Early detection of cancer can potentially offer clinical benefits, particularly for those without effective screening methods. The PREDICT study (NCT 04383353) is a prospective, multi-center, longitudinal study that aims to identify multiple cancers non-invasively in early stages. As a pilot project, the THUNDER (THe UNintrusive Detection of Early-stage canceR) study is designed for development and validation of ELSA-seq, a sensitive targeted methylation sequencing assay that interrogates epigenetic alterations from circulating cell-free DNA (cfDNA). Herein we report results from the second THUNDER sub study (THUNDER-II), which focused on malignancies developed in liver, colon/rectum, esophagus, pancreas, lung and ovary.
THUNDER-II comprises four independent steps: marker discovery, model training, validation, and single-blind test. By combining data generated in-house and from public sources, a targeted methylation panel was designed. A total of 625 patients and 483 non-cancer controls were enrolled and divided into a training set (274 cancer and 195 non-cancer) and an independent validation set (351 cancer and 288 non-cancer).
The cancer patients and non-cancer controls were generally comparable with respect to age, gender, and smoking status. Various stages were represented in the cancer group, and 79.5% patients were diagnosed at early stages (I-III). At 99.5% training specificity (95%CI: 96.7-100%), the cross-validated sensitivity was 79.9% (95%CI: 74.6-84.4%). The results were consistent in the validation set, with 98.3% specificity (95%CI: 95.8-99.4%) and 80.6% (76.0-84.6%) sensitivity across stages and cancer types. In terms of tracking diseased organ(s), the classifier returned a tissue-of-origin (TOO) result in 98.6% cases, and 81.0% (95%CI: 77.2-84.3%) of these predictions were correct.
Results from the THUNDER-II study demonstrated that early cancer signals could be identified by ELSA-seq with high specificity. This method also enabled accurate prediction of TOO, offering guidance for subsequent diagnostic work-up. Together these findings highlight the potential implementation of this sensitive and robust assay as a multi-cancer detection test.
The authors.
Burning Rock Biotech.
B. Li: Shareholder/Stockholder/Stock options, Full/Part-time employment: Burning Rock Biotech. S. Cai, J. Xu, C. Wang, S. Fang, F. Qiu, J. Su, F. Xu, X. Wen, Y. Zhang, G. Wang: Full/Part-time employment: Burning Rock Biotech. H. Liu, Z. Zhang: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Burning Rock Biotech.
Entrectinib efficacy was established in an integrated analysis of 3 trials (ALKA-372-001 EudraCT 2012-000148-88; STARTRK-1 NCT02097810; STARTRK-2 NCT02568267) in adult pts with
Enrolled pts were NTRK and ROS1 TKI naïve with locally advanced/metastatic solid tumours or NSCLC, with/without baseline CNS metastases. Tumour response was assessed by blinded independent central review (BICR) using RECIST v1.1 after 4 wks and every 8 wks thereafter. Primary endpoints were ORR and duration of response (DoR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety.
The Asian efficacy-evaluable populations comprised 13 pts (17.6% of total population) with
Entrectinib treatment achieved high response rates with a manageable safety profile in Asian pts with NTRK-fp solid tumours or ROS1-fp NSCLC, with/without baseline CNS metastases, consistent with findings in the total populations. Median follow-up:
Efficacy parameter Overall (n=13) Intracranial (n=3)* Overall (n=41) Intracranial (n=17)* ORR, n (%); 9 (69.2); 3 (100) 32 (78.0); 7 (41.2); CR 0 2 (66.6) 5 (12.2) 3 (17.6) PR 9 (69.2) 1 (33.3) 27 (65.9) 4 (23.5) SD 0 0 2 (4.9) 0 PD 1 (7.7) 0 3 (7.3) 4 (23.5) Non-CR/non-PD 0 0 1 (2.4) 4 (23.5) Missing/unevaluable 3 (23.1) 0 3 (7.3) 2 (11.8) Median time to event, mos (95% CI) DoR in responders 10.4 (5.7–NE) 8.0−12.8† 14.9 (9.1–NE) NE (4.6–NE) PFS 14.9 (6.4–NE) 8.9−13.8† 13.6 (7.7–NE) 5.4 (2.6–15.7) OS NE (14.9–NE) – NE (28.3–NE) –
ALKA-372-001 (EudraCT 2012-000148-88); STARTRK-1 (NCT02097810); STARTRK-2 (NCT02568267).
Third-party medical writing assistance, under the direction of the authors, was provided by Cassidy Bayley, PhD, of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
F. Hoffmann-La Roche Ltd.
D.S.W. Tan: Honoraria (self): Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli Lilly, and Loxo; Research grant/Funding (institution): Novartis, Bayer, AstraZeneca, Pfizer, GlaxoSmithKline; Travel/Accommodation/Expenses: Novartis, Boehringer Ingelheim, Celgene, Merck, Pfizer, Roche, Takeda. M-J. Ahn: Honoraria (self): AstraZeneca, Eli Lilly, Takeda, Roche, MSD; Advisory/Consultancy: AstraZeneca, Eli Lilly, Takeda, Roche, MSD, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Alpha Pharmaceutical, Progeneer. C-H. Chiu: Honoraria (self): Pfizer, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, Roche; Advisory/Consultancy: AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, Roche. Y. Ohe: Honoraria (self): AstraZeneca, Chugai, Eli Lilly, Ono, BMS, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Pharmaceutical, Nippon Kayaku, Kyowa Hakko Kirin; Advisory/Consultancy: AstraZeneca, Chugai Pharmaceutical, Ono, BMS, Kyorin, Celltrion, Amgen, Nippon Kayaku; Research grant/Funding (institution): AstraZeneca, Chugai Pharmaceutical, Lilly, Ono, BMS, Kyorin, Dainippon-Sumitomo, Pfizer, Taiho Pharmaceutical, Novartis, Kissei Pharmaceutical, Ignyta, Takeda, Daiichi-Sankyo, Janssen, Loxo; Officer/Board of Directors: JSMO, JLCS. H.H.F. Loong: Advisory/Consultancy: Boehringer-Ingelheim, Celgene, Eli Lilly, Novartis, Merck, Roche, Takeda; Speaker Bureau/Expert testimony: AbbVie, Bayer, Eisai, Eli Lilly, Guardant Health, Novartis; Travel/Accommodation/Expenses: Bayer, MSD, Novartis, Pfizer; Research grant/Funding (institution): MSD, Mundipharma, Novartis. S-W. Kim: Advisory/Consultancy: AstraZeneca, Boehringer-Ingelheim, Lilly, Novartis; Research grant/Funding (self): AstraZeneca. M. Takeda: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Novartis Pharma, Ono Pharmaceutical. Y-C. Li: Advisory/Consultancy: Roche, AstraZeneca, Foundation Medicine, Boehringer Ingelheim, Lilly Oncology, Merck, Pfizer, Novartis, Takeda, MSD; Research grant/Funding (self): Roche; Travel/Accommodation/Expenses: Roche, Taiho Pharmaceutical, Eisai, Sanomic, Xcelom, Takeda, AstraZeneca, MSD, Boehringer Ingelheim, Pfizer, Mundipharma. A. Cheng: Research grant/Funding (institution): Roche. T. Hida: Honoraria (self): Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, Novartis, Bristol-Meyers Squibb, Kissei Pharmaceutical, Taiho Pharmaceutical, Pfizer, MSD, Takeda; Research grant/Funding (institution): Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, Novartis, Bristol-Meyers Squibb, Kissei Pharmaceutical, Taiho Pharmaceutical, Pfizer, MSD, Takeda, Merck, Abbvie, Daiichi Sankyo, Astellas, Janssen. D-W. Kim: Research grant/Funding (institution): Alpha Biopharma, Amgen, AstraZeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche, Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen, Daiichi-Sankyo. N. Nogami: Honoraria (self): MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb, Ono Pharmaceutical, Kyowa Hakko Kirin, Taiho, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim. H. Tanaka: Honoraria (self): Pfizer, Novartis, Bristol-Myers Squibb, Eli Lilly, MSD, Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Ono Pharmaceutical; Research grant/Funding (institution): Bristol-Myers Squibb, Eli Lilly, MSD, Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Ono Pharmaceutical. S. Osborne, R. Freund: Full/Part-time employment: F. Hoffmann-La Roche. D. Chen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Genentech. T. Seto: Honoraria (self): Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyowa Hakko Kirin, MSD, Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific; Research grant/Funding (institution): AbbVie, AstraZeneca, Bayer Yakuhin, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kissei Pharmaceutical, Loxo, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda; Full/Part-time employment: Precision Medicine Asia. All other authors have declared no conflicts of interest.
Fluoropyrimidine is a key drug for a variety of cancers but rarely associated with severe toxicities such as diarrhea, mucositis, hand-foot syndrome, and neutropenia. Dihydropyrimidine dehydrogenase (DPD) plays a pivotal role in fluoropyrimidine metabolism and dozens of genetic variant are known to reduce the activity of this gene. Approximately 3-5% of patients are estimated to have reduced DPD genotype in Caucasian population and Clinical Pharmacogenetics Implementation Consortium (CPIC) has released 82 DPD variants which could increase the risk of fluoropyrimidine-related severe toxicity; however, it remains unclear whether DPD genotype-guided fluoropyrimidine dosing strategy is applicable for Asian population. We aimed to clarify the prevalence of impaired DPD genotype and its association with fluoropyrimidine-related severe toxicities.
We comprehensively searched nonsynonymous variants in DPD using Japanese Haplotype Reference Panel (JHRP, n = 3,135). Then the variants and 82 DPD variants listed in the CPIC guideline were investigated for the 1,362 patients with colon cancer who were enrolled in adjuvant clinical trials (JOIN and ACHIEVE) and received mFOLFOX6 or CAPOX, with documented informed consent for the prospective pharmacogenomics study.
We found 39 nonsynonymous variants among 12,611 DPD variants in the JHRP. Of those variants, only 7 variants were listed in CPIC guideline. In our study cohort of 1,362 patients with colon cancer, 74 variants were genotyped among the 82 DPD variants listed in the CPIC guideline and only 8 variants were confirmed. Minor allele frequency of these 8 variants ranged from 0.0003.6 to 0.28. Association study between these 8 variants and fluoropyrimidine-related toxicities (diarrhea, mucositis, hand-foot syndrome, and neutropenia) revealed no significant correlation. Lower prevalence of DPD variants were consistent with the registry data of JHRP, which represented the general Japanese population.
Considering the lower prevalence of impaired DPD genotype, the distinct ethnic difference exists. DPD genotype-guided fluoropyrimidine dosing strategy may not be applicable in Japan.
The authors.
Yakulto Honsha Co., Ltd.
M. Kanai: Shareholder/Stockholder/Stock options: TheraBioPharma Inc.; Honoraria (self): Chugai Pharam. M. Kotaka: Honoraria (self): Chugai; Yakult; Takeda. J. Hasegawa: Speaker Bureau/Expert testimony: Chugai ; Honoraria (self): Yakult. T. Kato: Honoraria (self): Ono; Honoraria (self), Research grant/Funding (institution): Chugai; Takeda; Honoraria (self): Taiho. T. Mizushima: Research grant/Funding (institution): Takeda; Shire Japan; Chugai; Yakult; Eli Lilly Japan; Ono; Sanofi; Mitsubishi Tanabe; Kaken; Japan Blood Products Organization; Tsumura; Astellas; Pfizer Japan; Daiichi Sankyo; Merck Biopharma; MSD. S. Matsumoto: Research grant/Funding (institution): NTT Ltd.; H.U. Group; Canon Medical Systems. A. Ohtsu: Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self): Ono; Taiho; Chugai. T. Yoshino: Honoraria (self), Research grant/Funding (institution): Taiho; Chugai; Honoraria (self): Eli Lilly Japan; Bayer; Merk; Takeda; Research grant/Funding (institution): MSD; Ono; Daiichi Sankyo; Sumitomo Dainippon Pharma; Parexel International Inc; Sanofi; Amgen; GlaxoSmithKline. F. Matsuda: Research grant/Funding (institution): Yakult. All other authors have declared no conflicts of interest.
We aimed to assess the role of genomic HLA-I/II homozygosity in the overall survival benefit in patients with unresectable locally advanced, metastatic non-small lung cancer treated by single agent PD1/PDL1 inhibitors.
We collected blood from 170 advanced lung cancer patients treated with immunotherapy at two major oncology centres in Western Australia. High quality DNA was extracted from white blood cells and used for HLA-I/II typing. We correlated between genomic HLA-I/II, overall survival (OS) and progression free survival (PFS) in a univariate analysis using a log rank test. Multivariate analysis was performed between HLA-I, OS and PFS including all the variables that influenced the effect of HLA-I homozygosity on OS in the subgroup analysis (age, PD-L1 expression, ECOG and therapy modality) using Cox regression analysis. We then investigated the correlation between indivdual HLA-A and -B supertypes with OS using log rank analysis.
Homozygosity at one or more HLA-I loci and type of checkpoint inhibitor used (anti-PD1 vs anti-PDL1) were the only statistically significant independent predictor of shorter OS (HR=2.17, 95%CI 1.13-4.17, P=0.02 and HR=3.16, 95%CI 1.66-5.99 respectively) in the univariate analysis. This was more significant in patients with tumour expressing PDL1 in more than 50% of cancer cells (HR=3.93, 95%CI 1.30-11.85, P<0.001). In the multivariate analysis, pre-treatment neutrophil to lymphocyte ratio (NLR) also emerged as a prognostic marker of OS (HR=2.17, 95% CI 1.12-4.20, P=0.02) together with HLA-I genotype (HR=2.07, 95% CI 1.07-4.01, P=0.03). The adverse effect of homozygosity at one or more HLA-I loci on PFS was only apparent after controlling for interactions between PD-L1 status and HLA-I genotype (HR= 2.37, 95%CI 1.12 – 5.01, P=0.02). No interactions were found between HLA-I and therapy type, neither its inclusion affected multivariate analysis results. The presence of HLA-A02 supertype was the only type of HLA-I supertypes to be associated with improved OS (HR=0.56 95%CI 0.34-0.93, P=0.023).
OS Univariate Multivariate Multivariate + Interactions p-value HR 95.0% CI p-value HR 95.0% CI p-value HR 95.0% CI Lower Upper Lower Upper Lower Upper HLA-I (hetero vs homo) 0.020 2.167 1.127 4.167 0.031 2.071 1.070 4.006 0.003 3.710 1.568 8.780 Age (<65 vs ≥65 ) 0.534 0.825 0.450 1.513 0.862 0.946 0.509 1.758 0.855 1.060 0.566 1.988 PDL1 (≥50% vs <50%) 0.916 0.968 0.531 1.765 0.522 0.820 0.447 1.505 0.589 1.225 0.588 2.553 ECOG (≤1 vs ≥2) 0.400 1.557 0.556 4.363 0.246 1.852 0.653 5.248 0.263 1.818 0.639 5.171 Therapy type (αnti-PD1 vs αnti-PDL1) >0.001 3.155 1.662 5.990 >0.001 3.316 1.725 6.373 >0.001 3.328 1.718 6.446
Homozygosity at one or more HLA-I loci was correlated with worse OS and PFS in patients with advanced or metastatic NSCLC treated with single agent immunotherapy. This is mainly in patients with tumours expressing PDL1 in more than 50% of cancer cells. HLA-A02 supertypes is the only positively influencing HLA-I supertype on OS.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
The predictive power of programmed cell death ligand 1 (PD-L1) for treatment response to PD-1/PD-L1 immune checkpoint inhibitors (ICI) is not satisfactory. Recent biomarker research focuses on early immunological changes in the peripheral blood to predict treatment response to ICI. Within this prospective ST-ICI trial, pre-planned biomarker analysis was performed and we developed a flow cytometry-based whole-blood prognostic immune signature (FCBPS) to predict overall survival (OS) benefit of cancer patients treated with ICI.
The predictive power of programmed cell death ligand 1 (PD-L1) for treatment response to PD-1/PD-L1 immune checkpoint inhibitors (ICI) is not satisfactory. Recent biomarker research focuses on early immunological changes in the peripheral blood to predict treatment response to ICI. Within this prospective ST-ICI trial, pre-planned biomarker analysis was performed and we developed a flow cytometry-based whole-blood prognostic immune signature (FCBPS) to predict overall survival (OS) benefit of cancer patients treated with ICI.
A total of 104 patients were prospectively enrolled. Eighty-nine patients provided blood samples. The identified FCBPS signature bases on five immune cell subtypes: neutrophils, plasmacytoid dendritic cells (pDCs), natural killer (NK)T cells (CD56+/CD16+), monocytes (CD14high) and CD8+ T cells (PD-1+). This signature achieved a high accuracy (C-index 0.74 vs 0.71) for predicting OS benefit in the training and validation cohort. Both in the training and validation cohort, the low-risk group had significantly longer OS than the high-risk group (HR 0.26, 95% CI: 0.12-0.56, p=0.00025; HR 0.30, 95% CI: 0.10 -0.91, p=0.024, respectively). In the whole cohort, FCBPS is a predictor of OS (HROS=0.28, 95% CI: 0.15-0.52) and progression-free survival (HRPFS=0.22, 95% CI: 0.12-0.39) that remained independent in multivariate analyses and subgroup analyses after adjusting for clinical and pathological factors.
The flow cytometry-based whole-blood prognostic signature (FCBPS) is a powerful predictor for metastatic cancer patients who benefit from ICI treatment.
NCT03453892; on January 24, 2018.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
This study aimed to characterize tumor microenvironment (TME) profile to predict clinical outcomes of cancer immunotherapy and to identify potential cellular mechanisms driving immunotherapy response and resistance.
This study analyzed single-cell or RNA sequencing data of 396 immunotherapy-treated patients from the phase II IMvigor210 trial and Gene Expression Omnibus, and also included 4,547 patients from The Cancer Genome Atlas. Using unsupervised hierarchical clustering, we combined immune checkpoints, human leukocyte antigens, and immune cells to construct a novel TME classification.
The clustering in IMvigor210 trial resulted in three immune subtypes, with the greatest overall survival (OS) benefit in Immune-Active Class (HR 0.69; 95% CI 0.56 to 0.84; P < 0.001), which was validated in TCGA cohort across multiple cancers (HR 0.86; 95% CI 0.80 to 0.92; P < 0.0001). The three immune subtypes exhibited distinct metabolic patterns, especially in the hypoxia signaling pathway; patients in Immune-Active Class had lowest hypoxia score (P<0.0001). Further single-cell profiling revealed that in patients who did not respond to immunotherapy, M2 macrophages increased after treatment but there was no significant difference in natural killer (NK) cells between pre- and post- immunotherapy treatment. Conversely, among responders, M2 macrophages showed little change but NK cells significantly increased after immunotherapy. Among non-responders, M2 macrophages had higher expression of hypoxia signature after treatment, but this change in responders was not evident. In agreement, IMvigor210 data showed longer OS in patients with low versus high M2 macrophages (HR 0.58; 95% CI 0.42 to 0.80; P < 0.001), and in patients with high versus low NK cells (HR 0.74; 95% CI 0.56 to 0.97; P = 0.03).
This study developed novel TME-based subtypes to facilitate cancer immunotherapy delivery. Additionally, M2 macrophages might induce immunotherapy resistance by causing NK cell exclusion or dysfunction via hypoxia-related pathways.
Herui Yao.
This work was supported by the National Science and Technology Major Project (grant number 2020ZX09201021); the National Natural Science Foundation of China (grant numbers 81572596, 81972471, U1601223); the Natural Science Foundation of Guangdong Province (grant number 2017A030313828); the Guangzhou Science and Technology Major Program (grant number 201704020131); the Sun Yat-Sen University Clinical Research 5010 Program (grant number 2018007); the Sun Yat-Sen Clinical Research Cultivating Program (grant number SYS-C-201801); the Guangdong Science and Technology Department (grant number 2017B030314026); and the Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (grant number pdjh2019a0212); National Students’ Innovation and Entrepreneurship training program (grant number 201910571001); and Guangdong Medical University College Students’ Innovation Experiment Project (grant number ZZZF001).
All authors have declared no conflicts of interest.
Envafolimab (KN035) is a novel anti-PD-L1 single domain antibody formulated for subcutaneous injection (SC). This single arm phase II study evaluated the efficacy and safety of KN035 in patients (pts) with advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) cancer.
The study included adult pts with MSI-H/dMMR advanced cancer who failed ≥ 1 line of systemic therapy in China. Pts received SC administration of KN035 at 150 mg weekly until progression, unacceptable toxicity, or withdrawal. The primary endpoint was ORR per RECIST v1.1 by blinded independent radiology review (BIRC).
As of 2019/12/5, 103 pts with dMMR/MSI-H advanced cancer were enrolled, including 65 with colorectal cancer (CRC, 41 failed ≥ 2 lines of prior therapies including a fluoropyrimidine (F), oxaliplatin (O) and irinotecan (I), 24 failed 1 line of prior therapy including F, O or I), 18 with gastric cancer (GC) and 20 with other tumors. As of data cut off on 2020/6/19, the median follow-up was 11.5 months in the overall population. Confirmed ORR per BIRC was 42.7% in the overall population, 43.1% in CRC, 44.4% in GC and 40.0% in other tumors population. Median duration of response was not reached for any populations. ORRs per investigators were consistent with BIRC assessment (Table). Confirmed ORR per BIRC and investigator assessment
ORR per BIRC ORR per investigator Overall population (n=103) 42.7% (95%CI: 33.0%-52.8%) 41.7% (95% CI: 32.1%-51.9%) CRC population (n=65) 43.1% (95% CI: 30.8%-56.0%) 40.0% (95% CI: 28.0%-52.9%) CRC failed prior 1 line (n=24) 62.5% (95%CI: 40.6%-81.2%) 58.3% (95% CI: 36.6%-77.9%) CRC failed prior ≥2 lines (n=41) 31.7% (95%CI: 18.1%-48.1%) 29.3% (95% CI: 16.1%-45.5%) GC population (n=18) 44.4% (95%CI: 21.5%-69.2%) 50.0% (95% CI: 26.0%-74.0%) Other tumors population (n=20) 40.0% (95%CI: 19.1%-63.9%) 40.0% (95% CI: 19.1%-63.9%)
The median progression-free survival (PFS) per BIRC was 7.2 months for CRC population, not reached for either GC or other tumors population, and 11.1 months for the overall population. Median overall survival (OS) was not reached for any populations. The 12 months OS rate was 72.9%, 83.3%, 75.0% and 74.6% for CRC, GC, other tumors, and overall population, respectively. All grade (G) and G3-4 treatment-related adverse events (TRAE) in overall population were 84.5% and 15.5% separately. No G5 TRAE occurred. The most common immune related AEs were hypothyroidism (15.5%) and hyperthyroidism (11.7%). No pneumonitis or colitis were reported. The occurrence of local injection-site reaction was 8.7% and were all G1-2.
Envafolimab demonstrated robust anti-tumor activity with a manageable safety profile in heavily pretreated pts with dMMR/MSI-H cancer.
NCT03667170.
3DMedicine Co. Ltd.
Has not received any funding.
All authors have declared no conflicts of interest.
OBI-833, a novel cancer active immunotherapy, consists of a synthetic Globo H combining with a recombinant CRM 197. Globo H is a tumor-associated carbohydrate antigen found in many epithelial cancers. A phase I trial assessed the safety and immune response of OBI-833 in subjects with advanced/metastatic gastric, lung, colorectal or breast cancer.
Subjects who failed to respond to at least one line of anticancer therapy were enrolled. For lung or breast cancer patients receiving targeted or hormone therapy, OBI-833 was added to their therapeutic regimen. Patients received a total of 10 subcutaneous injections of OBI-833/OBI-821. Three escalated doses of 10 μg, 30 μg, and 100 μg of OBI-833 were studied. A standard 3+3 rule was applied for dose escalation and DLT assessment.
Eleven patients were enrolled, and all patients are now off study treatment. These patients include one lung cancer, seven colorectal cancer and three breast cancer patients. No patients in any of the three cohorts developed a DLT. The most common treatment-related AE was grade 1–2 injection site reaction, including erythema, induration, soreness, pruritus, etc. occurring on the day of injection and recovering within 2–3 days without requiring further medical treatment. Five treatment-unrelated SAEs were reported, including acute respiratory failure leading to death, bilateral malignant pleural effusion associated with disease progression, death associated with disease progression, hyponatremia, and acute kidney injury, which were all related to their underlying disease. All three doses of OBI-833/OBI-821 elicited anti-Globo H IgM and IgG antibody response, at least once during the course of therapy. Only one patient with NSCLC had a robust anti-Globo H IgG response. A positive correlation between complement-dependent cytotoxicity activities at a given time point and the anti-Globo H IgM level was observed. However, only minimum anti-Globo H IgG level and antibody-dependent cell-mediated cytotoxicity activity were detected.
OBI-833/OBI-821 had a favorable safety profile and generated detectable anti-Globo H IgM/IgG responses. The 30 μg dose of OBI-833 and NSCLC cancer type were selected for the cohort expansion.
NCT02310464.
OBI Pharma.
OBI Pharma.
C-C. Ou: Full/Part-time employment: OBI Pharma. Y. Yen: Advisory/Consultancy: OBI Pharma. All other authors have declared no conflicts of interest.
Selinexor, an orally bioavailable selective inhibitor of nuclear exporter Exportin-1 (XPO1), was shown to not only lessen DNA damage repair proteins but also potentiate cancer cells to DNA damaged-based therapies in in vivo studies.
This was an open label, single-center, multi-arm phase Ib study utilizing a “3 + 3” design and a “basket type” expansion. Selinexor with carboplatin, irinotecan, doxorubicin and cyclophosphamide (DC), irinotecan with fluorouracil and folinic acid (FOLFIRI), and capecitabine and oxaliplatin (XELOX), were employed as separate parallel arms. Selinexor was dosed at either 40mg QW with XELOX and FOLFIRI, or 60mg QW with irinotecan, and DC. Selinexor was dosed at 60 mg QW or BIW with carboplatin. Patients with advanced solid tumors whose disease was refractory or relapsed following prior systemic therapy or where the addition of selinexor to standard chemotherapy deemed appropriate, were eligible.
Of 19 patients treated in 5 arms, 14 patients were evaluable for response. The most common cancers were breast (n=3), colorectal (n=3) cancers, and 2 each with neuroendocrine, ovarian and pancreas cancers. All patients had at least one treatment emergent adverse events (TEAE) and the most prevalent were thrombocytopenia (84%), leukopenia (84%), nausea (73%), neutropenia (63%), anemia (63%), fatigue (58%), and vomiting (52%). The commonest grade (G) ≥ 3 TEAE were neutropenia (42%), leukopenia (31%), hyponatremia (29%), anemia (26%), thrombocytopenia (25%), and hyponatremia (25%). Three patients had DLT; a patient dosed at selinexor 60mg BIW with DC reported G3 leukopenia and G4 neutropenia whereas others dosed at selinexor 40mg QW with XELOX or FOLFIRI had G3 diarrhea and febrile neutropenia, respectively. No patients achieved partial or complete response (PR/CR) while 7 patients (50%) obtained stable disease (SD). Clinical benefit rate (CR+PR+SD ≥4 months) was 35.7%. Treatment time to progression ranged from 2 to 30 weeks.
Oral selinexor in combination with standard chemotherapies was practical and showed some clinical activity. The RP2D of selinexor was 40 mg once weekly in combination with XELOX or FOLFIRI.
NCT02419495.
The authors.
Karyopharm.
All authors have declared no conflicts of interest.