On September 16, 2021 Boehringer Ingelheim reported a clinical phase I collaboration with Amgen to evaluate the combination of BI 1701963, the first and most advanced SOS1::pan-KRAS inhibitor exhibiting activity against a broad spectrum of KRAS alleles, and LUMAKRAS (sotorasib), the first US Food and Drug Administration (FDA) approved KRASG12C inhibitor for adult patients with locally advanced or metastatic non-small cell lung cancer (Press release, Boehringer Ingelheim, SEP 16, 2021, View Source [SID1234587821]). The trial will investigate potential synergistic effects of this combination, possibly improving therapeutic outcomes beyond those of KRASG12C inhibitor therapy alone, specifically for people living with lung and colorectal cancers.

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Preclinical data suggest that the combination of a KRASG12C inhibitor with a SOS1::pan-KRAS inhibitor may result in increased anti-tumor activity in KRAS G12C-driven cancers based on the complementary mechanisms of these targeted oncology agents.1,2 By shifting the equilibrium from active KRAS towards the inactive form, SOS1::pan-KRAS inhibitors have the potential to sensitize KRAS G12C-mutant tumors to covalent KRASG12C inhibitors that bind to inactive KRAS. In addition, SOS1 inhibitors block feedback reactivation which occurs upon pathway inhibition.

"We are excited to partner with Amgen, who have pioneered KRAS G12C inhibition, and to further expand our program to make a difference for people living with KRAS-driven cancers," said Francesco Di Marco, Ph.D., Corporate Senior Vice President, Global Therapy Area Head Oncology at Boehringer Ingelheim. "Boehringer Ingelheim follows an ‘all-in’ research approach to taking cancer on, including the first and most advanced SOS1::pan-KRAS inhibitor which we investigate in several combinations and cancer types to realize even more opportunities to deliver potential therapeutic benefits to cancer patients."

Under the terms of the non-exclusive collaboration, Amgen will be the sponsor of the trial and Boehringer Ingelheim and Amgen will jointly share the costs of and oversee clinical development for the combined therapy.

About BI 1701963
BI 1701963 is an investigational, orally available small molecule, that binds to the catalytic domain of SOS1 preventing the interaction with inactive KRAS. This reduces the formation of active KRAS and in consequence inhibits MAPK pathway signaling in KRAS-dependent cancers. SOS1 inhibition also simultaneously blocks feedback driven reactivation of the MAPK pathway. The selective inhibition of SOS1 is a therapeutic concept that could allow KRAS blockade irrespective of KRAS mutation type (pan-KRAS approach). SOS1::KRAS inhibitors exhibit activity on a broad spectrum of KRAS alleles, including all major G12D/V/C and G13D oncoproteins, as published by Hofmann MH, et al. in Cancer Discovery, a journal of the American Association of Cancer Research (AACR) (Free AACR Whitepaper). BI 1701963 is currently being evaluated in phase I clinical trials in patients with advanced KRAS-mutated cancers to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and preliminary efficacy of BI 1701963 alone and in combination with MEK inhibitors, KRASG12C inhibitors or irinotecan.

On September 16, 2021 Herantis Pharma Plc ("Herantis" or the "Company"), an innovative drug development company pioneering new disease modifying and regenerative biologic and gene therapies, reported on 15 September 2021 the result of the offering of new shares (the "Placing Shares") in a private placement to institutional and other qualified investors (the "Placing") (Press release, Herantis Pharma, SEP 16, 2021, View Source;1-346-500-new-shares-registered-with-the-trade-register,c3416563 [SID1234587820]). In the Placing, the Company issued a total of 1,346,500 Placing Shares. The Placing Shares have today been registered with the trade register maintained by the Finnish Patent and Registration Office.

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Following the registration of the Placing Shares, the total number of registered shares in the Company is 11,103,568. The Placing Shares will be issued in the book-entry system (ISIN code FI4000087861) on or about 20 September 2021. After this, and registration on the investors’ book-entry accounts, they will confer shareholder rights in the Company. The Placing Shares are expected to be ready for delivery to the investors against payment through Euroclear Finland Ltd or, as applicable, through Euroclear Sweden AB on or about 20 September 2021.

Trading in the Placing Shares is expected to commence on Nasdaq First North Growth Market Finland and Nasdaq First North Growth Market Sweden on or about 20 September 2021.

On September 16, 2021 Instil Bio, Inc. ("Instil") (NASDAQ: TIL), a clinical-stage biopharmaceutical company focused on developing tumor infiltrating lymphocyte, or TIL, therapies for the treatment of patients with cancer, reported that a subset analysis of treatment outcomes with unselected autologous tumor infiltrating lymphocytes (TILs) in patients with checkpoint inhibitor-refractory advanced cutaneous melanoma was presented today at the 2021 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, taking place virtually from September 16-21, 2021 (Press release, Instil Bio, SEP 16, 2021, View Source [SID1234587819]).

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Among the 12 patients featured in this subset analysis who had disease progression following treatment with a PD-1 inhibitor, all were also resistant to CTLA-4 inhibition with ipilimumab. Seven (58%) patients achieved an objective response, with 1 (8%) achieving a complete response. With a median duration of follow-up of 45.5 months, the median overall survival was 21.3 months with nearly half of patients experiencing long term survival. Side effects of treatment were largely transient, manageable with supportive care, and generally attributable to the lymphodepleting chemotherapy regimen and post-TIL high-dose IL-2 treatment. Outcomes in this highly treatment-refractory subgroup were similar to those observed in all 21 treated patients, with high response rates and an expected safety profile.

"The results of this analysis of a difficult-to-treat subgroup of patients further demonstrate that TIL therapy may offer benefit to patients with advanced melanoma once standard treatments have failed," said Zachary Roberts, M.D., Ph.D., Chief Medical Officer of Instil Bio. "We eagerly anticipate building on these results in DELTA-1, our Phase 2 study of ITIL-168 in patients with advanced melanoma."

Poster Presentation Details
Title: Treatment outcomes with unselected autologous tumor infiltrating lymphocytes (TILs) in patients (pts) with checkpoint inhibition–refractory advanced cutaneous melanoma
Poster Session: ePoster Display
Poster Number: 1058P

About ITIL-168

ITIL-168 is an investigational, autologous cell therapy made from tumor infiltrating lymphocytes, or TILs. Made from each patient’s digested and cryopreserved tumor, ITIL-168 is a TIL cell therapy manufactured to offer an unrestricted T cell receptor (TCR) repertoire. Instil’s proprietary, optimized, and scalable manufacturing process has been designed to capture and preserve the maximum diversity of each patient’s TILs. By collecting the patient’s tumor and immediately processing and then cryopreserving it, our process offers significant scheduling flexibility for patients and physicians at the time of both tumor resection and TIL treatment. In addition to DELTA-1, Instil plans to investigate ITIL-168 in additional solid tumor indications in Phase 1 clinical trials beginning in 2022.

About DELTA-1

DELTA-1 is a global, multicenter Phase 2 clinical trial of ITIL-168 in adult patients with advanced melanoma. Using an open-label, single-arm design, the main study cohort will evaluate the efficacy and safety of ITIL-168, when administered after a 5-day course of lymphodepleting chemotherapy and followed by up to 8 doses of high-dose interleukin-2 (IL-2), in patients whose cancer has progressed following a PD-1 inhibitor and, if positive for a BRAF-activating mutation, a BRAF inhibitor. Approximately 80 subjects are planned for enrollment and treatment in Cohort 1. Cohort 2 is anticipated to enroll approximately 25 subjects and is designed to evaluate the efficacy and safety of the regimen in patients who required discontinuation of PD-1 inhibitor(s) due to unacceptable toxicity, regardless of best overall disease response. Cohort 3 is also anticipated to enroll approximately 25 subjects and will evaluate efficacy and safety in patients whose best ongoing response to PD-1 inhibitor(s) is stable disease. Patients in Cohorts 2 and 3 whose cancer expresses a BRAF-activating mutation will be required to have experienced disease progression following BRAF inhibitor therapy. The primary endpoint of DELTA-1 is the objective response rate (ORR) according to RECIST v1.1 as assessed by independent central review. Secondary endpoints include disease control rate, duration of response, progression-free survival, overall survival, and safety.

On September 16, 2021 Oncxerna Therapeutics, Inc. ("OncXerna"), a precision medicine company using an innovative RNA-expression based biomarker platform to predict patient responses to its targeted oncology therapies, reported new clinical and biomarker data from its bavituximab program in an electronic poster at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 (Press release, OncXerna Therapeutics, SEP 16, 2021, View Source [SID1234587818]).

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Data presented in the poster are from ONCG100, an open-label Phase 2 clinical trial evaluating bavituximab, a potentially first-in-class phosphatidylserine (PS) inhibitor designed to reverse immune suppression, in combination with the PD-1 inhibitor pembrolizumab (KEYTRUDA) in patients with advanced gastric or gastroesophageal junction (GEJ) cancer. Patients participating in the trial were required to undergo pre-treatment biopsies to allow for pre-specified biomarker analysis using the Xerna TME Panel.

"Predictive biomarkers are an urgent need in gastric cancer where treatment options are limited and only a small fraction of patients’ treatment is biomarker driven," said Dr. Ian Chau, consultant medical oncologist at the Royal Marsden Hospital. "This study used OncXerna’s novel RNA expression-based algorithm to classify the biology of the tumor microenvironment of individual gastric cancer patients and prospectively test the hypothesis that patient tumors classified as having a high immune score by the Xerna TME Panel are more likely to benefit from treatment with bavituximab in combination with pembrolizumab. The results support this hypothesis by showing that the Xerna TME Panel biomarker was predictive of improved treatment response rates. This finding represents a promising new development that warrants further testing."

Key data and conclusions from the ESMO (Free ESMO Whitepaper) poster and corresponding abstract include:

Bavituximab appeared to sensitize cancers to pembrolizumab, suggesting the potential for the use of the combination for patients typically less responsive to immune checkpoint inhibitor monotherapy
Objective response rates (ORR) in:
Patients with PD-L1 combined positive score (CPS) < 1: 18% (3/17)
Patients with CPS ≥ 1: 13% (5/40)
Microsatellite stable (MSS) patients: 14% (6/43)

The Xerna TME Panel biomarker predicted treatment response
ORR in biomarker positive (B+) patients: 22% (7/32)
ORR in biomarker negative (B–) patients: 4% (1/25)
B+ patients had an increased ORR vs. B– patients across MSS, CPS ≥ 1, and CPS < 1 subgroups

The combination of bavituximab and pembrolizumab was well tolerated, with no additional toxicities observed above those expected with pembrolizumab alone
The most common toxicities observed were decreased appetite and fatigue (both, 31%), constipation (29%), and nausea (26%)
No treatment related deaths were reported
Efficacy data presented in the poster are from patients in Group 1 of the ONCG100 study, who were naïve to checkpoint inhibitor therapy. Efficacy data from Group 2 patients, who previously relapsed on checkpoint inhibitor therapy, were not presented as they are not yet mature due to the majority of these patients enrolling within three months of the data cut-off date.

Laura Benjamin, Ph.D., President and Chief Executive Officer at OncXerna, commented, "These results demonstrate the potential of bavituximab to overcome checkpoint inhibitor resistance mechanisms and highlight the predictive power of the Xerna TME Panel. Data showing that patients with CPS less than one had response rates that were similar to those of patients with CPS greater than one are particularly exciting, as patients with low CPS are typically less likely to respond to pembrolizumab monotherapy. We were also thrilled to see that biomarker positive patients had an ORR that was more than five times greater than that of biomarker negative patients. Looking forward, we plan to conduct a prospective study to confirm the anti-tumor activity of bavituximab in combination with an immune checkpoint inhibitor and the ability of the Xerna TME Panel to accurately identify patients most likely to respond. This will be an important step that we expect will further demonstrate the ability of the Xerna platform to drive the development of our precision medicine pipeline."

A link to the on-demand ESMO (Free ESMO Whitepaper) poster (#1386P), entitled: "Phase 2 Study of Bavituximab, a First-in-class Antibody Targeting Phosphatidylserine, Plus Pembrolizumab in Advanced Gastric or Gastroesophageal Junction Cancer," can be found here.

About ONCG100

ONCG100 is a Phase 2, multicenter, open-label, two-cohort global study designed to assess the safety, tolerability, and antitumor activity of bavituximab (3 mg/kg, QW) in combination with pembrolizumab (200 mg, Q3W) in patients with advanced gastric or GEJ cancer regardless of PD-L1 status who have progressed on ≥ 1 prior standard therapy. Patients were either naïve to checkpoint inhibitors (Group 1) or previously relapsed on a checkpoint inhibitor (Group 2). If known, microsatellite instability-high (MSI-H) patients were excluded. Pre-treatment biopsies were required for pre-specified biomarker analysis using the Xerna TME Panel. For more information, see ClinicalTrials.gov Identifier: NCT04099641.

About Bavituximab

Bavituximab is an antibody designed to reverse immune suppression by inhibiting phosphatidylserine (PS) signaling and is currently in Phase 2 clinical trials to treat a specific subset of patients with advanced gastric cancer to improve their response to anti-PD-1 treatment. The mechanism of action of bavituximab is to block tumor immune suppression signaling from PS to multiple immune cell receptor families (e.g., TIMs and TAMs). The dominant biology targeted by bavituximab may be relevant for patients with many types of solid tumors whose immune systems are too suppressed to benefit from currently available immune oncology therapies. A Phase 2 clinical trial is evaluating the combination of bavituximab with KEYTRUDA to test the hypothesis that relieving immunosuppression can enhance responses to checkpoint inhibitors. Bavituximab is an investigational agent that has not been approved, and it has not been demonstrated to be safe or effective for any use, including for the treatment of advanced gastric cancer.

KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

About the Xerna TME Panel

The Xerna TME Panel uses proprietary RNA-based gene expression data and a machine learning-based algorithm to classify patients based on the interplay between angiogenic and immunogenic dominant biologies of the tumor microenvironment (TME) and has been developed as a clinical assay. The Xerna TME Panel is an investigational assay that has not been approved and has not been demonstrated to be safe or effective for any use.

On September 16, 2021 BeyondSpring Pharmaceuticals (the "Company" or "BeyondSpring") (NASDAQ: BYSI), a global pharmaceutical company focused on the development of innovative cancer therapeutics, reported new positive data on plinabulin from its chemotherapy-induced neutropenia (CIN) prevention program with three poster presentations at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2021 Congress taking place from September 16-21, 2021 (Press release, BeyondSpring Pharmaceuticals, SEP 16, 2021, View Source;utm_medium=rss&utm_campaign=beyondspring-pharmaceuticals-announces-new-positive-data-on-plinabulin-from-its-chemotherapy-induced-neutropenia-prevention-program-at-the-european-society-for-medical-oncology-2021-congress [SID1234587817]). Plinabulin, the Company’s first-in-class lead asset, in combination with G-CSF for the prevention of chemotherapy-induced neutropenia (CIN) is currently under U.S. and China regulatory review with an FDA PDUFA date of November 30, 2021. The posters will be made available for viewing on the ESMO (Free ESMO Whitepaper) website starting on September 16 at 8:30 a.m. CEST and will remain available on the ESMO (Free ESMO Whitepaper) website throughout the entire duration of the Congress.

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"We’re pleased to present additional positive data at this year’s ESMO (Free ESMO Whitepaper) Congress to show that the Grade 4 neutropenia endpoint is correlated with clinically meaningful endpoints in a meta-analysis with >7000 patients in various cancer and various chemotherapy. This adds to our existing body of data in CIN prevention, a critically important indication for cancer patients," said Dr. Ramon Mohanlal, executive vice president, R&D, and chief medical officer at BeyondSpring Pharmaceuticals. "Over the last few years, plinabulin has continued to show its potential in preventing this life-threatening side effect of chemotherapy, and we remain committed to bringing this therapy to patients in need globally as we eagerly await November’s PDUFA date."

A summary of the data can be found below:

Severe Neutropenia (Grade 4, Gr4N) as a Population-Based Predictor for Adverse Clinical Outcome of Chemotherapy Induced Neutropenia (CIN). Poster #3574.

Ramon Mohanlal, M.D., Ph.D., executive vice president, R&D, chief medical officer, BeyondSpring Pharmaceuticals

The meta-analysis dataset included data from 36 published world literature (n > 7000) in various cancers and chemotherapy as well as the plinabulin CIN program including all 105 and 106 CIN studies (n=496).
Correlations of exponential equations between rate of febrile neutropenia (FN), duration of severe neutropenia (DSN) and absolute neutrophil count (ANC) nadir were statistically significant (p<0.0001) and in agreement with each other.
Grade 4 neutropenia (Gr4N) is a valid binary predictor of CIN outcomes, and a 65% Gr4N threshold depicts low vs. high CIN outcome risk.
Prediction of Febrile Neutropenia (FN), Hospitalization (Hosp) Rates, and Infection (Inf) Rates in Chemotherapy-Induced Neutropenia (CIN) Patients (pts) Treated with the Plinabulin and Pegfilgrastim Combination (Plin+Peg) using a Meta-Analysis (MA)-based Tool. Poster # 3627.

Stephan Ogenstad, Ph.D., founder and president of Statogen Consulting LLC, North Carolina

In the PROTECTIVE-2 Phase 3 trial, the combination of plinabulin and pegfilgrastim had superior efficacy in preventing Gr4N versus pegfilgrastim alone; Gr4N of 68% in the combination vs. Gr4N of 86% for pegfilgrastim alone, p = 0.0015.
Based on the meta-analysis detailed above in n>7000 patients, the reduction in Gr4N frequency from 86% in pegfilgrastim alone to 68% in the combination is predicted to result in a statistically significant and clinically meaningful reduction (approximately 50% reduction) in key clinically relevant CIN outcomes including mean DSN, FN rate, mean ANC nadir, hospitalization rate and infection rate (all p<0.0001), if used in an "all chemotherapy and all cancers" setting.
Impact of Adding Plinabulin to Pegfilgrastim for the Prevention of Chemotherapy Induced Neutropenia (CIN), on Patient Quality of Life (QoL). Poster# 3857.

Douglas W. Blayney, M.D., professor of medicine (oncology), Stanford Medicine

The physical wellbeing (in particular, pain and energy levels) of patients receiving plinabulin and pegfilgrastim was significantly less impacted by TAC compared to those receiving pegfilgrastim alone.
In addition, patients receiving plinabulin and pegfilgrastim recovered to their pre-chemotherapy physical wellbeing levels more rapidly and experienced less deterioration in their QoL over the duration of the 4-cycle trial.
About Plinabulin

Plinabulin, BeyondSpring’s lead asset, is a selective immunomodulating microtubule-binding agent (SIMBA), which is a potent antigen presenting cell (APC) inducer. It is a novel, intravenous infused, patent-protected, NDA stage asset for CIN prevention and a Phase 3 anti-cancer candidate for non-small cell lung cancer (NSCLC). Plinabulin triggers the release of the immune defense protein, GEF-H1, which leads to two distinct effects: first is a durable anticancer benefit due to the maturation of dendritic cells resulting in the activation of tumor antigen-specific T-cells to target cancer cells, and the second is early-onset of action in CIN prevention after chemotherapy by boosting the number of hematopoietic stem/progenitor cells (HSPCs). It is being developed as a "pipeline in a drug" in multiple cancer indications.