Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Updated safety and efficacy of a phase 1b/2 study (RAMP 205).

Journal of Clinical Oncology · 2025-05-28 · 2 citations

e16403 Background: Activating KRAS mutations in pancreatic ductal carcinomas (PDAC) occur in > 90% of patients (pts). Avutometinib (A) is a RAF/MEK clamp that potently inhibits MEK kinase while blocking compensatory reactivation of MEK. Defactinib (D) is a selective inhibitor of FAK, a target shown to mediate resistance. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing A/D + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Preliminary data suggest synergistic activity with this combination. Updated data on additional dosing cohorts are presented here. Methods: Eligible pts had histologically confirmed newly diagnosed metastatic PDAC and measurable disease, ECOG PS ≤1, adequate organ function, and no prior treatment for metastatic disease. Pts were treated in 3+3 cohorts with escalating oral doses of A and D in combination with IV doses of GnP on a 4-week schedule (Table). Results: At data cutoff (03Jan2025), 54 pts were enrolled and included in the safety analysis: 46% men, median age 59 years (range, 36-79), and 42.5% (23/54) ECOG PS of 1. Pts were enrolled in the following dose levels: DL1 (n = 12), DL0 (n = 6), DL-1 (n = 12), DL1a (n = 12), and DL2a (n = 12). The MTD has not been reached. There was one DLT: grade 3 febrile neutropenia in DL1, that resolved within 3 days. The most common treatment-related adverse events (all grades, all dose groups) were fatigue (63%), nausea (46%), neutropenia (46%), alopecia (41%), diarrhea (39%), anemia (30%), maculo-papular rash (30%), peripheral edema (28%), hyperbilirubinemia (24%), vomiting (24%), dermatitis acneiform (22%), thrombocytopenia (22%), and blurred vision (22%). The most common grade ≥3 treatment-related adverse events were neutropenia (39%), anemia (20%), fatigue (7%), and increased ALT (7%). Thirty-nine efficacy evaluable pts were enrolled at least 6 months prior to data cutoff. Objective Response Rate (ORR) and Disease Control Rate (DCR) for ≥4 cycles are listed in the Table. Conclusions: A/D + GnP have been combined in 5 dose cohorts. The MTD has not been reached. Enrollment and evaluation of mature data are ongoing to identify the recommended phase 2 dose. Clinical trial information: NCT05669482 . RAMP 205 dose levels and efficacy for patients enrolled ≥6 months prior to data cutoff. Dose Level A(mg) BIW* D(mg) BID* Gemcitabine (mg/m 2 ) Nab-Paclitaxel (mg/m 2 ) Days Chemo Dosing ORR% (n/N) DCR≥4 cycles% (n/N) 1 2.4 200 800 125 1,8,15 83% (5/6) 83% (5/6) 0 3.2 200 800 100 1,8,15 100% (1/1) 100% (1/1) -1 ^ 2.4 200 800 100 1,8,15 27% (3/11) † 82% (9/11) 1a # 3.2 200 800 125 1,15 33% (3/9) ◊ 56% (5/9) 2a 3.2 200 1000 125 1,15 25% (3/12) 58% (7/12) *Dosing 3 / 4 weeks. ^ 1 pt excluded from efficacy analysis due to no post baseline scan. # 3 pts excluded from efficacy analysis: 1 due to no post baseline scan and 2 due to incorrect histology per eligibility criteria. † Includes 2 unconfirmed responses. ◊Includes 1 unconfirmed response.

Reviving Vavilov’s vision: The tragedy of biodiversity governance and principles for reform

Proceedings of the National Academy of Sciences · 2025-12-12

This perspective addresses two of humanity's greatest challenges: feeding a growing population and conserving biodiversity. We begin by examining the legacy of Nikolai Vavilov, who pioneered the improvement of crops such as wheat and beans by hybridizing them with their wild relatives. This strategy used wild species biodiversity to introduce new genetic variation into crops, making them more resilient and productive. Its adoption around the world greatly increased food security and brought lasting benefits to humanity. However, since the 1990 s, well-intentioned laws shifted the governance of biodiversity from a shared global resource to the sovereign control of nation states, with serious unintended consequences. These changes have disrupted the collection, preservation, exchange, and use of biodiversity, all of which are central to Vavilov's strategy for crop improvement and to biodiversity science more broadly. Efforts at reform have been frustrated as the issues became moralized, inhibiting the open dialogue needed for change. Using foundational concepts shared by science and good governance, we propose seven empirically grounded principles for reform, to help realign biodiversity governance with its intended aims. We then illustrate one possible framework-underpinned by global financing to protect biodiversity hotspots-that would align incentives and work in synergy with the principles to foster practical reform. The principles, together with frameworks that align incentives, would create the conditions for stronger biodiversity conservation and research, agricultural development, global food security, and all the associated benefits to humanity.

A cautious approach to subsidies for environmental sustainability

Science · 2024-10-03 · 22 citations

Transformational change is possible, but design and implementation must seek to avoid lock-in.

Property Rights to the World’s (Linear) Ocean Fisheries in Customary International Law

Journal of the Association of Environmental and Resource Economists · 2023-08-07 · 2 citations

I model the ocean as an array of lines set within a two-dimensional frame and show how the exclusive economic zone (EEZ) emerged as an equilibrium in customary international law. I find that custom codifies the efficient Nash equilibrium of enclosure for nearshore fisheries. For highly migratory and offshore fisheries, enclosure is inefficient, and customary law supports a more efficient “free sea” regime. The model also identifies the trigger for changes in property rights and the reason choice of a particular limit, like the current 200-mile zone, is arbitrary. In an asymmetric, regional sea, I find that the scope of the EEZ is determined by the relative power of coastal and distant water states, and need not be efficient. Finally, I find that proposals to nationalize the seas or ban fishing on the high seas are neither efficient nor supportable as equilibria in customary law.

Abstract A134: Predicting activity of IMM-1-104 as single agent and in combination for patients with RAS or RAF mutant tumors

Molecular Cancer Therapeutics · 2023-12-01

Abstract Introduction: Many tumors are addicted to MAPK pathway activation, including the >20% of human tumors with mutations in RAS or RAF1. IMM-1-104 is an oral once-daily treatment currently in Phase 1 in patients with RAS-mutant solid tumors [NCT05585320]. To date, drugs disrupting the MAPK pathway have done so chronically, leading to dose-limiting toxicities (DLTs) and poor response durability. In contrast, IMM-1-104 was designed to provide deep cyclic inhibition (DCI) of the MAPK pathway via a unique pharmacokinetic (PK) profile with high peak plasma drug levels and a near zero drug trough between doses. This promotes pulsatile inhibition of MEK, depriving tumors of sustained signaling of a critical oncogenic pathway while limiting toxicity and durability issues associated with chronic MEK inhibition. In Phase 1a dose escalation, no DLTs were observed, the plasma drug half-life was ~2-hours, and pharmacodynamic (PD) data were consistent with DCI. Phase 1b dose expansion is underway. Translational efforts are focused on identifying MAPK pathway addiction and sensitivity to IMM-1-104. Tumor models displaying patient-aligned genomic profiles against large patient databases such as AACR Project GENIE1 were tested in humanized 3D tumor growth assays (3D-TGA). Computational modeling based on response and in-house genomic data was used to inform identification of patient populations for IMM-1-104 monotherapy and potential combination opportunities. Experimental Procedures: Using cancer-specific, patient-aligned cell lines, IMM-1-104 activity was characterized in the 3D-TGA. Whole exome sequencing was performed to confirm alteration status, and a further subset subjected to RNA sequencing. Pharmacogenomic data were used to generate a model predictive of response to IMM-1-104 and identify biomarker-aligned patient subpopulations. Selected model predictions were then tested in subcutaneous tumor xenograft models in female BALB/c nude mice. Summary of New Data: Assessment of IMM-1-104 across >190 patient-aligned models demonstrated diverse responses across a wide range of MAPK-driven tumor types, including those with RAS or RAF mutations. In addition to RAS, these data suggested additional potential for IMM-1-104 in BRAF-mutant disease. Therefore, IMM-1-104 was tested alone and with encorafenib in the HT-29 colorectal BRAFV600E mutant xenograft model. Monotherapy with either encorafenib or IMM-1-104 displayed superior tumor growth inhibition to binimetinib. IMM-1-104 in combination with encorafenib drove deeper regressions and superior durability of response in a head-to-head in vivo comparison versus binimetinib plus encorafenib. Conclusions: We used an integrated platform of translational experiments and informatics to identify patient-aligned model systems, prioritize factors relevant for response to IMM-1-104’s unique DCI profile, and elucidate combination opportunities to potentially inform clinical development strategies. Citation Format: Praveen Nair, Sarah Kolitz, Jason Funt, Jan de Jong, Peter King, Amy Yamamura, Mai Johnson, Jenny Zhang, Kevin D Fowler, Anna Travesa, Amy Axel, Chris Walker, Scott Barrett, Benjamin J Zeskind, Brett Hall. Predicting activity of IMM-1-104 as single agent and in combination for patients with RAS or RAF mutant tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A134.

Response diversity as a sustainability strategy

Nature Sustainability · 2023 · 69 citations

• Political Science
• Computer Science
• Business

Property Rights to the World's (Linear) Ocean Fisheries in Customary International Law

SSRN Electronic Journal · 2023-01-01

449 Cyclic disruption of the mitogen-activated protein kinase (MAPK) pathway by the dual MEK inhibitor, IMM-6-415, enhances PD1 and CTLA4 checkpoint blockade in RAS mutant tumors

Regular and Young Investigator Award Abstracts · 2022-11-01 · 2 citations

<h3>Background</h3> KRAS is the most frequently altered RAS gene (~85%) and is often mutated in pancreatic ductal adenocarcinoma (PDAC; 95%), non-small cell lung cancer (NSCLC; 40%) and colorectal cancer (CRC; 45%). KRAS-G12C inhibitors (sotorasib/adagrasib) have demonstrated single-agent activity in all three tumor types. However, acquired resistance and limited biomarker positive patients (e.g., only 1-3% of PDAC and CRC) limit broader access and overall response to G12C inhibitors, prompting evaluation of combination partners including immune therapies. In contrast to G12C-mutant focused KRAS inhibitors, MEK inhibitors may broaden the potential for immune therapy in RAS-mutant tumors but have largely proven ineffective in this setting. <h3>Methods</h3> IMM-6-415 is a novel, third-generation dual MEK inhibitor that reduces both pMEK and pERK in RAS-mutant tumor models at sub-100 nM potencies. IMM-6-415 drug-like properties have been evaluated across a series of preclinical <i>in vitro</i> and <i>in vivo</i> models focusing on activity in those with mutant RAS. Cell-based 2D and 3D biochemical and pharmacologic assays were performed across multiple models, and several <i>in vivo</i> studies have been completed, including: (1.) A549 (KRAS-G12S NSCLC) xenograft model, (2.) Colon-26 (KRAS-G12D CRC) syngeneic model, (3.) CT-26 (KRAS-G12D) syngeneic model. The CT-26 <i>in vivo</i> study evaluated both single-agent IMM-6-415 and combinations with PD1 or CTLA4 checkpoint inhibitors. <h3>Results</h3> IMM-6-415 reduced pERK and pMEK across all RAS mutant models tested. Humanized 3D tumor models revealed a promising sensitivity profile for IMM-6-415 in RAS-mutant CRC and PDAC. The maximum tolerated dose (MTD) of IMM-6-415 was 175 to 180 mg/kg BID PO from the Colon-26 (96.4% TGI) and A549 (93.9% TGI) studies, yet the optimal MEKio combination dose/schedule was 120 mg/kg BID PO in the CT-26 study. At 28 days treatment, 33% (4/12) mice remained on study in either the (10 mg/kg BIW IP) anti-PD1 or anti-CTLA4 alone treated groups, whereas 58% (7/12) mice remained in the IMM-6-415 treatment arm at 120 mg/kg BID PO. However, 92% (11/12) and 83% (10/12) mice remained in the IMM-6-415 plus anti-PD1 or anti-CTLA4 combination at the same doses, respectively. <h3>Conclusions</h3> We demonstrate that IMM-6-415 displays single-agent activity in multiple RAS-mutant models, has a 0.3h half-life, is well tolerated in mice, and when combined at sub-MTD levels with either PD1 or CTLA4 checkpoint inhibitors, significantly improved responses in the CT-26 model (p-value &lt; 0.05). Our data suggest that moderated, cyclic inhibition of the MAPK pathway in RAS mutant tumors is active and may enhance therapeutic activity of immune checkpoint inhibitors. <h3>Ethics Approval</h3> The protocol and any amendment(s) or procedures involving the care and use of animals in this study were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of CrownBio prior to execution. During the study, the care and use of animals was conducted in accordance with the regulations of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

Head-to-head comparison of the dual-MEK inhibitor IMM-1-104 versus sotorasib or adagrasib in KRAS mutant pancreatic tumors.

Journal of Clinical Oncology · 2022-06-01

e16297 Background: KRAS mutations are common in pancreatic ductal adenocarcinoma (PDAC). While 90% of PDAC tumors display activating mutations in KRAS, only ̃2% are G12C, a specific KRAS mutation targeted by inhibitors such as sotorasib or adagrasib. MEK, which lies downstream of KRAS, is an attractive target to more broadly counteract elevated MAPK signaling regardless of the upstream mutation. However, FDA registered MEK inhibitors are prone to pathway reactivation events, which limit their utility in RAS mutant disease and necessitate chronic pathway inhibition that contributes to on-target toxicity. In contrast, IMM-1-104 is a novel, allosteric dual-MEK inhibitor designed to block pathway reactivation by disrupting phosphorylation of both MEK and ERK and has a short plasma drug half-life. These characteristics enable IMM-1-104 to drive deep cyclic MAPK pathway inhibition, with the potential to inhibit tumors driven by diverse RAS mutations. Methods: IMM-1-104 was tested head-to-head versus sotorasib, adagrasib, selumetinib and binimetinib in a series of preclinical models to characterize differential activity of each compound against tumors driven by diverse KRAS mutations. Cell-based 2D biochemical and 3D growth assays were performed across nine PDAC models, and the Capan-2 PDAC xenograft animal model was used to evaluate single agent activity of IMM-1-104 (75, 100, 150 mg/kg BID p.o. or 150 mg/kg QD p.o.) vs. sotorasib or adagrasib (30 and 100 mg/kg QD p.o. each) for 21 days treatment after tumors had reached volumes of 150 to 200 mm3. Results: IMM-1-104 alone led to reductions in both pERK and pMEK across all 9 PDAC models tested (KRAS status shown), including Hs766T (Q61H), MIA PaCa-2 (G12C), Capan-2 (G12V), AsPC-1 (G12D), CFPAC-1 (G12V), BxPC3 (wild type), Panc 10.05 (G12D), Capan-1 (G12V) and PSN1 (G12R). A head-to-head comparison in vivo demonstrated no Tumor Growth Inhibition (TGI) by sotorasib and adagrasib in KRAS-G12V mutant Capan-2 PDAC tumors, while IMM-1-104 prompted TGIs of 49 to 84% across all doses and schedules tested. Conclusions: Despite multiple clinical studies, including Phase 2 studies for the MEK inhibitors trametinib and selumetinib, limited progress has been made in PDAC treatment since FOLFIRINOX’s approval in 2011. The Phase 2 KRYSTAL-1 and Phase 1/2 CodeBreaK 100 studies recently reported promising activity in KRAS-G12C PDAC, suggesting an opportunity for disruption of KRAS addiction. IMM-1-104 and sotorasib previously demonstrated comparable tumor regressions in vivo in a KRAS G12C mutant model, MIA PaCa-2 (2021 EORTC). Examining the broader activity of IMM-1-104 across 9 PDAC tumor models yielded data suggesting that deep, cyclic MEK inhibition by IMM-1-104 has the potential to offer a unique advantage over first generation MEK inhibitors and KRAS-G12C inhibitors in PDAC by inhibiting tumors driven by a broader range of more common KRAS mutations.

Translational modeling for patients with RAS mutant tumors: Profiling the dual-MEK inhibitor IMM-1-104 in a humanized 3D assay.

Journal of Clinical Oncology · 2022-06-01

e15084 Background: Elevated RAS-RAF-MEK-ERK (MAPK pathway) signaling is observed in over half of all solid human tumors, and mutations in RAS or RAF account for a large fraction. Given MEK’s unique position in the MAPK cascade, it remains an attractive target in cancer. However, FDA-registered MEK inhibitors are susceptible to pathway reactivation events that limit their use to RAF mutant disease and cause on-target toxicities stemming from chronic target engagement. IMM-1-104 is a novel, allosteric dual-MEK inhibitor designed for better applicability to RAS mutant tumors by preventing MEK reactivation. Endowed with a short plasma half-life, IMM-1-104 promotes deep cyclic inhibition with a near-zero drug trough, affording normal cells a chance to recover between doses. Methods: We characterized IMM-1-104’s pharmacologic activity across 52 tumor cell lines that spanned 11 distinct tumor types in a humanized, ECM-based 3D tumor growth assay (3D-TGA). The 3D-TGA has better predicted in vivo tumor responses versus 2D culture and more accurately reflects human tumor biology. Tumor models were categorized based on in vivo drug PK limits as sensitive to IMM-1-104 (EC50 &lt; 1uM), intermediate (1uM≤EC50≤10uM and ≥25% inhibition at 10uM) or resistant otherwise. Models were evaluated by whole exome sequencing, along with RNA sequencing in the 3D context, to profile determinants of sensitivity and resistance and to prioritize patient populations most likely to respond to IMM-1-104. Results: Models sensitive to IMM-1-104 were enriched for MAPK driver mutations, consistent with pathway addiction. We reasoned that activation of parallel compensatory pathways that can reduce reliance on MAPK signaling may increase the likelihood of resistance to IMM-1-104. Pathways and genes suspected of contributing to resistance helped refine signatures based on 3D-TGA outcome data. Models with a MAPK driver mutation and compensatory mutations such as PIK3CA or PTEN deletion were more likely to show intermediate response than those with a greater addiction to MAPK drivers. Models lacking a clear MAPK driver mutation but harboring other putative resistance alterations were more likely to be resistant in the 3D-TGA. Conclusions: To better understand the relevance of tumor model responses in the 3D-TGA relative to RAS mutant patient populations, we computationally compared tumor model data to patient somatic alterations, identified in the public resource GENIE, which has cataloged the molecular profiles of over 100,000 cancer patients. Based on model-to-patient molecular mapping, we identified biomarker-defined subsets of sensitive KRAS mutant lung and colorectal models. The most broadly sensitive patient-aligned models in the 3D assay were KRAS mutant pancreatic cancer and NRAS mutant melanoma patients, supporting the inclusion of such patients in planned clinical studies of IMM-1-104.