigms informed by comprehensive genomic profiling of tumors."

"We utilized an RBPMS-NRG1 fusion cholangiocarcinoma PDX model that also contained mutations in both ERBB4 and IDH1," continued Dr. Odintsov. "While treatment with monotherapy seribantumab or afatinib in this model produced mixed results, by applying a triple combination of seribantumab with afatinib to target the entire ERBB family, and AG-120 to target the IDH1 mutation, we were able to achieve regressions in the majority of tumors. This suggests that tumors harboring multiple oncogenic drivers may benefit from combination therapy that addresses the contribution of each genomic alteration in disease progression."

In totality, the data reported support the use of monotherapy seribantumab to treat GI and other cancers that are uniquely driven by an NRG1 fusion in the ongoing Phase 2 CRESTONE study. Patients and physicians can learn more about the CRESTONE study at www.NRG1fusion.com or on www.ClinicalTrials.gov under the NCT number NCT04383210.

On April 10, 2021 ITM AG reported the presentation of a trial-in-progress poster highlighting its ongoing Phase III trial COMPETE with n.c.a. 177Lu-Edotreotide in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, ITM Isotopen Technologien Munchen, APR 10, 2021, View Source [SID1234577857]). The poster will be presented in video format as part of the Phase III trials in progress poster session by Mona M. Wahba, MD, Deputy Chief Medical Officer at ITM. It will be available following the e-poster website launch on April 10, 2021, at 8:30 am ET / 2:30 pm CET and remain available for viewing through June 21, 2021.

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"GEP-NETs are often diagnosed at an advanced stage in patients who have a high unmet medical need. N.c.a. 177Lu-Edotreotide has already shown very promising signs of efficacy and safety in this patient population in a Phase II study and we look forward to building on these results in COMPETE, with the goal of improving the treatment options that are available for these patients," stated Philip E. Harris, PhD, Chief Medical Officer at ITM. "The AACR (Free AACR Whitepaper) Annual Meeting is one of the key oncology conferences in our industry and we welcome the opportunity to present our lead program as well as to discuss the potential benefits of targeted radiopharmaceuticals such as n.c.a. 177Lu-Edotreotide with the global scientific community."

The presented COMPETE trial (NCT03049189) is a prospective, randomized, controlled, open-label, multi-center Phase III study to evaluate the efficacy and safety of n.c.a. 177Lu-Edotreotide PRRT compared to mTOR inhibitor everolimus in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+) GEP-NETs. The study is currently recruiting patients in 14 countries. As part of the study, 300 patients with progressive SSTR+ Grade 1 and 2 GEP-NETs are being randomized, of which 200 receive up to 4 cycles of n.c.a. 177Lu-Edotreotide (7.5 GBq/cycle) every 3 months or until diagnosis of progression, while 100 patients receive 10 mg everolimus daily for 24 months, or until diagnosis of progression. The overall study duration per patient will be 30 months. Primary objective of the study is to demonstrate prolonged progression free survival (PFS) in patients in the n.c.a. 177Lu-Edotreotide arm vs. everolimus, while secondary objectives include safety, objective response rates and overall survival after 5 years follow-up.

The initiation of the Phase III study was based on the successful completion of a Phase II study that evaluated the efficacy and safety of n.c.a. 177Lu-Edotreotide (177Lu-DOTATOC) in 56 patients with metastasized and progressive NETs (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites). The results demonstrated the promising efficacy and safety that ITM’s lead candidate can provide in this advanced patient population, achieving a median PFS (mPFS) of 17.4 months and an overall survival of 34.2 months, respectively, with a mPFS of 34.5 months for GEP-NETs. Objective response rates (Complete/Partial Responses) were 54.2% in GEP-NETs, with complete response rates of 25%, of which 78% were maintained throughout the follow-up period. In addition, no serious adverse events were observed. These results indicate that n.c.a. 177Lu-Edotreotide has a major potential to induce objective tumor responses and sustained disease control in progressive neuroendocrine tumors. The observed safety profile suggests a particularly favorable therapeutic index, including in patients with impaired bone marrow or renal function, reflecting the low uptake of n.c.a. 177Lu-Edotreotide by normal organs. The ongoing Phase III COMPETE study will now aim to confirm and further build on these results.

Presentation information
Title: COMPETE Phase III Trial – Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide vs. Everolimus in Progressive GEP-NET
Abstract No: 5201
Session: Phase III Clinical Trials in Progress
Presenter: Mona M. Wahba, MD

Mona M. Wahba is available for questions and discussions via the chat box function of the AACR (Free AACR Whitepaper) poster section and will respond within 24 hours. Meetings can also be requested using the AACR (Free AACR Whitepaper) system.

The poster will also be made available on the company’s website under the event section.

On April 10, 2021 Gracell Biotechnologies Inc. (NASDAQ: GRCL) ("Gracell"), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, reported long-term follow-up data on their TruUCAR-enabled allogeneic product candidate GC027 for the treatment of adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) in an e-poster presentation at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting on April 10 (Press release, Gracell Biotechnologies, APR 10, 2021, View Source [SID1234577873]).

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TruUCAR-enabled GC027 is a first-in-human, off-the-shelf allogeneic CAR-T stand-alone therapy targeting CD7. An ongoing, multi-center investigator-initiated Phase 1 trial in China is evaluating the safety and efficacy of GC027 for the treatment of adults with r/r T-ALL. We first reported results as oral presentation at the AACR (Free AACR Whitepaper) 2020 Annual Meeting.

The updated data with a February 4, 2021 data cut-off represents long-term follow-up as well as additional patients treated. Patients had received a median of six prior lines of therapy and received a single infusion of TruUCAR GC027 in one of three dose levels: 0.6x107cells/kg, 1.0x107cells/kg or 1.5x107cells/kg. Six patients (100%) treated achieved a complete remission with or without complete blood count recovery (CR/CRi) and five of the six patients (83%) achieved minimum residual disease negative complete remission (MRD- CR). At 6 months post treatment, three out of five patients (60%) had maintained MRD- CR. After 18.5 months of follow up for the initial patients treated, one patient continued to be MRD- CR at 16.8 months. One patient maintained MRD- CR until 9 months and one patient with primary refractory disease (no response to VDP) maintained his MRD- CR status until month 7. One additional patient treated presented initially with a high tumor burden and extensive extramedullary (EM) disease. After treatment with GC027 and as confirmed by PET CT scan, all EM lesions resolved. The patient achieved MRD- CR at day 28.

All six patients tolerated a single infusion of TruUCAR GC027. No neurotoxicity events (ICANS) or acute graft-versus-host disease (aGvHD) were observed. Cytokine release syndrome (CRS) occurred in all patients and was managed with standard of care including Tocilizumab. Overall safety findings were consistent with previous observations.

"These data show promising long-term follow-up results in r/r T-ALL patients who have very limited treatment options available," commented Dr. Martina Sersch, M.D., Chief Medical Officer of Gracell. "With these findings, GC027 may have the potential to be developed as a single-infusion stand-alone allogeneic CAR-T therapy. We are looking forward to expediting the clinical development of our TruUCAR-enabled GC027 globally, as well as expanding into additional indications beyond T-ALL."

Presentation link: View Source
Abstract link: View Source!/9325/presentation/4633

About GC027
TruUCAR-enabled GC027 is a first-in-human, off-the-shelf allogeneic CAR-T therapy targeting CD7, currently being developed for the treatment of T-ALL in adults. GC027 is manufactured from T cells of human leukocyte antigen (HLA) unmatched healthy donors. Developed on our proprietary TruUCAR platform, GC027 utilizes dual-function CAR to specifically target a patient’s own T cells and natural killer (NK) cells that would otherwise be directed against the foreign, or allogeneic, CAR-T cells resulting in rejection by the patients. This novel design allows this allogeneic cell therapy to survive a patient’s immune system without the need for combination treatment with additional potent immunosuppressant and represents a differentiated monotherapy approach.

About T-ALL
T cell malignancies are a group of cancers involving T lymphocytes, including acute T cell lymphoblastic leukemia or T-ALL. Standard of care treatment for T-ALL includes chemotherapy, radiation therapy and stem cell transplantation. Standard chemotherapy regimens only result in 30% – 40% response rate with 6 months median Overall Survival among responders. Patients with T cell malignancies usually have high relapse and mortality rates. Relapsed patients have dismal prognosis with very limited treatment options and <10% of patients surviving beyond 5 years. Due to shared common surface antigens and potential contamination by malignant cells, development of CAR-T cell therapies for T-ALL is lagged behind. In addition, no new therapies have been approved for the treatment of T-ALL since the approval of Nelarabine (marketed by GlaxoSmithKline) by the FDA in 2005. Globally, approximately 64,000 patients are diagnosed with ALL every year with over approximately 6,000 expected to be diagnosed in the United States in 2020. T-ALL accounts for approximately 25% of ALL diagnoses in adults. 1

About TruUCAR
TruUCAR is Gracell’s proprietary technology platform and is designed to generate high-quality allogeneic CAR-T cell therapies that can be administered "off-the-shelf" at lower cost and with greater convenience. With differentiated design enabled by gene editing, TruUCAR is designed to control host vs graft rejection (HvG) as well as graft vs host disease (GvHD) without the need of being co-administered with immunosuppressive drugs.

The lead program of TruUCAR platform, GC027, is manufactured using T cells from non-HLA matched healthy donors. The TruUCAR platform utilizes novel designs of a dual-function CAR or dual-CAR to reduce HvG, eliminating the need of combination therapy with additional potent immunosuppressant to induce deeper immune suppression and enabling stand-alone allogeneic CAR-T cell therapy.

On April 10, 2021 F-star Therapeutics, Inc. (NASDAQ: FSTX), a clinical-stage biopharmaceutical company dedicated to developing next generation bispecific immunotherapies to transform the lives of patients with cancer, reported that preclinical data from FS222, a potentially best-in-class tetravalent bispecific antibody targeting both CD137 and PD-L1 will be presented in a poster at the 2021 American Academy of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place virtually from April 10-15 and May 17-21 (Press release, F-star, APR 10, 2021, View Source [SID1234578009]). Poster #1864, entitled ‘FS222, a Tetravalent Bispecific Antibody Targeting CD137 and PD-L1, is Designed for Optimal CD137 Interactions Resulting in Potent T cell Activation Without Toxicity’ will be available via on-demand viewing starting today, April 10, at 8:30 a.m. ET.

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FS222 targets PD-L1, the immune checkpoint protein that regulates the balance of activated T cells in the immune system and is overexpressed on many solid tumors and CD137, a co-stimulatory molecule from the tumor necrosis factor receptor superfamily (TNFRSF), which is widely known to be upregulated on tumor-reactive CD8+ T cells or "killer T cells". Currently, only a minority of patients have a long-lasting response to monotherapies that block the PD-(L)1 pathway.

Neil Brewis, Chief Scientific Officer at F-star Therapeutics, said: "We are encouraged by the results of these latest preclinical studies of FS222, our tetravalent bispecific antibody targeting PD-L1 and CD137. This work further demonstrates that FS222’s tetravalent binding mechanism is the most efficient and effective format for bispecific antibodies. The early onset of activity and T cell proliferation gives us confidence that FS222 will allow for a wide range of treatment options."

FS222 was designed to be a potent human CD137/PD-L1 tetravalent conditional agonist with a unique combination of high affinity PD-L1 binding, and moderate affinity, but with high avidity, binding to CD137 on activated T cells to result in optimal receptor clustering. Previously, FS222 has been shown to exhibit a favorable safety profile in preclinical safety studies.

Tetravalent binding by FS222 demonstrated optimal activity in multiple preclinical pharmacology studies, outperforming classic heterodimeric bispecific antibodies. These data showed that there was no evidence of a hook effect, or bell-shaped dose response curve, in vitro, and coupled with FS222’s favorable safety profile, presents a potentially broad and differentiated therapeutic window. A murine surrogate mAb2 for FS222 had peripheral immunopharmacology, as shown by CD8+ T cell proliferation, at high dose levels, mirroring the in vitro data, whereby the tetravalent FS222 surrogate mAb2 outperforms other lower valency formats.

In January 2021, F-star announced that the first patient had been dosed in a Phase 1 clinical trial of FS222, a multicenter, open-label, first-in-human trial to evaluate the safety, tolerability, and early signs of efficacy of FS222 in adult patients diagnosed with advanced malignancies. The adaptive study design will allow for the early exploration of clinical activity of FS222 in a range of selected solid tumors that will guide future targeted clinical development.

On April 10, 2021 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that Phase 1 clinical data from studies exploring Rubraca in combination with Xtandi for the treatment of advanced prostate cancer (RAMP) and Rubraca monotherapy in advanced solid tumors in Japanese patients (RUCA-J) will be presented during week one of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting (AACR) (Free AACR Whitepaper), taking place April 10-15, 2021 (Press release, Clovis Oncology, APR 10, 2021, View Source [SID1234577825]).

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"We remain committed to understanding how Rubraca may benefit patients with cancer, and the data presented at AACR (Free AACR Whitepaper) further enhance our understanding in different patient populations and solid tumor types," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "The Phase 1b RAMP data for the combination of Rubraca and Xtandi in unselected mCRPC patients help inform the Alliance for Clinical Oncology-sponsored CASPAR Phase 3 trial which is expected to begin enrolling patients soon, and we look forward to learning more about the combination."

Following are details of the Clovis-sponsored presentations at AACR (Free AACR Whitepaper) 2021:

Poster Presentation 445: Genomic Characteristics and Response to Rucaparib and Enzalutamide in the Phase 1b RAMP Study of Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients

Lead author: Arpit Rao, MBBS, University of Minnesota, Minneapolis, USA
Session: Clinical Research
Date/Time: April 10, 2021, 8:30 a.m. – 11:59 p.m. ET
Key Takeaways: The results of this study demonstrated that unselected patients with mCRPC who had progressed on androgen receptor (AR)-directed therapies reported declines in prostate-specific antigen (PSA) following treatment with a combination of rucaparib 600 mg twice daily and enzalutamide 160 mg once daily, and these declines were observed even in the presence of AR alterations and the absence of DNA damage repair gene alterations. The safety profile was consistent with that associated with each drug as a monotherapy, with no clinically significant drug-drug interactions observed with the combination. These data support further study of the combination in this patient population and the Phase 3 CASPAR study (Alliance A031902; NCT04455750) is expected to begin enrolling biomarker-unselected patients with mCRPC shortly.
Poster Presentation CT124: Evaluation of Rucaparib in Japanese Patients with a Previously Treated Advanced Solid Tumor

Lead author: Kenji Tamura, MD, PhD, National Cancer Center Hospital, Tokyo, Japan
Session: Phase I Clinical Trials
Date/Time: April 10, 2021, 8:30 a.m. – 11:59 p.m. ET
Key Takeaways: This study suggests rucaparib 600 mg taken twice daily had a manageable safety profile for Japanese patients with advanced solid tumors, including ovarian, prostate, endometrial, and pancreatic cancer. The pharmacokinetic profile of rucaparib in Japanese patients overlapped with that of Western patients. Among patients with measurable disease, 18.5% (5/27) achieved an objective response rate and 51.9% (14/27) had stable disease per RECIST v1.1. These results support further exploration of rucaparib 600 mg twice daily in Japanese patients.
The presentations can also be viewed at View Source .

About Rubraca (rucaparib)

Rucaparib is an oral, small molecule inhibitor of PARP1, PARP2 and PARP3 being developed in multiple tumor types, including ovarian and metastatic castration-resistant prostate cancers, as monotherapy, and in combination with other anti-cancer agents. Exploratory studies in other tumor types are also underway.

Rubraca U.S. FDA Approved Indications

Ovarian Cancer

Rubraca is indicated for the maintenance treatment of adult women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Rubraca is indicated for the treatment of adult women with a deleterious BRCA mutation (germline and/or somatic)-associated epithelial ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for Rubraca.

Prostate Cancer

Rubraca is indicated for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. Patients should be identified for treatment with Rubraca based on the presence of a deleterious BRCA mutation (germline and/or somatic) and selected for therapy based on an FDA-approved companion diagnostic for Rubraca. This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select Important Safety Information

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur in patients treated with Rubraca, and are potentially fatal adverse reactions. In 1146 treated patients, MDS/AML occurred in 20 patients (1.7%), including those in long term follow-up. Of these, 8 occurred during treatment or during the 28 day safety follow-up (0.7%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 53 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing regimens and/or other DNA damaging agents. In TRITON2, MDS/AML was not observed in patients with mCRPC (n=209) regardless of homologous recombination deficiency (HRD) mutation.

Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (> 4 weeks), interrupt Rubraca or reduce dose and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca.

Based on its mechanism of action and findings from animal studies, Rubraca can cause fetal harm when administered to a pregnant woman. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca. For males on Rubraca treatment who have female partners of reproductive potential or who are pregnant, effective contraception should be used during treatment and for 3 months following the last dose of Rubraca.

Most common adverse reactions in ARIEL3 (≥ 20%; Grade 1-4) were nausea (76%), fatigue/asthenia (73%), abdominal pain/distention (46%), rash (43%), dysgeusia (40%), anemia (39%), AST/ALT elevation (38%), constipation (37%), vomiting (37%), diarrhea (32%), thrombocytopenia (29%), nasopharyngitis/upper respiratory tract infection (29%), stomatitis (28%), decreased appetite (23%), and neutropenia (20%).

Most common adverse reactions in Study 10 and ARIEL2 (≥ 20%; Grade 1-4) were nausea (77%), asthenia/fatigue (77%), vomiting (46%), anemia (44%), constipation (40%), dysgeusia (39%), decreased appetite (39%), diarrhea (34%), abdominal pain (32%), dyspnea (21%), and thrombocytopenia (21%).

Most common adverse reactions in TRITON2 (≥ 20%; Grade 1-4) were fatigue/asthenia (62%), nausea (52%), anemia (43%), AST/ALT elevation (33%), decreased appetite (28%), rash (27%), constipation (27%), thrombocytopenia (25%), vomiting (22%), and diarrhea (20%).

Co-administration of rucaparib can increase the systemic exposure of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, which may increase the risk of toxicities of these drugs. Adjust dosage of CYP1A2, CYP3A, CYP2C9, or CYP2C19 substrates, if clinically indicated. If co-administration with warfarin (a CYP2C9 substrate) cannot be avoided, consider increasing frequency of international normalized ratio (INR) monitoring.

Because of the potential for serious adverse reactions in breast-fed children from Rubraca, advise lactating women not to breastfeed during treatment with Rubraca and for 2 weeks after the last dose.