On April 10, 2021 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported new preclinical data on JTX-8064, the first tumor-associated macrophage program from their Translational Science Platform, at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting being held April 10-15, 2021 (Press release, Jounce Therapeutics, APR 10, 2021, View Source [SID1234577840]). The poster presentation includes data showing a high Leukocyte Immunoglobulin Like Receptor B2 (LILRB2) to interferon gamma (IFNγ) ratio is associated with resistance to PD-(L)1 inhibitor treatment in humans, JTX-8064’s ability to bridge innate and adaptive immunity, and how Jounce’s Translational Science Platform informed indication selection for the Phase 1 INNATE trial.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The translational analyses presented at AACR (Free AACR Whitepaper) link JTX-8064’s mechanism to tumor types that may respond better to LILRB2 inhibition," said Elizabeth Trehu, M.D., chief medical officer of Jounce Therapeutics. "The Phase 1 INNATE trial is designed to move as quickly as possible to proof of concept and this new data enabled the prioritization of tumor-specific expansion cohorts, which are on track to start enrolling in the second half of 2021. Furthermore, the negative prognostic implications of a high LILRB2 to IFNγ ratio support the role of LILRB2 in resistance to PD-(L)1 inhibitors and highlight the potential for JTX-8064 to reverse this resistance."

In a poster titled "Tumor associated macrophages and resistance to immune checkpoint blockade: Consideration of cancer indications for the clinical development of JTX-8064, an anti-LILRB2/ILT4 monoclonal antibody" Jounce demonstrated:

JTX-8064 can induce T cell activation in co-culture with macrophages, demonstrating its potential to bridge the gap between innate and adaptive immune responses;
CD163+ M2 macrophages co-localize with T cells in the tumor microenvironment, and patients with high levels of LILRB2 or a proprietary tumor-associated macrophage (TAM) signature score relative to an IFNγ signature score are less responsive to PD-(L)1 inhibitors, providing evidence that LILRB2+ macrophages may be involved in mechanisms of primary resistance to PD-(L)1 inhibitors; and
Expression profiles of LILRB2 mRNA, TAM signatures, and other inflammatory cell signatures were used to identify tumor types that may benefit most from JTX-8064 treatment and used to inform indication selection for expansion cohorts of the Phase 1 INNATE trial.
The poster is available on the "Our Pipeline" section of the Jounce Therapeutics website at www.jouncetx.com.

About JTX-8064

JTX-8064 is a humanized IgG4 monoclonal antibody designed to specifically bind to Leukocyte Immunoglobulin Like Receptor B2 (LILRB2/ILT4) and block interactions with its ligands. JTX-8064 is the first tumor-associated macrophage candidate developed from Jounce’s Translational Science Platform. Preclinical data presented at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s Annual Meeting and the 2019 and 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meetings support the development of JTX-8064 as a novel immunotherapy to reprogram immune-suppressive macrophages and enhance anti-tumor immunity. A Phase 1 clinical trial named INNATE (NCT04669899), of JTX-8064 as a monotherapy and in combination with either JTX-4014, or pembrolizumab, is currently enrolling patients with advanced solid tumors.

On April 10, 2021 ImmunoGen Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported that a poster highlighting preclinical data for its novel ADAM9-targeting ADC, IMGC936, which is being investigated in multiple solid tumor types, is being presented at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting April 10-15, 2021 (Press release, ImmunoGen, APR 10, 2021, View Source [SID1234577856]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"ADAM9 is overexpressed in a wide range of solid tumors and minimally expressed on normal tissue, which makes it an ideal ADC target," said Eric Westin, MD, Vice President, Clinical Development and Translational Sciences at ImmunoGen. "IMGC936 showed compelling anti-tumor activity against multiple patient-derived xenograft models with clinically relevant levels of ADAM9 and was well-tolerated across all models tested. We continue to enroll patients in our Phase 1 dose-escalation study of IMGC936 in multiple tumor types and look forward to sharing initial data by the end of 2021 or early 2022."

POSTER PRESENTATION

Title: "IMGC936, an investigational ADAM9-targeting antibody-drug conjugate, is active against patient-derived ADAM9-expressing xenograft models"
Day/Time: Saturday, April 10, 2021 at 8:30 AM ET
Session Category: Immunology
Session Title: PO.IM02.10 – Therapeutic Antibodies, Including Engineered Antibodies
Abstract: 1841
Additional information can be found at www.aacr.org.

ABOUT IMGC936
IMGC936 is a first-in-class ADAM9-targeting antibody-drug conjugate (ADC) that is comprised of a humanized antibody engineered to include a YTE mutation for enhanced exposure through improved recycling, a tri-peptide cleavable linker stable in circulation, and a next-generation DM21 maytansinoid payload, which is more potent and hydrophobic, resulting in increased bystander activity.

ADAM9 is a cell surface protein that belongs to the ADAM (a disintegrin and metalloproteinase) family of proteases, which have been implicated in cytokine and growth factor shedding and cell migration. Dysregulation of ADAM9 has been involved in tumor progression and metastasis, as well as pathological neovascularization. ADAM9 is overexpressed in multiple solid tumor types (e.g., non-small cell lung, gastric, pancreatic, triple-negative breast, and colorectal cancers) and minimally expressed on normal tissue, making ADAM9 an attractive target for ADC development.

IMGC936 is being co-developed with MacroGenics and is currently in a Phase 1 study enrolling patients with solid tumors that express ADAM9.

On April 10, 2021 Jubilant Therapeutics Inc., a biopharmaceutical company advancing oral, small molecule modulators to address unmet medical needs in oncology and autoimmune diseases, reported that preclinical data from two programs evaluating the company’s PRMT5 inhibitor and PD-L1 inhibitor as anti-cancer agents, will be presented today in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting taking place virtually from April 10-15, 2021 (Press release, Jubilant Therapeutics, APR 10, 2021, View Source [SID1234577872]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We are excited to announce these important data from our PRMT5 and our PD-L1 programs that show efficacy and tolerability in preclinical models," said Syed Kazmi, President and Chief Executive Officer of Jubilant Therapeutics Inc. "Our oral PRMT5 inhibitor has good plasma and sustained brain exposure which results in strong target inhibition, tumor growth delay and survival advantage in both xenografts and orthotopic brain models. Our oral anti-PDL1 immunotherapeutics, with a shorter half-life, are an attractive alternative to current intravenous antibody therapies especially in the maintenance settings with potential to limit immune-mediated toxicities and side effects via innovative dosing approaches, while maintaining the class-based wide anti-tumor efficacy. We look forward to continuing our work on these programs as we see great potential for treating multiple cancers."

A link to the e-posters, listed below, is available through the AACR (Free AACR Whitepaper) website.

Title: Novel, small molecule PRMT5 inhibitors for treatment of cancer
Poster Number: 1128
Date and Time: April 10, 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Epigenetic Targets
Presenter: Dhanalakshmi Sivanandhan, et al.

Title: Novel, small molecule inhibitors of PD-L1/PD-1 interaction
Poster Number: 1630
Date and Time: April 10, 2021 at 8:30 a.m. Eastern Daylight Time (EDT)
Session Title: Immune Checkpoints
Presenter: Dhanalakshmi Sivanandhan, et al.

PRMT5 over-expression, shown in several cancers including lymphoid, lung, breast, glioblastoma, gastric etc., is thought to be an important factor in its tumorigenicity due to its repressive function on tumor suppressor gene expression. Key highlights from an evaluation which examined the tumor growth inhibition of PRMT5 inhibitor JBI-778 in multiple cancer cell lines as well as glioblastoma, include the following:

JBI-778 is a potent PRMT5 inhibitor that is selective against other PRMTs;
JBI-778 shows potent anti-proliferative activity against a number of cancers;
This oral small molecule demonstrated anti-tumor efficacy in a Mantle Cell lymphoma model with an ED50 of < 10 mg/Kg and a complete tumor growth inhibition (97%) at a dose of 50mg/kg; and
JBI-778 exhibited sustained brain exposure and significant tumor growth inhibition in an orthotopic glioblastoma model, translating into substantial survival advantage.
JBI-778 is currently being evaluated for the treatment of multiple cancers and IND-enabling studies have commenced.

PD-L1 expression is an immune evasion mechanism exploited by many cancers, such as melanoma, non-small cell lung cancer and breast cancer, which permits cancer progression and metastasis. Key highlights from the PD-L1/PD-1 study which examined the ability of JBI-1527 to inhibit PD-L1 and restore T-cell proliferation and function, include the following:

JBI-1527 is a potent, selective inhibitor of PD-L1 which induces dimerization of the protein thereby alleviating PD-L1-induced suppression of T cell activation;
The inhibitor shows similar modulation of cytokines as Pembrolizumab in BioMAP assay and competes with anti-PD-L1 blocking antibody suggesting similar binding site on PD-L1; and
In CT-26 and MC38-hPD-L1 syngeneic models, the small molecule showed strong tumor growth inhibition comparable to anti-PD-L1 mAb/Atezolizumab, and was well tolerated.
Studies to further assess JBI-1527 and additional compounds are underway.

Jubilant Therapeutics Inc. is developing a pipeline of novel, differentiated therapeutic assets; for partnership opportunity inquiries please contact [email protected].

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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"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.