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CEND-1 is a novel cyclic peptide that targets αV integrins and neuropilin-1 and enhances tumour delivery of co-administered anticancer drugs. We investigated the safety, tolerability, and biological activity of CEND-1 in patients with metastatic pancreatic ductal adenocarcinoma in combination with nab-paclitaxel and gemcitabine.This open-label, multicentre, phase 1 study, conducted at three hospitals in Australia, enrolled participants aged 18 years or older with histologically confirmed metastatic pancreatic ductal adenocarcinoma who had one or more lesions measurable on MRI or CT, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a life expectancy of at least 3 months. Exclusion criteria included previous chemotherapy and brain metastases or other malignancy (unless receiving curative intent). There was no randomisation or masking. CEND-1 monotherapy was given as an intravenous fluid bolus on day 1 of a run-in phase of 7 days (0·2-3·2 mg/kg) followed by CEND-1 plus intravenous gemcitabine (1000 mg/mBetween Aug 13, 2018, and Nov 30, 2019, 31 patients were enrolled (eight in the dose-escalation phase [cohort 1a] and 23 in the expansion phase [cohort 1b]). Two patients were excluded from the efficacy population. No CEND-1 dose-limiting toxicities were observed in the safety population (n=31). The most common grade 3 or 4 events were neutropenia (17 [55%] patients), anaemia (eight [26%]), leukopenia (five [16%]), and pulmonary embolism (four [13%]). Serious adverse events occurred in 22 (71%) patients, mostly related to disease progression. Ten deaths occurred during the study due to progression of metastatic pancreatic cancer (n=9) and a left middle cerebral artery stroke (n=1). In the efficacy population (n=29), 17 (59%) patients had an objective response, including one complete response and 16 partial responses. After a median follow-up of 26 months (IQR 24-30), median overall survival was 13·2 months (95% CI 9·7-22·5).CEND-1 with nab-paclitaxel and gemcitabine has an acceptable safety profile, with no dose-limiting toxicities and encouraging activity. Adverse events were generally consistent with those seen with nab-paclitaxel and gemcitabine. Further randomised trials to determine the efficacy of CEND-1 are warranted.DrugCendR Australia Pty.

Five patients who were RAS mutant at baseline reverted to wild-type at SFU

Net Change of Mutational Load

Plasma-Select Sequence Mutations Gene List

Peritonoid sensitivity to standard care chemotherapeutic regimens ex vivo.

Kaplan-Meier Survival Curves for Biomarker Substudy (n=33)

Supplemental Tables and Figure Caption

Purpose:Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.Experimental Design:CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.Results:Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.Conclusions:Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

Supplemental Figure 1

Purpose: The accumulation of emergent RAS mutations during anti-EGFR therapy is of interest as a mechanism for acquired resistance to anti-EGFR treatment. Plasma analysis of circulating tumor (ct) DNA is a minimally invasive and highly sensitive method to determine RAS mutational status.Experimental Design: This biomarker analysis of the global phase III ASPECCT study used next-generation sequencing to detect expanded RAS ctDNA mutations in panitumumab-treated patients. Plasma samples collected at baseline and posttreatment were analyzed categorically for the presence of RAS mutations by the PlasmaSelect-R 64-gene panel at 0.1% sensitivity.Results: Among panitumumab-treated patients with evaluable plasma samples at baseline (n = 238), 188 (79%) were wild-type (WT) RAS, and 50 (21%) were mutant RAS. Of the 188 patients with baseline ctDNA WT RAS status, 164 had evaluable posttreatment results with a 32% rate of emergent RAS mutations. The median overall survival for WT and RAS mutant status by ctDNA at baseline was 13.7 (95% confidence interval, 11.5–15.4) and 7.9 months (6.4–9.6), respectively (P < 0.0001). Clinical outcomes were not significantly different between patients with and without emergent ctDNA RAS mutations.Conclusions: Although patients with baseline ctDNA RAS mutations had worse outcomes than patients who were WT RAS before initiating treatment, emergent ctDNA RAS mutations were not associated with less favorable patient outcomes in panitumumab-treated patients. Further research is needed to determine a clinically relevant threshold for baseline and emergent ctDNA RAS mutations. Clin Cancer Res; 24(22); 5602–9. ©2018 AACR.

Summary of drug panels and peritonoid genomic information

Purpose:Expanded RAS/BRAF mutations have not been assessed as predictive for single-agent cetuximab in metastatic colorectal cancer (mCRC), and low mutant allele frequency (MAF) mutations are of unclear significance. We aimed to establish cetuximab efficacy in optimally selected patients using highly sensitive beads, emulsion, amplification, and magnetics (BEAMing) analysis, capable of detecting alterations below standard clinical assays.Patients and Methods:CO.17 trial compared cetuximab versus best supportive care (BSC) in RAS/BRAF-unselected mCRC. We performed RAS/BRAF analysis on microdissected tissue of 242 patients in CO.17 trial using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Patients without BEAMing but with previous Sanger sequencing–detected mutations were included.Results:KRAS, NRAS, and BRAF mutations were present in 53%, 4%, and 3% of tumors, respectively. Cetuximab improved overall survival [OS; HR, 0.51; 95% confidence interval (CI), 0.32–0.81; P = 0.004] and progression-free survival (PFS; HR, 0.25; 95% CI, 0.15–0.41; P < 0.0001) compared with BSC in RAS/BRAF wild-type patients. Cetuximab did not improve OS/PFS for KRAS-, NRAS-, or BRAF-mutated tumors, and tests of interaction confirmed expanded KRAS (P = 0.0002) and NRAS (P = 0.006) as predictive, while BRAF mutations were not (P = 0.089). BEAMing identified 14% more tumors as RAS mutant than Sanger sequencing, and cetuximab lacked activity in these patients. Mutations at MAF < 5% were noted in 6 of 242 patients (2%). One patient with a KRAS A59T mutation (MAF = 2%) responded to cetuximab. More NRAS than KRAS mutations were low MAF (OR, 20.50; 95% CI, 3.88—96.85; P = 0.0038).Conclusions:We establish single-agent cetuximab efficacy in optimally selected patients and show that subclonal RAS/BRAF alterations are uncommon and remain of indeterminate significance.

Supplementary Methods

Purpose:Mutations in EGFR pathway genes are poor prognostic indicators in patients with metastatic colorectal cancer. Plasma analysis of cell-free DNA is a minimally invasive and highly sensitive method to detect somatic mutations in tumors.Experimental Design:Plasma samples collected from panitumumab-treated patients in the ASPECCT study at baseline and safety follow-up (SFU) were analyzed by a next-generation sequencing–based approach for extended RAS mutant allele frequency as a continuous variable and their association with clinical outcomes and the mutational prevalence of 63 cancer-related genes. The correlation between patient outcome and baseline mutational status of EGFR pathway genes was also examined.Results:Overall, 261 patients in the panitumumab arm had evaluable plasma samples. Patients with a higher RAS mutant allele frequency at baseline had worse clinical outcomes than those with a lower frequency (P < 0.001, Cox PH model); however, RAS mutations did not necessarily preclude patients from deriving benefits. The objective response rate (complete or partial response) was 10.8% for patients with baseline RAS mutations and 21.7% for those with BRAF mutations. The 63-gene panel analysis revealed an increase in tumor mutational burden from baseline to SFU (P < 0.001, Wilcoxon signed rank test). Baseline mutations in EGFR pathway genes, when analyzed both categorically and continuously, were associated with shorter survival.Conclusions:When mutations in EGFR pathway genes were analyzed continuously, higher mutant allele frequency correlated with poorer outcomes. However, extended RAS mutation, by itself, did not preclude clinical responses to panitumumab in a monotherapy setting.

BackgroundThe number of clinical studies evaluating the benefit of cytokine-induced killer cell (CIK) therapy, an adoptive immunotherapy, for colorectal cancer (CRC) are increasing. In many of these trials CIK therapy was co-administered with conventional cancer therapy. The aim of this review is to systematically assess the available literature, in which the majority were only in Chinese, on CIK therapy for the management of CRC using meta-analysis, and to identify parameters associated with successful CIK therapy implementation.MethodsProspective and retrospective clinical studies which compared CIK therapy to non-CIK therapy in CRC patients were searched for electronically on MEDLINE, Embase, CNKI and Wanfang Data databases. The clinical endpoints of overall survival (OS), progression-free survival (PFS), OS and PFS rates, overall response rate (ORR) and toxicity were meta-analysed using hazard (HR) and relative ratios (RR), and subgroup analyses were performed using Chi-square (Chi2) test and I-square (I2) statistics for study design, disease stage, co-therapy type, and timing of administration.ResultsIn total, 70 studies involving 6,743 patients were analysed. CIK therapy was favoured over non-CIK therapy for OS (HR=0.59, 95% CI: 0.53-0.65), PFS (HR=0.55, 95% CI: 0.47-0.63), and ORR (RR=0.65, 95% CI: 0.57-0.74) without increasing toxicity (HR=0.59, 95% CI 0.16-2.25). Subgroup analyses on OS and PFS by study design (randomised versus non-randomised study design), disease stage (Stage I-III versus Stage IV), co-treatment with dendritic cells (CIK versus DC-CIK therapy), or timing of therapy administration (concurrent versus sequential with co-administered anti-cancer therapy) also showed that the clinical benefit of CIK therapy was robust in any subgroup analysis. Furthermore, co-treatment with dendritic cells did not improve clinical outcomes over CIK therapy alone.ConclusionsCompared with standard therapy, patients who received additional CIK cell therapy had favourable outcomes without increased toxicity, warranting further investigation into CIK therapy for the treatment of CRC.Key MessageWhat is already known on this topicCytokine-induced killer cell (CIK) therapy is an adoptive immunotherapy used to treat both solid and haematological cancers for over 20 years. It is predominantly used in China, with multiple studies reporting benefit in colorectal cancer (CRC) patients. Despite this, CIK therapy treatment regimens are not widely used, possibly due in part to the majority of the literature about CIK therapy in CRC being reported in Chinese. Further, CIK therapy is commonly combined with other therapies but it is currently not known if there is a specific combination or treatment regimen that is optimal for CRC.What this study addsWe report the most comprehensive systematic review to date of CIK therapy for CRC patients, combining both Chinese and English language reports. Patients with CRC who received additional CIK therapy had better survival outcomes than with standard therapy alone. We also showed that the addition of dendritic cells (DC) to CIK therapy, common for CRC treatment, did not provide any clinical benefit over CIK therapy alone, and that CIK therapy is effective whether given concurrently or sequentially to standard treatment regimens.How this study might affect research, practice, or policyOur systematic review of Chinese and English publications shows that CRC patients benefit from the addition of CIK therapy to standard treatment protocols and warrants further international studies.

Kirsten rat sarcoma (KRAS) is one of the most frequently mutated oncogenes in solid tumours. It encodes an important signalling pathway that drives cellular proliferation and growth. It is frequently mutated in aggressive advanced solid tumours, particularly colorectal, lung and pancreatic cancer. Since the first mutated KRAS was discovered in the 1980s, decades of research to develop targeted inhibitors of mutant KRAS have fallen short of the task, until recently. Multiple agents are now in clinical trials, including specific mutant KRAS inhibitors, pan-KRAS inhibitors, therapeutic vaccines and other targeted inhibitors. Mutant-specific KRAS G12C inhibitors are the most advanced, with two inhibitors, adagrasib and sotorasib, achieving approval in 2021 for the second-line treatment of patients with KRAS G12C mutant lung cancer. In this review, we summarise the importance of mutant KRAS in solid tumours, prior attempts at inhibiting mutant KRAS, and the current promising targeted agents being investigated in clinical trials, along with future challenges.

The incidence of oesophageal adenocarcinoma (OAC) is rising in Western countries, with a 5-year overall survival (OS) rate of 14%. Curative treatment based on oesophagectomy is only suitable for ~50% of patients due to late-stage diagnosis. While the addition of preoperative chemotherapy or chemoradiotherapy has improved OS in OAC patients, little is known about the molecular basis of treatment response and patient outcomes. We investigated multi-omics data including whole-genome sequencing, RNA sequencing, methylation profiles and immunohistochemistry from 115 OAC patients mostly from DOCTOR phase II clinical trial that utilized neoadjuvant therapy (ANZCTR-ACTRN12609000665235). We identified genomic features associated with poor OS, such as the APOBEC mutational signature. We also showed that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. RNA sequencing and methylation profiles suggested four immune clusters associated with OS and progression-free survival. The immune-suppressed cluster was associated with worse survival and epithelial-mesenchymal transition signature and enriched with myeloid-derived cells. The immune hot cluster was associated with better survival and enriched with T-cells, myeloid-derived cells, interferon-gamma and alpha responses, and immune markers such as CCL5, CD8A, and NKG7. We investigated multi-omic features of OAC tumours from patients who were part of phase II clinical trial. We discovered prognostic features such as mutational signatures and complex genomic events. We identified distinct immune clusters associated with patient outcomes and the potential of immunotherapy for select clusters. We characterized molecular features of OAC patients which has the potential to predict responses to neoadjuvant therapy and develop better-selected therapy, monotherapy, or combination therapy in the future.

BackgroundThe number of clinical studies evaluating the benefit of cytokine-induced killer cell (CIK) therapy, an adoptive immunotherapy, for colorectal cancer (CRC) is increasing. In many of these trials, CIK therapy was coadministered with conventional cancer therapy. The aim of this review is to systematically assess the available literature, in which the majority were only in Chinese, on CIK therapy for the management of CRC using meta-analysis and to identify parameters associated with successful CIK therapy implementation.MethodsProspective and retrospective clinical studies which compared CIK therapy to non-CIK therapy in patients with CRC were searched for electronically on MEDLINE, Embase, China National Knowledge Infrastructure, and Wanfang Data databases. The clinical endpoints of overall survival (OS), progression-free survival (PFS), OS and PFS rates, overall response rate (ORR), and toxicity were meta-analyzed using HR and relative ratio (RR), and subgroup analyses were performed using chi-square (χ2) test and I-squared (I2) statistics for study design, disease stage, cotherapy type, and timing of administration.ResultsIn total, 70 studies involving 6743 patients were analyzed. CIK therapy was favored over non-CIK therapy for OS (HR=0.59, 95% CI: 0.53 to 0.65), PFS (HR=0.55, 95% CI: 0.47 to 0.63), and ORR (RR=0.65, 95% CI: 0.57 to 0.74) without increasing toxicity (HR=0.59, 95% CI: 0.16 to 2.25). Subgroup analyses on OS and PFS by study design (randomized vs non-randomized study design), disease stage (Stage I–III vs Stage IV), cotreatment with dendritic cells (DCs) (CIK vs DC-CIK therapy), or timing of therapy administration (concurrent vs sequential with coadministered anticancer therapy) also showed that the clinical benefit of CIK therapy was robust in any subgroup analysis. Furthermore, cotreatment with DCs did not improve clinical outcomes over CIK therapy alone.ConclusionCompared with standard therapy, patients who received additional CIK cell therapy had favorable outcomes without increased toxicity, warranting further investigation into CIK therapy for the treatment of CRC.

In the context of coastal climate adaptation, coastal protection interventions involving soft and dynamic structures have noticeably gained popularity over the past decades. Huge sand nourishments of the order of Mm3 to tens of Mm3 have already been implemented along several stretches of vulnerable coastline. In most cases the added sediment concerned well-sorted sand with a D50 often very similar to that of the host area and was deposited in an open-coast system, where the morphodynamics are dominated by waves. Consequently, most of our understanding of nourishment dynamics stems from well-sorted sediment in wave-dominated environments. However, sand nourishments are increasingly applied to more sheltered systems, where tidal currents become dominant over wave-driven processes. Here, sand deposits are usually retrofitted to inadequate, hard flood defences to act as a buffer against erosion of such infrastructure. Frequently, coarser sediment than that of the host area is used in parts of the design to enhance this buffering capacity. Introducing different grain sizes into a system is expected to result in more complex, differentiated sediment transport, as coarser fractions are mobilised at different moments and places than finer fractions. By focussing on a nourishment on the leeward side of a barrier island, we aim to find quantitative answers to the questions when and how the mixed-sediment composition changes and what implications that has for the morphologic evolution of the area.This research is based on an extensive 6-week field campaign in the early fall of 2021 at the 3-km long Prins Hendrikzanddijk, a retrofit nourishment on the island of Texel. We deployed long- and cross-shore arrays of instruments that measured a range of parameters such as pressure, flow velocity, suspended sediment concentration and bedforms. These measurements were further complemented by almost daily DGPS-measurements of the bed levels and a spatially extensive set of sediment samples which had been collected from the foreshore and upper shoreface at various time intervals. The conditions captured during the study period ranged from very calm (no waves) to stormy (Hm0 up to 0.6 m), while tidal currents reached velocities up to 0.6 m/s. Throughout these varying conditions, we encountered wide grain-size distributions in the top 5-6 cm of the bed almost everywhere, which sometimes also revealed multimodality. From a longshore perspective, D50 was generally largest in the centre, decreasing in either direction away from it. The beach surface was further characterised by transient bands/patterns of surfacing coarse and shell-rich material, which could disappear altogether overnight –often hand in hand with a smoothening of the cross-shore profile and a shift in beach-step position– after a period of increased wave activity. We will further elaborate on our obtained results and findings at the conference.

Cancers of the upper gastrointestinal tract are a leading cause of cancer-related death world-wide and historically have a poor prognosis. The incidence and histology of these cancers have varied temporally and geographically over the last three decades, with an emerging understanding of the differences in the molecular and genetic profiles across different subgroups. Management of oesophagogastric cancers is by a multidisciplinary team with utilisation of surgery, radiotherapy and systemic treatments in combinations where appropriate. Immune checkpoint inhibition (ICI) has drastically changed the treatment landscape of multiple solid malignancies in the last 5 years. In oesophagogastric cancer, clinical trials have only recently shown activity that is often associated with the molecular characteristics of these tumours, in particular PD-L1 scores or microsatellite instability (MSI-H). This review looks to present the pivotal trials in this space, discuss the complexities between trials that may explain the disparate results and assess the benefit ICI offers in the treatment landscape at present.

42 Background: The anti-EGFR monoclonal antibodies panitumumab (Pmab) and cetuximab (Cmab) and the anti-VEGF antibody bevacizumab (bev) have demonstrated clinical efficacy in mCRC in combination with first-line chemotherapy. Clinical and molecular characteristics, such as primary tumour sidedness, RAS, BRAF and MMR status are prognostic and predictive biomarkers for response to treatment. Our aim was to compare the survival and tumour characteristics of patients receiving first-line chemotherapy and antibody combinations using the SA mCRC Registry. Methods: This real-world registry has collected data from all patients diagnosed with mCRC in SA prospectively since 2006. We identified patients who had received first-line Pmab, Cmab or bev. Survival was analysed using the Kaplan-Meier method and log-rank test to compare outcomes based on primary tumour location. Results: Of the 5537 patients currently entered onto the registry, 1313 with RAS results available had received first-line anti-EGFR/VEGF antibodies and had colon tumour side recorded. The table summarises median overall survival (mOS) and patient characteristics. Survival was significantly shorter for those with right colon cancers (P < 0.001). There were more high-grade (P < 0.001), KRAS mutant (P = 0.004) and BRAF mutant (P = 0.036) tumours in those with right colon cancers, and a trend towards fewer curative liver resections (P = 0.059). There was no significant difference in mOS seen between Pmab, Cmab or bev for both left (P = 0.14) and right-sided (P = 0.88) primary tumours. Conclusions: There were more high-grade, BRAF and KRAS mutant patients with right colon tumours, and lower rates of liver resection, which may explain the significantly shorter mOS. The survival seen for Pmab and Cmab was almost identical for both right and left primary tumours. When comparing Pmab, Cmab and bev as first-line therapy, there was no significant difference in mOS for both left- and right-sided CRC. [Table: see text]

Aim The aim of this study was to complete a descriptive qualitative investigation of parents’ perceptions of the barriers and facilitators to flu vaccination for pre-school children. Subject and method Participants were recruited through various communication channels to maximize sample variation. Invitations to participate in the study were sent to members of the Newcastle University Parent Network and to parents who had participated in previous research conducted at Newcastle University. Twelve participants (six with vaccinated children, six whose children were not vaccinated) took part in a semi-structured interview via Zoom. Transcripts were coded using Nvivo 12 and data were thematically analyzed using the COM-B model of health behavior change. Results Participants whose children were not vaccinated against flu nonetheless generally held favourable views of vaccination and reported low concern about side-effects. Barriers involved a combination of internal and external factors, mainly a lack of convenient access to vaccination opportunities and flu vaccination being a low priority for busy parents. Conclusion Our findings suggest that socioeconomic status, which is known to influence other vaccination behaviors, may influence uptake of the flu vaccine in this population. Inconvenient vaccination opportunities and a lack of awareness of the need to vaccinate are major barriers to uptake for some parents. The finding that belief that flu vaccination is a civic responsibility is a new contribution to the literature.

With the identification of the COVID-19 pandemic in early 2020, cancer-based clinical services in South Australia moved quickly to protect patients on active anti-cancer treatment who are particularly vulnerable to infective complications. This took the form of shifting 600 chemotherapy visits into the patients’ homes via expansion of an existing arrangement between a public hospital network and an established private home chemotherapy service. Despite calls for caution from some oncology organisations and a relative paucity in specific clinical data supporting this approach, it proved to be a safe and efficient transition with additional unexpected benefits.

PRS-344/S095012 is a bispecific antibody-Anticalin® fusion protein targeting PD-L1 and 4-1BB. It is designed to block the PD-1/PD-L1 axis and localize 4-1BB co-stimulation to PD-L1-positive tumor microenvironment (TME) or tumor draining lymph nodes with the aim of maximizing antitumor immunity and increasing the therapeutic window of 4-1BB monoclonal antibodies (mAbs). Multiple in vitro assays have shown that PRS-344/S095012 inhibits PD-1/PD-L1 signaling while simultaneously activating 4-1BB signaling on T cells. This resulted in a synergistic effect on both pathways leading to anti-tumor immune responses. PRS-344/S095012 presents mAb-like pharmacokinetics in vivo and non-clinical mouse models demonstrated dose-dependent efficacy in anti-PD-L1 refractory tumors. In the higher dose range, complete tumor regression was achieved in PD-L1 high and PD-L1 low expressing xenograft mouse models. This first-in-human (FIH), phase 1/2, open-label, multi center, dose escalation and cohort expansion study is designed to determine the safety and tolerability of intravenously administered PRS-344/S095012 in patients with advanced and/or metastatic solid tumors (NCT05159388). Patients with histologically confirmed diagnosis of unresectable, locally advanced, or metastatic solid tumors for which standard treatment options are not available, no longer effective, or not tolerated are eligible. Patients must have Eastern Cooperative Oncology Group (ECOG) status 0 or 1, RECIST 1.1 measurable disease and should have documented progression on prior therapy. Prior therapy with 4-1BB agonists is prohibited. Phase 1 is a dose escalation guided by a Bayesian Logistic Regression Model and a 28-day dose limiting toxicities (DLT) period. Primary objectives are safety and tolerability of PRS-344/S095012; secondary objectives include exploration of antitumor activity and evaluation of pharmacokinetics. Pharmacodynamics and comprehensive biomarker program will be explored. Additional patients may be enrolled to backfill cohort(s)to further explore pharmacokinetic/pharmacodynamic signals. Phase 2 is an expansion with primary objective of anti-tumor activity. First patient was dosed in November 2021 and the study is planned to enroll at sites in Belgium, Spain and Australia. Citation Format: Christiane Jungels, Nuria Kotecki, Emiliano Calvo, Elena Garralda, Timothy Price, Xiaojiang Zahn, Atif Abbas, Lisa Mahnke, Winrich Rauschning, Aizea Morales-Kastresana, Lucia Pattarini, Birgit Bossenmaier, Alix Scholer-Dahirel, Tim Demuth, Julie Legrande. Study of PRS-344/S095012 a PD-L1/4-1BB bispecific antibody-Anticalin®-fusion in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT255.

Background: KRASG12C mutation is an oncogenic driver that occurs in approximately 15% of non-small cell lung cancer (NSCLC), 3% of colorectal cancer (CRC), and ~1% of several other solid tumors. D-1553 is a novel, potent and orally bioavailable KRASG12C inhibitor. Here we present the safety, tolerability and PK and preliminary efficacy of D-1553 from a phase I trial in patients (pts) with advanced or metastatic solid tumors harboring KRASG12C mutation. Method: Key inclusion criteria: KRASG12C identified by molecular testing, measurable disease, and refractory to or intolerant of standard therapy. D-1553 dose escalation included oral daily (QD) doses of 150, 300, 600, 800, and 1200 mg, and twice daily (BID) doses of 400, 600, and 800 mg. Primary endpoint: safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary endpoints: PK parameters, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and duration of response (DOR), evaluated per RECIST 1.1. Results: As of Dec 27, 2021, 22 pts (12 [54.5%] male, median age 65 [range: 49-90]), including 14 pts with CRC, 6 pts with NSCLC, and 2 pts with other solid tumors, were enrolled. D-1553 was well absorbed, with a median time to reach maximum plasma concentration (Tmax) of 1-4 hours. The Cmax and AUC of each dose group (150-600 mg, QD; 400-600 mg, BID) increased linearly as the dose increased. However, the changes of Cmax and AUC in 600-1200 mg (QD), 600-800 mg (BID) groups were not in a dose-dependent manner. The most frequently reported treatment-related adverse events (TRAEs) (frequency ≥ 10%) were diarrhea, nausea, vomiting, headache, and lethargy, all grade ≤ 2. Thirteen pts (59.1%) had TRAEs: 11 pts (52.4%) had grade 2 or lower TRAEs; 2 (9.1%) had three grade ≥3 TRAEs (hypokalemia, hypertension, anaemia). No DLT has been reported. MTD was not reached. One pt (4.5%) discontinued the D-1553 therapy due to cerebral hemorrhage. This event was evaluated by investigator as unlikely related to the drug. Among 21 evaluable pts (including 14 CRC, 6 NSCLC, and 1 endometrial carcinoma (EC), confirmed ORR and DCR were 19.0% (4/21) and 85.7% (18/21), respectively. One pt with EC achieving PR had the best tumor burden reduction of 80%. Conclusion: In patients with KRASG12C mutated solid tumor, D-1553 is well tolerated with no DLTs at studied doses. The RP2D has been determined to be 600 mg BID. Preliminary efficacy results demonstrate promising clinical activity of single-agent D-1553 in pts with KRASG12C mutated solid tumor. This study is ongoing (NCT04585035) and more results will be presented at the meeting. Citation Format: Timothy Price, Jaspreet Grewal, Afaf Abed, Melissa Moore, Yu-Min Yeh, Shirish Gadgeel, Gary Richardson, Craig Underhill, Vinod Ganju, Keun-Wook Lee, Seok Jae Huh, Sang-We Kim, Chih-Hsin Yang, Yuh-Min Chen, Ziyong Xiang, Zhe Shi, Yaolin Wang, Ling Zhang, Michael Millward. A phase 1 clinical trial to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of D-1553, a novel KRASG12C inhibitor, in patients with advanced or metastatic solid tumor harboring KRASG12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT504.

Body surface area (BSA)-based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization.Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwentAnalysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLThe identified UGT1A3_c.31 T C and ABCB1_c.3435C T variants, from wild type to homozygous, were included in the final model for SN38 clearance.