tbuckley/cabot-search huggingface dataset:
Comprehensive genomic profiling in advanced/metastatic colorectal cancer: Number needed to test and budget impact of expanded first-line use.
Authors: David Proudman, Nicholas C. DeVito, Suzanne Belinson, Mina Alsaraf Allo, Eric D. Morris, James Signorovitch, Anuj K. Patel
Journal: Journal of Clinical Oncology (2021)

e18834 Background: A growing number of genomic alterations inform treatment of advanced/metastatic colorectal cancer (mCRC). However, use of comprehensive genomic profiling (CGP) is limited in the first-line (1L) setting. Based on the Tempus xT next-generation sequencing assay, we estimated the impact of expanded 1L CGP on the detection of currently actionable alterations in mCRC and associated diagnostic testing costs in a modeled US health plan setting. Methods: A decision analytic model was used to compare testing scenarios over a two-year time horizon: current 1L testing with a mix of CGP and non-CGP diagnostics vs. replacing 20% of usual testing with Tempus CGP. The incidence of 1L mCRC, current testing rates, prevalence of actionable alterations, and test sensitivity were drawn from a literature review and clinical expert input. Currently actionable alterations included KRAS, NRAS, RAF, BRAF, dMMR/MSI, NTRK, RET, EGFR, HER2, MET, PIK3CA and POLE1. Cost components included initial and repeat testing, physician-associated and administrative costs. Opportunities for genomically-informed therapy or clinical trials were assessed under each testing scenario. A forward looking scenario, with additional informative alterations, was also explored. Results: In a hypothetical five million-member health plan, with 50% Medicare and 50% commercial insurance, 1,112 incident cases of mCRC (22 per 100,000 patients) are expected in a typical year. Among these cases, 566 (51%) are expected to undergo 1L molecular diagnostic testing, with 55 projected to undergo repeat testing upon progression within the next year. Based on current real-world testing rates, there are an expected 521 missed opportunities for genomically informed treatment (47% of the incident mCRC population), with 442 missed due to lack of testing and 79 due to testing without CGP. Replacing 20% of usual testing with Tempus CGP in the modeled scenario was associated with up to a $0.003 per member per month (PMPM) testing cost increase and an additional 15.5 patients with an opportunity for genomically-informed care (12.7 patients for guideline-recommended treatment and 2.8 for a clinical trial). The number needed to test (NNT) with Tempus CGP versus the usual mix of testing was 7.8 1L patients to identify one actionable alteration. Scenario analyses projecting the advent of additional genomically-informed treatments and clinical trials resulted in smaller numbers needed to test. Conclusions: Replacing 20% of usual testing with Tempus CGP is associated with a small incremental testing cost but can identify actionable alterations for a meaningful number of patients. For every eight 1L mCRC patients tested with Tempus CGP rather than the usual mix of molecular testing, one additional patient is expected to be identified as having currently actionable alterations.
Author Correction: Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation
Authors: Nisha Padmanabhan, Huang Kie Kyon, Arnoud Boot, Kevin Lim, Supriya Srivastava, Shuwen Chen, Zhiyuan Wu, Hyung-Ok Lee, Vineeth T. Mukundan, Charlene Chan, Yarn Kit Chan, Ong Xuewen, Jason J. Pitt, Zul Fazreen Adam Isa, Manjie Xing, Ming Hui Lee, Angie Lay Keng Tan, Shamaine Ho Wei Ting, Micah A. Luftig, Dennis Kappei, Warren D. Kruger, Jinsong Bian, Ying Swan Ho, Ming Teh, Steve George Rozen, Patrick Tan
Journal: Genome biology (2021)
KEYNOTE-B61: Open-label phase 2 study of pembrolizumab in combination with lenvatinib as first-line treatment for non-clear cell renal cell carcinoma (nccRCC).
Authors: Chung-Han Lee, Chenxiang Li, Rodolfo F. Perini, Daniela Hoehn, Laurence Albiges
Journal: Journal of Clinical Oncology (2021)

TPS4595 Background: Most RCCs contain clear cell histology; the remainder of cases are summarized as nccRCC. nccRCC is a heterogeneous group of tumors and, with advanced metastases, survival is uniformly worse than with clear cell RCC (ccRCC) because of the aggressiveness of these cancers and a lack of effective systemic treatment options. Because data are limited for patients with nccRCC, the role of various agents in the treatment of nccRCC is poorly defined and there is no standard of care; treatment guidelines recommend clinical trials as preferred strategy. Inhibition of the PD-1/PD-L1 pathway is an effective treatment option for nccRCC, and pembrolizumab monotherapy has shown efficacy with an acceptable safety profile as first-line treatment. The VEGF TKI lenvatinib has also shown efficacy with a tolerable safety profile as combination therapy with everolimus for nccRCC. Also, in the phase 3 KEYNOTE-581 study (NCT02811861), the combination of lenvatinib + pembrolizumab as first-line therapy showed antitumor activity in patients with metastatic ccRCC, suggesting this combination might be an excellent therapeutic option for nccRCC. The phase 2, open-label, single-arm, KEYNOTE-B61 study (NCT04704219) is being conducted to evaluate pembrolizumab in combination with lenvatinib as first-line treatment for nccRCC. Methods: Patients with centrally confirmed nccRCC, locally advanced/metastatic measurable disease per RECIST v1.1 per blinded independent central review (BICR), no prior systemic therapy for nccRCC, and KPS score ≥70 will be enrolled. Approximately 152 patients will receive pembrolizumab 400 mg every 6 weeks and lenvatinib 20 mg once daily. Pembrolizumab treatment will continue for up to approximately 2 years or until a discontinuation criterion is met (disease progression, unacceptable toxicity, or withdrawal of consent); lenvatinib treatment can continue beyond 2 years or until one of the same discontinuation criterion is met. Participants who discontinue one of the treatments can continue to receive the other treatment as monotherapy. A second-course treatment phase is available for patients who meet specific criteria. CT/MRI will be performed at 12 weeks from the start of treatment, every 6 weeks until week 54, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and graded using CTCAE, version 5.0, guidelines. The primary end point is objective response rate based on RECIST v1.1 per BICR. Secondary efficacy end points for this study are clinical benefit rate, disease control rate, duration of response, progression-free survival, overall survival, and safety. Tertiary/exploratory end points are biomarker analysis and association with clinical response/disease etiopathogenesis. Clinical trial information: NCT04704219.
CheckMate 9KD cohort A1 final analysis: Nivolumab (NIVO) + rucaparib for post-chemotherapy (CT) metastatic castration-resistant prostate cancer (mCRPC).
Authors: Russell Kent Pachynski, Margitta Retz, Jeffrey C. Goh, Mauricio Burotto, Gwenaelle Gravis, Daniel Castellano, Aude Flechon, Stefanie Zschaebitz, David R. Shaffer, Juan Carlos Vazquez Limon, Marc-Oliver Grimm, Steven L. McCune, Neha P. Amin, Jia Li, Xuya Wang, Keziban Unsal-Kacmaz, Fred Saad, Daniel P. Petrylak, Karim Fizazi
Journal: Journal of Clinical Oncology (2021)

5044 Background: CheckMate 9KD is a phase 2 trial of NIVO (anti-PD-1) combined with either rucaparib, docetaxel, or enzalutamide for mCRPC. PARP inhibitors, like rucaparib, increase cellular DNA damage, particularly in tumors with DNA repair defects, leading to genomic instability and cell death. This DNA damage promotes immune priming and adaptive PD-L1 upregulation. Consequently, dual PD-(L)1 and PARP inhibition is a plausible therapeutic strategy for mCRPC. We report final results for cohort A1 (NIVO + rucaparib for post-CT mCRPC) of CheckMate 9KD. Methods: Cohort A1 enrolled patients (pts) with post-CT mCRPC (1–2 prior taxane regimens), ongoing ADT, ≤ 2 prior novel hormonal therapies (abiraterone, enzalutamide, etc) for mCRPC, and no prior PARP inhibitor treatment. Pts received NIVO 480 mg Q4W + rucaparib 600 mg BID until disease progression/unacceptable toxicity (NIVO dosing limited to 2 yrs). Coprimary endpoints: objective response rate (ORR) per PCWG3 criteria and prostate-specific antigen response rate (PSA-RR; ≥ 50% PSA reduction) in all treated pts and pts with homologous recombination deficiency positive (HRD+) tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Of 88 treated pts, median age 66 yrs (range, 46–85), 34.1% had visceral metastases and 65.9% had measurable disease. Median follow-up was 11.9 mo. Pts had a median of 4.5 NIVO doses and 3.8 mo of rucaparib. The table summarizes primary and key secondary efficacy results, and shows better outcomes for HRD+ vs HRD–/not evaluable (NE) tumors. In pts with BRCA2 mutations, confirmed ORR was 37.5% (3/8 pts) and confirmed PSA-RR was 45.5% (5/11 pts). Any-grade treatment-related AEs (TRAEs) occurred in 93.2% of pts, most commonly nausea (40.9%) and fatigue (33.0%). Grade ≥ 3 TRAEs occurred in 54.5% of pts, most commonly anemia (20.5%) and neutropenia (10.2%). TRAEs led to discontinuation in 27.3% of pts. One pt had a stroke, considered related to rucaparib by the investigator, after 28 days on rucaparib and 2 NIVO doses and died 2 months later due to post-thrombolysis hematoma. Conclusions: NIVO + rucaparib is active in pts with HRD+ post-CT mCRPC, although the trial design and short follow-up limit assessment of benefits of the combination vs individual components. Pts with HRD– tumors did not appear to benefit from either drug. No new safety signals were observed with NIVO + rucaparib. Additional biomarker analyses are ongoing. Clinical trial information: NCT03338790. [Table: see text]
Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial.
Authors: Hirohito Tada, Tetsuya Mitsudomi, Takeharu Yamanaka, Kenji Sugio, Masahiro Tsuboi, Isamu Okamoto, Yasuo Iwamoto, Noriaki Sakakura, Shunichi Sugawara, Shinji Atagi, Toshiaki Takahashi, Hidetoshi Hayashi, Morihito Okada, Hiroshige Yoshioka, Hidetoshi Inokawa, Kazuhisa Takahashi, Masahiko Higashiyama, Ichiro Yoshino, Kazuhiko Nakagawa
Journal: Journal of Clinical Oncology (2021)

8501 Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor is a standard of care for EGFR mutation-positive, untreated metastatic non-small cell lung cancer (NSCLC). However, the efficacy and safety of adjuvant gefitinib for patients with completely resected lung cancer harboring EGFR mutation over cisplatin-based adjuvant chemotherapy were not known in 2011 when this study was initiated. Methods: From September 2011 to December 2015, we randomly assigned 234 patients with completely resected, EGFR mutation-positive (exon 19 deletion or L858R), stage II–III NSCLC to receive either gefitinib (250 mg, once daily) for 24 months or cisplatin (80 mg/m 2 on day 1) plus vinorelbine (25 mg/m 2 on days 1 and 8) (cis/vin) every 3 weeks for four cycles. The primary endpoint was disease-free survival (DFS) according to a central review in the intent-to-treat (ITT) population. Results: Two patients in the gefitinib arm withdrew consent and were excluded from the ITT population. No treatment-related deaths were seen in the gefitinib arm, but three treatment-related deaths were reported in the cis/vin arm. Median duration of follow-up was 71 months. Median DFS was numerically longer in the gefitinib arm (36 months) than in the cis/vin arm (25.2 months). However, Kaplan-Meier curves began to overlap around 5 years after surgery, and no significant difference in DFS was seen, with a hazard ratio (HR) of 0.92 (95% confidence interval (CI), 0.67–1.28; P = 0.63). Overall survival was also not significantly different (median not reached in either arm). Five-year survival rates for gefitinib and cis/vin arms were 78.0% and 74.6%, respectively, with an HR for death of 1.03; 95%CI, 0.65–1.65; P = 0.89. Exploratory subset analysis revealed that patients ³70 years old in the gefitinib arm (n = 19/27 with G to cis/vin) survived longer than those in the cis/vin arm (HR 0.31; 95%CI, 0.10–0.98; P = 0.046). Conclusions: Adjuvant gefitinib appeared to prevent early relapse, but did not significantly prolong DFS or OS in patients with completely resected stage II–III, EGFR-mutated NSCLC. The apparent non-inferiority of DFS/OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for cis/vin adjuvant therapy. Clinical trial information: UMIN000006252.
First-in-human dose-finding study of venadaparib (IDX-1197), a potent and selective PARP inhibitor, in patients with advanced solid tumors.
Authors: Yong Man Kim, Kyun-Seop Bae, Nam Seok Baek, Kyungun Kim, Won Sik Lee, Eun-Jihn Roh, Chan-Young Ock, Sung-Bae Kim
Journal: Journal of Clinical Oncology (2021)

3107 Background: Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors known as single-strand breaks (SSBs). PARP inhibitors are currently approved for ovary, breast, pancreatic and prostate cancers which harbor germline or somatic BRCA1/2 mutations (g/sBRCAmt) and/or homologous recombinant repair mutation (g/sHRRmt). In this phase 1 dose finding study of venadaparib, we determined the maximum tolerated dose for venadaparib monotherapy and explored the safety, tolerability, pharmacokinetics, pharmacodynamics and anticancer efficacy of venadaparib in patients with advanced solid tumor which progressed after an attempt of standard-of-care therapy and for which effective therapy does not exist. Methods: Subjects who satisfied all of the inclusion/exclusion criteria and provided written informed consent were enrolled in this study. The investigational product was administered orally once daily continuously in a 3 weekly cycle. Enrolled subjects were assessed for safety and evaluated on tumor response using RECIST 1.1. The study was carried out in a conventional 3+3 design, starting from 2 mg up to 240 mg. Dose limiting toxicities (DLTs) and pharmacokinetics were assessed during the first cycle. Results: As of 08 Feb 2021, enrollment is completed with 32 patients enrolled. Most common tumor types enrolled are breast cancer (16 patients) and ovarian cancer (11 patients). Other tumor types include cancers of endometrium, fallopian tube, uterus and prostate. No DLTs were observed up to the maximum tested dose of 240 mg. Frequently observed adverse drug reactions were as follows – Anemia (56%), nausea (38%) and neutropenia (25%). Overall objective response rate (ORR) was 16% and clinical benefit rate (CBR) was 47%. Partial response was observed starting from 40 mg and clinical benefit was observed from the lowest dose of 2 mg. From optional tumor tissue samples, venadaparib exhibited ≥ 90% PAR inhibitory effect in pharmacodynamic analysis from 10 mg. For patients with known germline or somatic BRCA status either from local lab results or examined at a central lab retrospectively, ORR and CBR was 22% and 44% respectively for BRCAm(+) (9) patients. Interestingly, clinical efficacy was observed in BRCAm(-) (18) patients also, with ORR and CBR of 17% and 50% respectively. Conclusions: Safety and tolerability of the venadaparib monotherapy was confirmed with preliminary efficacy signals observed, even in BRCAm(-) patients. Clinical benefit was observed from the lowest tested dose, suggesting the potential to combine with other chemotherapeutic agents. Further studies to explore efficacy and safety of venadaparib in other tumor types and combinations, as well as to explore adequate biomarkers are warranted. Clinical trial information: NCT03317743.
Improving consent forms for first-in-human trials through participant feedback.
Authors: Hannah Claire Sibold, Gavin Paul Campbell, John Bourgeois, Margie D. Dixon, R Donald Harvey, Rebecca D. Pentz
Journal: Journal of Clinical Oncology (2021)

e13563 Background: Risks and benefits of investigational agents that have not been tested in humans are, at best, incompletely characterized in nonclinical investigations. Despite the growing emphasis to include patient voices in clinical trial design, no published research has explored patient preferences on how best to convey the information that the agent has not been tested in humans. This study established that First in Human (FIH) consent forms present this information in different locations and queried participants for their input on the preferable FIH consent form structure. Methods: Consent forms for FIH oncology trials open to accrual at Winship Cancer Institute in 2019-2020 were analyzed for (1) the location of the mention that the study drug has not been used in humans before (FIH information), (2) the location of animal and other nonclinical data, and (3) placement of the risks section. Patients offered enrollment in a FIH trial were eligible for this study. Participants were interviewed during a clinic visit after consent was obtained. An ethics researcher asked questions about the participant’s opinions on the wording and placement of the FIH, nonclinical, and risk information in the specific trial consent form. All interviews were audio-recorded and double coded by two independent coders. The location of FIH and nonclinical data in the consent forms was compared to the patient’s suggested location for this information. Results: Saturation of themes was reached after interviewing 17 (17/19, 89% accrual) participants who were enrolled in 9 different FIH trials. Twenty FIH consents were qualitatively analyzed. Preferred placement compared to actual consent placement is listed in the table. 82% (14/17) of participants thought that nonclinical data on risks and efficacy was important to mention. 95% (19/20) of consents listed nonclinical data and most participants thought the placement in the consent was appropriate but 18% (3/17) of participants wanted the information earlier in the consent. No consent forms that were analyzed had the risks section before the study schedule; however, 47% (8/17) of participants wanted to move the risks sections before the study schedule. Conclusions: There is considerable variation in the layout of FIH consent forms that does not align with patient preferences. Standardization of FIH consent forms to better reflect patient input is essential in order to promote understandability of these important yet sometimes misunderstood clinical trials and to ensure ethical informed consent.[Table: see text]
Factors of VEGF, IGF, and TGF-<b>β</b>1 families in omentum tissues to mark premetastatic niches in ovarian cancer.
Authors: Anna P. Menshenina, Elena M. Frantsiyants, Tatiana I. Moiseenko, Ekaterina V. Verenikina, Natalia D. Cheryarina, Darya Yu. Yakubova, Meri L. Adamyan, Natalia V. Chernikova, Tatiana G. Chalabova
Journal: Journal of Clinical Oncology (2021)

e17535 Background: Analysis of the nature of cancer cell release and interaction with the microenvironment determines the fundamental basis of ovarian cancer pathogenesis, which is necessary for the development of new methods for peritoneal dissemination treatment and prevention. The purpose of the study was to analyze levels of VEGF-A, VEGFR1, VEGF-C, VEGFR3, TGF-β, IGF-1, IGF-2 and IGFBP3 in omental tissues (O) with and without metastasis (Mts) in ovarian cancer patients. Methods: Samples of O tissues were obtained from 51 ovarian cancer patients aged 60±1.9 years (G2-G3 serous cystadenocarcinoma – AC, Т2-3NxM0-1). 17 non-cancer patients of similar age were controls (C). Levels of VEGF-A, VEGFR1, VEGF-C, VEGFR3, IGF-1, IGF-2, IGFBP3 and TGF-β1 were measured in Mts and O tissues by standard ELISA test systems. Results: VEGF-A levels in O of AC patients were 2.6 times higher than in C. In Mts, VEGF-A and VEGFR1 exceeded the levels in C (by 6.3 and 3.1 times) and O (by 2.5 and 2.8 times, respectively). VEGF-C in O was lower than in C by 5.5 times, while VEGFR3 was 2.2 times higher. In Mts, VEGF-C and VEGFR3 exceeded the levels in C (by 7.8 and 3.6 times) and O (by 43.3 and 1.6 times, respectively, p&lt;0.05). Levels of IGF-2 and IGFBP3 in O were similar to the levels in C, while IGF-1 was twice higher. In Mts, IGF-1, IGF-2 and IGFBP3 exceeded the levels in C (by 4.9, 2.8 and 3.4 times) and O (by 2.5, 2.2 and 3.6 times, respectively). Levels of TGF-β1 were higher in O by 2.9 times and in Mts – by 2.3 times. Conclusions: The interaction between VEGF-A, IGF-1, and TGF-β can serve as a regulator of the metabolic state of the “soil” for tumor dissemination, marking the premetastatic niche and providing mesenchymal-epithelial transition of circulating tumor cells.
The Israeli study of Pfizer BNT162b2 vaccine in pregnancy: considering maternal and neonatal benefits
Authors: Irina Burd, Tomoshige Kino, James Segars
Journal: Journal of Clinical Investigation (2021)

Pregnant patients with COVID-19 are more likely to require intensive care and die compared with noninfected pregnant women. While the consequences of COVID-19 disease in pregnancy prompted many health care organizations to support vaccination in pregnancy, vaccine effects for mother and infant remained unclear. In this issue of the JCI, Beharier and Mayo et al. explored maternal and neonatal responses to the Pfizer BNT162b2 SARS-CoV-2 mRNA vaccine. The authors examined blood samples from women and cord blood of neonates following childbirth. Samples were stratified into three groups: vaccine recipients, unvaccinated participants with past positive SARS-CoV-2 test, and unvaccinated participants without prior infection. Vaccinated mothers and mothers with previous infection generated and transferred protective IgG antibodies across the placenta. This study provides evidence to support the safety and efficacy of COVID-19 vaccination in pregnancy with protection to the neonate against infection, outlining clear vaccine benefits for both maternal and child health.
All-trans retinoic acid overcomes solid tumor radioresistance by inducing inflammatory macrophages
Authors: Enyu Rao, Yuzhu Hou, Xiaona Huang, Liangliang Wang, Jiaai Wang, Wenxin Zheng, Hengjin Yang, Xinshuang Yu, Kaiting Yang, Jason Bugno, Xingchen Ding, Everett E. Vokes, Yang-Xin Fu, Ralph R. Weichselbaum, Hua Laura Liang
Journal: Science Immunology (2021)

All-trans retinoic acid induces inflammatory myeloid cells to enhance antitumor adaptive immunity after radiation therapy.