On April 9, 2024 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage biotechnology company developing first-in-classi targeted and immune-mediated therapeutics to fight cancer, reported that collaborators at the Beth Israel Deaconess Medical Center (BIDMC) at Havard Medical presented preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting demonstrating that TPST-1120 reduces kidney cancer (RCC) growth as a monotherapy, while also showing increased inhibition when combined with frontline chemotherapy and immunotherapy (Press release, Tempest Therapeutics, APR 9, 2024, View Source [SID1234641944]). These new data further support the clinical benefit observed in the TPST-1120 Phase 1 data presented in an oral presentation at ASCO (Free ASCO Whitepaper) 2022.

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"Preclinical data presented at AACR (Free AACR Whitepaper) further demonstrate that TPST-1120 has the potential to positively transform the tumor microenvironment and expand the activity of anti-tumor immunity in kidney cancer," said Sam Whiting, M.D., Ph.D., chief medical officer and head of R&D at Tempest. "The expanding positive preclinical and clinical findings of TPST-1120 reinforce our excitement for this program and support the next phase of clinical development into a pivotal HCC study and the potential to expand into RCC and multiple other cancer types."

Preclinical data presented at AACR (Free AACR Whitepaper) showed that TPST-1120 increases infiltrating cytotoxic CD8+ T cells in the tumor microenvironment, consistent with modulation of the tumor microenvironment to a more immune responsive environment that allows for the influx of tumor specific CD8+ T cells.

In preclinical models of renal cell carcinoma (RCC), treatment with TPST-1120 reduced tumor growth by 52%-56% as monotherapy. Additional improvement in anti-cancer activity was demonstrated in combination treatment with standard first-line RCC cabozantinib or anti-PD1 therapy, where tumor inhibition was 81% and 74%, respectively.

These data reinforce previously reported Phase 1 clinical data where objective responses were observed in patients with late line, immune refractory RCC treated with TPST-1120 and the immune therapy, nivolumab, and complement the positive Phase 1b/2 data reported in October 2023 from a global randomized study of TPST-1120 in combination with atezolizumab and bevacizumab in first-line patients with advanced HCC, which showed clinical superiority of the TPST-1120 arm over the control arm across multiple study endpoints and relevant biomarker-defined patient subpopulations.

About TPST-1120

TPST-1120 is an oral, small molecule, selective PPAR⍺ antagonist. Tempest’s data suggest that TPST-1120 treats cancer by targeting tumor cells directly and by modulating immune suppressive cells and angiogenesis in the tumor microenvironment. In an ongoing global randomized phase 1b/2 study of TPST-1120 in combination with atezolizumab and bevacizumab in first-line patients with advanced HCC, the TPST-1120 arm showed clinical superiority across multiple study endpoints when compared to atezolizumab and bevacizumab alone, the standard of care. These randomized data were supported by positive results observed in the Phase 1 clinical trial in patients with heavily pretreated advanced solid tumors. TPST-1120 is wholly-owned by Tempest.

On April 9, 2024 Sensei Biotherapeutics, Inc. (Nasdaq: SNSE), an immuno-oncology company focused on the discovery and development of next generation therapeutics for cancer patients, reported that Company management will participate in a panel titled ‘KRAS and VISTA – Better Approaches for Key Targets’ at Canaccord Genuity’s Horizons in Oncology Virtual Conference on Monday, April 15th at 2:00 p.m. ET (Press release, Sensei Biotherapeutics, APR 9, 2024, View Source [SID1234641943]).

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The panel will feature Dr. Shiraj Sen, M.D., Ph.D., Medical Oncologist and Director of Clinical Research at NEXT Oncology-Dallas. Dr. Sen is an investigator on the ongoing Phase 1/2 clinical trial for SNS-101.

On April 9, 2024 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, reported the publication of a peer-reviewed research paper in Cancer Discovery (Press release, Revolution Medicines, APR 9, 2024, View Source [SID1234641942]). The scientific paper details the discovery and preclinical to clinical translation for RMC-6236, an investigational RAS(ON) multi-selective inhibitor, and includes exemplary case studies from the current Phase 1/1b clinical trial demonstrating the initial anti-tumor activity of RMC-6236. This original research was led by scientists at Revolution Medicines and conducted in collaboration with researchers from across the U.S. and Europe.

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Oncogenic RAS proteins drive up to 30 percent of all human cancers, most notably non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). RAS G12 mutations, such as G12D, G12V and G12C, predominate in human cancers. Currently approved KRAS-targeted cancer therapies target one particular KRAS mutation, KRAS G12C, in the GDP-bound (OFF) state. The paper describes the discovery of RMC-6236, an oral, multi-selective inhibitor of the active GTP-bound (ON) state of both mutant and wild-type RAS. In preclinical studies, RMC-6236 was effective in inhibiting the growth of RAS-dependent tumor cells, while sparing normal tissues. RMC-6236 was found to be well-tolerated and drove deep and durable tumor regressions across multiple cancer types including NSCLC, PDAC, CRC, gastric and gynecologic cancers, with tumor models dependent on KRAS G12 mutations being particularly sensitive. This benefit was found to extend to models with K/N/HRAS hotspot mutations at G13 and Q61 as well.

The paper also highlights translational pharmacokinetics (PK)/efficacy and PK/pharmacodynamics modeling, which predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, case studies from the Phase 1/1b RMC-6236 monotherapy clinical trial are featured, describing two patients with advanced KRAS-G12V NSCLC and KRAS-G12D PDAC, respectively, who were treated with 300 mg of RMC-6236 daily. Each of these two patients achieved a complete response as best response demonstrating the potential anti-tumor activity of RMC-6236.

"The discovery of RMC-6236 allowed for the first-ever therapeutic evaluation of targeted concurrent inhibition of both canonical mutant and wild-type RAS-GTP (RAS(ON)) in RAS-driven cancers. The RMC-6236 clinical data that we have shared not only provide platform validation of our tri-complex inhibitor approach, but also refute the dogma that one could not induce anti-tumor activity by broad inhibition of multiple RAS variants, including wild-type RAS, at doses that would be well tolerated," said Steve Kelsey, M.D., president, research and development of Revolution Medicines. "The research summarized in our Cancer Discovery paper, combined with the preliminary RMC-6236 clinical data presented in late 2023, provide us and our investigators with the confidence to advance and expand our RMC-6236 clinical development program."

Revolution Medicines is currently evaluating RMC-6236 as monotherapy in a Phase 1/1b trial in patients with advanced solid tumors harboring G12X, G13X and Q61X mutations (NCT05379985). Following promising preliminary data in this Phase 1/1b study, planning is underway to initiate pivotal studies of RMC-6236 as monotherapy in NSCLC and PDAC. RMC-6236 is also being evaluated in combination with pembrolizumab with or without chemotherapy in patients with advanced RAS-mutated solid tumors (NCT06162221) and in combination with RMC-6291, the company’s investigational RAS(ON) G12C-selective inhibitor, for patients with advanced KRAS G12C-mutated solid tumors (NCT06128551).

Today’s publication coincides with the company’s presentation of RMC-6236 preclinical data and additional clinical case studies during the "KRAS: Broadening the Attack Beyond G12C with Small Molecules and Immuno-Oncology" session today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in San Diego.

The scientific paper can be accessed at the following link: View Source

On April 9, 2024 RAPT Therapeutics, Inc. (Nasdaq: RAPT), a clinical-stage, immunology-based therapeutics company focused on discovering, developing and commercializing oral small molecule therapies for patients with significant unmet needs in inflammatory diseases and oncology, reported safety and efficacy data from its ongoing Phase 2 trial of tivumecirnon in combination with the anti-PD-1 checkpoint inhibitor (CPI) pembrolizumab in the cohort of patients with advanced head and neck squamous cell carcinoma (HNSCC) whose disease progressed despite previous treatment with CPI therapy (CPI-experienced) (Press release, RAPT Therapeutics, APR 9, 2024, https://investors.rapt.com/news-releases/news-release-details/rapt-therapeutics-announces-promising-results-phase-2-trial [SID1234641941]). The results were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in San Diego, CA.

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The AACR (Free AACR Whitepaper) poster highlighted data from the 32-patient CPI-experienced HNSCC cohort in the trial evaluating tivumecirnon, an oral small molecule CCR4 antagonist designed to block the migration of regulatory T cells, in combination with pembrolizumab. Patients in this cohort had heavily pretreated disease, with 69% of patients having received three or more (up to six) prior lines of treatment. In the entire cohort, confirmed responses were observed in 5/32 patients (15.6%) regardless of PD-L1 or HPV status. In the 23 patients known to have PD-L1+ disease (CPS ≥1), an ORR of 17.4% (4/23) was observed, and in the 18 patients known to have HPV+ disease, an ORR of 22.2% (4/18) was observed. These findings compare favorably to the expected ORR of anti-PD-1 monotherapy in patients with recurrent or metastatic HNSCC who have progressed on, or relapsed after, previous anti-PD-1 therapy, which is believed to be <5-10%.

Phase 2 Data Summary in HPV+ CPI-experienced HNSCC Patients (n=13)

PD-L1+ Status (n) Confirmed ORR
All (regardless of PD-L1 or HPV status) 5/32 15.6% (95% CI 6-32%)
PD-L1+ (CPS ≥1) 4/23 17.4% (5-39%)
HPV+ 4/18 22.2% (9-46%)

These data complement previously reported clinical data for tivumecirnon, which has now been dosed in more than 350 patients with various advanced cancers either as monotherapy or in combination with pembrolizumab. Findings to date have shown the combination treatment to be well tolerated with no signal of increased immune-related toxicity over that expected with pembrolizumab alone.

"As the trial progresses and cohorts mature, we continue to be impressed by the promise and expanded clinical activity of tivumecirnon," said Brian Wong, M.D., Ph.D., President and Chief Executive Officer of RAPT. "These results add to the growing data supporting the efficacy of tivumecirnon across a number of oncology indications, including non-small cell lung cancer, head and neck cancer, gastric cancer and non-Hodgkin lymphoma, and we are evaluating the next steps to advance its development."

Phase 1/2 Clinical Trial Design
The ongoing open-label Phase 1/2 study enrolled patients with multiple types of cancer at leading cancer centers across the United States, Australia and Asia. The Phase 2 portion is designed to evaluate the degree of antitumor activity of tivumecirnon as monotherapy and in combination with pembrolizumab specifically in patients with several types of Treg and CCR4 pathway-enriched tumors. Changes in the tumor microenvironment and other biomarkers are being evaluated in both phases of the study. For more information please visit clinicaltrials.gov identifier NCT03674567.

About Tivumecirnon (FLX475)
Tivumecirnon is a small molecule CCR4 antagonist designed to block the migration of regulatory T cells (Treg) specifically into tumors, but not healthy tissues. Treg represent a dominant pathway for downregulating the immune response, generally correlate with poor clinical outcomes and may limit the effectiveness of currently available therapies such as checkpoint inhibitors. Tivumecirnon may restore naturally occurring antitumor immunity alone and may synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, immune stimulators, cancer vaccines and adoptive T cell therapy.

On April 9, 2024 Onchilles Pharma, a private biotech company developing cancer therapeutics that leverage a novel innate immune mechanism of action for potent and selective cancer killing, reported the presentation of new preclinical data for systemically delivered N17465 in an oral presentation and tumor-directed N17350 in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, taking place April 5 to 10 at the San Diego Convention Center (Press release, Onchilles Pharma, APR 9, 2024, View Source [SID1234641939]).

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N17350 and N17465 are novel first-in-class oncology programs that harness the potent efficacy of the innate immune system and have the potential to become a major new treatment modality for a wide range of cancer types. Onchilles has engineered N17350 for intratumoral delivery and N17465 for systemic IV delivery and generated significant preclinical data validating the novel mechanism of action that delivers efficacy independent of tumor genetics and immune status by targeting the histone H1-death domain axis. Upregulation of histone H1 is a property common to many cancer cells and responsible for the selectivity of cancer cell killing seen in the N17350 and N17465 programs via immunogenic cell death.

Lev Becker, Ph.D., Scientific Founder, Onchilles Pharma, said, "We are excited to unveil systemically delivered N17465 that has the potential to redefine the treatment of solid tumors. The data presented today demonstrate that N17465 exhibits potent and tumor-selective efficacy, mobilizes the immune system for anti-tumor immunity, and produces durable responses in mouse models as a monotherapy. These data mark a major step forward in our quest to bring N17465 to patients."

Dr. Becker continued, "The new data presented today for N17350 add to our large preclinical data package validating the mechanism of action, confirming it induces immunogenic tumor cell death, and demonstrating selective cancer-cell killing in patient-derived chemotherapy-naive or -experienced ovarian cancer cell lines and CDX models. We believe that these data underscore the potential of N17350 as a potent and safe cancer treatment, and we look forward to advancing tumor-directed N17350 into first-in-human clinical trials this year."

Court R. Turner J.D., Co-Founder & Executive Chair of Onchilles Pharma, said, "The latest data revealed at AACR (Free AACR Whitepaper) on primary tumor samples introduce a significant layer of human validation to our approach before our planned clinical trials. The potent single-agent activity and selectivity of N17350 distinguish it from other tumor-directed approaches currently in development that only show modest to no monotherapy efficacy. We are confident that N17350 and N17465 represent a novel class of molecules that could become the new foundation of cancer treatment. We anticipate strong monotherapy efficacy of N17350 in our upcoming Phase 1 trial with potential approvals in many types of solid tumors by 2028, marking a significant milestone in oncology."

Details of the data presented are as follows:

In a talk for abstract 6578, entitled, "N17465, a systemically deliverable elastase, attenuates tumorigenesis and stimulates anti-tumor immunity," the following data were presented:

N17465 resisted inhibition by serine protease inhibitors found in the blood and maintained its ability to cleave the death domain of CD95 (therapeutic target) to selectively kill cancer cells.
N17465 induced immunogenic cell death (ICD) markers in cancer cell lines and patient ovarian cancer cells and was also well tolerated by non-cancer cells.
Systemically delivered N17465 produced tumor-free mice in a murine CT26 colon cancer model and induced a favorable immune profile
N17465 also exhibited efficacy across a range of xenograft models spanning human lung, colon, breast, and prostate cancer, as well as ovarian cancer patient-derived CDX models.
In a poster for abstract 5895 entitled, "N17350 kills cancer cells, spares immune cells, and regresses CDX tumors from chemotherapy-naive and experienced patients," the following data were presented:

N17350 killed primary cancer cells from all ovarian cancer (OvCa) patients tested but was well tolerated by non-cancer cells from the same patients; in contrast, doxorubicin and oxaliplatin showed similar toxicity to both cell types.
N17350 killed cancer cells from chemotherapy-naïve and -experienced patients with equal efficacy, while doxorubicin and oxaliplatin showed less efficacy in patients previously treated with chemotherapy.
N17350 rapidly regressed tumors in all OvCa CDX models and exhibited markedly improved efficacy over carboplatin.
N17350 mobilizes anti-tumor immunity in the 4T1 model of metastatic breast cancer and outperforms standard-of-care chemotherapy
About N17350 and N17465 and Their Novel Mechanism of Action
First described in research published in Cell from the lab of Onchilles’ Co-Founder Lev Becker, human neutrophils release catalytically active neutrophil elastase (called ELANE), which selectively and potently kills cancer cells independent of their genetics and anatomical origin, mobilizes adaptive immunity, and avoids resistance mechanisms. The team at Onchilles translated this ground-breaking discovery into a proprietary set of molecules, including N17350 and N17465, with the potential to treat a wide variety of tumor types with an optimal efficacy and safety profile.