tbuckley/cabot-search huggingface dataset:
Role of capmatinib in MET exon 14-mutated advanced non-small cell lung cancer (NSCLC): A systematic review.
Authors: Israr Khan, Faiza Ahmed, Nazma Hanif, Mobeen Zaka Haider, Farhan Khalid, Sakshi Mishra, Radhika Garimella, Kim Andrews, Ramya Pakala, Sirisha Gara, Prathima Guntipalli, Faris Pacha, Karthik Mohan, Andre Thompson, Mohamad Mouchli, Godsgift Enebong Nya
Journal: Journal of Clinical Oncology (2021)

e21150 Background: Capmatinib is a selective inhibitor of MET receptor that got accelerated FDA approval in May 2020 to treat NSCLC with MET ex 14 mutation (METex14). Here, we proclaim the first review of capmatinib efficacy and safety profile in METex14 positive NSCLC patients. Methods: A systematic literature search was conducted using PubMed, Cochrane Library, Clinicaltrials.gov, and Google Scholar. We compiled and analyzed the original studies evaluating the clinical response of capmatinib in MET ex14 mutated advanced NSCLC. Results: The most recent results (as of January 6, 2020) of the GEOMETRY Mono-1 phase 2 study showed an overall response rate (ORR) of 41% (69/97; 95% CI, 29-53) with 41% partial response (PR), and 36% stable disease (SD) in patients who previously received 1-2 prior therapy lines (cohort 4). While the ORR, PR, and SD were 68% ( n = 29/97; 95% CI, 48-84), 64%, and 25%, respectively in treatment naïve patients (cohort 5b). Median progression-free survival (mPFS) and duration of response (DOR) were 5.4 months (mon) and 9.7 mon (95%CI, 5.6-13.0) in cohort 4 vs. 12.4 mon and 12.6 mon (CI, 5.6- not estimated), respectively in cohort 5b. Moreover, disease control was shown in n = 54/69 patients in cohort 4 (95% CI 78 (97-87) and n = 27/28 patients (95% CI 96 (82-100). A post-hoc analysis of 19 patients out of 69 who were pre-treated with immunotherapy demonstrated an ORR of 57.9% (n = 11/19; 95%CI 33.5-79.7) with capmatinib. In contrast, treatment-naive had an ORR of 34% (n = 17/50; 95%CI 21.2-48.8) as per the investigator. Median PFS was 3.29 mon noted on prior therapy. In the phase 1 retrospective analysis reported by Choi et al., ORR was 50% with a median duration of 16.1 (5.3-36.4) mon. Among 45 Japanese pts with MET ex 14 mutated or MET amplified status, the ORR was 36.4% (95% CI 10.9%-69.2%) with a PFS of 4.70 mon in the MET ex 14 mutated groups who had received a second or third line of therapy. Most commonly reported adverse events were peripheral edema, nausea, vomiting, and elevated creatinine across all studies and were mostly grade 1-2. Conclusions: Our results showed that capmatinib has promising anti-tumor activity in patients with NSCLC harboring MET exon 14 skipping mutation. The efficacy and tolerability profile of capmatinib is remarkable, particularly in treatment-naïve patients. Although the GEOMETRY Mono-1 trial is still ongoing, further clinical studies with long-term follow-up are needed.
Phase II trial of stereotactic ablative radiation (SAbR) for oligoprogressive kidney cancer.
Authors: Raquibul Hannan, Michael Christensen, Aurelie Garant, Hans J. Hammers, Waddah Arafat, Kevin Dale Courtney, Isaac Alex Bowman, Suzanne Cole, David Sher, Chul Ahn, Robert D. Timmerman, James Brugarolas
Journal: Journal of Clinical Oncology (2021)

4564 Background: Metastatic renal cell carcinoma (mRCC) patients on systemic therapy may experience oligoprogression. SAbR has been demonstrated to be safe and is associated with high local control rates in mRCC. In this prospective phase II single arm trial, we investigated SAbR to control oligoprogressive mRCC. Methods: Patients with mRCC who demonstrated response to systemic therapy with subsequent radiographic evidence of three or fewer sites of progression were treated with SAbR to all progressive sites. Systemic therapy was held during SAbR at the discretion of the treating oncologist. Follow-up included radiographic imaging at three-month intervals. Sequential SAbR for continued oligoprogression was allowed. The primary objective was extension of ongoing systemic therapy by &gt;6 months in 40% of the patients. Progression was defined by any of these 3 criteria: (1) local failure at a radiated site; (2) progression ineligible for additional SAbR (&gt;3 sites) or involving &gt;30% of metastasis; or (3) progression as clinically determined by treating physicians. An exact binomial test was used to test the probability of postponing systemic therapy. Secondary endpoints focused on overall survival (OS), local control (LC) rates, toxicity, and health-related quality of life (QOL). Results: The trial completed accrual with enrollment of 20 patients who received SAbR to a total of 36 sites. At enrollment four, twelve, three, and one patients were on first, second, third, and fourth line of systemic therapy, respectively. Eleven were on immunotherapy and nine on a tyrosine-kinase inhibitor. Three patients required repeat SAbR to a new site for sequential disease control. At a median follow-up of 8.3 months (interquartile range 3.9 – 15.1), SAbR extended the duration of the ongoing systemic therapy by &gt;6 months in 12 out of 17 patients (70.6%, 95% CI: 48.9%-92.3%). Thirteen out of 20 patients progressed with a median PFS of 8.7 months (95% CI: 3.2-12.4). Five patients died and the OS did not reach the median. LC was 36/36 (100%). Treatment related grade 1 and grade 2 toxicity was experienced by three and one patient, respectively; no grade 3 toxicities were reported. When compared to baseline, no significant decline in QOL was detected. Conclusions: SAbR extended PFS of ongoing systemic by &gt;6 months in oligoprogressive patients with mRCC. SAbR was safe and did not adversely affect QOL. These data support further evaluation of SAbR for oligoproressive mRCC in a prospective randomized setting. Clinical trial information: NCT03696277.
Transjugular intrahepatic portosystemic shunt plus sequential systemic therapy for advanced hepatocellular carcinoma with tumor thrombus-related symptomatic portal hypertension: A multicenter retrospective study.
Authors: Zhenkang Qiu, Guobao Wang, Fujun Zhang, Jingbing Xue, Huzheng Yan, Guisong Wang, Kai Feng, Xuan Wu, Zhijiang He, Weiwei Jiang, Guang Yang, Zixiong Chen, Fei Gao
Journal: Journal of Clinical Oncology (2021)

e16116 Background: Portal vein tumor thrombus (PVTT) and symptomatic portal hypertension severely affect the survival and quality of life of hepatocellular carcinoma (HCC) patients. The aim of this study was to evaluate the clinical outcomes of the transjugular intrahepatic portosystemic shunt (TIPS) plus sequential systemic therapy in advanced HCC patients with tumor thrombus-related symptomatic portal hypertension. Methods: This multi-center retrospective study explored 142 advanced HCC patients with PVTT and symptomatic portal hypertension who received either TIPS plus sequential systemic therapy (group A) or only symptomatic and supportive treatment (group B) for from April 2016 to January 2020. The Kaplan-Meier method and log-rank test were performed to determine the survival differences of variables. Univariable and multivariable Cox proportional hazards regression analyses were used to identify prognostic factors of overall survival (OS). We used independent factors for the nomogram to predict OS. Results: The median OS of group A was significantly better than that of group B (7.6 [95% CI: 4.6, 10.6] vs. 4.5 [95% CI: 2.7, 6.4], months, P &lt; 0.001). Multivariable analysis also showed that PVTT degree (I/II) (Hazard ratios [HR] = 0.679; 95% CI: 0.465, 0.994; P = 0.046), variceal bleeding (HR = 1.686; 95% CI: 1.059, 2.684; P = 0.028), Child-Pugh Class A (HR = 0.450; 95% CI: 0.272, 0.746; P = 0.002), and BCLC stage C (HR = 0.434; 95% CI: 0.222, 0.850; P = 0.015) were significant predictors of OS. These five indicators were included in the nomogram model to predict survival probabilities in 6- and 12-months OS. Conclusions: TIPS plus sequential systemic therapy is safe and feasible for the treatment of advanced HCC with tumor thrombus-related symptomatic portal hypertension.
Evaluation of intra-tumoral (IT) SD-101 and pembrolizumab (Pb) in combination with paclitaxel (P) followed by AC in high-risk HER2-negative (HER2-) stage II/III breast cancer: Results from the I-SPY 2 trial.
Authors: Amy Jo Chien, Hatem Hussein Soliman, Cheryl Ann Ewing, Judy Caroline Boughey, Michael J. Campbell, Hope S. Rugo, Anne M. Wallace, Kathy S. Albain, Erica Michelle Stringer-Reasor, An L Church, Kevin Kalinsky, Anthony D. Elias, Zahi Ibrahim Mitri, Amy Sanders Clark, Rita Nanda, Alexandra Thomas, Christina Yau, Donald A Berry, Laura Esserman
Journal: Journal of Clinical Oncology (2021)

508 Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. SD-101 is an investigational Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide that stimulates the production of IFN-α and interleukin (IL)-12, functional maturation of plasmacytoid dendritic cells, and production of cytotoxic antibodies. IT SD-101 was combined with systemic anti-PD-1 antibody Pb to investigate the antitumor and immunologic activity of this novel immunotherapeutic strategy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts (pts) with HER2- disease were eligible for this treatment. Treatment included weekly P x 12 in combination with IT SD-101 2 mg/ml (1 ml for T2 tumors, 2 ml for &gt;T3 tumors) weekly x 4, then q3 weeks x 2, and IV Pb q3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x 4 (SD-101+Pembro 4). Pts in the control arm received weekly P x 12 followed by AC q2-3 weeks x 4. The I-SPY 2 methods have been previously published. This investigational arm was eligible for graduation (&gt;85% chance of success in a 300-person phase 3 neoadjuvant trial) in 3 of 10 pre-defined signatures: HER2-, hormone receptor (HR)+/HER2- and HR-/HER2-. Results: 75 pts were randomized and evaluable in SD-101+Pembro 4 treatment arm. The control arm included 329 historical controls enrolled since April 2010. The study arm was stopped due to maximal patient accrual. Pt characteristics were balanced; 56% HR+, 44% HR-. The probability that SD-101+Pembro4 was superior to control exceeded 97% for all eligible tumor signatures, but did not reach the threshold for graduation in any of the signatures. However, it is notable that the rate of pCR/Residual Cancer Burden 1 (RCB1) in the HR+/HER2- signature was 51%. Preliminary safety events for SD-101+Pembro 4 include increased rates of fever, neutropenia, febrile neutropenia, transaminitis, and immune-related events, including adrenal insufficiency. Conclusions: The SD-101+Pembro 4 regimen was active but did not meet the pre-specified threshold for graduation in I-SPY 2. pCR/RCB 1 analysis suggests improved response in the HR+/HER-negative signature compared to control. The clinical significance of these findings needs to be weighed against the potential risk of immune-related toxicities. Clinical trial information: NCT01042379. [Table: see text]
RARE-01. ASSESSING THE SYMPTOM DIAGNOSTIC INTERVAL FOR CHILDREN WITH CENTRAL NERVOUS SYSTEM TUMOURS
Authors: Cameron Crowell, Bruce Crooks, Simon Walling, Kelly Boileau, Lynette Bowes, Robert Rutledge, Ketan Kulkarni, Daniel McNeely, Craig Erker
Journal: Neuro-Oncology (2021)

Abstract Background Diagnostic delays in pediatric neuro-oncology is a subject of distress for families and providers. We aimed to evaluate the symptom diagnostic interval (SDI) and influencing variables for children with CNS tumors. Methods This retrospective study analyzed 210 patients diagnosed from 2001–2018 and managed at the tertiary care facility in Halifax, Canada. SDI was defined as time from first symptom until tissue diagnosis or, if not available, imaging diagnosis. Non-parametric tests were used to compare SDI between groups. Results Median SDI was 12.4 weeks (IQR 4.3–30), longer than 7 other studies of 1308 children reporting medians of 4.5–10 weeks (p &amp;lt; 0.01). Most common tumors and their median SDI included low-grade glioma (LGG) (n=97, 46%; 17.9 weeks), medulloblastoma (n=31, 15%; 8.7 weeks), high-grade glioma (HGG) and DIPG (n=23, 11%; 5.6 weeks), and ependymoma (n=13, 6%; 13.6 weeks). The most common initial reported symptom included headache (n=63; 30%), nausea/vomiting (n=27, 18%), seizure (n=24, 12%), and visual impairment (n=13, 6.3%). Patients aged 0–3 years had a shorter SDI than patients 10 years and older (SDI 8.7 vs 14.6 weeks; p = 0.03). Tumor category showed longer SDI for LGG versus HGG (p = 0.003), DIPG (p = 0.02), medulloblastoma (p = 0.03) and other embryonal tumors (p = 0.03). Longer SDI was not associated with increased risk of disease progression for LGG (p = 0.93), medulloblastoma (p = 0.89), or ependymoma (p = 0.5). No difference in SDI was found with regard to diagnosis era, ethnicity, socioeconomic status, or distance to the tertiary care facility. Conclusion SDI at our centre is longer than previously reported studies. SDI is linked to tumor biology and its relevance within specific tumor groups deserves further investigation given it doesn’t appear to predict tumor progression/recurrence, yet families and providers feel distress when delays in diagnosis are perceived.
Feasibility and clinical utility of cancer whole genome and transcriptome sequencing for pediatric and young adult solid tumors.
Authors: Neerav Shukla, Max Levine, Gunes Gundem, Barbara Spitzer, Jesus Gutierrez-Abril, Nancy Bouvier, Juan E. Arango Ossa, Juan Medina-Martinez, Emily Stockfisch, Tara O'Donohue, Ahmet Zehir, Agnes Viale, Shakeel Modak, Filemon S. Dela Cruz, Emily K Slotkin, Matthias A. Karajannis, Julia Lynne Glade Bender, Michael Francis Walsh, Andrew Kung, Elli Papaemmanuil
Journal: Journal of Clinical Oncology (2021)

3063 Background: Next generation sequencing (NGS) assays have accelerated the identification of mutations and potential matched targeted therapies for patients with cancer. However, a significant proportion of patients do not derive clinical benefit from targeted panel sequencing approaches. Cancer whole genome and transcriptome sequencing (cWGTS) offers the opportunity to fully characterize tumors, but are challenged by significant cost and computational resource requirements, concerns of assay sensitivity, and the need to deliver curated results within clinically relevant time frames. We performed a prospective study to evaluate the feasibility and utility of cWGTS in pediatric and young adults with solid tumors. Methods: We developed an automated analytical workflow (Isabl) for the QC and processing of cWGTS data to include ensembl variant calling for germline and somatic substitutions, indels, and structural variants; fusion genes; gene expression; and mutation signatures. Treatment biomarkers were annotated using OncoKB with generation of a clinical prototype report. We tested the feasibility of cWGTS implementation, evaluated its analytical validity compared to standard diagnostic assays, and characterized the clinical utility of incremental findings in a prospective study of children and young adults treated at Memorial Sloan Kettering Cancer Center. Results: A total of 114 patients were enrolled. Standard NGS assays (MSK-IMPACT, MSK-Fusion) identified clinically relevant biomarkers in 22% of cases. The cWGTS process was completed, from sample acquisition to summary report, in less than 12 days. Comparison against clinically reported NGS results demonstrated high precision and recall for reported mutations (98.8%) with high concordance across variant allele representations (r 2 &gt; 0.73). cWGTS identified additional oncogenic mutations not captured by targeted sequencing in 49% of patients. Furthermore, incremental findings, beyond those identified by NGS assays, of direct clinical relevance (diagnostic, prognostic, therapy guiding) were identified in 26% of patients. Importantly, &lt; 5% of the incremental findings would have been captured by whole exome or transcriptome sequencing alone. Of possible therapeutic relevance, cWGTS analyses revealed a significantly higher tumor mutation burden than previously reported (range: 0 - 11.23). Conclusions: We demonstrate feasibility, analytical validity and clinical utility of cWGTS approaches in pediatric and young adult cancer patients, with nearly half of all patients having incremental findings that were not captured by standard targeted NGS approaches.
Activity of erlotinib in patients (pts) with advanced chordoma: A retrospective study.
Authors: Olivier Mir, Sylvain Briand, Thierry Lazure, Julien Adam, Rastilav Bahleda, Jean-Yves Blay, Andrea Cavalcanti, Ali N. Chamseddine, Aurélie Dutour, Matthieu Faron, Leila Haddag, Clemence Henon, Cecile Le Pechoux, Antonin Levy, Carine Ngo, Benjamin Verret, Charles Honoré, Charles Court, Axel Le Cesne
Journal: Journal of Clinical Oncology (2021)

11528 Background: Chordoma is a rare tumor with no approved therapy. Preclinical studies have shown expression of EGFR and activated EGFR family kinases (EGFR, HER2 and HER4). Erlotinib and other anti-EGFR agents (gefitinib and cetuximab) have shown clinical activity in advanced chordoma in single case reports or small series. We aimed to evaluate the activity of erlotinib in a larger, homogeneous series of pts with advanced chordoma. Methods: We retrospectively reviewed the electronic medical records of consecutive adult pts with advanced chordoma progressive over 6 months (+/- 2 weeks, according to RECIST 1.1), treated with erlotinib (150 mg daily) at Gustave Roussy (Villejuif, France) following multidisciplinary tumor board discussion, from January 2010 to January 2021. All cases were confirmed by an expert pathologist. Response was evaluated according to RECIST 1.1, and survival was estimated using the Kaplan-Meier method. Results: Thirty-one pts [median age : 60 years (range : 32-88), median PS : 2 (range : 1-3), 30 males)] were identified. Twenty-seven (87%) had locally advanced disease; the median number of metastatic sites was 1 (range : 1-2) in the remaining 4 pts. Primary tumor site was sacral (25), lumbar (3) or cervical (3). All pts but 6 had undergone prior surgery, and 29 (94%) had undergone radiotherapy of the primary tumor. Eight pts had received previous systemic treatments (imatinib in 4, sorafenib and regorafenib in 2 each). Best tumor response by RECIST 1.1 was PR (4 pts, 13%), SD (14 pts, 45%) or PD (13 pts, 42%). Median PFS was 6.2 months (95%CI : 4.5-9.8), and median OS was 15.9 months (95%CI : 10.6-20.2). Fourteen pts (45%) remained progression-free after 1 year, and three (10%) after two years under erlotinib. Grade 3 diarrhea occurred in 4 pts (13%) and grade 3 skin rash in 13 pts (42%). Twelve pts (39%) required dose reduction to 100 mg daily due to multiple grade 2 toxicities. Ongoing studies are exploring whether candidate biomarkers such as EGFR and HER2 expression or amplification, and their mutational status could help predicting the benefit of erlotinib in pts with advanced chordoma. Conclusions: Erlotinib has clinically meaningful but unpredictable activity in advanced chordoma. Molecular profiling would probably be of high interest in this setting. This series may serve as a benchmark for future clinical trials in chordoma.
Obinutuzumab short-duration infusion (SDI) in previously untreated advanced follicular lymphoma: Results from the end of induction analysis of the phase IV GAZELLE study.
Authors: Miguel Angel A. Canales Albendea, Thomas A. Buchholz, Koji Izutsu, Takayuki Ishikawa, Laura Maria Fogliatto, Ekaterina Vorozheikina, Dirk Klingbiel, Sunny Pokala, Monique Tomiczek, Joana Parreira, Kai Hübel
Journal: Journal of Clinical Oncology (2021)

7545 Background: Obinutuzumab (G)-chemotherapy (chemo) has demonstrated improved progression-free survival compared with rituximab (R)-chemo in previously untreated advanced follicular lymphoma (FL). G is currently administered by IV infusion over ̃3–4 hours. A shorter duration of infusion in Cycle (C) 2 and subsequent cycles, as is standard practice with R, could improve convenience for patients (pts) and efficiency for infusion facilities. We report the primary analysis of the prospective, open-label, multicenter, single-arm, Phase IV, GAZELLE study (NCT03817853), which evaluated the safety of G administered as a 90-minute (min) SDI from C2 onwards in pts with FL. Methods: Pts with previously untreated FL received G (1000mg) intravenously on Day (D) 1, 8, and 15 of C1, and on D1 thereafter, plus chemo (bendamustine, CHOP, or CVP) for 6–8 cycles. In C1, pts received G at the standard infusion rate. Pts without a Grade (Gr) ≥3 infusion-related reaction (IRR) in C1 were eligible to receive G as a 90-min SDI from C2. Pts with a Gr 3 IRR in C1 received the standard G infusion in C2, and were eligible for G SDI in subsequent cycles if no Gr ≥3 IRRs occurred. Pts with a second Gr 3/4 IRR discontinued G. At the end of induction (EOI), responding pts received maintenance G (1000mg) as SDI for 2 years or until disease progression (PD). The primary endpoint was incidence of Gr ≥3 IRRs during C2. IRRs were defined as any event occurring ≤24 hours from infusion judged to be related to treatment. Secondary endpoints included adverse events (AEs) and investigator-assessed overall response rate at EOI. Results: As of December 3, 2020, 113 pts had received study treatment. Median age was 62.0 years, 50.4% were male, 61.9% had stage IV FL, and 45.1% were classified as high-risk FLIPI. Of the 110 pts who were eligible for G SDI from C2, no pt experienced a Gr ≥3 IRR with SDI in C2 (Table). One pt experienced a Gr 3 IRR with SDI in C5, presenting hypertension. All other IRRs with SDI were Gr 1/2. No Gr 4/5 IRRs were reported. Other AEs were similar to those observed in previous studies. At the clinical cut-off date, 104 pts had a CT imaging-based response assessment at EOI and 9 pts had no response assessment; 76/113 (67.3%) had a complete response, 22 (19.5%) had a partial response, and six (5.8%) had PD. Conclusions: In GAZELLE, G SDI in C2 and beyond appeared to be safe. No Gr 3 IRRs were observed in C2 and only one Gr 3 IRR was reported in subsequent cycles. The safety profile of G SDI was comparable with the established profile of G in advanced FL. Clinical trial information: NCT03817853. [Table: see text]