Advanced Solid Cancers Research Articles

A phase I/II, open-label, dose-escalation, and cohort-expansion study evaluating the safety, pharmacokinetics, and therapeutic activity of OBI-999 in patients with advanced solid tumors.

TPS3657 Background: Aberrant glycosylation is a hallmark of cancer. Glycosphingolipids (GSLs), glycans conjugated to a lipid (ceramide) core, are essential for the recruitment of immune-related proteins to specific membrane microdomains. Globo H (GH) is a GSL found on normal cells but highly overexpressed on various epithelial tumors playing a role in tumor development and progression. GH is a promising target for immunotherapy. OBI-999 is an ADC composed of a human recombinant immunoglobulin G (IgG) monoclonal antibody that selectively and specifically binds to GH, attached by a linker to the antimitotic agent monomethyl auristatin E (MMAE). Its mechanism of action is based on tumor-selective delivery of MMAE to GH-expressing tumors with subsequent tumor cell death. Preclinical studies demonstrated that OBI-999 antibody binds specifically to the GH antigen, and antitumor efficacy was noted in breast, gastric, pancreatic, and lung cancer xenograft models. The pharmacokinetics (PK) of OBI-999 were determined in normal and tumor-bearing mice, rats, and monkeys. Exposure of OBI-999 increased proportionally with dose. No sex difference or accumulation was seen. The primary objectives are to determine dose limiting toxicities (DLTs), the maximum tolerated dose (MTD), and the phase 2 recommended dose (P2RD). The secondary objectives are to assess the rates of objective response and clinical benefit, the duration of progression-free survival, the immunogenicity of OBI-999, and the PK and pharmacodynamics (PD) of OBI-999 and MMAE. Methods: In Part 1, a "3+3" dose-escalation part of the study, up to 30 patients with advanced solid tumors refractory to ≥1 line of systemic therapy, who cannot tolerate standard therapy, or for whom no standard treatment is available, regardless of GH status will be treated. OBI-999 will be administered as a 60-minute IV infusion using a dose range of 0.4, 0.8, 1.2, 1.6, and 2.0 mg/kg on day 1 of every 21-day cycle. In Part 2, the cohort-expansion portion of the study, patients will be treated at the MTD or at a lower RP2D as determined by cumulative toxicities and tolerability profile. The study will determine the preliminary clinical activity and safety of OBI-999 in up to 155 patients with advanced solid tumors, pancreatic, gastric, esophageal, and colorectal cancer according to a Simon two-stage phase 2 design. Patients must have GH overexpression defined as an H-score of ≥100 according to an FDA Investigational Device Exempt (IDE) validated IHC assay. Clinical trial information: NCT04084366 .

Landscape of targetable alterations discovered by next generation sequencing demonstrates the role a community hospital can play in precision-guided oncology: Experience from Lenox Hill Hospital.

e19279 Background: Next generation sequencing (NGS) has become standard of care in aiding diagnosis and treatment of advanced solid cancers, and in conducting clinical trials at large centers. It is imperative that this is expanded to other hospitals that care for the majority of cancer patients. We analyzed NGS reports from our hospital to assess the number of patients who can benefit from approved or investigational targeted therapies. Methods: We analyzed NGS data for 511 solid tumor samples sequenced between January 1, 2018 and December 31, 2019. NGS was performed by GenPath Dx (77%), Caris Life Sciences (16%) or Foundation Medicine (7%). Results: The majority of samples represented advanced stage malignancies and 21% were stage I or II. They originated from the following primaries: 195 lung (37%), 150 gastrointestinal (29%), 64 primary brain (12%), 20 gynecological (4%), 14 skin (3%), 13 head and neck (3%) and 11 sarcomas (1%). 72 samples had mutations in EGFR (14%), 170 in TP53 (33%), 124 in KRAS (24%), 28 in BRAF (6%), and 3 in RET (0.6%). 34/107 (32%) early stage samples harbored an actionable mutation (20 EGFR mutations, 1 MET exon 14 skipping, 4 KRAS G12C, 7 BRAF V600E, 1 FGFR3 amplification and 1 CD74/NRG1 fusion). In contrast, only 58/317 (18%) advanced stage samples had a targetable mutation (p-value = 0.02, χ² test). 76% of EGFR-mutated samples were lung adenocarcinomas, and 19% were primary brain tumors; 54% of these are targetable by FDA-approved EGFR inhibitors. KRAS mutations were found in gastrointestinal (54%), lung (37%) and pancreatic (5%) malignancies. 17 patients had a KRAS G12C mutation and, therefore, could benefit from one of the KRAS G12C inhibitors in early clinical trials. Four samples harbored crizotinib-sensitive mutations (2 MET amplifications and 2 MET exon 14 skipping mutations). Regarding gene fusions, one glioblastoma sample had a PTPRZ-MET fusion and one lung adenocarcinoma sample harbored a CD74-NRG1 fusion. Conclusions: We identified 92/511 samples (18%) with clinically actionable mutations; distributed in 32% early stage and 18% advanced stage disease, indicating that actionable mutations are present at an increased frequency in early stage solid malignancies in our data set and trials to investigate targeted therapy in such settings should be considered. Furthermore, we show that a community-based hospital can be a site for future clinical trials of small molecule inhibitors and bring precision-guided medicine to additional patients.

A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies.

1049 Background: HER2 is an effective therapeutic target for breast and gastric cancer. A166 is an antibody-drug conjugate composed of a novel cytotoxic drug site-specifically conjugated to transtuzumab sequence via a stable protease-cleavable valine citrulline linker. Methods: This was a single arm, open-label, multicenter, dose escalating Phase 1 first-in-human study of A166 as monotherapy in solid tumor patients. Dose escalation and MTD identification was directed using a Bayesian logistic regression model with overdose control. The following dose levels were evaluated in this study: 0.3, 1.2, 3.6, 4.8 mg/kg. (ClinicalTrials.gov NCT03602079) Results: As of November 1, 2019 35 pts have completed the DLT evaluation period across 4 dose levels. Overall, A166 had an acceptable toxicity profile with no unexpected toxicities related to the study drug. No adverse events recorded met the protocol specified definition of a dose limiting toxicity at any studied dose level. Most frequently (≥10%) occurring TEAEs include were Keratitis, Decreased appetite, Dry eye, Vision blurred etc. Overall incidence of ophthalmic toxicities in the 3.6 mg/kg cohort was 80% and in the 4.8 mg/kg cohort it was 83%. Among the 27 patients evaluable for efficacy, best response was progression of disease in 11 patients (41%), stable disease in 9 patients (33%) and partial response in 7 patients (26%), for the total disease control rate of 59%.Responses were seen only at the dose levels of 3.6 mg/kg and 4.8 mg/kg. Conclusions: A166 demonstrated clinically meaningful efficacy in heavily pretreated patients with relapsed or refractory advanced solid cancers. The achievement of an ORR of 36% at efficacious dose levels and up to 100% in HER2 positive patients regardless of histology (2 CRC, 1 BC and 1 NSCLC) at the highest studied dose level exceed Clinical trial information: NCT03602079 .

Trends in patient misperception and decisional regret during treatment for advanced cancer: A prospective study.

e24190 Background: Cancer patients receiving palliative therapy often misperceive the likelihood of benefits and toxicity. Change in misperception during treatment and decisional regret after has not been studied. We assessed shifts in perception of treatment outcomes and decisional regret after treatment in a single-center prospective study. Methods: We enrolled patients with advanced solid cancer starting palliative intent treatment. At baseline, both patients and their treating physicians were asked about their perceived likelihood of treatment response, symptom palliation, survival benefit, and treatment toxicity on scale of 0-100% at start of treatment and at follow-up. The Signed Rank tested whether patient perception changed significantly over time. After treatment, patients alive and not in hospice were asked about their decision to undergo treatment. Results: Of 122 patients with baseline estimates, 65% completed at least one follow-up survey while undergoing treatment. At enrollment, respondents’ mean age was 65 years (range: 32–89); 54% were male. Compared to baseline, there was no change in patients’ perceptions of treatment response, survival benefit, toxicity (all P≥0.52) at follow-up; a trend toward change in perceived curative potential (P = 0.06); an increase (of 7 points) of perceived likelihood of symptom relief (P = 0.04). Perceived likelihood of treatment response and symptom relief increased (both P < 0.03) among patients whose baseline estimates of treatment response were lower than or similar to their physicians’ estimates. Conversely, perceived likelihood of treatment response (P = 0.01) and curative potential (P = 0.02) decreased among patients with more optimistic estimates than their physicians’. Of the surviving 63 patients, 33 (52%) completed the end of treatment survey, 24 were unreachable and 6 declined. Median time of survey response was at 41.2 weeks (IQR: 36.4 – 47.9). Nearly all (95%) agreed that treatment was the right decision. None regretted their choice; 79% agreed they would make the same choice if they had to do it again; 12% agreed that treatment did them a lot of harm. Conclusions: Patients’ perceptions of treatment response converged during therapy as compared to their physicians at baseline. Of surviving patients surveyed, none regretted their decision to receive palliative cancer treatment. Treatment expectations evolve over time, highlighting opportunities for enhanced communication and patient education beyond initial consent procedures.

Inmunotherapy related hepatitis: A retrospective study of Chilean patients.

e15144 Background: Immune checkpoint inhibitors (ICI) have shown dramatic efficacy in many trials of advanced solid cancer. Data of toxicity for these agents setting in Chilean patients is lacking and is of importance to confirm the tolerance of immunotherapy in different population. Immunotherapy-related hepatitis (liver irAEs) represents a diagnostic and management challenge, and its frequency varies according to various factors. We aim to report the incidence, features and treatments used to manage liver irAEs in Chilean population. Methods: A retrospective review of 139 patients with diagnosis of NSCLC, Renal Cancer, Urothelial, Melanoma, treated with ICI from April 2013 until November 2019. Baseline clinical factors (age, ECOG score, cancer type, stage, Type and number of cycles of immunotherapy, comorbidities), biochemistries and treatment received were recorded for all patients with liver irAEs. Checkpoint-inhibitor-associated liver disease was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) V.4 Treatment outcomes were analyzed by measuring progression free (PFS) and overall survival (OS). Results: 32 (23%) patients developed liver irAEs. Median age at diagnosis was 62 years (range 37-86). 62% patients were male, 59% ECOG 1, 96% had de novo metastatic disease. The most frequent primary sites of cancer were Renal Cancer 71% and NSCLC 9%. 78% of patients received treatment with both anti-PD-1/PD-L1 and CTLA-4 drugs. Liver irAEs G2 and G3 were 43.7% and 56.2% respectively. 31,2% and 12,5% of patients treated with single agent immunotherapy developed G2 and G3 Liver irAEs respectively. The total averages of cycles administered were 12, 4 cycles. 28% of patients developed liver irAEs after the first cycle of treatment and 12.5% after the second cycle. 6.2% patients required hospitalization and 78.1% required treatment with steroids. Conclusions: Liver irAEs was more frequent in Chilean population than data reported on previous clinical trials with a high incidence caused by ICI monotherapy and further reinforced by combination therapy. Local registries play an important role in recognizing different patterns of toxicity according to different population. Early recognition and management of liver irAEs should be of vital importance in clinical practice and as prescribing physicians we must maintain strict vigilance of liver irAES in Chilean population.

Return of results after somatic tumor mutation profiling in advanced cancer: Psychological impacts.

1541 Background: Somatic tumor mutation profiling (STMP) is entering clinical practice. We aimed to investigate psychological impacts of receiving results. Methods: Eligible participants had: advanced solid cancers of any histological type; accessible tissue for STMP; and enrolled in the Molecular Screening and Therapeutics (MoST) Program. 1074 participants (91%) completed a baseline assessment prior to STMP (T0), of whom 570 (47%) received results and completed a post-result assessment (T1) of impact of genetic results (MICRA), anxiety and depression (HADS), cancer-specific anxiety (IES), and satisfaction with decision to have STMP. Linear regression models controlling for age, gender, parental status, cultural diversity, education and ECOG status explored associations between result received and psychological outcomes. Results: 360 participants received an actionable result and were recommended personalised treatment: 152 via a MoST sub-study (G1) and 208 via their treating oncologist (G2). 210 received a non-actionable result (G3). At T1, G3 were significantly more distressed and less positive about their result (MICRA subscales) and less satisfied with their decision to have STMP than both G1 and G2; G2 was less positive than G1. IES and HADs were not impacted by type of result. Interactions between gender and age, and result were non-significant for all psychological outcomes. Perceived self-efficacy in coping with results (p=0.015) and knowledge (p=0.04) at T0 was significantly correlated with satisfaction with decision at T1; self efficacy (T0) was also correlated with MICRA total (T1) (p=0.006). Conclusions: Pathway to treatment receipt is less important to advanced cancer patients than actionability. Patients’ self-efficacy to cope with results prior to testing can identify patients vulnerable to distress post-receipt of STMP results who should be offered psychological counseling. Ensuring good knowledge of STMP at consent may avoid decisional regret. [Table: see text]

Assessment of the Value of Tumor Variation Profiling Perceived by Patients With Cancer

Use of tumor molecular profiling (MP) is entering routine clinical practice; however, little is known about how much and why patients value MP. To examine the perceived value of MP to patients with advanced cancer and factors associated with perceived value. A cross-sectional survey that included willingness-to-pay trade-off scenarios was administered to participants after consent and before MP. A total of 777 participants (94% response rate) were recruited from the Molecular Screening and Therapeutics Program. Eligible patients had advanced solid cancers of any histologic type, were receiving or had completed their last line of effective therapy, had an Eastern Cooperative Oncology Group Performance Status 0 to 3, and had sufficient accessible tissue for MP. The participants were recruited between October 24, 2017, and March 12, 2019, and data analysis was conducted from March 13 to April 14, 2019. Willingness to pay for MP was assessed via hypothetical trade-off scenarios varying in the actionable return rate (1%, 20%, or 40%) and cost (A$0, A$300 [US$210], A$1000 [US $700], A$3000 [US $2100], or A$10 000 [US $7000]). Ordinal regressions were used to explore factors associated with willingness to have and pay for MP. Of 777 participants (405 women [52%]; mean [SD] age, 55.47 [14.26] years), 689 patients (89%) would have MP for as little as a 1% actionable return rate. Fifty-six patients (7%) would require at least a 20% return rate and 11 patients (1%) would require at least a 40% return rate. Fifteen patients (2%) consistently chose not to have the test; 6 participants (0.8%) had missing values on this item. Participants were willing to pay a median of A$1000 if the actionable return rate was 1% and A$3000 for an actionable return rate of 20% to 40%. Of 762 individuals who agreed to testing, 482 patients (64%) were consistently unwilling to pay A$10 000, regardless of the actionable return rate. Patients born in Australia or New Zealand were more likely to want MP (eg, participants born in South Asia had an ordered odds for the tipping point of 7.74 [95% CI, 1.67-36.05; P = .009] times higher than Australian- and/or New Zealand-born participants). Patients born in Australia or New Zealand were also more willing to pay A$1000 or A$3000 (eg, participants born in Western Europe had an ordered odds for the tipping point for paying A$1000 of 1.74 [95% CI, 1.01-3.00; P = .048] times higher than Australian- and/or New Zealand-born participants). People with a medical- or science-related occupation and with more negative attitudes toward uncertainty were more likely to pay A$10 000 (eg, A$10 000 tipping point-ordered odds of participants with a medical- or science-related occupation was 0.49 [95% CI, 0.7-0.87; P = .02] times that of participants without a medical- or science-related occupation). This study found apparent high interest in but lower willingness to pay for MP among patients with advanced cancer. Ability to pay may limit access to MP. Ongoing societal debate is required to establish the value of MP and whether subsidization is needed to ensure equity of access.

A single administration of Fc-fused recombinant human IL-7 induces expansions of T lymphocytes in healthy adults and cancer patients

Abstract Interleukin-7 (IL-7) is a cytokine that plays important roles in T cell development and homeostasis. IL-7 is a potent agent for promoting T cell reconstruction in lymphopenia patients. In this study, we investigated the effects of GX-I7 (human IL-7 fused to hyFcTM for half-life extension and improved stability) in healthy volunteers (20~60 μg/kg, n=24) and advanced solid cancer patients who had no available effective treatments (60~1,200 μg/kg, n=33). We observed significant increases in the number of circulating CD8+ and CD4+ T cells in healthy volunteers, the peak of which was seen on days 14-21. Importantly, naïve, TEM, and TCM subsets of CD8+ and CD4+ T cells increased, coupled with upregulation of Ki-67. TCR diversity of the naïve T cells tends to be increased in healthy adults by single administration of GX-I7. In addition, cytokine secretion assay using PBMCs revealed that Ag–specific (CMV-specific) T cell responses were maintained after GX-I7 administration in healthy volunteers. Moreover, in advanced solid cancer patients, GX-I7 administration significantly increased the number of all subsets (naïve, TEM, TCM and TEMRA) of both CD8+ and CD4+ T cells in a dose-dependent manner. More importantly, single GX-I7 administration increased the absolute lymphocyte count above the normal range in all patients with lymphopenic conditions (ALC < 1,000/mm3). In conclusion, following GX-I7 administration, dose-dependent increase of ALC and T cell subsets were observed. Our study suggests that GX-I7 as a T cell amplifier provides a unique opportunity for immuno-oncology combination strategies by reconstituting persistent T cell immunity, where anti-tumor effects are mediated by T cells.

UPAR antibody (huATN-658) and Zometa reduce breast cancer growth and skeletal lesions

Urokinase plasminogen activator receptor (uPAR) is implicated in tumor growth and metastasis due to its ability to activate latent growth factors, proteases, and different oncogenic signaling pathways upon binding to different ligands. Elevated uPAR expression is correlated with the increased aggressiveness of cancer cells, which led to its credentialing as an attractive diagnostic and therapeutic target in advanced solid cancer. Here, we examine the antitumor effects of a humanized anti-uPAR antibody (huATN-658) alone and in combination with the approved bisphosphonate Zometa (Zoledronic acid) on skeletal lesion through a series of studies in vitro and in vivo. Treatment with huATN-658 or Zometa alone significantly decreased human MDA-MB-231 cell proliferation and invasion in vitro, effects which were more pronounced when huATN-658 was combined with Zometa. In vivo studies demonstrated that huATN-658 treatment significantly reduced MDA-MB-231 primary tumor growth compared with controls. In a model of breast tumor-induced bone disease, huATN-658 and Zometa were equally effective in reducing skeletal lesions. The skeletal lesions were significantly reduced in animals receiving the combination of huATN-658 + Zometa compared with monotherapy treatment. These effects were due to a significant decrease in osteoclastic activity and tumor cell proliferation in the combination treatment group. Transcriptome analysis revealed that combination treatment significantly changes the expression of genes from signaling pathways implicated in tumor progression and bone remodeling. Results from these studies provide a rationale for the continued development of huATN-658 as a monotherapy and in combination with currently approved agents such as Zometa in patients with metastatic breast cancer.

Impact of panel design and cut-off on tumour mutational burden assessment in metastatic solid tumour samples

Tumour mutational burden (TMB) has emerged as a promising biomarker to predict immune checkpoint inhibitors (ICIs) response in advanced solid cancers. However, harmonisation of TMB reporting by targeted gene panels is lacking, especially in metastatic tumour samples. To address this issue, we used data of 2841 whole-genome sequenced metastatic cancer biopsies to perform an in silico analysis of TMB determined by seven gene panels (FD1CDx, MSK-IMPACT™, Caris Molecular Intelligence, Tempus xT, Oncomine Tumour Mutation Load, NeoTYPE Discovery Profile and CANCERPLEX) compared to exome-based TMB as a golden standard. Misclassification rates declined from up to 30% to <1% when the cut-point for high TMB was increased. Receiver operating characteristic analysis demonstrated that, for correct classification, the cut-point for each gene panel may vary more than 20%. In conclusion, we here demonstrate that a major limitation for the use of gene panels is inter-assay variation and the need for dynamic thresholds to compare TMB outcomes.

Telomere maintenance in interplay with DNA repair in pathogenesis and treatment of colorectal cancer.

Colorectal cancer (CRC) continues to be one of the leading malignancies and causes of tumour-related deaths worldwide. Both impaired DNA repair mechanisms and disrupted telomere length homeostasis represent key culprits in CRC initiation, progression and prognosis. Mechanistically, altered DNA repair results in the accumulation of mutations in the genome and, ultimately, in genomic instability. DNA repair also determines the response to chemotherapeutics in CRC treatment, suggesting its utilisation in the prediction of therapy response and individual approach to patients. Telomere attrition resulting in replicative senescence, simultaneously by-passing cell cycle checkpoints, is a hallmark of malignant transformation of the cell. Telomerase is almost ubiquitous in advanced solid cancers, including CRC, and its expression is fundamental to cell immortalisation. Therefore, there is a persistent effort to develop therapeutics, which are telomerase-specific and gentle to non-malignant tissues. However, in practice, we are still at the level of clinical trials. The current state of knowledge and the route, which the research takes, gives us a positive perspective that the problem of molecular models of telomerase activation and telomere length stabilisation will finally be solved. We summarise the current literature herein, by pointing out the crosstalk between proteins involved in DNA repair and telomere length homeostasis in relation to CRC.

Study to Assess AFM24 in Advanced Solid Cancers

Study to Assess AFM24 in Advanced Solid Cancers

Safety, pharmacokinetics, and efficacy of RC48-ADC in a phase I study in patients with HER2-overexpression advanced solid cancer.

334 Background: HER2 overexpression is common in many malignancies and contributes to tumor growth. Unlike the varied options of anti-HER2 target therapies for breast cancer, there is a huge unmet medical need for HER2 overexpressing non-breast solid tumor (NBST) such as gastric cancer and urothelial cancer. Therefore, we conducted the first study of RC48-ADC, a novel humanized anti-HER2 antibody conjugate, in NBST. Methods: This was an open-label, dose-escalation and expansion study in patients with HER2-overexpression (IHC 2+ and 3+) advanced solid cancers after failure of standard treatment. The dose escalation consisted of accelerated (0.1 and 0.5 mg/kg) and “3+3” titrations (1.0, 2.0, 2.5 and 3.0 mg/kg). In dose expansion stage, patients were given RC48-ADC at 2.0 mg/kg, Q2W. Results: As of Aug 20, 2019, 57 patients (including 47 with gastric cancer and 4 with urothelial cancer) were treated at 0.1 (1 patient), 0.5 (1 patient), 1.0 (3 patients), 2.0 (6 patients in dose escalation and 32 patients in dose expansion), 2.5 (11 patients), and 3.0 mg/kg (3 patients), respectively. Most of them were Stage IV (91.2%) or with metastasis (96.5%). DLT was observed in 1, 2, and 1 patient at 2.0, 2.5, and 3.0 mg/kg, respectively. The MTD was 2.5 mg/kg. Most commonly reported TRAEs were WBC count decreased (66.7%), fatigue (56.1%), neutrophil count decreased (54.4%) and hemoglobin decreased (52.6%). Grade 3/4 TRAEs were reported in 28 patients (49.1%). Confirmed ORR was 21.1% (8/38) for 2.0 mg/kg, and 17.5% (10/57) for all patients. DCR was 52.6% and 49.1%, respectively. PFS was 3.6 months (95% CI: 4.1, 11.3) for 2.0 mg/kg. Subgroup ORR was 20.7% (6/29) at 2.0 mg/kg and 18.2% (2/11) at 2.5 mg/kg for gastric cancer, and 50.0% (2/4) for urothelial cancer. Conclusions: RC48-ADC demonstrated a good safety profile and promising anti-tumor activity in the late stage solid tumor including gastric cancer and urothelial cancer. Response and PFS benefits were clinical meaningful at 2.0 mg/kg and 2.5 mg/kg. Phase 2 pivotal study (NCT03556345) in gastric cancer is ongoing. Clinical trial information: NCT02881190.

Nationwide large-scale investigation of microsatellite instability status in more than 18,000 patients with various advanced solid cancers.

803 Background: The recent success of immunotherapy in high-frequency microsatellite instability (MSI-H) and/or mismatch repair protein deficient (MMR-D) tumors now supports testing for MSI in all advanced solid tumors. We previously reported using the quasi-monomorphic variation range (QMVR), the MSI status can be determined without matched normal DNA (Bando H, et al. Cancer Sci. 2018). Here, we investigate the proportion of the MSI status across various advanced solid tumors by this method. Methods: The MSI analysis was performed centrally by CLIA-certified, CAP-accredited, the single laboratory using tumor DNA from formalin-fixed paraffin embedded (FFPE) tissues with the MSI test kit (FALCO), which includes fluorescent-labelled primers for co-amplification of five mononucleotide markers (NR-21, BAT-25, MONO-27, NR-24 and BAT-26). The MSI-H was defined as positive if 2 or more makers showed instable. Results: A total of 18,250 patients with advanced solid tumors were registered from Dec 2018 to Aug 2019, and the MSI status was confirmed in 18,088 patients (99%). Among them, 51.9% were male, with median of 62.0 y/o. Overall prevalence of the MSI-H was3.3% (2.3% in male and 4.5% in female); the highest was 16.2% (149/916) in endometrial cancer, followed by 13% (13/100) in small intestinal cancer, 5.9% (74/1277) in gastric cancer, 3.3% (236/7190) in colorectal cancer, 2.6% (4/154) in prostate cancer, 2.5% (20/806) in ovarian cancer, 2.1% (9/426) in cervical cancer, 1.6% (13/831) in biliary tract cancer, 1.5% (4/271) in hepatocellular carcinoma, 0.9% (16/1852) in pancreas cancer. Interestingly, among biliary tract cancers, all MSI-H cases were arising from gall bladder (13/152) but no other sites. High prevalence was observed in cancer of teens or twenties (7.9%) and over 80y/o (5.6%), compare with others (3.0%) in this study (p &lt; 0.001, both). Conclusions: These data show the MSI-H advanced solid tumors are distributed across a much broader tumor spectrum, and confirm the clinical relevance of the screening in patients with most advanced solid tumors, which can select patients sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors.

Molecular‐targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK‐PI3K drug therapy against KRAS mutated mucin 2 (MUC2)‐secreting LS174T cells and patient‐derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co‐therapy. Co‐treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)‐induced synergistic cytotoxicity and intrinsic mitochondrial‐mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)‐associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock‐down assays demonstrated that mitochondrial‐mediated apoptosis in LS174T cells was not ERS‐dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post‐translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient‐derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK‐PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co‐treatment based on their unique phenotypic and genotypic characteristics.

Experience with Large Panel Next-generation Sequencing in Patients with Advanced Solid Cancers at Juntendo University Hospital

Experience with Large Panel Next-generation Sequencing in Patients with Advanced Solid Cancers at Juntendo University Hospital

Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody-drug conjugates as lead drug candidates for clinical trials.

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro, efficacy in tumor models, and toxicological activities in primates.

Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer-Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy.

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring the AKT1E17K mutation, was performed at the recommended phase 2 dose (R2D) of 60 mg BID. Dose-limiting toxicities (Grades 3–4) were increased in transaminases, γ-glutamyltransferase (γ-GT), and alkaline phosphatase in four patients in both schedules and stomach pain in one patient. Of the 78 patients enrolled, one patient had a partial response, 30 had stable disease, and 38 had progressive disease. The clinical benefit rate was 27.9% among 43 patients treated at the R2D. AKT1E17K mutation status was not associated with tumor response. Genetic analyses revealed additional mutations that could promote tumor cell growth despite the inhibition of AKT1/2. BAY 1125976 was well tolerated and inhibited AKT1/2 signaling but did not lead to radiologic or clinical tumor responses. Thus, the refinement of a selection of biomarkers for AKT inhibitors is needed to improve their monotherapy activity.

Abstract B109: Oral dual PI3K/mTOR inhibitor bimiralisib demonstrates tolerability and a signal of activity in head and neck squamous cell cancer with NOTCH1 loss-of-function mutation

Abstract Background: Bimiralisib is a balanced dual panPI3K/mTOR inhibitor, which demonstrated anti-cancer activity in a number of preclinical models. Pharmacokinetic (PK) data suggested that intermittent targeting of the PI3K/mTOR pathway could be preferable to continuous daily dosing. Preclinical models in squamous cell head and neck cancer (SCCHN) demonstrated that NOTCH1 Loss of Function (LoF) mutations were associated with efficacy of bimiralisib and other PI3K inhibitors. Methods: We conducted a first-in-human dose-escalation study (3+3 design) to identify the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), dose-limiting toxicities (DLT) and overall safety (CTCAE v4) of bimiralisib administered either as a continuous (80 mg – 120 mg daily) or one of two intermittent schedules (schedule A: twice weekly 80 mg – 200 mg on Day 1 and 2, or schedule B: twice weekly 80mg – 200 mg on Day 1 and 4) until disease progression or unacceptable adverse events (AEs). Eligible patients had histologically confirmed solid cancers refractory to standard therapies, ECOG &amp;lt;1, life expectancy &amp;gt;12 weeks, adequate bone marrow, liver, and renal functions, HgbA1c &amp;lt;7%, and fasting plasma glucose &amp;lt; 7.0mmol/L. Tumor responses were evaluated according to RECIST v1.1 every 6 weeks. PK and blood biomarkers were analyzed. Results: 70 patients (female, 70%; white, 93%; median age 57 years [range, 49-65]) with heavily pretreated advanced solid cancers were enrolled (continuous schedule, 21; intermittent schedule A, 25; intermittent schedule B, 24). The MTD for the continuous schedule was established as 80 mg daily. For all treatment groups, DLTs included grade 2 and 3 fatigue. Clinically significant treatment-related AEs included fatigue in the continuous schedule, none in the intermittent schedule A and diarrhea, hyperglycemia in the intermittent schedule B. Intermittent schedules A and B did not reach the MTD, and after review of PK data, 140 mg administered in schedule A was selected as the RP2D for further exploration. Day 1 peak plasma concentration proportionally increased with increasing doses of bimiralisib only up to 140mg. Weekly AUC on intermittent dosing at all dose levels studied were considerably lower than continuous daily dosing at 80mg. There was one partial response (PR, -85% per RECIST) in a heavily pretreated patient with SCCHN and NOTCH1 LoF mutation, which was maintained for 8.2 months until death from pulmonary artery rupture in the setting of known fistula (assessed as unrelated to bimiralisib). In addition, 30 (42.9%) pts achieved stable disease (SD) including one with anal SCC carrying a NOTCH1 LoF mutation. SD &amp;gt; 6 months was observed in five pts (23.8%) in continuous schedule, 12 (48%) in intermittent schedule A, and 13 (54.2%) in intermittent schedule B. Results on patients, who consented to the serial circulating tumor DNA collection will be presented. Conclusions: Bimiralisib was well tolerated and RP2D of 140 mg given orally twice weekly on Days 1 and 2 was selected for further studies. In agreement with our preclinical models, there was an encouraging activity in a SCCHN patient with NOTCH1 LoF mutation and this observation is now being validated in a proof-of-concept phase 2 study (NCT03740100). Citation Format: Filip Janku, Faye M. Johnson, Mateusz Opyrchal, Afshin Dowlati, Cinta Hierro, Martin Forester, Sarah P. Blagden, Andreas Wicki, Debora Schmitz, Alex A. Adjei. Oral dual PI3K/mTOR inhibitor bimiralisib demonstrates tolerability and a signal of activity in head and neck squamous cell cancer with NOTCH1 loss-of-function mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B109. doi:10.1158/1535-7163.TARG-19-B109

Talabostat and Pembrolizumab for the Treatment of Advanced Solid Cancers

Talabostat and Pembrolizumab for the Treatment of Advanced Solid Cancers