Advanced Solid Cancers Research Articles

BOLD-100-001 (TRIO039): A phase 1b dose-escalation study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastrointestinal solid cancers: Interim safety, tolerability, and efficacy.

3031 Background: BOLD-100 is a first-in-class ruthenium-based anticancer agent in Phase 1b / 2 clinical development for the treatment of advanced gastrointestinal (GI) cancers in combination with FOLFOX. Being developed primarily as a combinational agent, BOLD-100 induces cellular stress through modulation of the unfolded protein response, production of reactive oxygen species and induction of DNA damage. BOLD-100 demonstrates synergy in established preclinical models in combination with various anticancer therapies, particularly in resistant cell lines. Methods: This is a prospective, Phase 1b dose-escalation (Part A) and Phase 2 dose-expansion (Part B) study of BOLD-100 in combination with FOLFOX for colorectal (CRC), pancreatic (PDAC), gastric (GC) and biliary tract (BTC) cancers. Patients (pts) receive BOLD-100 with FOLFOX on day 1 of each 14-day cycle. In Part A, pts are enrolled in a 3+3 design to determine the combination recommended Phase 2 dose (RP2D), with BOLD-100 dose-escalation (420, 500 and 625 mg/m2) up to dose level 3. Part B comprises 5 cohorts treated at the RP2D until progressive disease or unacceptable toxicity. In Part A, reported here, the primary endpoints are safety, tolerability and maximum tolerated dose; the Part B endpoints are efficacy (primary), pharmacokinetic (PK) and pharmacodynamic parameters (secondary), and duration of response (exploratory) (NCT04421820). Results: As of 07 Feb 2022 (contains Part A preliminary data), 19 pts (mean age 65 years) were treated: 9 (47%) CRC, 5 (26%) BTC, 4 (21%) PDAC, 1 (5%) GC. Patients had a median of 3 prior systemic therapies, and 18 (95%) were enrolled with stage IV disease. Median number of cycles completed was 5 (range 1-15). 18 pts reported ≥1 treatment-emergent adverse events (AEs), most commonly fatigue (n = 12, 63%), nausea (n = 9, 47%) and stomatitis (n = 8, 42%). The majority of AEs were grade (G) 1-2. 7 G4 AEs (all neutropenia), and 1 unrelated G5 AE of pulmonary embolism occurred. There were 8 serious AEs in 6 different pts, with 1 SAE of dyspnea reported as related to BOLD-100. 2 pts experienced infusion-related reactions, related to chemotherapy. 2 dose-limiting toxicities have been observed: G3-4 neutropenia complicated by fever > 38.5°C or infection (n = 1, cohort #2) and inability to receive planned doses due to AEs (n = 1, cohort #3). To date for evaluable pts (n = 16), disease control rate of 75%, 1 partial response (48% target lesion reduction) and 11 stable disease have been observed. Conclusions: BOLD-100 plus FOLFOX is well-tolerated with no clinically significant safety findings. Dose-escalation data supports a BOLD-100 RP2D of 625 mg/m2 for the expansion phase. Progression-free survival, overall survival, and PK data are forthcoming. Clinical trial information: NCT04421820.

BASECAMP-1: Leveraging human leukocyte antigen (HLA) loss of heterozygosity (LOH) in solid tumors by next-generation sequencing (NGS) to identify patients with relapsed solid tumor for future logic-gated Tmod CAR T-cell therapy.

TPS2676 Background: Solid tumors comprise > 90% of cancers. Metastatic colorectal cancer, non-small cell lung cancer, and pancreatic cancer are among the leading causes of cancer-related mortality (5-year overall survival: 14%, 6%, and 3%, respectively) (ACS. 2021). Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical efficacy in hematologic malignancies (Neelapu S. et al. N Engl J Med. 2017). Translating engineered T-cell therapies to solid tumors has proven to be challenging due to a lack of tumor-specific targets that can discriminate cancer cells from normal cells. Previous studies using carcinoembryonic antigen (CEA) T-cell receptors and mesothelin (MSLN) CARs resulted in dose-limiting on-target, off-tumor toxicities (Parkhurst M, et al. Mol Ther. 2011; Tanyi J. Cellicon Valley '21). To create a therapeutic safety window, Tmod CAR T-cell therapy utilizes dual-signaling receptors to create a robust NOT logic gate capable of killing tumor cells, while leaving healthy cells intact (Hamburger A, et al. Mol Immunol. 2020). The 2 receptors in Tmod CAR T-cell therapy comprise an activator that recognizes an antigen on the surface of tumor cells that may also be present on normal cells, such as CEA and MSLN, and a blocker that recognizes a second surface antigen from an allele lost only in tumor cells. The frequency of HLA LOH among advanced GI solid tumor cancers in the Tempus real-world dataset is 16.3% with a range of 15.6%-20.8% between colorectal, pancreatic, and gastroesophageal tumors (Hecht R. et al. ASCO-GI 2022. Abstract #190). As such, HLA LOH offers a definitive tumor versus normal discriminator target for CAR T-cell therapy. Different activator/blocker combinations can be engineered with the Tmod platform technology and may be applied to T cells and natural killer cells in autologous and allogeneic settings. BASECAMP-1 is a currently enrolling observational study with key objectives of 1) To identify patients with somatic HLA LOH eligible for Tmod CAR T-cell therapy, and 2) To obtain leukapheresis and feasibility for the future EVEREST Tmod CAR T-cell trial. Methods: BASECAMP-1 (NCT04981119) patient eligibility has 2 parts: 1) Patients will be initially screened to identify germline HLA-A*02 heterozygosity by central NGS. If HLA-A*02 heterozygosity is confirmed, primary archival tumor tissue will be analyzed for somatic mutations by xT-Onco NGS testing. 2) If the tumor demonstrates HLA-A*02 LOH and the patient is eligible after screening, the patient will undergo leukapheresis. Banked T cells will be available for the autologous EVEREST Tmod CAR T-cell therapy interventional study to reduce waiting time at relapse. Clinical trial information: NCT04981119.

Evaluation of an automated artificial intelligence (AI)/ natural language processing (NLP) engine to match patients (pts) with advanced solid cancers to biomarker-driven early phase (EP) clinical trials.

e13513 Background: The increasing complexity of precision medicine in oncology creates significant challenges in identification of pts for biomarker-driven clinical trials. Worldwide expansion of genomic testing will identify more pts with potentially actionable alterations, but the manual task of matching pts to clinical trials requires laborious interpretation of fragmented medical information and knowledge of suitable trial eligibility criteria. Inspirata’s Trial Navigator (TN) solution uses AI and NLP to automatically extract relevant information from both patient medical records and trial protocols to identify appropriate trials. We conducted a retrospective study to evaluate the ability of TN to match pts referred to the Guy’s Hospital EP trials unit. Methods: Anonymised referral letters and genomic reports for pts referred from Jan 2019 to Dec 2020 were used. A subset was used to train TN to extract relevant variables for matching against eligibility criteria for all UK Experimental Cancer Medicine Centre (ECMC) Network trials open within 160 km of Guy’s Hospital at the time of referral, favouring biomarker-matched studies. Finally, TN was tasked with finding 5 ECMC trial matches for 40 referred pts. Matches were scored for eligibility and tumour and/ or biomarker suitability using a quality index (QI): 0, ineligible; 1, generic match; 2, tumour match; 3, biomarker match; 4, tumour and biomarker match. Results: Of 40 pts, most common tumour groups included gastrointestinal (55%), HNSCC (20%) and gynae (10%). TN was able to correctly identify at least 1 suitable trial (median = 4) for 39/40 pts (97%). Selection biomarkers were available for 27 pts, of whom 21 (78%) were matched to at least one appropriate biomarker-directed trial, 5 (12%) were matched to biomarker-agnostic trials and one was not correctly matched due to exclusion for progressive CNS metastases. Of 13 pts without biomarker information, 11 (84%) were matched to at least 1 tumour-appropriate trial and 2 to tumour-agnostic trials. Of all 200 trial matches, 134 (67%) were appropriately matched, of which 80 (59%) were external to Guy’s Cancer centre. Conclusions: TN successfully matched 90% of these preselected cancer pts to an appropriate biomarker- or tumour-directed trial, indicating potential to improve access and recruitment to early phase cancer trials, including those external to the primary treating site with which referrers may not be familiar. A prospective multicentre evaluation of TN is warranted to further define improvements in trial recruitment and efficiency.[Table: see text]

TARGET National: A U.K.-wide liquid-based molecular profiling program to enhance recruitment to early-phase trials.

TPS3163 Background: Precision medicine programs have largely focused on tissue-based assays to screen patients for genomic variants amenable to experimental targeted therapies. Challenges faced in such studies include time taken to acquire archival biopsies and limitation in capturing tumor heterogeneity and clonal evolution. The TARGET study (Rothwell, Nature Medicine 2019) previously demonstrated feasibility of using ctDNA to match patients to early phase trials with the benefit of rapid turnaround of results. With an ever-increasing number of novel therapies in development targeting rare genomic alterations across different tumor types, ctDNA holds great promise in enhancing recruitment to studies with rapid and efficient comprehensive genomic profiling assays covering a broad range of variants. There is need to perform profiling at scale to identify rare alterations and to utilise networks for identification of suitable clinical trials across the country. ctDNA is not detectable in all patients (owing to differences across disease types/ burden), thus tissue analysis still plays an important role. Methods: TARGET National is an investigator-initiated multi-centre molecular profiling study. The primary endpoints are to establish a national framework to offer profiling from blood samples (or tissue if appropriate) for patients being considered for early phase clinical trials across the UK Experimental Cancer Medicine Centre (ECMC) Network, and to measure the number of patients receiving matched therapy (MT). Secondary endpoints include curating the genomic landscape of the early phase population in the UK, and outcomes for patients receiving MT versus unmatched. Enrolment began in July 2021 and >250 patients have been recruited across 9 ECMCs with plans to expand to 20 centres by Q3 2022. Planned enrolment is 6000 patients over 5 years. Patients must be ≥ 16 years old, provide written consent, have histologically confirmed advanced solid cancer, progressing disease and be considered fit enough to receive an experimental therapy. ctDNA is analysed with Foundation Medicine Liquid CDx with option for other providers. A multi-disciplinary national Molecular Tumor Board enables interpretation of genomic reports and identifies suitable clinical trials, supported by eTARGET; a bespoke clinical-genomic data capture solution including trial finding software. The study provides broad access to genomic profiling throughout the UK, increasing experience with ctDNA assays, and will improve opportunities for patients to participate in early phase research. The UK database will provide means for identification of rare genomic patient groups for new first-in-human studies, and the program provides a national infrastructure to collect additional samples for translational research and pre-clinical models to progress understanding of biological predictors of response and resistance. Clinical trial information: NCT04723316.

Psychological outcomes in advanced cancer patients after receiving genomic tumor profiling results.

Comprehensive tumor genomic profiling (CGP) offers hope for personalized treatment for cancer patients when other treatment options have been exhausted. However, receipt of nonactionable or ambiguous results could be an ongoing source of distress. We investigated patterns of hope, anxiety, depression, and CGP-specific anxiety in advanced cancer patients after receiving CGP results and 2-3 months later. Participants were enrolled in a longitudinal psychosocial substudy, embedded in the Molecular Screening and Therapeutics Program, and had advanced solid cancers of any histological type with sufficient and accessible tissue for CGP. At T0 (before receiving CGP results), 1,431 participants completed sociodemographic, disease and psychosocial measures. At T1 (1-4 weeks after receiving CGP results) and T2 (2-3 months post-T1), 374 participants completed psychological outcome measures. Predictors of outcomes at T2 were identified using multinomial logistic regression. Approximately 75% of participants did not experience significant hopelessness or distress at T1 and T2. Hope decreased by T2, yet general anxiety and CGP-specific anxiety also decreased. Receiving actionable results did not impact psychological outcomes at T2. At T2, lower hope, and higher anxiety, depression and CGP-specific anxiety were associated with lower self-efficacy. Psychological and demographic factors (age, socioeconomic status, language, medical occupation, urban living, family history of cancer) independently predicted one or more psychological trajectories. Worse health status and perceived susceptibility to cancer progression predicted hope and anxiety trajectories. Further research on interventions to best support patients undergoing CGP with high anxiety, hopelessness, fear of cancer progression, and poorer health is urgently needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Personalised selection of experimental treatment in patients with advanced solid cancer is feasible using whole-genome sequencing

BackgroundBiomarker-guided therapy in an experimental setting has been suggested to improve patient outcomes. However, trial-specific pre-screening tests are time and tissue consuming and complicate the personalised treatment of patients eligible for early-phase clinical trials. In this study the feasibility of whole-genome sequencing (WGS) as a one-test-for-all for guided inclusion in early-phase trials was investigated.MethodsPhase I Molecular Tumor Board (MTB) at the Erasmus MC Cancer Institute reviewed patients with advanced cancer without standard-of-care treatment (SOC) options for a ‘fresh-frozen’ (FF) tumour biopsy for WGS based on clinical-pathological features. Clinical grade WGS was performed by Hartwig Medical Foundation. MTB matched the patient with a trial, if available.ResultsFrom September 2019–March 2021, 31 patients with highly diverse tumour types underwent a tumour biopsy for WGS. The median turnaround time (TAT) was 15 days [10–42 days]. At least one actionable event was found in 84% of the patients (26/31). One-third of the patients (11/31) received matched experimental treatment.ConclusionsWGS on fresh FF biopsies is a feasible tool for the selection of personalised experimental therapy in patients with advanced cancer without SOC options. WGS is now possible in an acceptable TAT and thus could fulfil the role of a universal genomic pre-screening test.

Molecular Profiles of Advanced Urological Cancers in the PERMED-01 Precision Medicine Clinical Trial.

Simple SummaryThe goal of precision medicine is to deliver therapy matched to a relevant actionable genetic alteration (AGA) identified in the tumor. Few data are available regarding precision medicine in advanced urological cancers (AUC), the prognosis of which remains unfavorable. Sixty-four patients with refractory AUC were enrolled in the PERMED-01 clinical trial and underwent a tumor biopsy that was then profiled using sophisticated molecular analyses. The results were discussed in real-time during a weekly molecular tumor board meeting, and patients with a relevant AGA became candidates for an eventual matched therapy. A complete molecular profile was obtained in 77% of cases and an AGA was identified in 59%. Nineteen percent of patients received a matched therapy on progression, of which 42% showed a clinical benefit. The objective response, disease control rates, and the 6-year overall survival were higher in the “matched therapy group” than in the “non-matched therapy group”.Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio ≥ 1.3 versus 5% in the “non-matched therapy group” (n = 25). The objective response and disease control rates were higher in the “matched therapy group” (33% and 58%, respectively) than in the “non-matched therapy group” (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to “matched therapy” in 19%, and provided clinical benefit in 8%.

Clinical Opportunities for Germline Pharmacogenetics and Management of Drug-Drug Interactions in Patients With Advanced Solid Cancers.

Precision medicine approaches, including germline pharmacogenetics (PGx) and management of drug-drug interactions (DDIs), are likely to benefit patients with advanced cancer who are frequently prescribed multiple concomitant medications to treat cancer and associated conditions. Our objective was to assess the potential opportunities for PGx and DDI management within a cohort of adults with advanced cancer. Medication data were collected from the electronic health records for 481 subjects since their first cancer diagnosis. All subjects were genotyped for variants with clinically actionable recommendations in Clinical Pharmacogenetics Implementation Consortium guidelines for 13 pharmacogenes. DDIs were defined as concomitant prescription of strong inhibitors or inducers with sensitive substrates of the same drug-metabolizing enzyme and were assessed for six major cytochrome P450 (CYP) enzymes. Approximately 60% of subjects were prescribed at least one medication with Clinical Pharmacogenetics Implementation Consortium recommendations, and approximately 14% of subjects had an instance for actionable PGx, defined as a prescription for a drug in a subject with an actionable genotype. The overall subject-level prevalence of DDIs and serious DDIs were 50.3% and 34.8%, respectively. Serious DDIs were most common for CYP3A, CYP2D6, and CYP2C19, occurring in 24.9%, 16.8%, and 11.7% of subjects, respectively. When assessing PGx and DDIs together, approximately 40% of subjects had at least one opportunity for a precision medicine-based intervention and approximately 98% of subjects had an actionable phenotype for at least one CYP enzyme. Our findings demonstrate numerous clinical opportunities for germline PGx and DDI management in adults with advanced cancer.

Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors.

Background: Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers. Methods: Twelve patients were enrolled. Eligible subjects received different dosages of GW5074 in one of the three dose cohorts (Cohort 1: 750 mg daily, Cohort 2: 1500 mg daily, Cohort 3: 750 mg twice daily) plus 200 mg of sorafenib daily to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) at phase 1. Furthermore, the expression level of phosphorylated DAPKS308 in primary tumor, metastatic tumor, and circulating tumor cells (CTC) were evaluated to investigate the relationship between biomarker and the efficacy profile. Results: Among the 12 enrolled patients in this phase 1 trial, most adverse effects (AE) were grade 1, with two being grade 3. The most frequent AE of all grades were weight loss and hypertension, occurring in 16.7% of participants. Eight patients (66.7%) had the disease controlled by receiving co-administration therapy of GW5074 and sorafenib. GW5074 was found to have poor absorption, as increasing the dosage did not result in a significant increase in the bioavailability of GW5074 in subjects. Furthermore, the expression level of phosphorylated DAPKS308 in tumor and CTCs were correlated with the disease control rate (DCR) and duration of response (DOR). Conclusions: Co-administration therapy of GW5074 and sorafenib demonstrated a favorable safety profile and showed anti-tumor activity in a variety of tumor types. However, the solubility of GW5074 is not satisfactory. A future phase 2a trial will be carried out using the new salted form that has been proven to be more effective.

Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers

BackgroundThe programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies.Patients and methodsThis phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged ≥18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR ≤20% was not of interest for development as monotherapy, and NPR ≥40% was defined as the threshold of benefit/success. If ≥3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated.ResultsOverall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively.ConclusionsAtezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.

Clinical Impact of High Throughput Sequencing on Liquid Biopsy in Advanced Solid Cancer.

Background: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. Methods: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. Results: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. Conclusions: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient’s outcomes was shown in this unselected pan-cancer study.

Targeting Angiogenesis in Breast Cancer: Current Evidence and Future Perspectives of Novel Anti-Angiogenic Approaches.

Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.

An Up-To-Date Investigation Into the Correlation Between Proton Pump Inhibitor Use and the Clinical Efficacy of Immune Checkpoint Inhibitors in Advanced Solid Cancers: A Systematic Review and Meta-Analysis

BackgroundAlthough immune checkpoint inhibitors (ICIs) have revolutionized the current anticancer therapies, a considerable proportion of patients are found to hardly benefit from these drugs. Accumulating studies have demonstrated that concomitant proton pump inhibitor (PPI) use may affect the clinical efficacy of ICIs; however, their results are inconsistent. In this study, based on updated evidence, we aimed to perform a meta-analysis to clarify the prognostic significance of PPI use in advanced solid cancer patients receiving ICI therapy.MethodsEligible literature was searched using PubMed, Cochrane Library, Web of Science, EMBASE, and other network resources before July 2021. Clinical outcome was evaluated using overall survival (OS) and progression-free survival (PFS). The correlation of PPI use with OS or PFS was determined based on hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsA total of 17 studies enrolling 9,978 ICI-treated cancer patients were included in our meta-analysis. The global analysis demonstrated that PPI use was significantly correlated with worse OS [HR = 1.29 (1.10–1.50)] instead of PFS [HR = 1.19 (0.98–1.44)] in solid cancer patients receiving ICI therapy. In a subgroup analysis, the negative correlation of PPI use with ICI efficacy was significant in patients with non-small cell lung cancer [PFS, HR = 1.27 (1.10–1.47)] and urothelial carcinoma [OS, HR = 1.55 (1.31–1.84), PFS, HR = 1.52 (1.13–2.06)] and mixed cohorts containing multiple cancer types [OS, HR = 1.40 (1.16–1.69)], while an opposite result was observed in the PFS of patients with melanoma [HR = 0.48 (0.25–0.90)]. Moreover, the unfavorable prognostic impact of PPI use was also significant in patients over 65 years old [OS, HR = 1.28 (1.05–1.55), PFS, HR = 1.32 (1.12–1.56)] or those receiving anti-PD-1 [OS, HR = 1.37 (1.04–1.79)] or anti-PD-L1 therapies (OS, HR = 1.49 (1.30–1.69), PFS, HR = 1.34 (1.20–1.50). Finally, PPI use was significantly correlated with a worse prognosis in patients receiving PPIs 30 days before and/or after ICI initiation (OS, HR = 1.38 (1.18–1.62), PFS, HR = 1.23 (1.06–1.43)).ConclusionAlthough our global analysis revealed PPI use was not correlated with the PFS of ICI-treated patients, considering the results of our subgroup analysis, PPIs should be still cautiously used shortly before or during ICI therapy. Furthermore, more clinical validations and related mechanism investigations are of great necessity to clarify the clinical correlation of PPI use with ICI efficacy.Systematic Review Registration[https://www.crd.york.ac.uk/prospero/], PROSPERO [No. CRD42021243707].

Liquid Biopsy-based Precision Therapy in Patients with Advanced Solid Tumors: A Real-world Experience from a Community-based Oncology Practice

BackgroundLiquid biopsy testing offers a significant potential in selecting signal-matched therapies for advanced solid malignancies. The feasibility of liquid biopsy testing in a community-based oncology practice, and its actual impact on selecting signal-matched therapies, and subsequent survival effects have not previously been reported.Patients and MethodsA retrospective chart review was conducted on adult patients with advanced solid cancer tested with a liquid-biopsy assay between December 2018 and 2019, in a community oncology practice. The impact of testing on treatment assignment and survival was assessed at 1-year follow-up.ResultsA total of 178 patients underwent testing. A positive test was reported in 140/178 patients (78.7%), of whom 75% had an actionable mutation. The actual overall signal-based matching rate was 17.8%. While 85.7% of patients with no actionable mutation had a signal-based clinical trial opportunity, only 10% were referred to a trial. Survival analysis of lung, breast, and colorectal cancer patients with actionable mutations who received any therapy (n = 66) revealed a survival advantage for target-matched (n = 22) compared to unmatched therapy (n = 44): patients who received matched therapy had significantly longer progression-free survival (PFS) (mPFS: 12 months; 95%CI, 10.6-13.4 vs. 5.0 months; 95%CI, 3.4-6.6; P = .029), with a tendency towards longer overall survival (OS) (mOS: 15 months; 95%CI, 13.5-16.5 vs. 13 months; 95%CI: 11.3-14.7; P = .087).ConclusionsImplementation of liquid biopsy testing is feasible in a US community practice and impacts therapeutic choices in patients with advanced malignancies. Receipt of liquid biopsy-generated signal-matched therapies conferred added survival benefits.

Direct comparison of the next-generation sequencing and iTERT PCR methods for the diagnosis of TERT hotspot mutations in advanced solid cancers

BackgroundMutations in the telomerase reverse transcriptase (TERT) promoter region have been proposed as novel mechanisms for the transcriptional activation of telomerase. Two recurrent mutations in the TERT promoter, C228T and C250T, are prognostic biomarkers. Herein, we directly compared the commercially available iTERT PCR kit with NGS-based deep sequencing to validate the NGS results and determine the analytical sensitivity of the PCR kit.MethodsOf the 2032 advanced solid tumors diagnosed using the TruSight Oncology 500 NGS test, mutations in the TERT promoter region were detected in 103 cases, with 79 cases of C228T, 22 cases of C250T, and 2 cases of C228A hotspot mutations. TERT promoter mutations were detected from 31 urinary bladder, 19 pancreato-biliary, 22 hepatic, 12 malignant melanoma, and 12 other tumor samples.ResultsIn all 103 TERT-mutated cases detected using NGS, the same DNA samples were also tested with the iTERT PCR/Sanger sequencing. PCR successfully verified the presence of the same mutations in all cases with 100% agreement. The average read depth of the TERT promoter region was 320.4, which was significantly lower than that of the other genes (mean, 743.5). Interestingly, NGS read depth was significantly higher at C250 compared to C228 (p < 0.001).ConclusionsThe NGS test results were validated by a PCR test and iTERT PCR/Sanger sequencing is sensitive for the identification of the TERT promoter mutations.

A monocentric, first-in-human (FIH), safety and preliminary efficacy study of (neo) adjuvant, model-based, whole-body hyperthermia (WBHT) treatment in advanced solid cancer patients or stage IV metastatic pancreatic adenocarcinoma patients.

TPS625 Background: Whole-Body Hyperthermia (WBHT) represents the only hyperthermia modality available for patients with disseminated malignancies. The rationale for the treatment of malignant disease by heat is based on a direct cell-killing effect at temperatures in the range of 41– 42°C and driven by a number of reasons. Phase-I mining and phase-I veterinary (dog) clinical study proved the safety of WBHT treatment alone and in combination with standard of care therapy in dogs with cancer. A systematic review addressed clinical trials that used WBHT in pancreatic cancer patients. In these trials, the weighted estimate of the treated population median overall survival was 11.7 compared to 5.6 for the control cohorts. Methods: The is a first in-human, mono-centric, non-randomized trial to establish the safety and preliminary efficacy of WBHT treatment with the TempoCure (medical device) alone in patients with advanced solid cancer (cohort A) or in combination to SOC chemotherapy treatment in patients with stage IV metastatic pancreatic adenocarcinoma (cohort B). The study of 12 to 20 patients is not powered for any statistical analysis. The analysis will be limited to descriptive statistics, considered the doses provided and the extra blood sampling taken at different time points. The treatment is applied under deep anaesthesia in a unit connected to the operating room at the hospital. Cohort A1. Three patients with advanced solid cancer will be subjected to repetitive WBHT starting with 2 hours (day 1), 4 hours (day 8) and 6 hours (day 15) using the TempoCure to keep the patient at a temperature of 41.5°C. The patient’s body temperature will be monitored by specific sensors (liver, oesophageal, rectal and cutaneous). Cohort A2. The highest WBHT duration with acceptable side effects from cohort A1 will be applied to three additional patients with advanced solid cancer, once a week and for 15 days in total. Cohort B1. Three pancreatic cancer patients will be subjected to repetitive WBHT starting with 2 hours (day 1), 4 hours (day 8) and 6 hours (day 15) using the TempoCure to keep the patient at a temperature of 41.5°C and in combination with the standard of care chemotherapy. Cohort B2. The highest WBHT duration with acceptable side effects from cohort B1 will be applied in combination with chemotherapy to three pancreatic cancer patients, once a week and for 15 days in total. Major inclusion criteria are: Adequate liver structure (confirmed by CT scan) allowing the placement of the liver sensor; Adequate coagulation defined as; PT (%) ≥ 70%; aPTT ≤ ULN; Von Willebrand Factor Antigen ≥ LLN; Von Willebrand Factor Activity ≥ LLN; PFA COL/EPI CT ≤ 1.15 ULN; PFA COL/ADP CT ≤ 1.15 ULN. Enrollment to Cohort A1 began in July 2021. Clinical trial information: NCT04467593.

Next generation sequencing (NGS) to identify relapsed gastrointestinal (GI) solid tumor patients with human leukocyte antigen (HLA) loss of heterozygosity (LOH) for future logic-gated CAR T therapy to reduce on target off tumor toxicity.

190 Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal (GE) cancers are the leading causes of GI cancer–related mortality (5-yr survival rate, 14%, 3% and ̃5-6%, respectively). T-cell immunotherapy targeting GI-associated tumor antigens has been attempted, but efficacy has been constrained by on-target off-tumor toxicity, limiting the therapeutic window. The Tmod (TM) platform is an AND-NOT logic-gated CAR T modular system, versions of which have a CEA- or MSLN-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor to protect normal cells. Tmod CAR T exploits HLA LOH, common in GI malignancies (10-33% in primary solid tumors [TCGA]) and can kill tumor cells without harming healthy cells in vitro and in vivo. However, the prevalence of HLA LOH across GI tumors is unknown in the real-world setting. We utilized the Tempus xT oncology NGS database of patients with multiple GI tumors. From a standard-of-care NGS assay, GI cancer patients can be readily identified for HLA LOH and future treatment with Tmod CAR T therapy. Methods: The occurrence of HLA LOH in GI tumors of 1439 patients was assessed using paired germline and somatic DNA sequencing using a research assay [6]. CRC, PANC and GE patients with ≥ stage 3 were then extracted, and rates of HLA LOH were identified (ie, whether loss occurred across high-frequency HLA-A alleles). In addition, mutations in KRAS and BRAF, as well as MSI status were stratified to determine any association with HLA-A LOH. Results: HLA-A LOH was detected in 830 (17.3%) of all solid tumor records, and a similar proportion when all GI cancer records were analyzed (17.0%). For GI subtypes, these values ranged from 13.5% to 23.1% (Table). No high-frequency HLA-A allele (A*01, A*02, A*03, A*11) was more likely to be lost. Clinical biomarkers ( KRAS, BRAF and MSI status) were not associated with HLA-LOH. Conclusions: The frequency of HLA LOH among advanced solid tumor cancers in this dataset is 17.3%, with a range of 13.5-23% between CRC, PANC and GE. The HLA LOH frequency observed in these GI tumors is consistent with that in primary tumors from TCGA, which also used germline-matched and tumor samples. Clinical biomarkers were not associated with HLA LOH. Tempus NGS was able to identify HLA LOH, which can be used for Tmod CAR T therapy to an enhanced therapeutic window. Identification of these patients in BASECAMP-1 (NCT04981119) will enable novel Tmod CAR T therapy. [Table: see text]

A Brief Review of Fungal Infection- Pityriasis Versicolor

The occurrence of fungal infections is increasing at a distressing rate, presenting an vast pressure and challenge to healthcare professionals for their diagnosis and treatment. Rising fungal infections is also cause of significant morbidity and mortality. This emergence is directly related to the increasing population of immune-compromised individuals. Patient with circumstance such as Granulocytopenia, advanced HIV infection, bone marrow and solid organ transplantation, cancer, diabetes mellitus, severe burn and trauma and severe malnutrition are amongst many others predisposing factor for low immunity. Pityriasis versicolor most normally affects young adults and is slightly more widespread in men than in women. It can also influence children, adolescents, and older adults. Pityriasis versicolor is more common in hot, humid climates than in cool, dry climates. It often affects people who perspire heavily. It may clear in the winter months and persist each summer.

Comparative effectiveness of larotrectinib and entrectinib for TRK fusion cancer.

Larotrectinib and entrectinib are tumor-agnostic tropomyosin receptor kinase (TRK) inhibitors that are indicated for the treatment of advanced or metastatic solid tumor cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Regulatory approval of both agents was based on data from single-arm phase 1/2 studies, including tumor-agnostic basket trials. In the absence of randomized controlled trials, there remains a paucity of data to demonstrate the comparative effectiveness of larotrectinib and entrectinib vs established standard-of-care treatments in cancers with NTRK gene fusions. Furthermore, no studies have directly compared the 2 agents. This article reviews what is known about the comparative effectiveness of larotrectinib and entrectinib vs standard therapies in TRK fusion cancer and examines the comparative effectiveness of the 2 TRK inhibitors. Historical and intrapatient comparisons suggest that TRK inhibitors improve disease response compared with preexisting treatments across most tumor histologies; indirect and limited comparisons of phase 1/2 data and preliminary simulation modeling suggest a potential advantage for larotrectinib over entrectinib in terms of clinical response and survival. Although limited, these data provide some insight into the position of these treatments in established treatment paradigms for TRK fusion cancer, a setting where real-world evidence will be slow to accrue due to the rare nature of these tumors but may be the only way in the future to answer the outstanding questions regarding these 2agents. Meanwhile, we need to try to obtain the maximum benefit that can be achieved for our patients using the currently available knowledge.

A Review on Pharmacognosy and Pharmacological Activity of Carica papaya Leaf

Carica papaya has been used for centuries in many non-Western medical practices (e.g., Ayurveda, Traditional Chinese and Vietnamese, Unani) for its homeostatic and health-promoting properties. Anecdotal reports have recently surfaced indicating the daily consumption of tea extract made from C. papaya has been related to cancer remission, including remission from certain advanced solid tumor cancers. As a result, we set out to investigate C. papaya leaf extract's in vitro effects on human cancer cells as well as its in vivo effects in cancer patients using scientific methodologies.The phytochemical composition of C. papaya leaf extract was determined using liquid chromatography-mass spectroscopy (LC-MS), immune-modulatory and anti-cancer properties were analyzed in peripheral blood mononuclear cells and various solid tumor cell lines, and clinical laboratory measurements were examined in 116 cancer patients who obtained capsules of C. papaya leaf extract.Our findings suggest that C. papaya has a lot of promise as an adjuvant therapy for certain cancers, and further research is required. In cultured cancer cells, papaya extract tends to be toxic, meaning that it may be used as a drug. For the first time, scientists discovered that papaya leaf extract increases the development of Th1-type cytokines, which are important signaling molecules. In addition to papaya's direct anti-tumor effect on a variety of cancers, this immune system control indicates potential cancer-fighting therapeutic strategies. Th1-type cytokines are important signaling molecules that are increased by papaya leaf extract. Researchers subjected 10 different types of cancer cell cultures to four strengths of papaya leaf extract and assessed the effect after 24 hours, preventing a typical and destructive outcome of many cancer therapy regimens. In every society, papaya inhibited tumor growth.