Despite recent advancements in oncology drug development, patient access to innovative cancer therapies remains inadequate. There is an urgent need for more patient-centric approaches, with meaningful patient input from trial design through to health technology assessment (HTA) consultation. Multi-stakeholder consensus calls for better representation of the diversity of the target population and integration of patients’ preferences in clinical cancer research by systematically collecting patient-reported outcomes using standardized methods, and acknowledging trade-offs between survival and long-term wellbeing. Furthermore, the generation of insufficiently robust data for regulatory and HTA decision-making continue to delay patient access to innovation. This could be mitigated through smarter study designs, including smaller, fit-for-purpose randomized studies and prospectively designed trials. Finally, concerted efforts are required to develop and validate novel intermediate/surrogate endpoints that enable earlier assessment of treatment outcomes to facilitate timely, evidence-based decisions that improve the patient experience across the cancer care continuum.

11501 Background: Resistance to kinase inhibitors in gastrointestinal stromal tumors (GIST) is mainly driven by secondary mutations in KIT, and currently available TKIs fail to inhibit the full spectrum of secondary KIT mutations.IDRX-42 is an oral, potent, and highly selective inhibitor of the KIT tyrosine kinase, active against multiple primary and secondary resistance mutations in KIT-driven GIST. We present data from the ongoing FIH phase (ph) 1 study evaluating IDRX-42 in patients (pts) with metastatic GIST in 2nd or later lines of therapy after failure of imatinib and other drugs. Methods: This ph 1 study evaluates the safety, tolerability, pharmacokinetics, and antitumor activity of oral IDRX-42 in adult pts with KIT-mutant GIST in dose escalation (ph1a) and defines the recommended dose for continued development (ph 1b). Ph 1b comprises 4 cohorts including pts without prior exposure to TKIs (1st line), pts treated with prior imatinib only (2nd line) and later line treatment cohorts. Correlative studies include sequential circulating tumor DNA (ctDNA) analyses and metabolic imaging using 18FDG-PET. Results: As of January 2, 2024, 42 pts received IDRX-42 in the ph 1a portion of the study with median treatment duration of 19+ (range 2-73+) weeks, with 30 pts remaining on treatment as of data cutoff. The median number of prior TKI therapy lines was 4 (range 1-6). Primary driver mutations were in KIT exon (ex) 11 (n = 27), ex 9 (n = 13) and ex 8 (n = 2). To date, five dose levels (120, 240, 400 and 600 mg QD; 400 mg BID) have been deemed safe to continue escalation. MTD has not been reached. A total of 39/42 pts are evaluable for efficacy; 9 achieved objective partial response (PR) per mRECIST (5 confirmed, 4 pending) across all doses studied. Three of 6 patients receiving IDRX-42 as 2nd line therapy have confirmed PRs at 120 mg QD, 400 mg QD, and 400 mg BID respectively. The clinical benefit rate (mRECIST PR or stable disease ≥16 weeks) is 71% overall and 100% in 2nd line. Sequential analyses of ctDNA show reductions across all primary and secondary KITmutations. Treatment-related adverse events (TRAE, CTCAE v5.0) were mainly low grade. The most frequently reported TRAE (≥25%) were gastrointestinal symptoms (diarrhea, nausea, vomiting, decreased appetite, dysgeusia) and fatigue. Eight of 42 pts reported Grade 3/4 TRAEs including gastrointestinal symptoms, fatigue and anemia. Two events qualified as DLT, 1 at 600 mg QD (syncope) and 1 at 400 mg BID (vomiting); after dose reduction both pts continued IDRX-42 for more than 8 and 5 months, respectively. Only two patients discontinued treatment due to TRAEs. Conclusions: IDRX-42 demonstrates promising clinical activity and a favorable safety profile in patients with advanced GIST following resistance to prior TKIs. Dose finding continues, and additional cohorts are ongoing. Clinical trial information: NCT05489237 .

Precision oncology has a significant role to play in delivering optimal patient care. Biomarkers are critical enablers for precision oncology across the continuum of cancer diagnosis, in defining patient prognosis, and in predicting the response to treatments and their potential toxicities, as well as delineating the risk of hereditary cancer syndromes. Biomarkers also potentiate cancer drug development, accelerating patient access to safe and effective therapies. However, despite an accurate and timely diagnosis being critical to patient survival, advances in genomic testing are not being fully exploited in daily clinical practice, leading to missed opportunities to deliver the most effective treatments for patients. Biomarker testing availability and implementation often lag behind approvals of respective biomarker-informed therapies, limiting prompt patient access to these life-saving drugs. Multiple factors currently impede the routine adoption of biomarker testing including, but not limited to, cost, lack of test reimbursement, limited access, regulatory hurdles, lack of knowledge, insufficient cooperation on assay development, and the urgent need to harmonize and validate testing assays, all leading to inefficient diagnostic pathways. Clinical guidelines increasingly include genomic profiling, and recent evidence suggests that precision oncology can be delivered in a cost-effective way for financially-challenged health systems. Therefore, precision genomic testing for cancer biomarkers must be embedded into the clinical practice of oncology care delivery going forward. We articulate a series of recommendations and a call to action to underpin the mainstreaming of a biomarker-informed precision oncology approach to enhance patient outcomes and deliver cost effective 21st century cancer care

Practical strategies are needed for strengthening the development of cancer drugs, focusing on optimization of treatment dosage, and improvements in the diversity of patients enrolled in clinical trials. Treatment optimization (both pre- and post-marketing) offers potential to deliver a range of benefits including a reduction in the burden of side-effects to patients and cost of drugs to health care systems. For immune checkpoint inhibitors (ICIs), dosage optimization involves reducing duration of treatment, extending interval administration, and a ‘stop and go’ approach where treatment is resumed if patients progress. Such initiatives will be necessary to optimize effectiveness and achieve the economic savings needed for global access to these drugs. Strategies are needed to increase patient diversity so that clinical trials start to represent the patient groups the interventions being studied intend to treat. The potential of decentralized trials is explored in greater depth as one of the ways to increase clinical trial diversity.

Supplementary Figure 1. Study flowchart

Supplementary table 3. Multivariate model for Overall Survival (Cytotoxic Agents)

Supplementary table 2. Multivariate model for overall survival (Molecularly Targeted Agents).

PDF file - 82K, Inclusion Criteria and Analysis

PDF file - 244K, Amplification plot.

CCR Translation for this Article from A CYP3A4 Phenotype–Based Dosing Algorithm for Individualized Treatment of Irinotecan

Supplementary Fig. S2 from Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors

Abstract Introduction. MNNG HOS transforming gene (MET) kinase inhibitors have demonstrated clinical activity in patients with non-small cell lung cancer (NSCLC) harboring exon14 (METex14) skipping mutations, validating this as an actionable drug target. High daily doses (500-800mg daily) are needed to reach sufficient plasma exposure of active drug to achieve sufficient target engagement to drive efficacy. However, these high doses are associated with toxicities that frequently lead to dose interruptions and reductions which negatively impact efficacy. Background. The 2nd generation of selective Type 1b MET inhibitors (capmatinib, tepotinib, savolitinib), with more soluble metabolites than the 1st generation inhibitors (SGX-523, JNJ-38877605, PF-04217903), have shown efficacy in the clinic. However, they still carry the metabolic liability of the 1st generation agents translating into high levels of circulating metabolites that are not active against the MET kinase, necessitating high daily doses to achieve sufficient active drug exposures. These inactive ‘de-hinged’ metabolites (which are unable to interact with a key recognition site located in the ‘hinge region’ of the MET kinase) remain in the circulation, leading to ‘off-target’ toxicities which are not linked to efficacy, but often necessitates dose reductions and/or-interruptions. Experimental procedures. Based on a detailed understanding of the metabolic liabilities of type 1b MET kinase inhibitors and using site specific deuteration of the key metabolic hotspot, we have used the Kinetic Deuterium Isotope Effect (KDIE) to overcome a metabolic liability that negatively impacts current agents. Summary of the new, unpublished data. The resulting deuterated compound DO-2, is well tolerated and highly potent in pre-clinical xenograft studies (MED ~0.2mg/kg: MTD >50mg/kg), brain penetrant (Kp, uu, brain ; 0.3 in rats), with low once daily doses (3mg/kg) causing complete and sustained cures of all animals (8/8) carrying well established ~300mm3 MET exon14 xenografts. IND enabling toxicology studies in rabbit (most relevant species for metabolism) have shown that the renal effects of the predecessor JNJ-38877605 were no longer apparent with DO-2 at efficacious exposure levels. Based on the pre-clinical efficacy and toxicology data, DO-2 has entered the clinic in a Phase 1 study (NCT05752552), where early data indicates that the improved preclinical profile translates into the clinic with increased active drug exposure when compared to the non-deuterated JNJ-38877605. Conclusion. Preclinical data and emerging clinical data from highly MET inhibitor sensitive MET exon14 tumours as well as in other less sensitive MET driven tumors indicate that DO-2 has the potential to mitigate the side effects seen with current approved MET kinase inhibitors, leading to better tolerability and lower inactive metabolite levels and at lower daily dose levels. Supporting preclinical data and emerging clinical data will be presented. Citation Format: Timothy P.S. Perera, Laurence Mevellec, Hans Prenen, Bernd Dekeyser, Debbie Robbrecht, Sander Bins, Barend Sikkema, Peter de Bruijn, Jean-Pascal Machiels, Rachel Galot, Damien Briol, Richard Knight, Irena Loryan, Yang Hu, Florence Wastelin, Jaap Verweij. Preclinical and emerging Phase 1 study data indicates that novel deuterated MET kinase inhibitor DO-2 mitigates the side effects seen with current approved MET kinase inhibitors: Preventing deleterious ‘de-hinging’ to improve tolerability [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 C152.

PDF file, 36KB, Progression-free survival of patients with advanced PDGFRA-mutant GIST on imatinib according to the type of PDGFRA mutation.

Supplementary table 1. Main characteristics of patients receiving different dose levels

PDF file - 74k, Complete Longitudinal Analyses of the Randomized, Placebo-controlled, Phase III Trial of Sunitinib in Patients with Gastrointestinal Stromal Tumor Following Imatinib Failure

PDF file, 104K, A: Digital Imaging and Communications in Medicine (DICOM) files were imported in OsiriX Imaging Software for MacOS X (OsiriX Foundation, Geneva, Switserland). Metastatic liver lesions were then drawn as areas of interest with the pencil selection tool. B: Volumes of 3-dimensional structures were automatically calculated by OsiriX Imaging Software.

Supplementary Data from Mapatumumab, a Fully Human Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and Cisplatin: a Phase I Study

PDF file, 60KB, Progression-free (panel A) and overall (panel B) survival according to the mitosis count. HPF: high power field.