bluuebunny/crossref_metadata_2025 huggingface dataset:
ctDNA from ascites as an alternative to tumor sampling for HRD (homologous recombination deficiency) testing in ovarian cancer (OC).
Authors: Leary Alexandra , el Hazzaz Reda , Le Formal Audrey , Lecerf Elodie , Brizais Chloé , Colomba Blameble Emeline , Gouy Sebastien , Maulard Amandine , Boursin Yannick , Pautier Patricia
Published: May 2020

6066

Background: Knowledge regarding HRD status is becoming crucial to guide maintenance strategies for patients with newly diagnosed OC. Unfortunately, for patients (pts) treated with neoadjuvant chemotherapy (NACT), HRD testing on small biopsies from diagnostic laparoscopies (Dx Lap) or interval debulking has a high failure rate. At relapse, biopsies may not be feasible. Aim: Evaluate the feasibility and usefulness of HRD testing on cfDNA from ascites Methods: Pts enrolled in a prospective biological study (OvBIOMark) consented to analysis of biological samples obtained as part of routine diagnosis. cfDNA was extracted from 1-2ml of double-centrifuged fresh ascites and subjected to 1) targeted NGS including the most common somatic mutations in high grade ovarian cancer ( TP53) to confirm presence of tumor cfDNA and 2) SNParray for copy number (CN) analyses to calculate a genomic instability score (GIS) for HRD. Results: Thirty four ascites samples were collected from 25 pts with suspected or confirmed OC. For 15/25 pts samples were obtained at Dx Lap, and for 10 pts samples were obtained at relapse. Seven pts underwent repeat ascitic drains during treatment or at relapse. 97% (33/34) of ascitic samples had detectable cfDNA (median = 980ng, range:80-5730ng) even when obtained during chemotherapy. A deleterious mutation was identified in 87% (29/33) of samples with high allelic frequencies (median allelic frequency, AF = 60%; 3.3-87%), confirming that most of detected cfDNA was tumoral. The most common mutation was a TP53m (86%; 25/29). We have performed CN analysis on cfDNA from ascites on 17 of these patients to evaluate their HRD status. Ten pts had a high GIS (HRD+), and 7 pts a low GIS (HRD-). The 4 pts with confirmed BRCAm included in this study had a high GIS on ascites. When available from the same patient, the CN profiles derived from ascites cfDNA and tumor sampling were superimposable. Conclusions: Ascites yields large amounts of cfDNA, which can be confirmed as tumoral based on TP53 mutation detection. CN analysis on ascitic cfDNA is feasible and can be used to detect the same HRD scar as tumor testing. Ascites is frequent at diagnosis, especially in pts with inoperable disease planned for NACT and could provide a useful alternative to tumor for HRD and BRCA testing.
Ovarian cancer clinical trials: Study the studies to terminate the terminations.
Authors: Spinosa Daniel , Howell Elizabeth , Williams D'Erryl , Watson Catherine , Akinyemiju Tomi F. , Previs Rebecca A.
Published: May 2020

6069

Background: Clinical trials safely expand the arsenal of treatments available to future patients while providing hope to current patients, particularly ovarian cancer patients who often have poor prognoses. Trial termination for lack of efficacy or unacceptable toxicity are consistent with the aim of protecting patients in the pursuit of knowledge, but those are not the only reasons trials terminate early. Understanding why some clinical trials do not achieve their stated goals may aid in the design of future trials. Methods: Data were gathered from clinical trials registered to ClinicalTrials.gov. Included trials were interventional (as opposed to observational), were closed between 2004 and 2019, enrolled ovarian cancer patients, had submitted results, and were open at one or more domestic sites. For each trial, data were captured regarding study completion, reason for non-completion (if applicable), sites, phase, sponsor (defined as the study initiator, not necessarily the funder), and intervention type. Results: A total of 313 trials were examined, of which 262 met inclusion criteria. Of the 262 evaluable trials, 189 (72%) were completed and 72 (27%) terminated early. The most common reasons for early termination were low accrual (27 trials, 38%), lack of efficacy (15 trials, 21%), or insufficient funding (9 trials, 13%). Five trials (7%) were terminated early due to toxicity. Early phase trials are less likely to complete enrollment, with 11 out of 16 (65%) phase 1 trials, 135 out of 180 (75%) phase 2 trials, and 15 out of 16 (94%) phase 3 trials completed. Trials initiated by an academic center were twice as likely to be terminated early (41/103, 40%) as those initiated by industry (16/80, 20%), with remaining trials initiated by consortia, NCI, or non-academic oncology practices. Terminated trials were open at an average of 11 sites (range 1-317), while completed trials were open at an average of 27 sites (range 1-632). Trials that had multiple types of interventions, for instance a drug and a procedure, had a 34% early termination rate which was higher than the rate for trials with any single type of intervention. Conclusions: More than one in four ovarian cancer clinical trials are terminated early, rarely due to treatment efficacy or tolerability. Trials terminated for reasons other than patient outcomes represent a misallocation of resources or a missed opportunity for innovation. Further research is needed to understand the circumstances that allow for clinical trial completion such that available resources maximize patient benefit.
Computerized features of spatial arrangement of tumor-infiltrating lymphocytes from H&E images predicts survival and response to checkpoint inhibitors in gynecologic cancers.
Authors: Azarianpour Esfahani Sepideh , Corredor Germán , Bera Kaustav , Fu PingFu , Joehlin-Price Amy , Mahdi Haider , Madabhushi Anant
Published: May 2020

6074

Background: Immune checkpoint inhibitors (ICI) have demonstrated success in solid tumors. In gynecologic cancers (GC), the response rate is still low (~10-15%) except in MSI-H endometrial cancer (~ 50%). Current biomarkers (e.g. PDL1 expression) have limited utility in identifying benefit from ICI in GC. In this work we evaluated the ability of computational measurements of spatial arrangement of tumor infiltrating lymphocytes (TIL) from H&E slide images in predicting overall survival (OS) and response to ICI in ovarian, cervical and endometrial cancers. Methods: The study included 151 patients, including 102 ovarian carcinomas treated with surgery and chemotherapy (D1) and another set (D2) of n=49 patients (n=14 ovarian, n=27 endometrial and n=8 cervical), treated with different ICI agents (Pembrolizumab, Nivolumab, Ipilimumab, Avelumab) in the second line setting. Progressors and non-progressors in D2 were classified according to clinical improvement and radiologic assessment by RECIST. A machine learning approach was employed to identify tumor regions on the diagnostic slides from D1 and D2 and then used to automatically identify TILs within the tumor regions. Subsequently machine learning was used to define TIL clusters based on TIL proximity, and graph network theory was used to capture measurements relating to spatial arrangement of TIL clusters. The multivariable Cox regression model (MCRM) was trained on n=51 patients from D1 to predict OS and then independently evaluated in predicting (1) OS on the hold-out n=51 patients in D1 and (2) response and progression-free survival (PFS) in D2. Results: Statistical analysis identified 7 prognostic features relating to interaction of TIL clusters with cancer nuclei. MCRM was prognostic of OS on the n=51 hold out patients in D1 (hazard ratio (HR)=2.06, 95% confidence interval [1.04- 4.07], p=0.008) and predictive of PFS in D2 (HR=2.24, CI=[1.13-4.44], p=0.03). The AUC for MCRM in predicting progression in D2 was 82%. Conclusions: Computerized features of spatial arrangement of TILs on H&E images were prognostic of OS and PFS and predicted response to ICI in three gynecological cancers. These findings need to be validated in larger, multi-site validation sets. [Table: see text]
Randomized phase II study of sapanisertib (SAP) + paclitaxel (PAC) versus PAC alone in patients (pts) with advanced, recurrent, or persistent endometrial cancer.
Authors: Scambia Giovanni , Han Sileny N. , Oza Amit M. , Colombo Nicoletta , Oaknin Ana , Raspagliesi Francesco , Wenham Robert Michael , Braicu Elena Ioana , Jewell Andrea , Makker Vicky , Guerra Eva M. , Moxley Katherine M. , Baurain Jean-Francois , Su Zhenqiang , Neuwirth Rachel , Vincent Sylvie , Sedarati Farhad , Faller Douglas V. , Krell Jonathan
Published: May 2020

6087

Background: SAP (TAK-228, MLN0128) is a selective dual inhibitor of mammalian target of rapamycin complexes 1 and 2. In endometrial tumor xenograft models, SAP+PAC exhibited stronger antitumor efficacy than PAC alone. Methods: Female pts with histologic/cytologic diagnosis of endometrial cancer were randomized to receive SAP 4 mg by mouth (days [d] 2–4, 9–11, 16–18, 23–25) plus PAC 80 mg/m2 intravenously (d 1, 8, 15), or PAC alone, in 28-day cycles until unacceptable toxicity or disease progression. Randomization was stratified by histologic subtype, lines of prior chemotherapy (1 vs. 2), and prior taxane therapy. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR; ORR + stable disease), and safety. Additional treatment arms of SAP alone (weekly dosing) and SAP+TAK-117 were closed after futility analyses. Results: 180 pts were randomized to SAP+PAC (n=90) or PAC (n=90); 86 and 87 pts received SAP+PAC and PAC, respectively; 3 pts from each arm were ongoing on treatment at data cut (30 July 2019). Baseline characteristics were balanced between arms. After a median follow-up of 17.2 vs. 14.4 mos with SAP+PAC vs. PAC, median PFS was 5.6 mos vs. 3.7 mos (hazard ratio [HR] 0.82; 95% CI 0.58–1.15). In pts with endometrioid histology (n=116), median PFS was 5.7 mos with SAP+PAC vs 3.3 mos with PAC (HR 0.66; 95% CI 0.43–1.03). In pts with nonendometrioid histology (n=64), median PFS was 3.6 mos with SAP+PAC vs. 5.4 mos with PAC (HR 1.09; 95% CI 0.62–1.90). Median OS was 13.7 mos with SAP+PAC vs. 14.6 mos with PAC (HR 1.01; 95% CI 0.67–1.53). Confirmed ORR was 24% with SAP+PAC vs. 18% with PAC (endometrioid, 23% vs. 16%; nonendometrioid, 28% vs. 22%); CBR was 80% vs. 58% (endometrioid, 84% vs. 55%; nonendometrioid, 72% vs. 63%). Median number of cycles received was 5 (range 1–23) with SAP+PAC and 4 (range 1–37) with PAC. Rates of grade ≥3 treatment-emergent adverse events (TEAEs) were 90% with SAP+PAC vs. 54% with PAC; the most common included anemia (21% vs.12%), neutropenia (12% vs. 3%), fatigue (12% vs. 5%), hypophosphatemia (12% vs. 1%), and pulmonary embolism (11% vs. 3%). Conclusions: Median PFS was longer with SAP+PAC vs. PAC in pts with endometrial cancer but did not reach statistical significance. PFS was particularly longer in the endometrioid subtype but again was not significant, and further studies are warranted. Incidence of grade ≥3 TEAEs was higher with SAP+PAC vs. PAC, but SAP+PAC toxicity was manageable, with no new safety signals. Clinical trial information: NCT02725268.
Uterine cancer histology and stage at presentation in black and white women: A cohort study of 488,000 patients.
Authors: Abel Mary Kathryn , Liao Cheng-I , Darcy Kathleen M. , Tian Chunqiao , Mann Amandeep Kaur , McDonald Yassmina , Williams Kenneth , Maxwell George Larry , Kapp Daniel Stuart , Chan John K.
Published: May 2020

6089

Background: Although mortality among black women diagnosed with uterine cancer is higher than in white women, the reason for this difference is not completely understood. We proposed to investigate the differences in the incidence and presentation of uterine cancer histology among black women compared to white women. Methods: Data were obtained from the United States Cancer Statistics (USCS) and the National Cancer Database (NCDB) between 2004 and 2016. Chi-squared tests were used for statistical analyses. Results: Of 488,811 patients with uterine cancer, 411,904 (84.3%) were white and 51,093 (10.5%) were black. Based on USCS data, the incidence of endometrioid carcinoma in white women was 19.63 (per 100,000 per year) compared to 12.53 in black women. However, the incidence of high-risk histologies was higher in black women, particularly for serous tumors (3.32 vs. 1.29), clear cell tumors (0.59 vs. 0.31), carcinosarcoma (2.88 vs. 1.05), and leiomyosarcoma (1.02 vs. 0.48). Using the NCDB database, we evaluated the proportion of these histologies based on race. Compared to white women, black women have a higher proportion of serous (14.2% vs. 5.6%), clear cell (2.4% vs. 1.3%), carcinosarcoma (12.3% vs. 4.5%), and leiomyosarcoma (4.3% vs. 1.7%). black women were less likely to have endometrioid (52.7% vs. 75.9%) and mucinous (0.4% vs. 0.8%) tumors. In addition, black women were more likely to have stage III or IV disease at presentation when all histological subtypes were combined (22.8% vs. 17.7%). However, of those with endometrioid and grade 1 tumors, black women did not have more advanced stage at presentation compared to white women (3.8% vs. 4.7%). Conclusions: Compared to white women, black women are more likely to be diagnosed with serous, clear cell, carcinosarcoma, and leiomyosarcomas at a more advanced stage upon presentation, but they are less likely to have endometrioid tumors. More research is needed to understand why this disparity exists.
Transoral robotic surgical resection followed by randomization to low- or standard-dose IMRT in resectable p16+ locally advanced oropharynx cancer: A trial of the ECOG-ACRIN Cancer Research Group (E3311).
Authors: Ferris Robert L. , Flamand Yael , Weinstein Gregory S. , Li Shuli , Quon Harry , Mehra Ranee , Garcia Joaquin J. , Chung Christine H. , Gillison Maura L. , Duvvuri Umamaheswar , O'malley Bert W. , Ozer Enver , Thomas Giovana R. , Koch Wayne , Kupferman Michael Elliot , Bell Richard Bryan , Saba Nabil F. , Lango Miriam , Mendez Eduardo , Burtness Barbara
Published: May 2020

6500

Background: ECOG-ACRIN 3311 examines reduced postoperative therapy in patients with “intermediate risk” p16+ oropharynx cancer (OPC) undergoing primary transoral surgical management. We report the primary endpoint of 2-year progression free survival (PFS) for patients randomized to 50Gy vs 60Gy without chemotherapy. Methods: Between December 2013 and July 2017, 82 credentialed surgeons performed transoral resection (TOS) for 519 OPC patients (cT1-2 stage III/IV AJCC7 without matted neck nodes); post-operative management was determined by pathologically assessed risk. Among 353 eligible and treated patients, Arm A enrolled 10% (N=37) for clear margins, 0-1 nodes, no extranodal extension (ENE)), Arms B (50Gy, N=102) or C (60Gy, N=104) randomized 58%, for clear/close margins, 2-4 + nodes, or ENE ≤1mm, while Arm D (N=110, 60-66Gy plus weekly cisplatin, 40 mg/m2, positive margin with any T stage, >4 + nodes, or >1mm ENE) enrolled 31%. Arm D assignment was based on >1mm ENE (76%), > 4 nodes (27%), and/or positive margins (11%). Intermediate-risk patients were stratified by smoking history (>10 pk-yr). Of the 80 pts (15%) deemed ineligible, 28 had scans/labs not done per protocol, however treatment arm distribution for all patients mirrored that for the 353 pts eligible and treated. Results: Median follow-up was 31.8 months. 2 yr PFS for Arms A, B and C were 93.9% (90% CI=87.3%, 100%), 95.0% (90% CI=91.4%, 98.6%) and 95.9% (90% CI=92.6%, 99.3%) respectively, while Arm D was 90.5% (90% CI=85.9%, 95.3%). The regimen of TOS + low-dose radiation is considered worthy of further study, since the primary endpoint of the upper bound of the 90% CI (in the intermediate risk group) exceeding 85% was met. Of 17 progression events, 7 were locoregional. There were 10 distant recurrences: Arm A=1, Arm B=2, Arm C=4, Arm D=3. Grade III/IV treatment-related AE rates were 15%/2% during surgery, 13%/2% for Arm B and 25%/0% for Arm C. There were 2 treatment-related deaths (one surgical and one Arm D). Conclusions: Transoral resection of p16+ OPC is safe and results in good oncologic outcome, presenting a promising deintensification approach. For patients with low-risk disease, 2-yr PFS is favorable without post-operative therapy. For those with uninvolved surgical margins, <5 involved nodes, and minimal (<1mm) ENE, reduced dose postoperative RT without chemotherapy appears sufficient. Transoral surgery plus 50Gy should be compared to optimal non-surgical therapy in a phase III trial. Clinical trial information: NCT01898494 .
Preliminary activity of tipifarnib in tumors of the head and neck, salivary gland and urothelial tract with HRAS mutations.
Authors: Ho Alan Loh , Hanna Glenn J. , Scholz Catherine Rose , Gualberto Antonio , Park Se Hoon
Published: May 2020

6504

Background: HRAS is a proto-oncogene overexpressed and mutated in some human carcinomas. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme for proper HRAS function. Methods: We report data from two phase 2 clinical trials investigating the activity of tipifarnib in HRAS mutant (HRASm) solid tumors: KO-TIP-001 (NCT02383927: Squamous carcinomas [SCC], thyroid and salivary gland tumors, among others) and IST-01 (NCT02535650: Urothelial carcinomas, UC).Primary endpoints were overall response rate (ORR, KO-TIP-001) and progression free survival (PFS) rate at 6 months (IST-01). All pts had RECIST v1.1. measurable disease at study entry. Pts receive a starting dose of tipifarnib of either 600 or 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. Results: Proof of concept was achieved in studies KO-TIP-001 and IST-01. Based on preliminary efficacy results (Ho, et. al, ESMO 2018), KO-TIP-001 was amended to continue enrolling only in Head & Neck SCC (HNSCC) pts (Cohort 2) and other SCC pts (Cohort 3) with tumors carrying high HRASm variant allele frequency (VAF) >20%. As of 17 October 2019, 21 HNSCC pts meeting the high HRASm VAF criteria had been treated with tipifarnib of whom 18 were efficacy evaluable at data cut off. Pts had received a median of 2 prior systemic regimens. Ten objective responses were observed in 18 evaluable pts for an ORR of 56%. No responses were observed on last therapy prior to study entry. PFS on tipifarnib and on prior last therapy were, respectively, 6.1 and 2.8 months. In addition, 13 pts with recurrent/metastatic salivary gland tumors (SGT) were treated in KO-TIP-001 or in extended access programs. One objective response was observed in 12 (8%) evaluable pts and an additional 7 (58%) had stable disease as best response. Median PFS in SGT pts was 7 months. In IST-01, 224 UC pts were screened of whom 16 (7%) carried HRAS mutations and 15 of those were enrolled into the study. Five responses were observed in 12 evaluable UC pts (42%) and 3 additional pts had tumor size reduction. Median PFS was 5.1 months. Conclusions: Encouraging activity of tipifarnib was observed in HRASm solid tumors. Clinical trial information: NCT02383927, NCT02535650 .
KEYNOTE-048: Progression after the next line of therapy following pembrolizumab (P) or P plus chemotherapy (P+C) vs EXTREME (E) as first-line (1L) therapy for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Harrington Kevin Joseph , Rischin Danny , Greil Richard , Soulieres Denis , Tahara Makoto , Castro Gilberto , Psyrri Amanda , Baste Neus , Neupane Prakash C. , Bratland Åse , Fuereder Thorsten , Hughes Brett Gordon Maxwell , Mesia Ricard , Ngamphaiboon Nuttapong , Rordorf Tamara , Wan Ishak Wan Zamaniah , Zhang Yayan , Gumuscu Burak , Swaby Ramona F. , Burtness Barbara
Published: May 2020

6505

Background: 1L P vs E improved OS in PD-L1 CPS ≥20 and CPS ≥1 populations, and led to noninferior OS in the total population, with favorable safety; 1L P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety in the phase 3 KEYNOTE-048 study (NCT02358031) in patients with R/M HNSCC. Neither P vs E nor P+C vs E improved PFS in the PD-L1 CPS ≥20, CPS ≥1, or total populations. Here, we present the progression after the next line of therapy (PFS2) to assess the effect of 1L P or P+C and subsequent anticancer therapy on patient outcomes. Methods: Patients with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting were randomly assigned 1:1:1 to P, P+C, or E. PFS2 was defined as time from randomization to objective tumor progression on next-line therapy or death from any cause. PFS2 was estimated using the Kaplan-Meier method as an exploratory outcome confined to those receiving subsequent therapy after 1L P. HR and 95% CIs were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate (stratified by ECOG performance status [PS], HPV status, and PD-L1 for CPS ≥1 and total populations; by ECOG PS and HPV status for CPS ≥20 population). Data cutoff: Feb 25, 2019. Results: Of 882 (301 [P]; 281 [P+C]; 300 [E]) treated patients,422 (P: 148 [49.2%]; P+C: 115 [40.9%]; E: 159 [53.0%]) received subsequent anticancer therapy after 1L P, most commonly C (P: 135 [44.9%]; P+C: 88 [31.3%]; E: 102 [34.0%]); EGFR inhibitor (P: 59 [19.6%]; P+C: 37 [13.2%]; E: 19 [6.3%]); and immune checkpoint inhibitor (P: 6 [2.0%]; P+C: 12 [4.3%]; E: 50 [16.7%]); patients may have received more than one type of subsequent therapy. Median PFS2 is reported in Table. Conclusions: In patients with R/M HNSCC, longer median PFS2 was observed in the CPS ≥20 and CPS ≥1 populations for P vs E, and in the CPS ≥20, CPS ≥1, and total populations for P+C vs E. These data further support use of 1L P or P+C in patients with R/M HNSCC. Clinical trial information: NCT02358031 . [Table: see text]
Evaluation of the correlation between antibiotic use and survival in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Vellanki Paz J. , Marur Shanthi , Bandaru Pradeep , Mishra-Kalyani Pallavi Shruti , By Kunthel , Girvin Andrew , Chatterjee Somak , Singh Harpreet , Keegan Patricia , Larkins Erin A. , Cross Frank , Pazdur Richard , Theoret Marc R.
Published: May 2020

6509

Background: Recent evidence suggests that treatment with systemic antibiotics (Abx) disrupts the intestinal microbiome and may be associated with decreased survival for patients receiving treatment with ICIs for advanced cancers, including R/M HNSCC. However, a potential confounder is that Abx use identifies a subgroup of patients with a worse prognosis. The FDA examined the association between Abx use and survival for ICIs and other drugs used for the treatment of patients with R/M HNSCC. Methods: Data submitted to the FDA from three randomized controlled trials with ICI as a single agent or with chemotherapy (ICI group) compared to chemotherapy and/or cetuximab (Control group) were pooled. The association between systemic Abx use within 30 days of initiating anticancer therapy and survival for the ICI and Control groups was evaluated using Kaplan-Meier (KM) estimates and compared using Cox proportional hazards regression models, controlling for ECOG performance status, line of therapy, HPV status, PD-L1 expression, and other important prognostic factors. Results: In the ICI and Control groups, 36% and 46% of patients received Abx, respectively. For the ICI group, the difference in KM-estimated median overall survival (OS) was 5.6 months based on receipt of Abx (hazard ratio [HR] 1.70). Abx had no impact on OS for the Control group. Similar trends were observed for progression-free survival (PFS). Conclusions: In this exploratory analysis, systemic Abx within 30 days of initiating treatment for R/M HNSCC was associated with decreased survival for patients treated with ICIs compared with patients who did not receive Abx. Use of Abx had no apparent difference in survival in the control group. Further examination of the association between Abx use and clinical outcomes for patients with R/M HNSCC treated with ICIs is needed. [Table: see text]
Lenvatinib plus pembrolizumab combination therapy in patients with radioiodine-refractory (RAIR), progressive differentiated thyroid cancer (DTC): Results of a multicenter phase II international thyroid oncology group trial.
Authors: Haugen Bryan , French Jena , Worden Francis P. , Konda Bhavana , Sherman Eric Jeffrey , Dadu Ramona , Gianoukakis Andrew G. , Wolfe Eric G. , Foster Nathan R. , Bowles Daniel W. , Wirth Lori J.
Published: May 2020

6512

Background: Lenvatinib is an approved therapy for patients with RAIR DTC. While the overall response rate (ORR) is high, few patients achieve a complete response (CR) and most patients eventually have progressive disease (PD). Combination lenvatinib and pembrolizumab is being explored in many different cancers, and this combination has been approved for advanced endometrial carcinoma. Methods: Patients with RAIR DTC with Response Evaluation Criteria in Solid Tumor (RECIST v1.1) measurable PD (<14 months (mo) prior to registration) were enrolled in this single-arm multicenter phase II study. Patients were excluded if they had received previous VEGFR-directed multikinase therapy. The lenvatinib starting dose was 20 mg/day orally and pembrolizumab was 200mg IV every 3 weeks. The primary endpoint was CR. ORR, progression-free survival (PFS) and safety graded by Common Terminology Criteria for Adverse Events v4.0 were secondary endpoints. Results: Thirty patients were enrolled. The median age was 62.5 years, and 53% of the patients were women. Seventy percent of patients had grade 3 adverse events (AEs) and 10 percent had grade 4 AEs. There were no treatment-related deaths. The most common > grade 3 AEs were hypertension (47%), weight loss (13%), maculopapular rash (13%), leukopenia (7%), diarrhea (7%) and oral mucositis (7%). Twenty-one patients (70%) required lenvatinib dose reduction. Of 29 evaluable patients, 18 (62%) had a partial response (PR) and 10 (35%) had stable disease (SD). The clinical benefit rate (ORR +SD) was 97%. Median time to tumor nadir was 7.4 mo (1.6-17.8 mo). Median PFS was not yet reached. The PFS at 12 months was 74%. Median time on therapy was 9.9 mo (3.2-18.9 mo). Fourteen patients are continuing therapy (7.6-18.9 mo). Six of these patients (43%) have not yet reached tumor size nadir. Three patients (10%) had > 80% target tumor shrinkage. Conclusions: Lenvatinib plus pembrolizumab is reasonably tolerated in patients with RAIR DTC. To date, there have been no documented complete responses. Combination lenvatinib plus pembrolizumab therapy has a high ORR in patients with RAIR DTC. Continuation of this study will help determine the depth and length of the responses. Clinical trial information: NCT02973997 .
Concurrent cetuximab (CTX) and nivolumab (NIVO) in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Results of phase II study.
Authors: Chung Christine H. , Bonomi Marcelo Raul , Steuer Conor Ernst , Schell Michael J. , Li Jiannong , Johnson Matthew , Masannat Jude , Hernandez-Prera Juan C. , McMullen Caitlin , Wadsworth J , Patel Krupal , Kish Julie Ann , Muzaffar Jameel , Kirtane Kedar , Rocco James William , Saba Nabil F.
Published: May 2020

6515

Background: While anti-Programmed Death-1 (anti-PD-1) inhibitors have efficacy, only some patients (pts) with R/M HNSCC achieve clinically significant benefits. We designed the study to determine the 1-year overall survival (OS) rate of concurrent CTX and NIVO in patients who had progressed on at least one prior treatment for their R/M HNSCC. Methods: Pts were treated with CTX 500 mg/m2 IV on Day (D) -14 as a lead-in followed by CTX 500 mg/m2 IV and NIVO 240 mg/m2 IV on D1 and D15 every 28-D cycle (C). Pts with CTX infusion reaction or who did not receive C1D1 for any reason were non-evaluable and replaced. NIVO dose reduction was not allowed but withheld/discontinued based on adverse event (AE) severity. Results: Total 47 pts are enrolled. 2 pts are non-evaluable. 45 evaluable pts are analyzed. Median age is 64 (24-77). ECOG performance status at baseline is 0 (9, 20%), 1 (33, 73%), and 2 (3, 7%). Primary sites are oral cavity 10 (22%), oropharynx 24 (53%), hypopharynx 3 (7%), larynx 6 (13%), and unknown primary 2 (4%). p16 status is available in 33 (73%). Prior treatments before the study enrollment are: chemotherapy (CT) 42 (93%), no CT 3 (7%), radiotherapy (RT) 38 (84%), no RT 7 (16%), checkpoint inhibitors (CPI) 23 (51%), and no CPI 22 (49%). PD-L1 combined positive scores (CPS) is available in 30 (67%). Median follow up time for overall survival (OS) is 12.6 months. The most common grade 3 treatment-related AE (TRAE) occurring ≥2 are fatigue 6 (13%) and rash-acneiform 2 (4.4%). The only grade 4 TRAE is CTX infusion reaction in 1 (2.2%). The most common grade 3 immune-related AE (IRAE) occurring ≥2 is fatigue 3 (6.7%). No grade 4 IRAE is observed. The median progression-free survival (PFS) and median OS are summarized in Table. Pts with no prior exposure to CPI have favorable PFS and OS relative to pts with prior CPI (PFS: HR 0.49, 95% CI 0.25-0.97, p=0.04 and OS: HR 0.5, 95% CI 0.22-1.14, p=0.09). Conclusions: Our data suggest the combination of CTX and NIVO is active in pts without prior CPI exposure and overall well tolerated in all pts. These preliminary results support further evaluation of the combination in CPI naïve pts. Clinical trial information: NCT03370276 . [Table: see text]
Phase II study of consolidative intensity-modulated radiation therapy following first-line palliative systemic chemotherapy for de novo previously untreated metastatic (M1) nasopharyngeal carcinoma.
Authors: Lee Victor Ho-Fun , Chan Ann SY , Kwong Dora LW , Leung To-Wai , Ng Sherry CY , Tong Chi-Chung , Lam Ka-On , Vardhanabhuti Varut , Chan Sik-Kwan , Choi Cheuk-Wai , So Tsz Him , Chan Wing-Lok , Luk Mai-Yee , Khong Pek-Lan , Lee Anne WM
Published: May 2020

6524

Background: The prognosis of de novo previously untreated metastatic (M1) nasopharyngeal carcinoma (NPC) at diagnosis is poor, and the role of consolidative intensity-modulated radiation therapy (IMRT) to the primary tumor and the neck following first-line palliative chemotherapy remains unknown. We report a phase II study of consolidative IMRT after first-line chemotherapy in previously untreated M1 NPC. Methods: Consolidative IMRT was given in prospectively recruited patients whose previously untreated M1 NPC did not progress after 6 cycles of first-line chemotherapy with gemcitabine and cisplatin. The primary study objective was overall survival (OS). Secondary objectives included progression-free survival (PFS), local relapse-free survival (LRFS), regional relapse-free survival (RRFS), response and toxicity. Results: Sixty-nine consecutive patients were enrolled. Sixty-four (92.8%) patients received first-line chemotherapy, of which 8 (12.5%) developed progressive disease and another 8 (12.5%) did not receive IMRT despite non-progression to first-line chemotherapy. The remaining 48 patients whose disease controlled after chemotherapy received IMRT, including 18 (37.5%) who received concurrent chemoradiation. OS was significantly better in those who received IMRT (35.1 versus 14.2 months; P < 0.001), after a median follow-up duration of 3.40 years (range 0.43 years to 12.14 years). PFS, LRFS, and RRFS were also significantly longer in those who received IMRT. Multivariable analyses revealed that IMRT was the only prognostic factor of all survival endpoints. Grade 3 adverse events were observed in 10 (20.8%) patients, mainly mucositis, dysphagia and desquamation. Conclusions: Consolidative IMRT was associated with an OS benefit and favorable tolerability among previously untreated M1 NPC patients who had non-progressive disease following first-line chemotherapy. These results support the rationale to further investigate IMRT as part of the initial treatment in this setting. Clinical trial information: NCT02476669 .
Pembrolizumab (P) or P + chemotherapy (C) versus EXTREME (E) as first-line (1L) therapy for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): analysis of KEYNOTE-048 by disease state.
Authors: Rischin Danny , Harrington Kevin Joseph , Greil Richard , Soulieres Denis , Tahara Makoto , Castro Gilberto , Psyrri Amanda , Baste Neus , Neupane Prakash C. , Bratland Åse , Fuereder Thorsten , Hughes Brett Gordon Maxwell , Mesia Ricard , Ngamphaiboon Nuttapong , Rordorf Tamara , Wan Ishak Wan Zamaniah , Lin Jianxin , Gumuscu Burak , Swaby Ramona F. , Burtness Barbara
Published: May 2020

6530

Background: In the phase 3 KEYNOTE-048 trial ( NCT02358031 ) in R/M HNSCC (N = 882), 1L P vs E showed superior OS in PD-L1 CPS ≥20 and CPS ≥1 populations, noninferior OS in the total population, no PFS benefit, and favorable safety; 1L P+C vs E showed superior OS in CPS ≥20, CPS ≥1, and total populations, no PFS benefit, and comparable safety. Results of P or P+C vs E in incurable recurrent only, metastatic only, and R/M subgroups are shown. The metastatic only and R/M subgroups were combined and classified as metastatic. Methods: Patients with incurable recurrent (local and/or regional node recurrent disease) or metastatic HNSCC were randomly assigned 1:1:1 to P, P+C, or E. OS and PFS were estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status, HPV status, and PD-L1 status. Data cutoff: Feb 25, 2019. Results: In the incurable recurrent only subgroup (n = 252), median OS was 11.5 vs 12.1 mo (P vs E) and 13.0 vs 11.1 mo (P+C vs E). In the metastatic subgroup (n = 620), median OS was 11.4 vs 9.7 mo (P vs E) and 13.0 vs 10.1 mo (P+C vs E). Median follow-up, OS, and PFS are shown in Table. Treatment-related adverse events (TRAE) in the incurable recurrent only subgroup: 49.4% (P), 94.7% (P+C), and 97.8% (E); grade 3-5 TRAEs rates: 16.0%, 78.7%, and 73.3%, respectively. TRAE rates in the metastatic subgroup: 61.6% (P), 96.4% (P+C), and 96.4% (E); grade 3-5 TRAEs rates: 17.6%, 69.5%, and 67.0%, respectively. Conclusions: P and P+C vs E were efficacious in the metastatic subgroup; in the relatively smaller subgroup of patients with incurable recurrent only HNSCC, the effect was less pronounced. Consistent with the total study population and regardless of disease state, the safety profile was favorable with P vs E and comparable with P+C vs E. These data further support use of 1L P or P+C in patients with R/M HNSCC. Clinical trial information: NCT02358031 . [Table: see text]
HANNA: Real-world outcomes from an observational study with nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck in Germany.
Authors: Dietz Andreas , Welslau Manfred , Hahn Dennis , Langer Christine , Bockmühl Ulrike , Müller-Huesmann Harald , Busch Chia-Jung , Riera-Knorrenschild Jorge , Büntzel Jens , Kubuschok Boris , von der Grün Jens , Gauler Thomas Christoph , Waldenberger Daniela , von der Heyde Eyck
Published: May 2020

6532

Background: Nivolumab has demonstrated efficacy in clinical trials of recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). As only limited real-world data are available, we describe the use of nivolumab and its outcomes in routine clinical practice. Methods: HANNA is a prospective, observational study of patients with R/M SCCHN treated with nivolumab in 56 hospitals and practices in Germany. In total, 385 patients will be followed for ≤ 5 years from treatment initiation until death, withdrawal of consent, loss of follow-up/record, or end of study. The primary objective is overall survival (OS). Secondary objectives include baseline characteristics, safety profiles, and quality of life (QOL) assessment. Results: By November 2019, data from 311 patients were available. Median follow-up was 3.5 months. Baseline characteristics were male, 81.7%; median age, 63 years; history of smoking, 73.3%; Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1, 60.8%; ECOG PS 2/3, 29.6%. Location of primary tumor was oropharynx, 38.3%; hypopharynx, 20.9%; oral cavity, 22.8%; larynx, 11.6%; others, 6.4%. 55.6% of R/M SCCHN patients progressed ≤ 6 months after platinum-based therapy, whereas 43.4% were platinum-sensitive (progressed > 6 months after platinum-based therapy). Nivolumab was received by 25.1% of patients as first therapy after platinum-based chemo- or radiochemotherapy, by 62.1% as second therapy, and by 12.9% as later line therapy. Median treatment duration was 4.6 months. OS at 1 year was 43.3%. 1-year OS for patients with ECOG PS 0 was 75.9%; ECOG PS 1, 41.2%; and ECOG PS 2, 27.3%. Platinum-sensitive patients had higher 1-year OS probability (51.6%). Drug-related adverse events (grade 1/2) and serious adverse events (grade 3/4) were observed in 28.9% and 10.0% of patients, respectively. Interim QOL data (per FACT-H&N and EQ-5D questionnaire) indicated a tendency toward stabilization or slight improvement. We will present an update of the data with longer follow-up (data cut March 2020). Conclusions: HANNA represents one of the largest real-world datasets for nivolumab in R/M SCCHN and comprises a more diverse set of patients than the phase 3 CheckMate 141 trial, including patients with higher ECOG PS, age, and platinum sensitivity. Outcomes from HANNA show that the improved OS, safety, and QOL seen with nivolumab in the real-world setting are consistent with the outcomes from CheckMate 141. Clinical trial information: NCT03114163 .
Selection of patients for surveillance imaging after radiotherapy for squamous cell carcinoma of oral cavity and oropharynx.
Authors: Zeng Johnathan , Fleming Christopher W , Lee Maxwell , Parikh Rujul H , Rybicki Lisa A. , Joshi Nikhil , Woody Neil McIver , Ku Jamie , Prendes Brandon , Lamarre Eric , Lorenz Robert R , Scharpf Joseph , Burkey Brian B. , Chute Deborah , Schwartzman Larisa , Geiger Jessica Lyn , Adelstein David J. , Koyfman Shlomo A.
Published: May 2020

6533

Background: NCCN guidelines do not recommend routine surveillance imaging for distant failure (DF) after definitive treatment of head & neck squamous cell carcinoma (SCC). We hypothesized that there exists a subset of patients with sufficiently high enough risk for DF to benefit from surveillance imaging. This study attempts to define high risk cohorts of oropharynx (OP) and oral cavity (OC) patients. Methods: A retrospective review was conducted of patients with SCC of the OP or OC at a single tertiary care institution from 1994-2019. Patients were staged according to AJCC 7th edition and included in this study if they completed definitive-intent treatment and received 60 Gray or higher of radiotherapy (RT). Local, regional, and distant failure were estimated with cumulative incidence. Univariable & multivariable risk factors for DF were identified with Fine & Gray competing risk regression. Significant variables were compiled to calculate a risk score. Results: 863 patients were included (676 OP/187 OC). OC patients were 60.4% male, median age 61, with median follow up of 77.5 months. Smoking status was 27.3% current, 44.4% former, 28.3% never, with 30 median pack years. Disease was 57.3% T1-2, 42.7% T3-4, 55.6% N0-2a, 44.4% N2b-3. 94.1% had surgery & 34.3% had concurrent systemic therapy. OP patients were 87.9% male, median age 58, 96.3% HPV+, with median follow up of 60.8 months. Smoking status was 20.9% current, 44.5% former, 34.6% never, with 20 median pack years. Disease was 67.9% T1-2, 32.1% T3-4, 29.9% N0-2a, 70.1% N2b-3. 11.5% had surgery & 87.3% had concurrent systemic therapy. Specifically, 52.2% of OP patients received concurrent cisplatin, 10.6% concurrent cetuximab, and 24.5% other systemic therapies. 11.7% of patients experienced DF, of which 77% failed in the lung. Within the OC cohort, nodal stage 2b or higher was the only predictive factor (HR 3.26, p < 0.001), conferring a 3 year risk of DF of 34% vs 10%. Within the OP cohort, a high risk cohort of 87 patients (12.9%) was identified with a 3 year incidence DF of 22%, compared to 10% or less in lower risk cohorts. This high risk cohort consisted of active smokers treated with definitive RT and either concurrent cisplatin or no concurrent therapy, with at least T3 and N2b disease, as well as any patients treated with definitive RT and concurrent cetuximab. Conclusions: We identified groups of OC & OP patients with greater than 20% risk of developing DF at 3 years, the majority of which occurred in the lung. Surveillance imaging of the chest should be considered for patients meeting these criteria.
Cisplatin every three weeks versus weekly cisplatin or carboplatin with definitive radiotherapy for squamous cell carcinoma of the head and neck is associated with improved overall survival in a representative national population.
Authors: McCusker Michael Gerard , Mehra Ranee , Molitoris Jason K. , Taylor Rodney , Cullen Kevin J. , Goloubeva Olga G.
Published: May 2020

6536

Background: For patients with primary untreated locally advanced head and neck squamous cell carcinoma (PULA-HNSCC), high dose once every 3 weeks cisplatin (HDC; 100 mg/m2) added to curative radiotherapy (RT) prolongs survival, but is associated with severe toxicities. Concurrent chemoradiation (CRT) with low dose weekly cisplatin (LDC; 30-40 mg/m2), carboplatin (C), or RT alone is often substituted for HDC. We estimated and compared overall survival (OS) and acquired toxicities among Medicare beneficiaries treated with CRT using HDC, LDC, C, or RT. Methods: Patients diagnosed from 2004-2011 with PULA-HNSCC (stages III-IVB AJCC 6th and 7th editions) of the oropharynx (OPC), hypopharynx (HP), or larynx (L) who received definitive RT or CRT were identified using the linked SEER-Medicare database. An analytic cohort of patients receiving CRT with HDC, LDC, or C was constructed using well-established eligibility criteria. OS was estimated and compared between patients grouped by treatment received utilizing a multivariable stratified propensity scores weighted Cox regression model, including demographic and disease characteristics. Toxicities were compared using exact common odds-ratio and Fisher’s tests. Results: We identified 1,335 patients that received RT: OPC (n = 731), HP (n = 174), or L (n = 430). Out of those, patients were treated with HDC (n = 264), LDC (n = 259), C (n = 353), or RT alone (n = 459). Median OS (years) was 5.61 (95% CI = 4.58-7.69) for HDC, 3.7 (95% CI = 3.1-4.79) for LDC, 3.1 (95% CI = 2.48-3.86) for C, and 1.36 (95% CI = 1.19-1.58) for RT, respectively. OS was significantly greater for HDC than for LDC (HR = 1.35, 95% CI = 1.06-1.72, p= 0.02), C (HR = 1.41, 95% CI = 1.12-1.76, p= 0.003), or RT (HR = 2.1, 95% CI = 1.68-2.61, p= < 0.001). Treatment with HDC compared to LDC was not associated with increased prevalence of dysphagia or neutropenia. HDC was associated with hearing loss when assessed at 9-12 months post-diagnosis ( p =0.03). Conclusions: In SEER-Medicare beneficiaries with PULA-HNSCC of the OPC, HP, or L, OS was significantly better for HDC than LDC when accounting for baseline clinical and demographic characteristics and propensity score weights. Toxicities were similar between regimens, except for an increased incidence of the late acute toxicity of hearing loss in HDC. A regimen of HDC improves OS, but needs to be carefully assessed against increased toxicity risk, with hearing loss in particular.
Combination of tumor multinucleation and spatial arrangement of tumor-infiltrating lymphocytes to predict overall survival in oropharyngeal squamous cell carcinoma: A multisite study.
Authors: Koyuncu Can , Corredor Germán , Lu Cheng , Toro Paula , Bera Kaustav , Fu Pingfu , Koyfman Shlomo A. , Chute Deborah , Adelstein David J. , Thorstad Wade , Bishop Justin A. , Faraji Farhoud , Lewis James S. , Madabhushi Anant
Published: May 2020

6566

Background: Oropharyngeal squamous cell carcinoma patients can have major morbidity from current treatment regimens, necessitating accurate identification of patients with aggressive versus indolent tumors. In this study, we sought to evaluate whether the combination of computer extracted features of tumor cell multinucleation (MN) and spatial interplay of tumor-infiltrating lymphocytes (TILs) is prognostic of overall survival (OS) in OPSCC patients. Methods: OPSCC specimens from 688 patients were retrospectively collected from 3 different sites. 141 patients from site 1 formed the training set (D1) and 322 patients from site 2 and 225 patients from site 3 formed the independent validation cohort (D2, n = 547). A machine learning (ML) model was employed to automatically calculate a Multi-nucleation risk index (MNI), which is the ratio of the number of MN to the number of epithelial cells, to each patient. A separate ML model was also used to capture measurements related to the interplay between TILs and tumor cells (SpaTIL), which were then used to compute a risk score using a Cox regression model. The median value of both the MNIs and the SpaTIL risk scores in D2 were used to identify patients as either low- or high-risk. A definitive label was assigned to each patient by combining the class labels obtained from the MNI and SpaTIL models using a logical AND operation. Results: In D2, the patients with high-risk scores had statistically significantly worse survival in univariate analysis. The univariate analysis yielded an HR = 1.91 (95% CI: 1.25-2.93, p = 0.0027) for D. Multivariate analysis controlling the effect of different clinical variables is shown in the table. Conclusions: We presented a computational pathology approach to prognosticate disease outcome in OPSCC by combining features relating to density of multinucleation and spatial arrangement of TILs and validated the approach on a large multi-site dataset. With additional validation the approach could potentially help identify OPSCC patients who could benefit from de-escalation of therapy. [Table: see text]