TPS8651 Background: The KRAS G12C mutation, present in ~12% of NSCLC patients, drives oncogenic signaling and cancer formation and is associated with poor prognosis. The current first-line treatment for advanced KRAS G12C+ NSCLC is checkpoint inhibitor (CPI) ± chemotherapy (CT). Novel combinations using a more targeted, biomarker-directed approach are supported by pre-clinical evidence and may further improve outcomes. Divarasib is an oral KRAS G12C inhibitor with potent pre-clinical and clinical anti-tumor activity. We hypothesize that divarasib + CPI ± CT may improve outcomes for patients with KRAS G12C+ NSCLC. Methods: Krascendo-170 Lung (NCT05789082) is a phase Ib/II, open-label study evaluating the safety and activity of divarasib + pembrolizumab in patients with PD-L1 tumor cell expression ≥1% (Cohort A) and of divarasib + pembrolizumab with platinum-based CT and pemetrexed in patients with any PD-L1 tumor cell expression level (Cohort B). Patients must be ≥18 years old with untreated unresectable/metastatic non-squamous NSCLC (measurable per RECIST v1.1), a confirmed KRASG12C mutation, and an Eastern Cooperative Oncology Group performance status 0/1. Each cohort will have two stages: divarasib combination dose finding and dose expansion, with two planned dose levels of divarasib (Table). Tumor assessments will be performed at baseline and every 6 weeks for 48 weeks, then every 9 weeks thereafter. Plasma samples will be taken at various timepoints before and after divarasib and pembrolizumab dosing to characterize pharmacokinetics. Patients will be treated until disease progression per RECIST v1.1 or unacceptable toxicity. The co-primary endpoints are adverse events and change from baseline in targeted safety parameters. Key secondary endpoints include objective response rate, progression-free survival and duration of response (all investigator assessed per RECIST v1.1). Enrollment into the combination dose finding stage of Cohort A has been completed without dose-limiting toxicities and enrollment into the dose expansion stage is continuing. Clinical trial information: NCT05789082 . [Table: see text]

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRA S G12C -positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS–MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRA S G12C -positive CRC ( n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients ( n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRA S G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRA S G12C -positive CRC. ClinicalTrials.gov identifier: NCT04449874

Background: GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor that demonstrated anti-tumor activity in patients with KRAS G12C-positive advanced solid tumors, including CRC. In a previously reported single-agent cohort, GDC-6036 achieved a best response of partial response or complete response in 35% (19/55) of patients, with a confirmed overall response rate (ORR) of 24% (13/55 patients) in KRAS G12C-positive CRC patients (Desai et. al., ESMO 2022). EGFR blockade may sensitize tumors to KRAS G12C inhibition and the combination of an anti-EGFR antibody (cetuximab) with a KRAS G12C inhibitor showed greater anti-tumor activity than single-agent KRAS G12C inhibition in preclinical models (Amodio et. al., 2020). Methods: In an ongoing Phase I study (NCT04449874), patients with advanced or metastatic KRAS G12C-positive CRC were administered GDC-6036 (200-400 mg orally once a day) with cetuximab (400 mg/m2 intravenously initially, then 250 mg/m2 weekly) until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1). Results: As of the clinical data cut-off date of 21 Nov 2022, 29 patients (enrolled by 07 Oct 2022) had received GDC-6036 and cetuximab. The median lines of prior metastatic therapy was 2 (range 1-8) and the median time on study treatment was 5.2 (range 1.4-11.2) months. All patients experienced at least one treatment-related adverse event (TRAE); the most common TRAEs (≥15%) were rash (grouped terms), diarrhea, nausea, vomiting, dry skin, and paronychia. Grade 3-4 TRAEs occurred in 11 patients (38%). Five patients (17%) experienced at least one serious AE, none of which were treatment-related (including 2 patients who died of CRC progression during the safety follow-up). AEs led to GDC-6036 modifications (interruptions and/or reductions) in 13 (45%) patients, dose reduction in 3 (10%) patients, and no patients discontinued due to AEs. Eleven patients discontinued from study treatment (10 due to disease progression and 1 due to physician’s discretion). The PK profile of GDC-6036 (400 mg once a day) was similar in combination with cetuximab when compared with single-agent. A partial response was achieved in 66% (19/29) of patients, with a confirmed ORR of 62% (18/29 patients). Conclusions: GDC-6036 in combination with cetuximab demonstrated a manageable safety profile and promising clinical activity. These data support that the addition of anti-EGFR therapy to GDC-6036 may lead to robust clinical benefit in patients with KRAS G12C-positive CRC. Citation Format: Jayesh Desai, Sae-Won Han, Jong-Seok Lee, Einat Shacham-Shmueli, Erminia Massarelli, Andrés Cervantes, Elena Garralda, Alejandro Falcon, Wilson H. Miller, Eelke Gort, Thomas Karasic, Salvatore Siena, Rafal Stec, Laura Medina, Luis Paz-Arez, Angelo Delmonte, Adrian Sacher, Hans Prenen, Martin Forster, Tae Won Kim, Matthew G. Krebs, Rasha Cosman, Yoonha Choi, Sandhya Mandlekar, Mark T. Lin, Kenneth K. Yau, Julie Chang, Stephanie Royer-Joo, Neekesh V. Dharia, Jennifer L. Schutzman, Manish Patel. Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT029.

BACKGROUND:Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS:In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS:A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS:Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8 + T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8 + T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer 89 ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed 89 ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection ( n = 38, median patient maximum standard uptake value (SUV max ) 5.2, IQI 4.0–7.4). Higher SUV max was associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8 + T cell distribution and pharmacodynamics within and between patients. In conclusion, 89 ZED88082A can characterize the complex dynamics of CD8 + T cells in the context of ICIs, and may inform immunotherapeutic treatments.

Abstract T cell enhancing immune checkpoint inhibitors (ICI) are effective across several tumor types in a subset of patients. Insights into systemic localization of cytotoxic CD8+ T cells might support early treatment decisions. To address this, we performed a PET imaging study with a zirconium-89 (89Zr) labeled one-armed CD8-specific antibody 89ZED88082A to assess tracer performance, safety, and pharmacokinetics (PK) before and during treatment. Here we report preliminary data on uptake in tumor lesions before ICI. Methods: Patients with locally advanced or metastatic solid tumors that may benefit from ICI are eligible. In part A (imaging before treatment) and part B (imaging before and during treatment), 37 MBq (1 mCi) 89ZED88082A is administered with unlabeled one-armed antibody CED88004S to vary total protein dose. PET images are acquired at up to 4 time points: 1 h, and days (d) 2, 4, 7 post-injection followed by a tumor biopsy for CD8 immunohistochemistry and autoradiography (NCT04029181). Subsequently, patients receive atezolizumab (NCT02478099) or standard of care nivolumab ± ipilimumab. Tumor and lymph node 89ZED88082A uptake are assessed as (geometric mean) maximum standard uptake value (SUVmax), in other organs as SUVmean. Serum 89ZED88082A/CED88004S levels are measured for PK. Tumor response is according to (i)RECIST1.1. Results: For pretreatment imaging results, 32 patients (9 part A, 23 part B) were evaluable; 3 received 4 mg total tracer protein dose, 29 received 10 mg. No tracer infusion-related reactions occurred. Here we show results on d2 PET imaging with 10 mg protein dose, which was considered optimal based on superior 89Zr blood pool activity, clinical feasibility and serum antibody PK with a half-life of 28.6 h. 89ZED88082A uptake was observed within 1 h in spleen, and strong d2 imaging signal was seen across lymphoid organs including spleen (\bar{x}$ SUVmean 47.2), lymph nodes (SUVmax 4.2), bone marrow (\bar{x}$ SUVmean 5.0), small bowel and Waldeyer's ring. 89ZED88082A tumor uptake was seen at all main metastatic organ sites (overall lesion SUVmax 5.5, range 0.6-30.9) and varied across patients (\bar{x}$ per patient SUVmax 5.4, IQR 3.8-7.4). Higher tumor uptake showed a trend with better response (p=0.059) and longer PFS (p=0.033). Tumor uptake was higher in patients with mismatch-repair deficient (dMMR) than MMR proficient tumors (SUVmax 9.3 vs 4.9, p<0.001). Tumors with immune desert vs CD8+ cell stromal/inflamed profile had a \bar{x}$ SUVmax of 4.7 vs 8.3 (p=0.042). In tumor biopsies, autoradiography signal and CD8 staining were linearly associated (p<0.001). Conclusion: 89ZED88082A PET imaging is safe and shows high uptake in normal lymphoid organs. Uptake in tumor lesions is heterogeneous within and between patients. Tumor uptake is higher pretreatment in dMMR tumors and correlated with patient outcome. 89ZED88082A uptake on PET and by autoradiography reflects CD8 expression in tumor biopsies. Citation Format: Laura Kist de Ruijter, Pim P. van de Donk, Jahlisa S. Hooiveld-Noeken, Danique Giesen, Alexander Ungewickell, Bernard M. Fine, Simon P. Williams, Sandra M. Sanabria Bohorquez, Mahesh Yadav, Hartmut Koeppen, Jing Jing, Sebastian Guelman, Mark T. Lin, Michael J. Mamounas, Jeffrey Eastham, Patrick K. Kimes, Andor W. Glaudemans, Adrienne H. Brouwers, Marjolijn N. Lub-de Hooge, Jourik A. Gietema, Carolina P. Schröder, Wim Timens, Mathilde Jalving, Sjoerd Elias, Sjoukje F. Oosting, Derk J. de Groot, Elisabeth G. de Vries. 89ZED88082A PET imaging to visualize CD8+ T cells in patients with cancer treated with immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB037.

Background: Colonoscopy is the procedure of choice for colon cancer screening, but is far from perfect, as lesions are missed due to lack of image contrast and due to their location behind haustral folds and at flexures.We have developed a novel dual-view optical probe that illuminates and images in the forward and omni-directional rear directions to provide a single registered video image.Objective: Evaluate the prototype dual-view probe in a standard colon model.Design: A colon model (Chamberlain Group, MA) was used for the study.Due to the stiffness of the model and the difficulty in advancing a colonoscope through it, the colon was cut into 3 sections (ascending, transverse, and descending colon)