On September 12, 2022 Servier, Taiho Oncology, Inc., and Taiho Pharmaceutical Co., Ltd., reported that the investigational combination of trifluridine/tipiracil plus bevacizumab showed a statistically significant improvement in the primary endpoint of overall survival (OS) compared to trifluridine/tipiracil alone in a Phase III clinical trial of participants with refractory metastatic colorectal cancer (mCRC) following two chemotherapy regimens (Press release, Servier, SEP 12, 2022, View Source [SID1234619448]).

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Further details about the OS benefit and other results from the primary analysis of the global SUNLIGHT trial will be presented at an upcoming international scientific conference.

"Findings from the SUNLIGHT trial could potentially represent a significant advancement in the treatment of patients with metastatic colorectal cancer who have progressed after two lines of standard chemotherapy," said Nadia Caussé-Amellal, M.D., Head of Global Development, GI Indications, Oncology and Immuno-Oncology Therapeutic Area, Servier. "Combining trifluridine/tipiracil with bevacizumab demonstrated the potential to extend survival in these patients who have limited therapeutic options."

Fabio Benedetti, M.D., Global Chief Medical Officer for Oncology at Taiho Pharmaceutical, said: "Trifluridine/tipiracil – discovered by Taiho and developed in our partnership with Servier with the cooperation of many patients and healthcare professionals – has had a significant impact on the management of colorectal cancer for thousands of patients. The results of this study may represent another advancement in the management of this disease, and we now look forward to the further analysis of secondary endpoints."

Nearly 1.4 million people are diagnosed with colorectal cancer (CRC) each year worldwide,1 equating to 10% of the global cancer cases.1 CRC is the second most common cause of cancer mortality, accounting for 881,000 deaths globally in 2018,2 and patients with metastatic disease have a five-year survival rate of just 11%.3 Standard chemotherapy regimens for mCRC usually include a fluoropyrimidine plus irinotecan and/or oxaliplatin, with a targeted treatment – an antivascular endothelial growth factor or antiepidermal growth factor receptor – frequently added.

"The worldwide incidence of colorectal cancer is forecasted to exceed 3 million cases annually by 2040,4 and the number of deaths is predicted to increase by 69% to approximately 1.6 million per year,5" said Professor Josep Tabernero, M.D., Ph.D., Head of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain, and Primary Investigator for the SUNLIGHT trial. "New treatment options are urgently needed as we seek to reduce the growing global burden of colorectal cancer."

About SUNLIGHT

SUNLIGHT is a multinational, open-label, active-controlled, two-arm Phase III trial to investigate the efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil alone, in patients with refractory mCRC following two chemotherapy regimens. A total of 492 patients were randomly allocated (in a 1:1 ratio) to receive trifluridine/tipiracil plus bevacizumab or trifluridine/tipiracil monotherapy. The primary objective was to demonstrate the superiority of trifluridine/tipiracil plus bevacizumab over trifluridine/tipiracil alone, in terms of OS (primary endpoint). Key secondary objectives were to compare the regimens in terms of progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR) and quality of life (QoL), as well as the safety and tolerability of trifluridine/tipiracil plus bevacizumab in comparison with trifluridine/tipiracil monotherapy.

For more information on SUNLIGHT, please visit: View Source

About trifluridine and tipiracil

Trifluridine and tipiracil is an oral nucleoside antitumor agent discovered and developed by Taiho Pharmaceutical Co., Ltd. Trifluridine and tipiracil consists of a thymidine-based nucleoside analog, trifluridine, and the thymidine phosphorylase (TP) inhibitor, tipiracil, which increases trifluridine exposure by inhibiting its metabolism by TP. Trifluridine is incorporated into DNA, resulting in DNA dysfunction and inhibition of cell proliferation.

On September 12, 2022 Plus Therapeutics, Inc. (Nasdaq: PSTV) (the "Company"), a clinical-stage pharmaceutical company developing innovative, targeted radiotherapeutics for rare and difficult-to-treat cancers, reported Phase 1 data from the ReSPECT-GBM Phase 1/2a dose escalation clinical trial evaluating the Company’s lead investigational targeted radiotherapeutic, Rhenium-186 NanoLiposome (186RNL), in recurrent glioblastoma (GBM) in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, being held September 9-13, 2022 in Paris, France (Press release, PLUS THERAPEUTICS, SEP 12, 2022, View Source;_hsmi=225740869&_hsenc=p2ANqtz–6YFoZ8ZUpThJHOJugmdD8dgg2haHyg6iYf86gY_0MCeKN2rY0_GGFEXgLIEtD4CesBA5r_5RUW2PTlyFZ_lP6B5F-qQ&utm_content=225740869&utm_source=hs_email [SID1234619446]).

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"Radiation is lethal to cancer cells and rhenium-186 is an ideal radioisotope for the treatment of glioblastoma. Furthermore, the unique drug formulation allows the radiation to stay in the brain for days, if not weeks," said Andrew J. Brenner, M.D., Ph.D., Professor of Medicine, Neurology, and Neurosurgery at The University of Texas Health Science Center at San Antonio and principal investigator of the ReSPECT-GBM clinical trial. "In the ReSPECT-GBM Phase 1 trial, we achieved up to 20 times the amount of radiation compared to external beam radiation therapy, and we observed a statistically significant improvement in survival in those patients receiving a therapeutic dose of radiation compared to those that did not."

The oral presentation titled, The ReSPECT-GBM Phase 1/2a Dose Escalation Trial of Rhenium-186 NanoLiposome (186RNL) in Recurrent Glioma via Convection Enhanced Delivery (CED) & Planned Phase 2b Trial [2770], reviews data from the Phase 1 ReSPECT-GBM trial which evaluated 23 adult patients with recurrent GBM across 8 cohorts of increasing dose and treated over a seven-year period.

Key findings include:

No dose-limiting toxicities (DLT) have been observed and the procedure is very well tolerated with a strong safety profile. Minimal systemic radiation has been observed and the majority of adverse events have been mild or moderate and considered causally unrelated to the procedure.
Improved median overall survival (OS) rates correlated with the absorbed tumor radiation dose. When patients were stratified based on receipt of either a therapeutic or a subtherapeutic absorbed dose of radiation to the tumor, a statistically significant improvement in survival was observed. Specifically, patients receiving a therapeutic absorbed radiation dose (>100 Gray) had a median OS of 22.9 (95% CI of 8.8-42.3) months compared to those receiving a subtherapeutic absorbed radiation dose (<100 Gray) whose median OS was 5.6 months (95% CI of 1.6-9.4). Currently, three patients remain alive, all in the therapeutic group.
Feasibility to deliver up to at least 20 times more radiation to the tumor than the standard of care, external beam radiation therapy (EBRT). A maximum of 32.2 mCi in 12.3 mL of volume has been delivered in and near the tumors, and a maximum average absorbed dose of radiation of 740 Gray has been successfully administered in a single procedure.
Average absorbed radiation dose to the tumor increased in latter dosing cohorts with greater administered doses of Re-186 β-particle radiation, larger drug convection enhanced delivery (CED) infusate volumes, more catheters used (up to 4 versus 1), and higher convection flow rates. In cohorts 5 and later, 82% of patients received a therapeutic radiation dose of >100Gray.
Single-photon emission computerized tomography and (SPECT)/CT scanning were used during treatment to compute tumor coverage and dosimetry. Post treatment imaging analyses, including MRI, relative cerebral blood volume (rCBV) analysis and treatment response assessment maps (TRAMs) correlated with a positive tumor response and confirmed the presence of pseudoprogression in patients with positive tumor responses.
ReSPECT-GBM will proceed to an NIH and U.S. Food and Drug Administration (FDA) approved Phase 2 trial in the U.S. at the current non-DLT 186RNL dose and will expand exploring higher radiation doses in larger volumes to treat larger tumors. Additionally, two or more 186RNL administrations, if indicated, will be evaluated and reviewed with the FDA, as well as expanded safety, imaging and efficacy data to support a planned future registrational trial.
"The Phase 1 data offer important and objective insight and data into 186RNL’s potential to safely prolong patient survival and suggests that there is an overall survival benefit when a 186RNL dose of more than 100 Gray is achieved," said Norman LaFrance, M.D., Chief Medical Officer and Senior Vice President at Plus Therapeutics. "The planned Phase 2 study using cGMP 186RNL will leverage a higher dose and volume that could potentially show a greater survival rate in patients with recurrent GBM."

Based upon feedback from a Type C meeting with the FDA, the Company plans to initiate the ReSPECT-GBM Phase 2 trial in the second half of 2022, funded principally by the NIH. The Company intends to begin the ReSPECT-GBM Phase 2 trial utilizing cGMP 186RNL drug, which will be available in the second half of 2022. In this study, researchers plan to administer the recommended non-DLT dose of 22.3 mCi (total 186RNL activity) at a concentration of 2.5 mCi/mL in 8.8 mL total volume to patients with a tumor size of less than or equal to 20 cm3 as a starting point. Furthermore, the Company plans to evaluate further doses, including both increased dosing and multiple doses, and collect additional safety and efficacy data for the planned future registrational trial.

A copy of the presentation will be available under the Presentations tab of the Investors section of the Company’s website at the time of presentation at View Source

On September 12, 2022 Agenus (NASDAQ: AGEN), an immuno-oncology company with an extensive pipeline of therapeutics designed to activate the immune response to cancers and infections, reported the initiation of a global Phase 2 program of botensilimab, an Fc-enhanced anti-CTLA-4 that activates innate and adaptive immune responses (Press release, Agenus, SEP 12, 2022, View Source [SID1234619445]). These trials include ACTIVATE-Colorectal, a Phase 2 study designed to evaluate botensilimab as monotherapy and in combination with balstilimab (anti-PD-1) for the treatment of microsatellite stable colorectal cancer (MSS CRC), and ACTIVATE-Melanoma, a Phase 2 study designed to evaluate botensilimab as a single agent for advanced melanoma, refractory to either prior anti-PD-1 or combined anti-PD-1/anti-CTLA-4 therapy. An additional Phase 2 study in pancreatic cancer is anticipated to begin later in 2022.

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"The Phase 1 botensilimab program demonstrated remarkable activity in poorly immunogenic and difficult to treat tumor types," said Steven O’Day, MD, Chief Medical Officer at Agenus. "In light of our compelling clinical data, we have received clearance from the FDA to initiate our Phase 2 development program in two indications and intend to expand to multiple additional indications as rapidly as possible with the aim of delivering a transformative new treatment option to patients in need."

ACTIVATE-Colorectal is a global, randomized, open-label, dose-optimization study evaluating the safety and efficacy of botensilimab as monotherapy and in combination with balstilimab in advanced refractory MSS CRC patients. Key elements of ACTIVATE-Colorectal include:

Patients must have received at least one prior chemotherapy regimen
Patients cannot have received prior PD-1, CTLA-4 or other immune checkpoint inhibitor therapy
Primary endpoint is overall response rate (ORR); secondary endpoints include duration of response (DOR), progression-free survival (PFS) and overall survival (OS)
Recruitment will be global, including sites in the United States and Europe
ACTIVATE-Melanoma is a global, randomized, open-label, multi-cohort, dose-optimization study evaluating the safety and efficacy of botensilimab as a single agent in advanced refractory melanoma. Key elements of ACTIVATE-Melanoma include:

Study will enroll patients who have failed prior anti-PD-1 therapy (cohort A) or both anti-PD1 and anti-CTLA-4 therapy (cohort B)
Primary endpoint is overall response rate (ORR); secondary endpoints include duration of response (DOR), progression-free survival (PFS) and overall survival (OS)
Recruitment will be global, including sites in the United States and Europe
About Microsatellite Stable Colorectal Cancer

Colorectal cancer remains the third most common cancer diagnosis and second-leading cause of cancer death worldwide, affecting 1.93 million and 916,000 individuals each year1. MSS colorectal cancer is a form of colorectal cancer where the cells’ DNA repair mechanisms remain intact2. It accounts for over 95% of metastatic colorectal cancer cases3 and has historically been unresponsive to immune checkpoint therapy4. Standard of care in pretreated metastatic MSS colorectal cancer offers limited benefit, with an approximate 1-2% response rate and a median of 6-7 months of survival5,6.

About Advanced Refractory Melanoma

Melanoma is a serious skin cancer that affects approximately 132,000 individuals each year and has been growing in incidence7. Advanced refractory melanoma refers to cancer that has spread to other parts of the body and stopped responding to medical therapy. Recent advances in the use of targeted therapy and immunotherapy, including anti-PD-1 and anti-CTLA-4, have improved survival for patients diagnosed with advanced melanoma. However, while anti-PD-1 monotherapy can be effective as a first-line treatment for some patients with metastatic melanoma, roughly half fail to achieve an objective response and those who do often subsequently relapse.8,9,10 Those patients with non-BRAF mutated tumors who are refractory to or who relapse after having received anti-PD-1 and anti-CTLA-4 therapy have few effective treatment options.

About Botensilimab

Botensilimab is a novel innate and adaptive immune activator that binds CTLA-4. The antibody was designed to enhance FcγR effector functions while avoiding complement-related toxicities and has demonstrated activity in cancer patients for whom current immuno-oncology agents have historically been ineffective. As presented at SITC (Free SITC Whitepaper) 2021, botensilimab is the first CTLA-4 inhibitor to demonstrate clinical responses across nine cold and treatment-resistant cancers. At ESMO (Free ESMO Whitepaper) GI 2022, botensilimab demonstrated unprecedented activity in combination with balstilimab in MSS colorectal cancer, with a 24% response rate and 73% disease control rate in heavily pre-treated patients with a median of 4 prior lines of therapy.

On September 12, 2022 Kiniksa Pharmaceuticals, Ltd. (Nasdaq: KNSA) (Kiniksa), a biopharmaceutical company with a portfolio of assets designed to modulate immunological pathways across a spectrum of diseases, reported the closing of the global license agreement with Roche and Genentech, a member of the Roche Group (Genentech), for the rights to develop and commercialize vixarelimab, a fully human monoclonal antibody targeting oncostatin M receptor beta (OSMRβ) (Press release, Kiniksa Pharmaceuticals, SEP 12, 2022, View Source [SID1234619444]). Closing of the transaction was subject to customary closing conditions and expiration of the waiting period under the Hart-Scott-Rodino (HSR) Antitrust Improvements Act of 1976.

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Under the terms of the license agreement, Kiniksa will receive $100 million in upfront and near-term payments, which include $80 million within 30 days of the closing of the transaction and $20 million within 30 days after Kiniksa’s delivery of certain drug supplies to Genentech. In addition, Kiniksa is eligible to receive up to approximately $600 million in certain clinical, regulatory, and sales-based milestones, before fulfilling upstream financial obligations. Kiniksa is also eligible to receive royalties on annual net sales. Genentech obtains rights for the global development and commercialization of vixarelimab.

Kiniksa expects that its cash and cash equivalents, including the proceeds received from the vixarelimab global license agreement with Genentech, will fund its current operating plan into at least 2025.

On September 12, 2022 Onconova Therapeutics, Inc. (NASDAQ: ONTX), ("Onconova"), a clinical-stage biopharmaceutical company focused on discovering and developing novel products for patients with cancer, reported updated data from an investigator-sponsored Phase 1/2a trial of oral rigosertib plus the anti-PD-1 immune checkpoint inhibitor (ICI) nivolumab in advanced KRAS-mutated (KRAS+) non-small cell lung cancer (NSCLC) (Press release, Onconova, SEP 12, 2022, View Source [SID1234619443]). The data, which are featured in a poster at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2022, show an early and encouraging signal of efficacy in the trial’s extensively pre-treated population. The studied doublet has been well tolerated to-date.

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"The emerging data being presented at ESMO (Free ESMO Whitepaper) are encouraging, as treatment with rigosertib plus nivolumab led to both complete and partial responses in patients with KRAS-mutated lung cancers who failed prior ICI therapy," said Dr Rajwanth Veluswamy, the principal investigator of the study. "Objective responses showcased rigosertib’s KRAS mutation-agnostic mechanism of action, as each responding patient had a tumor with a different underlying variant. This differentiates rigosertib from agents targeting a single KRAS mutation variant, and positions it to potentially address the unmet needs of a much broader patient population. In addition, the ESMO (Free ESMO Whitepaper) data demonstrated activity in multiple patients with both low PD-L1 expression at diagnosis and STK11/LKB1 co-mutations, both poor predictive features for current lung cancer treatments."

Key data from the presentation include:

Demographics:

All enrolled patients failed at least one line of prior therapy with a PD-1 checkpoint inhibitor (includes evaluable and non-evaluable patients)
80% of enrolled patients failed at least two lines of prior therapy
Response results (as of August 15th, 2022-data cutoff date):

3 of 14 evaluable patients achieved an objective response
1 patient achieved a complete response (CR) as per RECIST Criteria, with complete resolution of the primary lung tumor as well as sites of metastatic disease.
2 patients achieved a partial response (PR)
Responses were achieved in patients with 3 distinct KRAS mutations (CR: KRAS G12V; PRs: KRAS G12C/STK11 and Q61H/STK11)
The mean duration of response is 6.75 months
4 of 14 evaluable patients achieved disease control (CR, PR, or stable disease)
Safety results:

The studied doublet has been generally well tolerated. Treatment-related adverse events (TRAE) have been mostly mild and manageable.
One dose limiting toxicity of grade 3 hyponatremia has been observed (previously documented with rigosertib)
Urinary toxicities well documented with rigosertib are the most common TRAE
No unexpected safety events or synergistic toxicities have been observed
Steven M. Fruchtman, M.D., President and Chief Executive Officer of Onconova, commented, "The evidence of efficacy observed in the trial’s highly challenging population suggests rigosertib may synergize with ICI and potentially provide clinical benefit to patients with limited therapeutic options. This hypothesis is supported both by these latest clinical data and the results of preclinical studies in multiple indications. Looking forward, we expect the maturation of the trial’s current results, as well as the new data we expect to collect by enrolling additional patients, to provide key insights that will inform the next steps for rigosertib’s current investigator-sponsored study program."

The ESMO (Free ESMO Whitepaper) poster (#1018P) is titled "Phase 1/2 Trial of Rigosertib and Nivolumab for KRAS Mutated Non-Small Cell Lung Cancer (NSCLC) Patients." It is currently available for viewing on the congress’s virtual platform and is being presented by the trial’s principal investigator, Rajwanth Veluswamy, M.D., Assistant Professor, Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, today during Poster Session 14. The poster is available on the "Scientific Presentations" section of the Onconova website.

About the Investigator-sponsored Phase 1/2a Trial

This Phase 1/2a trial is designed to evaluate the combination of rigosertib and nivolumab in advanced KRAS+ metastatic NSCLC patients who have progressed on standard-of-care with anti-PD-1 monotherapy or anti-PD-1 in combination with chemotherapy. It includes a dose-escalating Phase 1 portion followed by a Phase 2a dose-expansion portion. Patients in the trial receive oral rigosertib twice daily on days 1-21, and intravenous nivolumab on days 1 and 15 of 28-day cycles. The primary endpoints of the trial are safety assessments to determine maximum tolerated dose, and overall response rate. Secondary endpoints include progression-free survival and overall survival. For more information on the trial, see ClinicalTrials.gov Identifier: NCT04263090.