On October 14, 2023 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported the poster presentation of a Phase I/II trial of alisertib plus pembrolizumab for the treatment of patients with Rb-deficient head and neck squamous cell carcinoma (Clinicaltrials.gov identifier NCT04555837) at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston, Massachusetts (Press release, NovoCure, OCT 14, 2023, View Source [SID1234635983]). The poster (number LB_C12), entitled "Alisertib and pembrolizumab in Rb-deficient head and neck squamous cell carcinomas (HNSCC)," was presented by Faye M. Johnson, M.D., Ph.D., Department of Thoracic/Head & Neck Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, in the Late-breaking Poster Session C on Saturday, October 14 at 12:30 pm ET. A copy of the poster is available on the Puma website.

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Alisertib is an adenosine triphosphate–competitive, reversible inhibitor of Aurora Kinase A (AURKA) that results in disruption of mitosis. Human papillomavirus (HPV) is a common cause of HNSCC, and infection leads to Retinoblastoma protein (Rb1) degradation. A synthetic lethal relationship between AURKA and Rb1 has been implicated preclinically, and alisertib has been shown to induce immunogenic cell death in HPV+ cancer cells.

The investigator-sponsored clinical trial was conducted sequentially in two parts: A Phase I study to determine the recommended dose for alisertib in combination with pembroluzimab in patients with advanced solid tumors, and a Phase II study to evaluate efficacy of alisertib and pembroluzimab in patients with recurrent or metastatic, Rb-deficient HNSCC who had progressed on prior anti-PD1 therapy. Biomarkers of response were also evaluated.

The Phase I portion of the study enrolled ten patients with advanced solid tumors. There was no requirement for Rb deficiency in the Phase I portion of the trial. Alisertib was dosed twice daily for seven days every twenty-one days at either 30 mg, 40 mg, or 50 mg, and pembrolizumab was dosed at 200 mg intravenously every three weeks. The observed dose-limiting toxicities were predominantly hematologic in nature and congruent with the expected safety profile. Based on these findings, the 40 mg dose level was selected for the Phase II portion of the study. The Phase I portion of the trial enrolled patients with several different solid tumors including small cell lung cancer, thyroid carcinoma showing thymic-like differentiation, oropharynx cancer, salivary cancer and head and neck squamous cell carcinoma. One patient with small cell lung cancer experienced stable disease lasting for 245 days, one patient with HPV-positive orpharynx cancer experienced stable disease lasting for 209 days, and one patient with thyroid carcinoma showing thymic-like differentiation experienced stable disease lasting 811+ days.

Fourteen patients with immunotherapy- and platinum-resistant HPV+ HNSCC were enrolled in the Phase II portion of the study. Two of the fourteen patients had confirmed Rb1 loss by next generation sequencing. No objective responses were observed, though seven patients, including three with progression-free survival (PFS) exceeding 8 months, experienced stable disease. The remaining seven experienced progressive disease. The median PFS was 1.4 months, and the median overall survival (OS) was 13.5 months. No new safety signals were observed.

The relationships between biomarkers and response were evaluated. Baseline plasma cytokines IL-2, IL-10, IL-17 and IL-1b were lower in patients with PFS > 6 months than in those with PFS ≤ 6 months (p=0.0186, 0.0189, 0.0199, and 0.0098, respectively). Baseline PDL1 expression (Combined Positive Score (CPS)) did not demonstrate a correlation with PFS (p=0.59) or OS (p=0.96). An increase in circulating CD8+, CD4+ and CD56+ immune cells between baseline and Cycle 3 Day 1, assessed by polychromatic flow cytometry, was observed in patients with PFS > 6 months, but not in those with PFS ≤ 6 months. Finally, an increase in quantitative levels of HPV cell-free DNA compared to baseline corresponded with disease progression.

"There remains a need for better treatment options for HNSCC, particularly in the context of immune checkpoint therapy resistance," said Dr. Johnson. "Although overall clinical response was modest, the combination of alisertib and pembrolizumab was well tolerated and led to prolonged stable disease in patients who had previously progressed on immunotherapy, supporting our hypothesis that Aurora Kinase A inhibition may reverse immunotherapy resistance in Rb-deficient HNSCC. These findings warrant further investigation into mechanisms to increase immunogenic cell death and apoptosis in Rb-deficient cancers treated with alisertib."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are intrigued by the results of this trial and remain committed to and focused on the development of alisertib. The prospect of biomarker-defined populations who may benefit most from alisertib treatment continues to be an area of great interest."

On October 14, 2023 Promontory Therapeutics Inc., a clinical stage biotech company advancing immunogenic small molecule approaches in oncology, reported data on its lead therapeutic candidate PT-112, detailing its early molecular effects that culminate in immunogenic cancer cell death (ICD) (Press release, Promontory Therapeutics, OCT 14, 2023, View Source [SID1234635978]). The presentation was made at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) – National Cancer Institute (NCI) – European Organisation for Research and Treatment of Cancer (EORTC) AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place October 11-15, 2023 in Boston.

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The study was designed to clarify early molecular effects of PT-112 that are known to culminate in ICD by assessing nucleolar protein phenotypes in human prostate cancer cells treated with PT-112 using antibody labeling, followed by confocal microscopy. Researchers also conducted nascent RNA sequencing in human cancer cells (non-small cell lung, prostate and renal cell carcinoma) following one and six hours of PT-112 treatment.

"Our study shows that PT-112 inhibits ribosomal biogenesis in cancer cells. This was observed in all the cell lines assessed after short exposure durations, indicating it is central to PT-112’s mechanism of action and its ability to induce selective immunogenic cancer cell death," said Tyler Ames, PhD, Promontory Therapeutics Senior Vice President of Research and Development. "While further validation of these findings is ongoing, this work deepens our understanding of PT-112’s specific molecular effects. The present findings, together with prior validation of its ICD effects, and evidence of durable clinical activity of PT-112, position it as a promising small molecule cancer immunotherapy."

Study findings include:

PT-112 rapidly causes ribosomal biogenesis (RiBi) inhibition and nucleolar stress, likely driving previously observed PT-112-induced cancer organelle stresses and ICD.
At early timepoints in prostate cancer cells, PT-112 caused evident nucleolar protein translocation, a hallmark of nucleolar stress and disruption of RiBi.
Consistent with the above, PT-112 induced statistically significant repression of pathways related to RiBi, ribosomal RNA (rRNA) processing and translation, crossing prostate, renal and lung cancer cell lines. Notably, a pattern across these pathways was the reduced expression of many ribosomal genes, consistent with RiBi inhibition.
Collaborating with the Baylor College of Medicine and with Arpeggio Biosciences in Boulder, Colorado, the Promontory research team used confocal microscopy and nascent RNA sequencing, and performed analysis using Enrichr across multiple databases to identify biological pathways linked to clusters of differentially expressed genes (p ≤ 0.001) in PT-112-treated cells.

PT-112 is currently in Phase 2 clinical trials in a late-line setting of metastatic castration-resistant prostate cancer, and in thymic epithelial tumors. The latter study is led by the National Cancer Institute under a formal collaboration.

For more information about Promontory Therapeutics and PT-112, visit www.PromontoryTx.com.

About PT-112
PT-112 is the first small-molecule conjugate of pyrophosphate in clinical development in oncology. PT-112 has numerous advantages — including its tolerability and inhibition of ribosomal biogenesis (RiBi) which leads to immunogenic cell death (ICD), through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a highly potent inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and data were published in eClinicalMedicine, part of The Lancet. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in a mini-oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress and the Phase 2a dose confirmation cohort in non-small cell lung cancer (NSCLC) patients was reported at ESMO (Free ESMO Whitepaper) I-O 2022. The Phase 1 study in patients with relapsed or refractory multiple myeloma presented at ASH (Free ASH Whitepaper) 2020 is the third completed Phase 1 study of PT-112. Monotherapy Phase 2 development is ongoing in mCRPC, and includes the Phase 2 proof of concept study in thymic epithelial tumors under the company’s formal CRADA with the NCI. Preliminary data from the NCI study were published at ASCO (Free ASCO Whitepaper) 2023 and at the ITMIG 2023 annual meeting, and show evidence of anti-cancer immune activation by PT-112.

On October 14, 2023 Verastem Oncology (Nasdaq: VSTM) (the "Company"), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported the initial safety, pharmacokinetics and recommended Phase 2 dose (RP2D) in the RAMP 203 trial evaluating the safety, tolerability and efficacy of avutometinib in combination with sotorasib in patients with KRAS G12C-mutant non-small cell lung cancer (NSCLC) (Press release, Verastem, OCT 14, 2023, View Source [SID1234635977]). The results will be presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) October 11-15, 2023 in Boston, Massachusetts.

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"The RAMP 203 study is investigating the potential benefits of a more complete vertical blockade of the RAS pathway with the combination of avutometinib and sotorasib in KRAS G12C-mutant locally advanced or metastatic NSCLC," said Mark Awad, M.D., Associate Professor of Medicine at Harvard Medical School and Director of Clinical Research of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, investigator on the trial, and presenting author. "These initial findings, including the recommended Phase 2 dose and the encouraging preliminary efficacy and safety results, provide support for the combination, and I look forward to completing the expansion phase of the trial."

RAMP 203 (NCT05074810) is a Phase 1/2, multicenter, open label, dose evaluation/expansion study evaluating the efficacy and safety of avutometinib + sotorasib in patients with KRAS G12C-mutant NSCLC who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have been previously treated with a KRAS G12C inhibitor. The confirmed objective response rate (ORR) was 25% (3/12) across efficacy-evaluable patients and seen in both KRAS G12C inhibitor resistant (14.3%; 1/7) and naïve (40%; 2/5) patients.

The pharmacokinetic profile of avutometinib in combination with sotorasib was similar to results in monotherapy studies. No drug-drug interactions were observed between avutometinib and sotorasib. Avutometinib 4.0 mg PO BIW 21/28 days + sotorasib 960 mg PO QD 28/28 days was selected as RP2D based on dose limiting toxicity (DLT) assessment. Enrollment of patients with KRAS G12C-mutant NSCLC who are either naïve to or previously treated with a KRAS G12C inhibitor is ongoing in the expansion phase of RAMP 203.

"The RAMP 203 trial builds on preclinical data which demonstrated the addition of avutometinib to sotorasib improved the depth of MAPK pathway inhibition and substantially enhanced tumor regression relative to sotorasib alone," said Dan Paterson, President and CEO, Verastem Oncology. "Given KRAS G12C mutations are the most common KRAS mutation in NSCLC and acquired mutations and amplifications occur upon clinical progression to KRAS G12C inhibitor monotherapy, the results of the RAMP 203 trial are important in understanding potential new treatment approaches for patients."

About the Avutometinib and Defactinib Combination

Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF, and CRAF potentially creating a more complete and durable anti-tumor response through increased RAS pathway inhibition. In contrast to currently available MEK inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other inhibitors. The U.S. Food and Drug Administration granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK clamp avutometinib, with defactinib, its FAK inhibitor, for the treatment of patients with recurrent low-grade serous ovarian cancer (LGSOC) regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy.

Verastem Oncology is currently conducting clinical trials with its RAF/MEK clamp avutometinib in RAS pathway-driven tumors as part of its Raf And Mek Program (RAMP). RAMP 301 is a Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent LGSOC. RAMP 201 is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and has completed enrollment in the dose optimization and expansion phases and is enrolling for low-dose evaluation. Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant-NSCLC as part of the RAMP 203 and RAMP 204 trials, respectively. Supported by the "Therapeutic Accelerator Award" Verastem Oncology received from PanCAN, the Company is conducting RAMP 205, a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer.

On October 14, 2023 Coherus BioSciences, Inc. ("Coherus", Nasdaq: CHRS), reported a presentation of toripalimab data at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) being held October 11-15, 2023 at the Hynes Convention Center in Boston (Press release, Coherus Biosciences, OCT 14, 2023, View Source [SID1234635971]).

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PD-L1, a protein found on the surface of some cancer cells, suppresses T cell activation and inhibits the ability of the body’s immune system to kill cancer cells. Toripalimab is an anti-PD-1 monoclonal antibody that binds with high affinity to a unique site on PD-1, thereby blocking the interaction of PD-1 and PD-L1. Preclinical mechanistic data demonstrate statistically significantly higher activation of T cells and higher expression of key immune system activators with toripalimab compared to pembrolizumab, clinically a widely used anti-PD-1 monoclonal antibody for the treatment of cancer patients. These data may provide a mechanistic explanation for the improvements in overall survival irrespective of PD-L1 expression levels observed in clinical trials in multiple tumor types evaluating toripalimab in combination with chemotherapy. A biologics license application (BLA) for toripalimab in combination with chemotherapy as treatment for recurrent or metastatic nasopharyngeal carcinoma (NPC) is currently under review by the U.S. Food and Drug Administration (FDA).

"PD-1 inhibition has been a significant advancement in cancer treatment across tumor types but better treatments are needed to increase response rates and drive improved outcomes for patients. These data support toripalimab as a next-generation PD-1 inhibitor that, in combination with chemotherapy, may have greater antitumor activity in less inflamed tumors than more commonly used PD-1 inhibitors in certain cancers due to its unique binding properties," said Theresa LaVallee, Ph.D., Coherus’ chief development officer. "We look forward to delivering this important new treatment option to patients, first in NPC, if approved, and continuing to evaluate its efficacy in combination with chemotherapy in multiple cancer types and in combination with novel I-O agents."

Poster presentation data are summarized as follows:

Toripalimab in combination with chemotherapy significantly improved overall survival irrespective of PD-L1 status in post hoc analyses of 3 randomized controlled clinical trials, including in NPC, non-small cell lung cancer (NSCLC) and esophageal squamous-cell carcinoma (ESCC)
Toripalimab exhibits a 12-fold higher binding affinity for PD-1 compared to pembrolizumab that is driven by a slow-off rate
Toripalimab is more potent than pembrolizumab in enhancing levels of Th1 cytokines and cytotoxicity in human peripheral blood mononuclear cells (PBMCs)
In comparison to pembrolizumab, binding of toripalimab to PD-1 induced low levels of SHP1 and SHP2 recruitment, thereby minimizing a key process of T cell suppression
Toripalimab induced and elevated IFN-y gene signature in NSCLC dissociated tumor cells with different kinetics and intensity compared to pembrolizumab
Poster presentation details:

Poster Number C069: Toripalimab, an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status
Session: Poster Session C
Date and time: Saturday, October 14, 12:30 pm-4:00 pm EDT
Location: Level 2, Exhibit Hall D
About toripalimab
Toripalimab is a next-generation anti-PD-1 monoclonal antibody that blocks PD-L1 binding to the PD⁠-⁠1 receptor at a unique site with high affinity and activates antitumor immunity demonstrating improvement in the overall survival of cancer patients in several tumor types. The BLA for toripalimab in combination with chemotherapy as the first-line treatment for recurrent or metastatic NPC and toripalimab monotherapy for the second-line or later treatment of recurrent or metastatic NPC after platinum-containing chemotherapy is under review by the FDA. In Europe, the marketing authorization applications (MAA) for toripalimab for the first-line treatment of NPC and esophageal squamous cell carcinoma (ESCC) are under review by the European Medicines Agency (EMA) and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA).

The FDA granted Breakthrough Therapy designation for toripalimab in combination with chemotherapy for the first-line treatment of recurrent or metastatic NPC in 2021 as well as for toripalimab monotherapy in the second or third-line treatment of recurrent or metastatic NPC in 2020. Additionally, the FDA has granted Fast Track designation for toripalimab for the treatment of mucosal melanoma and Orphan Drug designations for the treatment of ESCC, NPC, mucosal melanoma, soft tissue sarcoma, and small-cell lung cancer (SCLC).

More than 40 company-sponsored toripalimab clinical studies covering over fifteen indications have been conducted globally by Shanghai Junshi Biosciences Co., Ltd (Junshi Biosciences), including in China, the United States, Southeast Asia, and European countries. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney, and skin.

On October 14, 2023 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported updated preclinical data from the Company’s next-generation selective fibroblast growth factor receptor 2 (FGFR2) program being presented today in a poster presentation at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) taking place in Boston (Press release, Cogent Biosciences, OCT 14, 2023, View Source [SID1234635970]).

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"We are excited to share these new data on our internally discovered and developed FGFR2 candidate, highlighting the strength and scientific expertise of the Cogent Research Team," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "We believe CGT4859 has the potential to become the best-in-class FGFR2 inhibitor, as it delivers coverage across all known resistance mutations, with selectivity to avoid FGFR1-mediated toxicity, along with a reversible profile which may improve upon tolerability challenges seen with other FGFR2-targeted agents. IND-enabling studies for CGT4859 are ongoing, putting us in position to initiate clinical trials in the second half of 2024."

Poster Details
The poster can be accessed in the ‘Posters and Publications’ page of Cogent’s website.

Title: Identification of a Reversible Selective FGFR2 Clinical Development Candidate with Potency Against Gatekeeper and Molecular Brake Mutations
Session: Poster Session C
Session Date and Time: Saturday, October 14, 2023 – 12:30 PM – 4:00 PM ET
Location: Level 2, Exhibit Hall D, Hynes Convention Center, Boston, MA
Poster Number: C161
Abstract Number: 35488

FGFR inhibitors are well-established oncogenic drivers in multiple diseases, but approved medicines fail to capture the full landscape of FGFR altered tumor types, with FGFR1-mediated hyperphosphatemia serving as the most common dose-limiting toxicity for pan-FGFR inhibitors. The poster presented today describes Cogent’s internally-developed FGFR2 inhibitor which exhibits low nM potency on WT FGFR2 and FGFR2 mutations and is selective against the kinome and a panel of channels and receptors. Exploratory pharmacokinetics (PK) studies conducted across species showed CGT4859 to be a low-clearance compound with high oral bioavailability. Further, in an AN3 CA model, CGT4859 demonstrated dose-responsive tumor growth inhibition with complete regressions at 5 mg/kg PO and was well-tolerated. Cogent plans to file an IND, and pending clearance from the FDA, initiate clinical trials in 2024.