bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of autologous expanded tumor infiltrating lymphocytes (TILs) in multiple solid tumors.
Authors: Amaria Rodabe Navroze , Vining David J. , Kopetz Scott , Overman Michael J. , Javle Milind M. , Antonoff Mara , Tzeng Ching-Wei D. , Wolff Robert A. , Pant Shubham , Lito Kathryn , Rangel Kelly M. , Wilson Louis , Fellman Bryan M. , Haymaker Cara L. , Yuan Ying , Forget Marie-Andree , Hwu Patrick , Bernatchez Chantale , Jazaeri Amir A.
Published: June 2022

2536

Background: TIL therapy has been used extensively in metastatic melanoma patients for many years, now with ongoing efforts to commercialize treatment. The efficacy of TIL outside of melanoma is largely unknown thus we designed and implemented a trial using TIL manufactured at a single academic center for treatment refractory metastatic colorectal (CRC), pancreas (PDAC) and ovarian (OVA) cancers. Methods: Patients with CRC, PDAC and OVA refractory to standard therapies with ECOG PS 0-1 and normal organ function were eligible for TIL harvest. Ex vivo TIL expansion and manufacturing was conducted at the MD Anderson TIL lab under conditions that included IL2 and 41BB stimulation (using urelumab). All patients received a lymphodepletion regimen consisting of cyclophosphamide 60mg/kg days -7 and -6 and fludarabine 25mg/m2 days -5 through day -1, followed by infusion of pooled ex-vivo expanded TIL. Patients received up to 6 doses of high dose IL-2 (600,000 IU/kg) after TIL infusion. The primary endpoint was evaluation of the objective response rate (ORR) using RECIST 1.1 criteria with secondary endpoints including disease control rate, duration of response, PFS, OS and safety. Results: A total of 17 patients underwent TIL harvest and 16 were treated on protocol; including 8 CRC, 5 PDAC and 3 OVA. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). Median number of TIL infused was 76 X 109 (range 20.3 x 109-150 x 109). Median doses of cyclophosphamide and fludarabine administered were 2 (range, 2-2) and 3 (range, 1-5), respectively. Median doses of IL-2 administered was 6 (range, 1-6). There were no responders. Best response included prolonged SD in a patient with PDAC lasting until 18 months. Grade 3 or higher toxicities attributable to therapy was seen in 14 subjects (87.5%; 95% CI: 61.7 – 98.4) with the majority of toxicities representing expected pancytopenia from lymphodepletion. Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type. Early on-treatment biopsy of PDAC patient with prolonged SD showed presence of proliferating (KI67+) CD4+ and CD8+ TIL. Conclusions: Generation of TIL at a single academic center for CRC, PDAC and OVA is feasible and treatment is associated with no new safety signals. For these tumor types, further research is required to identify host factors associated with resistance to TIL therapy and optimize manufacturing processes to create more effective TIL cell therapy. Clinical trial information: NCT03610490.
The addition of fludarabine to cyclophosphamide for lymphodepleting chemotherapy enhances the persistence of infused NY-ESO-1 TCR anticancer therapy TBI-1301.
Authors: Butler Marcus O. , Saibil Samuel , Sotov Valentin , Boross-Harmer Sarah , Scheid Elizabeth , Gray Diana , Van As Brendan , Trang Aileen , Ross Kendra , Ohashi Pamela S. , Tanaka Shinya , Takahashi Shuichi , Hirano Naoto
Published: June 2022

2539

Background: Adoptive transfer of T cell receptor (TCR) gene-engineered T cells can induce durable anti-cancer responses. TBI-1301 is a novel gene therapy produced by engineering autologous lymphocytes to express an NY-ESO-1-specific TCR using a retrovirus vector that encodes siRNA to silence endogenous TCR. In this study, we examined a repeat infusion of TBI-1301 and the addition of fludarabine to cyclophosphamide for pre-infusion lymphodepletion. Methods: Eligibility included informed consent, HLA-A*02:01 or A*02:06 haplotype, and NY-ESO-1 expression by IHC. Eligible patients underwent harvest of PBMC which were processed at the treating site to generate engineered TBI-1301 cells. The study design infused 5x109 cells on day 0 and day 14 to patients following lymphodepletion with cyclophosphamide (CY; 750 mg/m2 on day -7 and -6) plus fludarabine (FLU; 30 mg/m2 on day -7 and -6). Repeat infusions were performed in two cohorts: Cohort B - patients who had previously received NY-ESO-1 TCR-transduced cells and Cohort C - NY-ESO-1 TCR treatment naïve patients. Endpoints included safety, efficacy, and biological correlates for persistence of NY-ESO-1-specific T cells post infusion. Results: Ten patients were enrolled in cohorts B and C. Nine patients in total are evaluable for response and toxicity, and no DLTs have been observed. In cohort B, 5 patients (5 synovial sarcoma) were treated, and 5 have received the target dose. In cohort C, 5 patients (3 synovial sarcoma, 2 melanoma) were treated, and 4 have received the target dose. One patient received a single infusion due to bacteremia on week 2. One of 5 patients in cohort B was previously treated with TBI-1301 cells in cohort C. In each cohort, 4 patients experienced grade 1-2 cytokine release syndrome. Best overall response by RECIST v1.1 was 3 stable disease, and 2 progressive disease in cohort B; and 2 stable disease and 2 progressive disease in cohort C. When compared to the earlier cohort, biomarker analysis demonstrated substantially longer persistence of transferred TBI-1301 cells in infused patients who received fludarabine (up to 372+ and 460+ days), and the cells displayed a less differentiated phenotype. Conclusions: Repeat infusions of TBI-1301 following lymphodepletion appears to be safe and to possess anti-tumor activity. Addition of FLU to the lymphodepletion regimen may contribute to longer persistence of gene-engineered T cells. Clinical trial information: NCT02869217.
Study to evaluate intraperitoneal (IP) ONCOS-102 with systemic durvalumab in patients with peritoneal disease who have epithelial ovarian (OC) or metastatic colorectal cancer (CRC): Phase 2 results.
Authors: Zamarin Dmitriy , Odunsi Kunle , Zsiros Emese , Slomovitz Brian M. , Pimentel Agustin , Duska Linda R. , Reilley Matthew , Nemunaitis John J. , Hamouda Danae M. , Patel Hitendra , Segal Neil Howard , Pesci Giulio , Holland Aliya , Shohara Lisa , Schwarzenberger Paul Otto , Ricciardi Toni , Macri Mary J. , Ryan Aileen , Jaderberg Magnus Erik , Venhaus Ralph Rudolph
Published: June 2022

2600

Background: Locoregional treatment with oncolytic viruses may be used to improve the efficacy of immune checkpoint inhibitors at both treated and distant tumor sites. This study evaluated the combination of IP-administered ONCOS-102, an oncolytic adenovirus encoding for granulocyte macrophage colony stimulating factor (GM-CSF), with systemic durvalumab (durva) in patients (pts) with advanced OC or CRC who have failed prior chemotherapy. Methods: This open-label study (NCT02963831) evaluated ONCOS-102 (IP 3 x 1011 VP in 500ml saline [recommended phase 2 dose] weekly x 6) + durva (IV 1500 mg every 4 weeks x 12). One dose of cyclophosphamide was given prior to first ONCOS-102 dose. Phase 2 evaluated the activity of the combination using Simon’s 2-stage MINIMAX design. In MINIMAX stage 1, if ≥ 5 of 18 OC pts or ≥ 1 of 13 CRC pts met the efficacy criteria (progression free at end of week 24), 15 additional OC pts or 14 additional CRC pts were to be enrolled in stage 2. The efficacy endpoint would be met if ≥ 11 OC pts or ≥ 4 CRC pts remained progression free at 24 weeks. Safety, response rate and progression-free survival (PFS) by RECIST 1.1, overall survival (OS), and immunologic effects in tumors were evaluated. ITT population = all pts who received at least one dose of durva or ONCOS-102; per protocol (PP) population = all pts who received at least 60% of ONCOS-102 doses and at least 1 durva dose in the first 2 cycles. Results: In MINIMAX stage 1, the OC cohort did not meet the efficacy criteria and was closed. For CRC, stage 1 efficacy criteria were achieved and the cohort was opened for stage 2. As of the 14 Dec 2021 cutoff, CRC enrollment was complete, and all pts were followed for 24 weeks or until progression or off study. Two pts were progression free at 24 weeks (see table). Treatment-related adverse events (TRAEs) occurring in > 30% pts were vomiting, nausea, fatigue, chills, and pyrexia. There were no grade 4 or 5 TRAEs. Grade 3 TRAEs were reported in 8 pts, 2 in the OC cohort and 6 in CRC. All grade 3 TRAEs occurred in no more than 1 pt for each AE except abdominal pain, which occurred in 2 pts. Conclusions: The combination of IP ONCOS-102 and durva was well tolerated. The study did not meet its efficacy endpoint. Evaluation of pre- and on-therapy translational parameters is ongoing. Clinical trial information: NCT02963831. [Table: see text]
First-line PD-1 inhibitors immunotherapy and chemotherapy combined with or without radiotherapy for patients with advanced non-small cell lung cancer.
Authors: Ding Peng , Huang Yu , Tong Fan , Chen Lingjuan , Wen Lu , Zhang Ruiguang , Cheng Shishi , Dong Xiaorong
Published: June 2022

2606

Background: Immunochemotherapy has become a standard first-line regimen for advanced non-small-cell lung cancer (NSCLC). Several studies showed the synergistic effects of immunotherapy and radiotherapy on local and abscopal tumour control. But the data of first-line immunochemotherapy combined with radiotherapy for the advanced NSCLC is still scarce. Methods: Patients with advanced NSCLC receiving first-line PD-1 inhibitors immunotherapy plus chemotherapy in a single center were retrospectively analyzed in this study. They were divided into two groups according to whether they had received radiotherapy. The efficacy and safety of first-line immunochemotherapy combined with radiotherapy (ICRT group) and immunochemotherapy alone (ICT group) were investigated. Results: A total of 135 patients were included; 65 patients received PD-1 inhibitors plus chemotherapy and radiotherapy, while other 70 patients were treated with immunochemotherapy alone. The median interval time between radiotherapy and PD-1 inhibitors immunotherapy was 5 days (range, 0-96 days). The overall response rate (ORR) was 50.8% in the ICRT group and 40.0% in the ICT group, respectively. Patients in the ICRT group achieved significant longer progression-free survival (PFS, median 16.5 vs 10.4 months, P= 0.043) and overall survival (OS, median not reached vs 21.0 months, P= 0.030) compared with those in the ICT group. The addition of radiotherapy was the only prognostic factor for PFS (HR = 0.617, 95%CI: 0.385-0.989, P= 0.045) and OS (HR = 0.512, 95%CI: 0.277-0.947, P= 0.033) by univariate Cox regression analysis. Patients were well tolerated and the overall incidence of adverse events was similar between the ICRT group and ICT group. One patient in ICRT group stopped immunotherapy because of severe immune-associated pneumonia. 3.1% of grade 3-4 radiation-related adverse events were observed. Conclusions: Adding radiotherapy to first-line PD-1 inhibitors immunotherapy and chemotherapy improved outcomes of patients with advanced NSCLC and showed acceptable toxicity. Additional prospective studies exploring the first-line combination of immunochemotherapy and radiotherapy are warranted.
Pan-cancer analysis of YAP1 expression as a predictive biomarker for cancer immunotherapy.
Authors: Owonikoko Taofeek K. , Elliott Andrew , Ivanov Andrey , Dwivedi Bhakti , Walker Phillip , Vanderwalde Ari M. , Puri Sonam , Dacic Sanja , Morgensztern Daniel , Liu Stephen V , Borghaei Hossein , Sica Gabriel
Published: June 2022

2629

Background: High YAP1 expression correlates with the ‘T-cell inflamed’ expression phenotype in small cell lung cancer (SCLC), but its association with other biomarkers of immune checkpoint vulnerability and in tumor types beyond SCLC is not known. We examined whether YAP1 expression correlates with other established markers of immune checkpoint blockade (ICB) efficacy (PDL1 expression and TMB) in a tumor agnostic manner to determine clinical relevance. Methods: Next-generation sequencing of DNA (592 gene panel or whole exome) and RNA (whole transcriptome) was performed for patient samples (n = 57,134), representing 13 cancer types, submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). The ‘T-cell inflamed’ signature (TIS) score was calculated as an 18-gene weighted coefficient composite value (Cristescu, 2018). PDL1 expression was assessed by immunohistochemistry (IHC) with cancer type-specific antibodies and thresholds, and high tumor mutational burden was defined as ≥10 mut/Mb. Patients were stratified into subgroups based on median YAP1 expression (YAP1-High/YAP-Low) within each cancer type. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: YAP1-High tumors were associated with significantly increased TIS scores compared to YAP1-Low across all 13 cancer types examined, with the largest fold increase observed in SCLC (1.33-fold, p < 0.0001), followed by pancreatic cancer (1.28-fold, p < 0.0001), while the smallest occurred in melanoma (1.13-fold, p < 0.0001). Spearman correlation strength (range 0.23-0.57) between YAP expression and TIS scores was consistent with increased TIS scores in YAP1-High samples. TMB-High rates were similar in YAP-High and YAP1-Low subgroups for most cancer types, with slightly lower rates in YAP1-High tumors observed for endometrial (23.0 vs 26.6%, p < 0.001) and esophageal (7.0 vs 9.5%, p < 0.05) cancers. YAP1 expression was not significantly increased in PDL1+ (IHC) tumors for most cancer types. However, significantly decreased YAP1 expression was associated with PDL1+ samples in RCC (Renal Cell Carcinoma) (0.91-fold change, P < 0.05), MM (0.90-fold change, P < 0.001), and ENCA (0.80-fold change, P < 0.0001) Conclusions: Our analyses provide confirmation that YAP1 expression positively correlates with the ‘T-cell inflamed’ phenotype across many cancer types, including those with approvals for (ICB) therapy. YAP1 expression was independent of established markers of ICB response, including TMB and PDL1. Further analysis of YAP1 expression as an additional tumor agnostic predictive biomarker is warranted.
Comparing rate of immunotherapy treatment change due to toxicity by gender.
Authors: Chua Kevin Joseph , Sterling Joshua , Doppalapudi Sai Krishnaraya , Kaldany Alain , Kronstedt Shane , Srivastava Arnav , Liu Hao , Singer Eric A.
Published: June 2022

2656

Background: Immunotherapy (IO) is associated with a variety of treatment related toxicities. However, the impact of toxicity on the treatment discontinuation rate between males and females is unknown. We hypothesized that immune related adverse events would lead to more frequent treatment changes in females since autoimmune diseases occur more frequently in females Methods: The Oncology Research Information Exchange Network (ORIEN) Avatar Database collects clinical data from ten different United States cancer centers, where patients receive IO. Of 1,035 patients receiving IO, 447 patients were analyzed, excluding those (N = 573) who did not have documentation noting if a patient changed treatment. 15 additional patients with an unknown or gender-specific cancer were excluded. All cancer types and stages were included. Primary endpoint was documented treatment change due to toxicity. Significance was calculated with logistic regression, linear regression, chi-squared test for categorical variables and Mann-Whitney U test for continuous nonparametric variables. Results: 447 patients (281 males and 166 females) received IO treatment for cancer. The most common cancers treated were kidney, skin, and lung for 99, 84, and 54 patients, respectively. Females had a shorter IO course compared to males on Mann-Whitney U test (median 3.7 vs 5.1 months, respectively, p=0.02) and multivariable linear regression (Beta -3.87, 95% CI -6.591, -1.149, p=0.005). 54 patients changed IO treatment due to toxicity. There was no significant difference in the rate of treatment change due to toxicity between females and males on chi-square test (11.4% vs. 12.5%, respectively, p = 0.75) and logistic regression (Table). Pembrolizumab, Nivolumab, Ipilimumab/Nivolumab, Ipilimumab, Durvalumab, Avelumab, and Atezolizumab were given to 16, 14, 9, 9, 3, 2 and 1 patients who changed treatment due to toxicity, respectively. The median length of time for IO treatment prior to change for toxicity was 3 months (IQR 1.4 – 5.9 months). Significantly more patients with COPD changed treatment due to toxicity (Table). Conclusions: Females received a shorter course of IO than males. However, there was no significant difference in the treatment discontinuation rate due to toxicity between males and females receiving IO. Toxicity related treatment change was associated with COPD. Studies with larger sample sizes with more granular data (i.e., type of adverse effects) are needed to truly characterize if a difference between genders and IO toxicity exists. [Table: see text]
Association between germ-line HLA and immune-related adverse events.
Authors: Jiang Ning , Yu Yue , Wu Dawei , Wang Shuhang , Ma Peiwen , Miao Huilei , Tang Yu , Li Ning
Published: June 2022

2658

Background: In recent years, great progress has been made in immune checkpoint inhibitors (ICIs), opening a new chapter for cancer treatment. However, accompanied by remarkable efficacy, immune-related adverse events (irAEs) also arose. Though some pilot studies have explored the possible factors that may influence the development of irAEs, the mechanism of irAEs remains unclear. Previous studies indicated a positive association between certain HLA types and irAEs. To uncover the relationship between irAEs and divergent HLA types, we initiated a large cohort study. Methods: We screened 626 patients who have been treated in the clinical research ward, Cancer Hospital of Chinese Academy of Medical Sciences. All participants included should be diagnosed with malignant tumors and have received at least 2 cycles of ICIs with complete security follow-up data in the original electronic medical records. The blood samples were collected before the first cycle of treatment. Sequencing libraries were generated using a customized panel. Six digit formatted HLA alleles were extracted from HLA-HD (v1.4.0) results for further analysis. Fisher-exact test was used to perform association analysis between HLA and different irAEs. To control the type I error, we introduce two external reference groups as well as the non-irAE control group. In addition, false discovery rate (FDR) correction was performed with the resulting p-values when comparing the HLA allele frequency between patients with irAEs and the MHC-han Chinese reference cohort. We also explored the relationship between zygosity of HLA genes, evolutionary divergence of HLA class I genotype (HED) and irAEs. Results: Of the 626 participants, 530 received at least 2 doses of ICIs. The median follow-up time was 10.3 months. 97% patients received anti-PD-1/PD-L1 treatment. Of all participants, 78% reported irAEs of any grade, with 10.2% reporting grade 3 and above irAEs. The occurrence of overall irAEs showed no significant difference between homozygous group and heterozygous group. We did not find any significant association between irAEs and HED. We found that some HLA types are associated with irAEs of different organs, including the significant association between HLA-DRB3*01:01 and thrombocytopenia (OR 3.48 (1.19,9.42), p = 0.011), HLA-DPB1*04:02 and hypokalemia/ hyponatremia (OR 3.44 (1.24,9.1), p = 0.009), leukopenia (OR 2.1 (0.92,4.8), p = 0.037) as well as anemia (OR 2.33 (1.0,5.41), p = 0.026), HLA-A*26:01 and bilirubin elevation (OR 2.67 (0.92,8.31), p = 0.037). Conclusions: IrAEs in specific organs and tissues may be associated with certain HLA types, while HLA heterogeneity have no significant influence on the happening of irAEs. More research is needed to explore the role of germline genetic changes in the risk assessment of irAEs, and potential therapies targeting irAE-inducing HLA types without influencing the anticancer effect may be considered to benefit the patients.
Management of infliximab-refractory immune checkpoint inhibitor gastrointestinal toxicity: A multicenter case series.
Authors: Harvey Catriona , Nahar Kazi Jannatun , Lo Serigne N. , Ahmed Tasnia , Farag Sheima , Yousaf Nadia , Young Kate , Tas Liselotte , Meerveld-Eggink Aafke , Blank Christian U. , Thomas Austin , McQuade Jennifer Leigh , Schilling Bastian , Johnson Douglas Buckner , Martin Huertas Roberto , Arance Ana Maria , Lee Joanna , Zimmer Lisa , Long Georgina V. , Menzies Alexander M.
Published: June 2022

2665

Background: Immune checkpoint inhibitor (ICI) GI tox (gastritis, enteritis, colitis) is a major cause of morbidity and treatment-related death. Guidelines agree steroid-refractory cases warrant infliximab (IFx); however not all pts respond and best management of IFx-Refractory ICI GI toxicity (IRIGItox) is not clear. Methods: We conducted an international multi-centre retrospective case series. IRIGItox was defined as failure of symptom resolution ≤ Gr 1 (CTCAE v5.0) following ≥ 2 IFx doses or failure of symptom resolution ≤ Gr 2 after 1 dose. Data were extracted regarding demographics, steroid use, response and survival. Tox was graded at symptom onset and time of IFx failure. Efficacy of IFx refractory therapy was assessed by symptom resolution, time to resolution and steroid wean. Results: 78 pts were identified; med age 60 yrs (95% CI 56-65), 56% male. 70 (90%) had melanoma, 55 (71%) had advanced-stage, 60 (77%) received anti-CTLA-4 (with anti-PD1 50, single agent 10). Most had colitis (N=75, 96%) and ≥ Gr 3 tox (N=74, 95%) at symptom onset. Pre-IFx investigation varied: imaging 37%; faecal calprotectin 29%; endoscopy 59%. All pts received Med time to steroid initiation was 3 days (95% CI 2-4). 46 (59%) had primary steroid refractory disease,. Med time from symptom onset to IFx was 18 days (95% CI 12-23), a med 2 (range 1-6) doses of IFx were given, 69 (88%) pts received > 1 IFx dose. Across 78 pts, 105 post IFx treatments were given: calcineurin inhibitors (ciclosporin, tacrolimus, 32); antimetabolites (mycophenolate, azathioprine, 26); non-TNF-α MABs (vedolizumab, ustekinumab, 20); non-targeted anti-inflammatory (mesalazine, 16); non-pharmacological (colectomy 5, faecal transplant 1, photophoresis 1). 4 pts did not receive therapy for IRIGItox. Of these, 2 died of melanoma prior to resolution of tox; 1 had resolution after 4 doses IFx, 1 had recurrent melanoma and flare of tox on PD1 re-challenge. IRIGItox outcomes by post IFx treatment are shown in Table. Conclusions: This retrospective case series confirms heterogeneous management of IRIGItox. Non-pharmacological interventions and calcineurin inhibitors appear most likely to result in tox resolution. Calcineurin inhibitors have the shortest time to resolution in responders. Further details on post-IFx management and oncological outcomes will be examined. [Table: see text]
AI-enabled identification prediction of homologous recombination deficiency (HRD) from histopathology images.
Authors: Shafi Gowhar , P.M. Shivamurthy , Ulle Anand , Srinivasan Krithika , Vasudevan Aravindan , Jadhav Vikas , Joshi Dr Sujit , Raut Nirmal Vivek , Khandare Jayant , Uttarwar Mohan , Bloom Kenneth Joel
Published: June 2022

3019

Background: Homologous recombination deficient (HRD) tumors are highly responsive to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitor (PARPi) therapy. Pathogenic BRCA-1 and BRCA-2 (BRCA1/2) alterations are key members of the HR DNA repair pathway but genomic instability status, including loss of heterozygosity, telomeric allelic imbalance and large scale state transitions across the genome are also predictive of HRD. HRD testing is currently performed by next generation sequencing which can take 2-4 weeks for results, has a high failure rate, requires significant tissue and is costly. We developed and tested the ability of an AI enabled platform to predict HRD status from the analysis of whole slide imaging of the diagnostic H&E slide. This platform, iPREDICT-HRD is rapid, precise, and cost effective. Methods: The AI engine was trained on 120 H&E slides that were used to identify tumor prior to manual microdisseection for HRD assessment by NGS. Histopathological features were extracted, followed by feature mapping to predict HRD status based on the results of NGS testing. ResNet AI algorithm was trained to segment, annotate and predict HRD status. 10 lac tiles of 256x256 size at 40x magnification were generated per pathological class. 70% of the data set was used for training and 30% for validation of the AI model. Results: Using single blinded clinical samples, iPREDICT-HRD tool detected HRD + ve samples with 99.3% accuracy with 100% sensitivity and 99% specificity in the test set. Patch-level predictions of HRD status demonstrated intra-tumor heterogeneity within the H&E slides. Visual inspection of the heatmap suggested the presence of patches with high predictive ability of HRD status and this outperformed an average HRD score for slides with heterogeneity. Conclusions: AI-enabled prediction of HRD status can be accurately performed on diagnostic H&E slides potentially yielding results quickly and afforadably, even when limited tissue is available for testing.
Safety of the cyclin dependent kinase 9 (CDK9) inhibitor FIT039 for cervical intraepithelial neoplasia (CIN) 1 or 2 in a phase I/II trial.
Authors: Hamanishi Junzo , Sumi Eriko , Miyamoto Taito , Uozumi Ryuji , Yamanoi Koji , Tada Harue , Amino Yoko , Hidaka Yu , Ukita Masayo , Yamaguchi Ken , Asada Ryuta , Ajiro Masahiko , Sawada Teruo , Hagiwara Masatoshi , Mandai Masaki
Published: June 2022

3022

Background: Human papillomaviruses (HPVs) infect uterine cervical epithelial cells, leading to cervical intraepithelial neoplasia (CIN) and cervical cancer. However, there is no treatment for HPV infection in the uterine cervix prior to vaccination. We recently reported that cyclin dependent kinase 9 (CDK9) plays a critical role in viral RNA transcription of DNA viruses such as HPVs in host cells, and that FIT-039, a specific inhibitor of CDK9, suppresses the proliferation of several DNA viruses. Here, we evaluated the safety and antiviral effect of a FIT039-releasing vaginal tablet (FIT039CT) for CIN1 or 2 (CIN1/2). Methods: A multi-institutional, single-blind, placebo-controlled randomized phase I/II clinical trial involving 2 cohorts was designed to evaluate the safety of transvaginal FIT039CT for CIN1/2 as follows:. In the first cohort, 8 healthy women were randomized into FIT039CT (50mg/day or 100mg/day) or control group. In the second cohort, 14 women with a primary diagnosis of CIN1/2 were randomized into either FIT039CT (100mg/day) or control group. The primary endpoints were adverse events and plasma concentrations of FIT039. Results: 22 patients (8 volunteers, 11 CIN1 and 3 CIN2) were enrolled. There were no serious adverse events. Adverse events considered related to treatment were mild (vaginal discharge Grade 1: FIT039CT 16/17 women [94%] vs placebo 2/6 [33%]) and self-limiting in both cohorts. No patient discontinued this study due to adverse events. Maximum concentration (C max) and terminal elimination half-life (t 1/2) of serum FIT039 concentrations after single transvaginal treatment of FIT039CT were similar between the two doses as follows; C max (mean ± standard deviation) was 4.5 ± 0.5 ng/mL (50mg/day) and 4.4 ±1.4 ng/mL (100mg/day) at 6-7 hours; mean t1/2 was 14.8 ± 2.1 hours (50mg/day) and 12.1 ± 2.6 hours (100mg/day) hours. Conclusions: This study demonstrated the safety and validity of transvaginal FIT039CT once a day and may contribute to the development of an antiviral agent that can cure CIN1/2, and supports the design of the ongoing phase 2 clinical study. Clinical trial information: jRCT2051180201.
First-in-human study of OBI-999: A globo H-targeting antibody-drug conjugate in patients with advanced solid tumors.
Authors: Tsimberidou Apostolia Maria , Hsu Pei , Pearce Tillman E.
Published: June 2022

3029

Background: OBI-999 is a novel antibody-drug conjugate, composed of a humanized monoclonal IgG1 antibody which targets the tumor-associated carbohydrate antigen Globo H, conjugated with monomethyl auristatin E (MMAE, vedotin). Upon binding to Globo H, OBI-999 is internalized into the tumor cell, and the linker (Thiobridge) connecting MMAE (an ultrapotent antimitotic agent) to the monoclonal antibody is cleaved by cathepsin B to release MMAE, thereby causing cell cycle arrest by inhibiting tubulin polymerization. We conducted a first-in-human, phase 1, dose-escalation study of OBI-999 monotherapy in patients with advanced cancer (NTC04084366). Methods: OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mg/kg on Day 1 of a 21-day cycle. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 15 adult patients were treated. OBI-999 administered on Day 1 of each 21-day cycle was well tolerated up to 1.2 mg/kg, the maximum tolerated dose (MTD). Treatment-related AEs (TRAEs) were noted in 40% (6/15) of patients. TRAEs ≥Grade 3 were noted in 27% (4/15) of patients; of whom 3 had neutropenia and 2 had anemia. OBI-999 exhibited non-linear pharmacokinetics from 0.4 mg/kg to 1.6 mg/kg, with lower clearance at higher doses. A retrospective validated automated immunohistochemistry assessment indicated 50% of patients with advanced solid tumors had high Globo H staining (H-score cutoff ≥100). Of 3 patients treated at the 1.6 mg/kg dose level; 2 developed Grade 4 neutropenia during Cycle 1 and the third developed Grade 4 neutropenia on Cycle 2 Day 15. One patient (1.6 mg/kg) with Grade 4 neutropenia also developed Grade 4 renal insufficiency and died from progressive disease (direct bilirubin, 3.5 mg/dL). Five (33.3%) patients had stable disease (SD), including 1 patient with adenoid cystic carcinoma of the oropharynx (SD for 13 cycles); 1 patient with gastroesophageal junction adenocarcinoma (SD for 8 cycles), and 3 patients with other tumor types (SD for 4, 2, and 2 cycles). Conclusions: We completed the dose-escalation portion of the study. OBI-999 was well tolerated. The recommended phase 2 dose was determined to be 1.2 mg/kg once every 3 weeks. Dose-dependent, non-cumulative neutropenia was dose limiting. We are currently enrolling patients with high Globo H expressing solid tumors (H-score ≥100) in the expansion phase of the study, which includes pancreatic, colorectal, and cancers of other histologic subtypes. Clinical trial information: NTC04084366.
Safety, pharmacokinetics, and clinical activity of OBI-3424, an AKR1C3-activated prodrug, in patients with advanced or metastatic solid tumors: A phase 1 dose-escalation study.
Authors: Tsimberidou Apostolia Maria , Verschraegen Claire F. , Hsu Pei , Pearce Tillman E.
Published: June 2022

3030

Background: OBI-3424 is a novel nitrogen mustard prodrug that can be selectively converted in the presence of the AKR1C3 enzyme into the bis-alkylating agent OBI-2660, which forms intra- and inter-strand DNA crosslinks resulting in cell death. This selective mode of activation distinguishes OBI-3424 from traditional alkylating agents, and potentially improves the safety profile and antitumor activity against chemo- and radio-resistant tumors. We conducted a first-in-human, phase 1, dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). Methods: OBI-3424 was administered intravenously at doses of 1, 2, 4, 6, 8, or 12 mg/m2 (Days 1 and 8 every 21 days, Schedule A) or 8, 10, 12, or 14 mg/m2 (Day 1 every 21 days, Schedule B). A “3+3” design was used for dose escalation. Patients received study treatment until disease progression, unacceptable toxicity, or up to 2 years of treatment. Results: Overall, 39 adult patients were treated. In patients receiving Schedule A, the maximum tolerated dose (MTD) of OBI-3424 was determined to be 8 mg/m2. Dose limiting toxicities (DLTs) were reported at the 12 mg/m2 dose level, including thrombocytopenia (Grade 3-4, 5 of 6 patients) and anemia (Grade 3-4, 5 of 6 patients). Platelet count nadirs were noted on Day 15 or Day 22. These cytopenias led to dose modification and resulted in protocol amendment (Schedule B). In Schedule B, the MTD was not reached at the maximum dose tested (14 mg/m2). Grade 3 or higher anemia was noted in 3 of 6 patients treated at 14 mg/m2; the recommended phase 2 dose (RP2D) is 12 mg/m2 (Day 1 every 21 days). Treatment-related AEs (TRAEs) were noted in 82% (32/39) of patients. The most common TRAEs were anemia (64%), thrombocytopenia (51%), nausea (26%), and fatigue (21%). No patient had a fatal TRAE, 49% had ≥Grade 3 TRAEs, including 3 patients who had serious TRAEs. OBI-3424 showed linear pharmacokinetics from 1 to 14 mg/m2, with minimal accumulation after repeated dosing. A retrospective validated automated immunohistochemistry assessment indicated that 27% of patients had high AKR1C3 staining (H-score ≥135). Best confirmed response was stable disease in 21 patients (54%). Conclusions: We completed the dose-escalation portion of the study. The RP2D was determined to be 12 mg/m2 once every 3 weeks. OBI-3424 was well tolerated. Dose-dependent, non-cumulative thrombocytopenia and anemia were dose limiting. We are currently enrolling patients with pancreatic cancer and other tumor types with overexpression of AKR1C3 (H-score ≥135) in the expansion phase of the study. Clinical trial information: NCT03592264.
Detection of homologous recombination deficiency (HRD) in cell-free DNA (cfDNA) using an amplicon-based next-generation sequencing (NGS) assay.
Authors: Poh Jonathan , Kaur Harvinder , Ho Jia Min , Choudhury Yukti , Tan Min-Han
Published: June 2022

3042

Background: Homologous recombination (HR) deficiency is characterized by tumor genomic instability, often due to alterations in BRCA1/2 and other HR-related genes. HRD predicts sensitivity to PARP inhibitors (PARPi) in prostate, ovarian and breast cancers. For the subset of cancers that have genomic instability without detectable alterations in HR genes, profiling biomarkers of HRD such as loss of heterozygosity (LOH) could identify additional HRD positive (HRD+) patients that may benefit from PARPi. Here, we present a novel cfDNA NGS assay that can detect tumor LOH non-invasively to improve assessment of HRD+ status. Methods: An amplicon-based HRD NGS assay covering > 1000 SNPs was developed to detect LOH both globally and on the gene level in cfDNA. Analytical validation was done using LOH+ BRCA-mutant cell lines in limiting dilution admixtures. Clinical performance was assessed by benchmarking findings from 46 tumor tissue DNA samples against results from an orthogonal NGS-based genomic scarring assay. Clinical utility of the HRD assay was evaluated in 75 cfDNA samples, including 72% (54/75) from BRCA-associated cancers (36 breast, 12 prostate, 4 ovarian, 2 pancreatic) and 28% from other cancer types. All cfDNA samples were previously clinically tested by an NGS assay that included BRCA1/2 (LiquidHALLMARK). A subset of cfDNA samples identified as HRD+ were further assessed for alterations in 26 key HR genes ( ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCC, FANCG, FANCL, MRE11, NBN, PALB2, PTEN, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, and XRCC2). Results: In analytical validation, the assay could detect HRD in admixtures with as low as 18% tumor fraction. In tissue samples, overall concordance of HRD status with the orthogonal test was 91.3% (42/46), with a positive percent agreement of 94.4% (34/36) and negative percent agreement of 80.0% (8/10). In cfDNA, 26.7% (20/75) of samples were HRD+, including 29.6% of BRCA-associated cancers (16/54; 12 breast, 2 prostate, 1 ovarian, and 1 pancreatic) and 19.1% (4/21) of other cancer types. In the three HRD+ breast cancers with pathogenic BRCA mutations, the assay also identified BRCA-specific LOH. Nine HRD+ breast cancers (two BRCA+ and seven BRCA-) were further analyzed for alterations in 26 HR genes. Of the two BRCA+ HRD+ breast cancers, one harbored an additional PTEN loss-of-function (LOF) mutation. Of the seven BRCA- HRD+ breast cancers, one harbored biallelic PALB2 and CDK12 LOF mutations, while another harbored a CDK12 LOF mutation. Conclusions: LOH detection in cfDNA provides additional diagnostic yield of HRD+ status in multiple cancer types, even in the absence of pathogenic HR gene alterations. Further clinical studies to evaluate the utility of HRD detection in cfDNA using LOH and to determine concordance with tumor tissue are ongoing.
Imaging of solid tumors using 68Ga-FAP-2286.
Authors: Hope Thomas A. , Aggarwal Rahul Raj , Dhawan Mallika Sachdev , Kelley Robin Kate , Flavell Robert R. , Lawhn Heath Courtney , Li Yan , Porten Sima P. , Rugo Hope S. , Yom Sue S. , Ippisch Robin , Koshkin Vadim S
Published: June 2022

3059

Background: Fibroblast Activation Protein (FAP) is a transmembrane protein overexpressed on cancer associated fibroblasts (CAFs), and is abundantly present in many epithelial cancers, suggesting FAP is an attractive imaging and therapeutic target. FAP-2286 is a cyclic peptide that binds to FAP and is currently being evaluated as a radioligand therapy to treat patients (pts) with FAP-positive solid tumors. The role of 68Ga-FAP-2286 as a diagnostic agent is unknown. We present an interim analysis of the ability of 68Ga-FAP-2286 to detect metastatic disease across multiple cancer types. Methods: This is a first in human Phase I/II study of 68Ga-FAP-2286 (NCT04621435) with a planned total enrollment of 65 pts across 3 cohorts: dosimetry cohort (n = 5), cohort with RECIST measurable disease (n = 30) and a cohort at risk for metastases without measurable disease (n = 30). By the cutoff date of February 12, 2022, 27 pts were enrolled (3 in cohort 1, 15 in cohort 2 and 9 in cohort 3). For each pt, the five largest lesions were included for analysis, and for each lesion, the maximum standardized uptake value (SUVmax) of the 68Ga-FAP-2286 and the size (short axis for lymph nodes) were documented. In pts who had an available FDG PET performed within 8 weeks of 68Ga-FAP-2286 PET, uptake on the two scans was compared. Results: Of the 27 enrolled pts, 9 had bladder cancer, 5 sarcoma, 4 head and neck squamous cell cancer (HNSCCA), 3 breast cancer (BC), and 3 castration resistant prostate cancer (CRPC). Most pts (89%, 24/27) had tumors positive for uptake on 68Ga-FAP-2286 PET, including 30 lesions < 1.5 cm, and 17 less than 1.0 cm. 16 pts had a paired FDG PET. In these pts, the average SUVmax on 68Ga-FAP-2286 PET was 244% higher than on FDG PET. Only two pts had higher uptake on FDG PET than on 68Ga-FAP-2286 PET (HNSCCA and DSRCT). The highest relative uptake was seen in 2 pts with BC (both 3.4 times higher on 68Ga-FAP-2286 PET); the average SUVmax in BC was 16.6. The lowest uptake on 68Ga-FAP-2286 PET was CRPC with an average SUVmax of 7.0. Sarcoma had variable uptake with one pt having an SUVmax of 4.5 (Ewing’s), while two pts had an SUVmax over 30 (both undifferentiated pleomorphic). Although sarcoma had high uptake on 68Ga-FAP-2286 PET, it was similar to FDG PET uptake across the 5 pts (ratio to FDG PET = 1.0). Conclusions: 68Ga-FAP-2286 is a promising imaging agent across cancers, although its benefit is not seen equally. BC had the highest absolute uptake and highest relative uptake compared to FDG PET; prostate cancer had the lowest uptake. Further work should be undertaken to define the settings where 68Ga-FAP-2286 PET may inform clinical decision making, and which pts may benefit from FAP-targeted radioligand therapy. Clinical trial information: NCT04621435.
Repeat large panel genomic sequencing identifies actionable alterations and characterizes the genomic landscape in patients with metastatic solid tumors.
Authors: Coleman Niamh , DiPeri Timothy P. , Nguyen Daniel , Naing Aung , Piha-Paul Sarina Anne , Tsimberidou Apostolia Maria , Zheng Xiaofeng , Johnson Amber , Wang Wanlin , Shaw Kenna R. , Dumbrava Ecaterina Elena , Fu Siqing , Rodon Ahnert Jordi , Hong David S. , Subbiah Vivek , Yap Timothy A. , Luthra Rajyalakshmi , Patel Keyur P. , Meric-Bernstam Funda
Published: June 2022

3076

Background: The implementation of genomic profiling with next generation sequencing has revolutionized the field of precision oncology. Comprehensive genomic testing of tumors to identify actionable genomic alterations is now commonly performed in the care of patients with advanced/metastatic disease. Although the genomic profile of tumors has been shown to evolve with progression and intervening treatments, the role of repeat genomic testing is not well established. We sought to determine the evolution of actionable genomic alterations in patients undergoing repeat genomic testing on the same comprehensive genomic panel. Methods: We retrospectively examined the molecular profiles and medical records of 262 patients with metastatic solid tumors treated in MD Anderson who underwent genomic testing on the same panel (Oncomine, Thermo Fisher) for the detection of somatic mutations in the coding sequence of 143 cancer-related genes, on at least 2 separate occasions. Genomic alterations were reviewed by a central Precision Oncology Decision Support (PODS) team in order to provide annotations at the alteration level on the functional significance. Results: 262 patients underwent repeat genomic testing using the same genomic panel on samples collected at different time points from July 2010 to Dec 2021 across tumor types. Changes in alterations (gain or loss) were identified on repeat testing in most patients (66%) We then specifically assessed changes in alterations that were categorized as actionable if annotated by the PODS team at the time of reporting. A gain or loss of an actionable alteration was detected in 38% (100/262) patients. New actionable alterations were frequently identified (73%; 73/100), while 41% had loss of an actionable alteration (41/100). 14% had both loss and gain of actionable alteration on repeat testing; 58% had new actionable alteration identified alone; 27% had loss of actionable alteration only. Actionable alterations identified on repeat testing included alterations in PI3K/AKT (27%), EGFR (15%), and MAPK (16%). On repeat testing, changes in ³2 actionable alterations were frequently identified in the same test (43%). Conclusions: Repeat large panel genomic testing identifies both gain and loss of actionable alterations in patients with advanced metastatic cancers. Actionable aberrations frequently co-exist with alterations in a variety of other genes, which highlights the complexities of treating patients with metastatic cancer on progression of disease and suggests that tailored combination strategies may be necessary in these patients.
Characterizing the genomic landscape of PIK3CA alterations from 121,221 adult patients with cancer: The next tissue-agnostic target?
Authors: Coleman Niamh , Roszik Jason , Reddy Neha K. , Subbiah Vivek
Published: June 2022

3088

Background: The PI3K–AKT–mTOR signaling pathway is frequently dysregulated in cancer and small molecule inhibitors targeting various nodes in the pathway have been pursued for decades. Activating mutations in PIK3CA are recognized potent drivers of oncogenesis, though the landscape of PIK3CA fusions and amplifications has yet to be well-defined. The field has been hampered by issues such as resistance and poor tolerance, however several isoform-specific PI3K inhibitors have now received regulatory approval and allosteric pan-mutant and specific mutant selective Inhibitors of PI3Kα are being investigated in early phase clinical trials. Here, we present a comprehensive analysis of PIK3CA alterations in pan-cancer adult malignancies. Methods: We analyzed 136096 samples from 121221 patients available from AACR Project GENIE v.11 database for the prevalence of PIK3CA mutations, fusions and copy number alterations in a range of cancer types. Results: 15712 alterations in PIK3CA were detected in profiled tumor samples (12%), in 14774 of patients profiled (12%), most frequently in endometrial (44% of 4135 cases), anal (35% of 286 cases), breast (35% of 14218 cases), cervical (27% of 761 cases) and colorectal cancer (20% of 3743 cases). PIK3CA alterations identified included 17740 mutations (11%) (including duplicate mutations in patients with multiple samples). 16685 missense mutations were identified (12%);14953 were identified as missense in driver mutation (likely oncogenic)(90% of missense); 1,732 were missense of variants of uncertain significance (VUS) using OncoKB database (11%). Missense mutations most frequently involved codons 545(3347, 20% of missense), codon 1047 (3644, 22%) and codon 542 (1881, 11%). 237 truncating mutations were identified (0.2%), 442 in-frame deletions, 29 in-frame insertion mutations. PIK3CA fusions were observed in 0.06% of tumor samples and were most identified in breast, colorectal, lung, GBM and ovarian cancer (24%, 17%, 13%, 7% and 6% of identified PIK3CA fusions respectively). PIK3CA fusions were most commonly intragenic fusions(36%);common fusion partners included TBL1XR1, FNDC3B and NAALADL2(17%, 7%, 5% of identified PIK3CA fusions, respectively). PIK3CA fusions were identified as VUS, aside from KMT2C-PIK3CA (2%) . PIK3CA amplification high level gain occurred in 0.5% of samples tested(662), deletion occurred in 0.16%(21). Conclusions: Activating PIK3CA mutations occur frequently across cancer types and could be considered for tissue-agnostic drug development. PIK3CA fusion and amplification events are extremely rare. Most PIK3CA missense mutation variants are described as oncogenic, while fusions are described as VUS, which may limit the impact of precision oncology for patients with this alteration. Further functional characterization of PIK3CA variants and basket trial enrollment are warranted.
Genomic and clinical characteristics of MET alterations in solid tumors among the 10,475 Chinese patients.
Authors: Li Yaping , Li Mingwei , Zhang Yanrui , Hao Xueyu , Zhang Yun , Liang Xiayuan , Lou Feng , Cao Shanbo , Wang Huina
Published: June 2022

3115

Background: Somatic alterations of the MET oncogene are emerging as an attractive target in human cancers, thus, understanding the molecular epidemiology of MET alterations is essential. While the occurrence of MET exon 14 skipping mutations (MET ex14) in US lung cancer patients is well defined, it is not widely published for Chinese patients. In addition, reports on the occurrence of METex14 outside lung cancer and other clinically relevant MET alterations across all cancers are limited. Methods: The MET ex14 alterations and amplification data of 10475 Chinese cancer patients from 16 types of cancer were obtained in Acronmed database, including non-small cell lung cancer (NSCLC, n = 5719), Hepatocellular carcinoma (HCC, n = 511), colorectal cancer (CRC, n = 1779), renal cell carcinoma (RCC, n = 1169), Gastric carcinoma (GC, n = 679), etc. Genomic profiling of DNA was performed through a next-generation sequencing. Results: Of all pan-cancer patients, 141 cases (1.3%) with MET alterations were identified, including MET Amp (0.9%) and MET ex14 (0.7%). Compared to Western population (̃3%), the frequency of MET alterations is much lower in Chinese cancer patients (1.3%). MET Amp were most commonly found in HCC (1.7%), GC (1.3%), NSCLC (0.7%), RCC (0.7%), CRC (0.2%). MET ex14 occurred most in NSCLC (0.5%), HCC (0.3%), CRC (0.2%). HCC were significantly to have MET Amp than NSCLC (P = 0.01), while MET ex14 mutations were more likely to be observed in NSCLC (p = 0.02). We further analyzed the MET mutation characteristics of NSCLC. The most frequently co-mutated genes in MET ex14 cohort were TP53 (48%,15/31), KMT2B (23%,7/31) and EGFR (16%, 5/31). Except for TP53 (65%,22/34) and EGFR (56%,19/34) mutations. Interestingly,other gene mutations were rare in the patients with MET Amp. In addition, MET ex14 patients showed significant lower EGFR mutation comparing to the MET amp patients (P = 0.002). Conclusions: Our study demonstrated a landscape of MET alterations among the Chinese population. MET mutations occurs in a variety of solid tumors, indicating that these patients may benefit from MET inhibitors.