On April 10, 2021 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biopharmaceutical company focused on novel and targeted oncology therapies, reported a data update on the safety and tolerability of twice daily (BID) administered poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations (Press release, Spectrum Pharmaceuticals, APR 10, 2021, View Source [SID1234577824]). These preliminary data, from Cohort 5 of the ZENITH20 clinical trial, continue to show improved tolerability with BID dosing, reduced dose interruption compared to once daily (QD) dosing, and a reduction in treatment emergent Grade 3 or higher adverse events. The preliminary data also demonstrate improved anti-tumor activity with 8mg BID dosing. The presentation is part of the AACR (Free AACR Whitepaper) Virtual Meeting 2021 taking place April 10-15, 2021.

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"The 8mg BID dosing arm is showing the best performance we have seen across the various dosing arms for a mixed population of EGFR and HER2 exon 20 insertion mutations in NSCLC patients. There is clearly an improved therapeutic effect and a lower adverse event rate which is highly encouraging," said Francois Lebel, M.D., Chief Medical Officer of Spectrum Pharmaceuticals. "We are currently expanding the 8mg BID dataset and look forward to evaluating this dose in additional NSCLC patients and other solid tumors."

A copy of the AACR (Free AACR Whitepaper) presentation titled "Poziotinib administered twice daily improves safety and tolerability in patients with EGFR or HER2 exon 20 mutations" is available on Spectrum’s website at View Source

ZENITH20 Trial Design and Preliminary Safety and Efficacy Data for Cohort 5

Cohort 5 of the ZENITH20 trial includes previously treated NSCLC patients with EGFR or HER2 exon 20 insertion mutations. This cohort is investigating the efficacy of poziotinib with various dosing levels including BID administration. For the 38 patients randomized to poziotinib 16mg QD or 8mg BID in Cohort 5, improved responses were reported in the BID arm with 31.6% of patients (6/19) reaching a partial response. For the 38 patients randomized to poziotinib 12mg QD or 6mg BID, these dosing levels were not as active as 8mg BID but showed improved tolerance with BID dosing relative to QD dosing.

Improved tolerability was also observed for the typical TKI related adverse events, with a clinically meaningful reduction in Grade 3 or higher adverse events for the 8mg BID dose relative to 16mg QD. In addition, there were fewer dose interruptions and dose reductions for the BID arms relative to the same QD dose. Cohort 5 is now enrolling exclusively in the 8mg BID arm and data collection is ongoing.

About Poziotinib

Poziotinib is a novel, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that inhibits the tyrosine kinase activity of EGFR as well as HER2 and HER4. Importantly this, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer. The company holds an exclusive license from Hanmi Pharmaceuticals to develop, manufacture, and commercialize poziotinib worldwide, excluding Korea and China. Poziotinib is currently being investigated by the company and Hanmi in several mid-stage trials in multiple solid tumor indications.

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.