bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of multicenter phase II WSG Neo-Predict trial: Predictive markers for evaluation of response to neoadjuvant paclitaxel+trastuzumab+lapatinib in HER2-positive early breast cancer.
Authors: Eichler Christian , Gluz Oleg , Nitz Ulrike , Christgen Matthias , Krabisch Petra , Hackenberg Reinhard , Skrobol Markus , Möbus Volker , Kates Ronald , Schumacher Johannes , Kreipe Hans Heinrich , Harbeck Nadia , Warm Mathias
Published: September 2018

582

Background: Trastuzumab (T) and Lapatinib (L) containing neoadjuvant chemotherapy (NACT) increases pathological complete response (pCR) (vs. T or nihil) in HER2+ early breast cancer (EBC). Early clinical response markers (e.g. Ki67) in a 3-week biopsy or in residual tumor correlate with therapy efficacy and risk of relapse. This WSG Neo-Predict trial aimed to define early predictive markers for therapy response in a dual blockade (T+L) NACT setting. Methods: Patients with cT1c-cT4c HER2+ EBC were treated by paclitaxel (P) (80 mg/m2weekly) with L (750 mg p.o. daily) + T (2 mg/kg) weekly for 12 weeks. Adjuvant treatment with 4 cycles of Epirubicin/Cyclophosphamide (omission allowed in patients with pCR) and T for an additional 40 weeks was recommended. Primary objectives were pCR (ypT0/is/ypN0) and identification of a dynamic predictive test for pCR using a re-biopsy after three weeks of NACT (early response defined as central Ki67 decrease >30% (vs. baseline) and/or low cellularity (<500 invasive tumor cells)). Results: From 2013-2015, 64 patients (n=80 planned) were recruited. Overall pCR was 41% (41% for HER2+/HR+ (n=34) and 45.5% for HER2+//HR- (n=22)). A 0% pCR in the “non-responder” (n=7) group (vs. 50% in the “responder” (n=34) and 42% in the “missing response” (n=20) groups) is intriguing despite methodological limitations. Missing data for early response assessment in a substantial number of patients and negative DFS data from the ALTTO trial did not justify trial continuation. 27% of patients experienced severe adverse events (AE). 11.5% had > grade 3 AEs (including diarrhea, septic shock, leukopenia, and pneumonia). Conclusions: We observed a clinically meaningful pCR with moderate toxicity with only 12 weeks of paclitaxel weekly with dual HER2 blockade (T+L). Effect of additional chemotherapy in patients with pCR after 12 weeks of monochemotherapy remains questionable due to a strong prognostic effect of pCR in HER2+ EBC. In view of 0% pCR (by hypothesis-generating explorative analysis), a different treatment approach should be investigated in patients without “early response” by further prospective trials. Clinical trial information: 2012-003679-21.
Post-operative concurrent chemo-radiotherapy versus post-operative radiotherapy in high-risk cutaneous squamous cell carcinoma of the head and neck: A randomized phase III trial (Trans Tasman Radiation Oncology Group 05.01 Trial; POST study).
Authors: Porceddu Sandro Virgilio , Poulsen Michael , Bressel Mathias , Stoneley Adam , Veness Michael , Kenny Lizbeth M. , Wratten Christopher , Corry June , Cooper Stephen , Fogarty Gerald , Collins Marnie , Collins Michael , Macann Andrew , Milross Christopher , Penniment Michael Gordon , Panizza Benedict , Rischin Danny
Published: September 2018

6008

Background: We report on the first multi-centre randomized phase III trial of post-operative radiotherapy (PORT) vs post-operative chemo-RT (CRT) in high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN) (NCT00193895). Methods: The primary objective was to determine whether there was a freedom from loco-regional relapse (FLRR) difference between patients randomly assigned to 60-66Gy (6-6.5 weeks) with or without weekly carboplatin (AUC 2) following resection of gross disease. Patients were stratified to high-risk nodal (either extracapsular nodal extension, intra-parotid nodal disease of any size or number, cervical nodal disease with ≥2 nodes or largest node > 3cm) or high-risk primary (T3-T4 or in-transit metastases). Patients with both features were stratified to the high-risk nodal group. Secondary objectives included disease-free survival (DFS), overall survival (OS) and acute & late toxicity (CTCAE V3). Results: 321 patients were randomly assigned between 2005-2014, with 11 not commencing treatment protocol due to disease progression or withdrawal of consent. Of the 310 patients commencing treatment protocol (157 RT and 153 CRT), 230 (74%) had high-risk nodal, 70 (22%) high-risk primary and 10 (3%) both. Median follow up was 60 months, median RT dose was 60Gy and 85% randomised to CRT completed 6 cycles of carboplatin. The 2- & 5-year FLRR (95% CI) for the RT arm was 88% (83-93%)/83% (77-90%) and for CRT 89% (84-94%)/87% (81-93%) (HR 0.85; 95%CI [0.46-1.55]; p = 0.59). The 2- & 5 year DFS (95% CI) for the RT arm was 78% (72-85%)/67% (60-76%) and for CRT 83% (77-89%)/73% (66-81%) (HR 0.85; 95%CI [0.55-1.29]; p = 0.43). The 2- & 5 year OS (95% CI) for the RT arm was 88% (83-93%)/76% (69-84%) and for CRT 88% (83-94%)/79% (72-86%) (HR 0.95; 95%CI [0.58-1.57]; p = 0.84). 134 (43%) experienced Grade 3/4 skin toxicity; 49% RT, 37% CRT (p = 0.039). 12 (3.9%) experienced Grade 3/4 subcutaneous fibrosis; 2.5% RT, 5.2% CRT. Conclusions: While surgery and PORT provided excellent FLRR with acceptable toxicity, the addition of weekly carboplatin did not improve outcomes in high-risk cSCCHN. Clinical trial information: NCT00193895.
Results of randomized phase II trial of dabrafenib versus dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma.
Authors: Shah Manisha H. , Wei Lai , Wirth Lori J. , Daniels Gregory A. , De Souza Jonas A. , Timmers Cynthia Dawn , Sexton Jennifer L. , Beshara Mamdouh , Nichols Debra , Snyder Norka , Devine Catherine E , Konda Bhavana , Busaidy Naifa Lamki
Published: September 2018

6022

Background: BRAF mutations are present in ~44% of papillary thyroid carcinoma (PTC) and its role in development of PTC is well established. We hypothesized that dabrafenib (BRAF inhibitor) would have efficacy in BRAF mutated PTC and that combining it with trametinib (MEK inhibitor) would result in greater clinical efficacy than dabrafenib alone, through vertical inhibition of the RAF/MAP/ERK pathway and mitigation of potential mechanisms of resistance. Methods: Patients (pts) with BRAF mutated radioiodine refractory PTC who had evidence of disease progression within 13 months prior were randomized to Arm A (dabrafenib 150 mg PO BID) or Arm B (dabrafenib 150 mg PO BID + trametinib 2 mg PO qd). Cross-over to Arm B was allowed at time of progression. Responses were assessed by modified RECISTv1.1 every 2 months. Primary endpoint was objective response rate (ORR) (complete-, partial- and minor-response). With assumed true ORR of 15% vs 35%; and 90% power to identify the correct regimen as most promising, 26 pts were to be accrued in each Arm. Results: In this randomized phase 2 trial, 53 pts (median age 63 years, 38 females) were enrolled; 25% of pts had 1-3 prior therapy with multi-kinase inhibitors. Median follow up was 13 months. Preliminary efficacy results are outlined in Table. The treatment-related adverse events were similar to previously reported phase III clinical trial of these drugs in melanoma. Conclusions: Single agent dabrafenib, as well as combination of dabrafenib/trametinib are well tolerated therapies that result in similar high objective response rates with durable responses in pts with progressive BRAF-mutated PTC. BRAF-pathway targeted therapies provide novel treatment options. Clinical trial information: NCT01723202. [Table: see text]
Notch pathway inhibition with LY3039478 in adenoid cystic carcinoma (ACC).
Authors: Even Caroline , Lassen Ulrik Niels , Merchan Jaime R. , Le Tourneau Christophe , Soria Jean-Charles , Ferte Charles , Diener Jon Thomas , Yuen Eunice , Smith Claire , Oakley Gerard Joseph , Benhadji Karim A. , Massard Christophe
Published: September 2018

6024

Background: ACCs have high levels of Notch-1 receptor expression and activation. LY3039478 (LY) is an orally bioavailable selective Notch inhibitor (Notch 1-4). Here we report on safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of LY in patients (pts) with ACC. Methods: Ongoing, multi-part, phase I trial enrolled pts with advanced or metastatic ACC, measurable disease, ECOG ≤1, and baseline tumor tissue. Eligible pts received LY 50 mg three times per week (TIW), on a 28-day cycle until disease progression. Safety assessments were based on CTCAE V4.0. Tumor responses were assessed using RECIST 1.1. Primary objectives are to confirm the recommended phase II dose of LY and document antitumor activity. Secondary objectives are safety and toxicity, PK and progression-free survival (PFS). Exploratory objectives include assessment for PET metabolic responses. Results: 22 pts have been enrolled and received LY 50mg TIW (13 men, 9 women; median age 60, range 41-82). All pts had metastatic disease; median treatment duration was 3 cycles (range 1-10) with 6 pts continuing on treatment. One pt had an unconfirmed partial response. Disease control rate (DCR) was 16/22 (73%), of which 4 pts had stable disease ≥ 6 months. In the overall group (n = 22) median PFS (mPFS) was 5.3 months (95% CI: 2.4, NE). mPFS was 7.7 (95% CI: 4.0, NE) for pts in second line (n = 7), while mPFS was 2.4 (95% CI: 1.1, NE) for pts in third line or more (n = 9). In pts without prior systemic therapy (n = 6) mPFS could not be estimated since 4 of those patients were censored. In preliminary analysis, 14 pts were assessed by PET, with 2 (14%) achieving partial metabolic response. Most frequent related adverse events (all grades) occurring in ≥20% of pts included diarrhea (55%), fatigue (45%), vomiting (36%), decreased appetite (27%), dry mouth (27%), and dry skin (23%). Grade 3/4 related treatment-emergent adverse events observed in more than one pt were diarrhea (n = 3) and squamous cell carcinoma of skin (n = 2). PK was assessed in 17 pts, with peak concentrations occurring approximately 2 hours post-dose. Biomarker and histologic analyses of pre and post treatment biopsies will be presented. Conclusions: LY showed activity (73% DCR) in ACC with a manageable safety profile. Clinical trial information: NCT01695005.
Long-term survival in oligometastatic head and neck cancer patients.
Authors: Leeman Jonathan Eric , Patel Suchit H. , Anderson Erik Steven , Tsai C. Jillian , McBride Sean Matthew , Dunn Lara , Sherman Eric Jeffrey , Lee Nancy Y. , Riaz Nadeem
Published: September 2018

6029

Background: Aggressive therapies for patients with oligometastatic disease are increasingly being administered with definitive intent in the context of clinical trials. However, outcomes in oligometastatic head and neck squamous cell carcinoma (HNSCC) patients have not been well characterized. Methods: We reviewed outcomes from 1147 patients who received intensity modulated radiotherapy (IMRT) as part of definitive management for stage I-IVB HNSCC from 2001-2013 at our institution. The primary sites included oropharynx (n=735), oral cavity (OCC, n=182), larynx (n=180) and hypopharynx (n=50). Among patients who developed distant metastasis (DM), the the number of clinically or radiographically apparent tumors was assessed. Survival estimates following DM were generated using the Kaplan-Meier method and compared using log-rank testing. Cox proportional hazards models were used for univariate (UVA) and multivariate analyses (MVA). Results: A total of 148 (13%) patients developed DM at a median time of 10.7 months (range 0.3-81.2) after IMRT. The median follow-up time following DM was 48 months. 5-year survival following DM was significantly longer in patients with a solitary metastatic lesion compared to multiple lesions (table 1, p=0.001). Of the 19 patients with solitary metastasis, the 14 who received definitive local therapy with either surgery or radiation survived longer than those who did not (5-year survival 55.7% vs 0%, p=0.001), though patients who did not receive local therapy were of poorer performance status. On UVA and MVA, longer survival after DM was associated with presence of a solitary metastatic tumor (MVA hazard ratio 0.31, 95% CI 0.16-0.59, p=0.001). Conclusions: An oligometastatic phenotype characterizes HNSCC patients with solitary metastasis, especially when amenable to definitive local therapy. These findings have important implications regarding clinical trial design for HNSCC in the recurrent and oligometastatic setting. [Table: see text]
Treatment patterns in recurrent/metastatic head and neck squamous cell carcinoma in the US.
Authors: Nadler Eric S. , Joo Seongjung , Black-Shinn Jenny , Boyd Marley , Zhuo Joseph , Chirovsky Diana Romana
Published: September 2018

6033

Background: Given the most recent FDA approval of cetuximab in 2008 for treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), the objective was to assess utilization of cetuximab and other treatments for R/M HNSCC in real world setting. Methods: Adult patients (pts) with R/M HNSCC who initiated systemic therapy between 9/1/2011-12/31/2014 were identified from iKnowMedelectronic health records database (McKesson Specialty Health) supplemented with chart abstraction. Pts were followed through 12/31/2015 to collect data on clinical characteristics, treatments and survival outcomes. Results: Among 325 pts with R/M HNSCC, median age was 62 yrs; 82% were male, and 67% had oropharyngeal cancer. The most common first line (1L) regimen consisted of platinum-based combinations (76%; Table 1); 63% received platinum+taxane +/-5FU and only 8% received platinum+cetuximab +/- 5FU. Median overall survival was 13.6 months (range 11.7-16.6). Following 1L therapy, 171 pts (53%) received a 2L regimen; 57 pts (18%) received platinum monotherapy and 8% received 2L platinum+taxane +/- 5FU, while only 12% received cetuximab mono- or platinum+cetuximab + /- 5FU. Among pts receiving 1L platinum combination, 32% were re-treated with platinum based therapy of which platinum monotherapy (23%) and platinum+taxane +/- 5FU (7%) were most common. Conclusions: Despite FDA approval and NCCN guidelines recommending use of cetuximab for palliative treatment of R/M HNSCC, our study demonstrates underutilization in both 1L and 2L settings, underscoring the need to understand reasons for underutilization and the need for newer efficacious treatments. [Table: see text]
A phase I clinical trial of AZD1775 in combination with neoadjuvant weekly cisplatin and docetaxel in borderline resectable head and neck squamous cell carcinoma (HNSCC).
Authors: Mendez Eduardo , Rodriguez Cristina P. , Kao Michael , Harbison Richard A. , Martins Renato G. , Futran Neal D. , Santana-Davila Rafael , Chow Laura Quan Man
Published: September 2018

6034

Background: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability. In TP53-deficient tumors (via mutation or HPV inactivation), inhibiting WEE1 with AZD1775 can lead to unrestrained mitosis and cell death. We conducted a Phase I clinical trial of AZD1775 in combination with chemotherapy to define the toxicity profile, establish the maximal tolerated dose (MTD) and assess preliminary efficacy in borderline resectable HNSCC. Methods: Stage III/IVB HNSCC deemed borderline resectable by a multidisciplinary team were enrolled in a phase 1, 3 + 3 design to evaluate escalating doses of AZD1775 starting at 125 mg PO BID x 2.5 days alone as lead-in and in combination with cisplatin (25mg/m2) and docetaxel (35 mg/m2) for three additional weeks. Tumors were sequenced with UWOncoPlex (262 cancer genes); HPV status assessed via p16 IHC; toxicities graded with CTCAE v. 4.04; responses measured via RECIST 1.1 and through pathologic assessment when available. Trial is open but primary endpoints were met. Results: Eleven patients were screened; 10 enrolled and were evaluable for toxicities. The most common Grade ≥ 2 toxicities were diarrhea (4), fatigue (4), neutropenia (3) and nausea (3). The drug-limiting toxicity was Grade 3 diarrhea (2). The MTD was established at 150mg PO BID x 2.5 days, alone and in combination with neoadjuvant cisplatin and docetaxel. Two patients were HPV+/TP53wt, 1 was HPV+/ TP53 mut; 6 were TP53mut/HPV-; 1 was TP53 wt/HPV-. Seven out 10 patients had a response. Two patients dropped out after the first week with AZD1775, one due to an allergic reaction to docetaxel and another due to non-compliance. Eight completed neoadjuvant therapy and 7 of those converted to surgery: 2 had pathologic CRs (both HPV+/TP53wt); 4 had PR (all TP53 mutants); 1 (TP53wt/HPV-) had a PR by RECIST, but SD by pathology and 1 had PD. Conclusions: AZD1775 is safe and tolerable in combination with neoadjuvant cisplatin and docetaxel. Results show this combination to have promising anti-tumor efficacy in borderline resectable HNSCC with TP53 deficiency, and merits further investigation with the established MTD as the recommended Phase II dose. Clinical trial information: NCT02508246.
A phase 1b/2 study of amcasertib, a first-in-class cancer stemness kinase inhibitor, in advanced adenoid cystic carcinoma.
Authors: Cote Gregory Michael , Edenfield William Jeffery , Laurie Scott Andrew , Chau Nicole Grace , Becerra Carlos , Spira Alexander I. , Li Youzhi , Li Wei , Hitron Matthew , Li Chiang
Published: September 2018

6036

Background: Amcasertib (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, amcasertib inhibits Nanog and other cancer stemness pathways. A phase I clinical trial of amcasertib demonstrated safety and signs of anti-cancer activity in patients (pts) with advanced solid tumors. Cancer stemness pathways have been implicated in adenoid cystic carcinoma (ACC). An RP2D expansion cohort was opened for patients with ACC. Methods: Pts with metastatic, unresectable ACC for whom systemic therapy was indicated were enrolled. Amcasertib was administered orally, once or twice daily, in continuous 28-day cycles at a starting dose of 110 mg to 300 mg total daily. Adverse events were categorized according to CTCAE v4.03 and tumor imaging was evaluated per RECIST 1.1 guidelines. Results: 14 pts with ACC were enrolled. Prior treatments included surgery and radiation in all pts (100%), while 57% (n = 8) had received prior systemic therapy (average 2 prior lines, range 1 to 4). Treatment with amcasertib was well tolerated, with grade 3 diarrhea reported in 1 patient and no related grade 4 AEs. The disease control rate (DCR, proportion with stable disease at 8-weeks, partial response, or complete response per RECIST) was 86% (n = 12) with prolonged disease control (≥ 6 months) achieved in 57% (n = 8) patients. At 12 months, 79% of pts were alive. Median overall survival (mOS) was 28.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with advanced ACC who received treatment with amcasertib. Long term follow-up demonstrates prolonged duration of disease control and that a majority of pts in this cohort have survived beyond 2 years. Further clinical evaluation of amcasertib in pts with ACC is warranted. Clinical trial information: NCT01781455.
Phase I study of the anti-HGF monoclonal antibody (mAb), ficlatuzumab, and cetuximab in cetuximab-resistant, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Bauman Julie E. , Duvvuri Umamaheswar , Ferris Robert L. , Ohr James , Gooding William E. , Kim Seungwon , Johnson Jonas Talmadge , Grandis Jennifer R. , Stabile Laura P.
Published: September 2018

6038

Background: Cetuximab, an anti-EGFR mAb, is approved for R/M HNSCC but only a minority benefits. Activation of cMet, the receptor for hepatocyte growth factor (HGF), overcomes EGFR inhibition in preclinical models and high serum HGF is associated with resistance in patients (pts). We conducted a phase I trial evaluating the combination of cetuximab and ficlatuzumab, an IgG1 anti-HGF mAb, in pts with cetuximab-resistant, R/M HNSCC. Methods: In this Narayana k-in-a-row phase I design, cetuximab 500 mg/m2 was administered every 2 weeks. Ficlatuzumab dose tiers were 10 mg/kg (tier 1) or 20 mg/kg IV every 2 weeks (tier 2), with inter-patient escalation or de-escalation based on cumulative dose-limiting toxicities (DLT). The recommended phase II dose (RP2D) was set at tier 2 if no DLTs were observed after 8 enrolled pts; expansion continued to n = 12. Key eligibility criteria: R/M HNSCC; recurrence within 6 months of cetuximab-radiation or progression during/within 6 months of palliative cetuximab; ECOG PS 0-1. Candidate biomarkers included serum Veristrat, a proteomic classifier in lung cancer where “good” predicts benefit from anti-EGFR therapy and “poor” indicates resistance and poor prognosis. Results: From Sept 2015–June 2016, 12 pts were enrolled and treated. Primary site: 1 oral cavity; 3 oropharynx (1 p16+); 2 hypopharynx; 5 larynx; 1 external auditory canal. Platinum-refractory: 11/12. Veristrat: 8 poor; 4 good. Three pts were treated at tier 1 and 9 at tier 2. No DLTs were observed. Grade 3 adverse events included: edema (1), hypoalbuminemia (1), infection (2), thromboembolic event (2). Median PFS and OS at RP2D were 6.0 mos (90% CI = 2.0 mos–not reached) and 8.2 mos (90% CI = 2.7 mos–not reached), respectively. Response rate was 17% (90% CI = 0–28%): 2/12 partial response (PR); 1/3 at 10 mg/kg; 1/9 at 20mg/kg. Clinical benefit rate (PR + stable disease) was 67%. Veristrat was not associated with PFS. Conclusions: The RP2D is cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks. This well-tolerated combination demonstrated promising activity in pts with poor prognosis, cetuximab-resistant R/M HNSCC. Phase II testing is justified. Clinical trial information: NCT02277197.
A retrospective cohort study of PD-L1 expression in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SUPREME-HN).
Authors: Pai Sara I. , Cohen Ezra , Lin Derrick , Fountzilas George , Kim Edward S. , Mehlhorn Holger , Baste Neus , Clayburgh Daniel , Lipworth Loren , Resteghini Carlo , Shara Nawar , Fujii Takashi , Zhang Jun , Stokes Michael , Lawrence David , Khaliq Asud , Melillo Giovanni , Shire Norah
Published: September 2018

6040

Background: Patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) have a poor prognosis. Targeting the PD-1/PD-L1 axis has resulted in clinically meaningful antitumor activity and improved overall survival (OS) in R/M HNSCC patients. Tumoral PD-L1 expression correlates with response to blocking PD-1/PD-L1 antibodies. We investigated the prognostic value of PD-L1 expression in R/M HNSCC patients. Methods: Archival tumor samples from R/M HNSCC patients diagnosed between March 2011 and June 2015 at 12 institutions in 6 countries were stained for PD-L1 and clinic-demographic data were abstracted from medical records. Tumoral PD-L1 protein expression was assessed with the validated Ventana SP263 assay and scored as high (≥25% of tumor cells [TC]) or low/negative ( < 25% of TC). Extracted data included demographic and tumor characteristics, treatment patterns, and clinical outcomes. Descriptive analyses were conducted and survival estimated by the Kaplan-Meier method. OS was defined from the diagnosis index date of R/M disease to time of death. Results: As ofSeptember 26, 2016 (interim analysis), data were available for 143 patients of whom 138 were eligible for analysis. Median age was 62.0 years (range, 28.0−88.0), 76.8% were male, and 84.0% were white. PD-L1 protein expression was high in 43 patients (31.2%), low/negative in 91 (65.9%), and unknown in 4 (2.9%). Median OS (8.2 vs. 8.8 months; P = 0.94) and progression-free survival (PFS) from the start of first-line (6.0 vs. 5.6 months; P = 0.29) or second-line therapy (7.1 vs. 1.8 months; P = 0.11) did not significantly differ between PD-L1 high and low/negative patients, respectively. There were no significant differences in OS based on PD-L1 status within subgroups defined by age, race, tobacco or alcohol use, primary tumor site, performance status, metastatic disease at diagnosis, or treatment with platinum-based chemotherapy. Conclusions: Interim analyses indicate that PD-L1 status is not associated with OS or PFS in R/M HNSCC patients.
Two-year clinical outcomes of de-intensified chemoradiotherapy for low-risk HPV-associated oropharyngeal squamous cell carcinoma.
Authors: Chera Bhishamjit S. , Amdur Robert J , Tepper Joel E. , Qaqish Bahjat F. , Hayes David N. , Weiss Jared , Grilley-Olson Juneko E. , Zanation Adam M , Hackman Trevor , Zevallos Jose , Patel Samip , Sheets Nathan Christopher , Weissler Mark Christian , Mendenhall William M.
Published: September 2018

6044

Background: We here-in report 2 year cancer control outcomes from a prospective phase II clinical trial evaluating de-intensified chemoradiotherapy (CRT) for patients with favorable risk, HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Methods: The major inclusion criteria were: T0-T3, N0-N2c, M0, HPV or p16 positive, and minimal smoking history. Treatment was limited to 60 Gy intensity modulated radiotherapy with concurrent weekly intravenous cisplatin (30 mg/m2). Patients neither received induction chemotherapy nor definitive surgery. The primary study endpoint was pathologic complete response rate (pCR) based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless of radiographic response. Secondary endpoint measures included 2 year local control (LC), regional control (RC), cause specific survival (CSS), distant metastasis free survival (DMFS), and overall survival (OS), and patient reported symptoms (PRO-CTCAE) and quality of life (EORTC QLQ-C30 & H&N35). Results: Forty-four patients enrolled and the median f/u was 36 months (range 5-53 months, 93% with > / = 1 year, 88% > / = 2 years). We have previously reported the pCR to be ~ 86%. Two year LC, RC, CSS, DMFS, and OS are the following: 100%, 100%, 100%, 100%, and 95%. All 6 patients who had pathological partial responses are alive with no evidence of disease with a median f/u of 34 months (range 9-48 months). Two patients have died (stroke and glioblastoma). Mean pre and 2-year post EORTC QOL scores were: Global 80/82 (lower worse), Swallowing 11/10 (higher worse), Dry Mouth 16/54, and Sticky Saliva 6/33. 39% of patients required a feeding tube (none permanent) for a median of 15 weeks (5 - 22 weeks). Mean pre and 2 year post PRO-CTCAE (1 to 4 scale, higher worse) scores were: Swallowing 0.4/0.8 and Dry mouth 0.4/1.8. There were no > / = Grade 3 late adverse events. Conclusions: The 2-year clinical outcomes with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatin are excellent in favorable risk OPSCC with evidence of better preservation of quality of life as compared to standard therapies. Clinical trial information: NCT01530997 .
Cellular immune biomarkers to prognosticate for survival to adoptive T-cell therapy in advanced nasopharyngeal cancer.
Authors: Toh Han Chong , Hopkins Richard , Ching Qian Ting , AU Veonice Bijin , WU Lynn Xue , Chia Whay-Kuang , Lee Bernett , WANG Who-Whong , Podinger Michael , Wee Joseph , Ng Joanna , Shuen Timothy , Connolly John E.
Published: September 2018

6047

Background: We have published a Phase II clinical trial in 35 advanced incurable stage 4c NPC patients employing upfront first line chemo-immunotherapy of four cycles of gemcitabine and carboplatin, followed by six cycles of adoptive transfer autologous EBV-specific cytotoxic T lymphocytes (CTL). The 2- and 3-year overall survival rates were 62.9 and 37.1% respectively, which represent the best reported survival outcome for first-line treatment of advanced NPC when compared to historical clinical trials. Methods: From this Phase II trial, we completed serial multiple deep immune phenotyping analyses including flow cytometry, nanostring, and multiplex ELISA assays. We then investigated how these factors influence and determine successful therapy using 2-year survival rates. Results: Longitudinal modular transcriptome analysis of patient PBMCs revealed significant increases in T cell, NK, and B cell modules post chemotherapy within the 2-year survivor group. Administration of CTLs restored expression of lymphocyte transcripts in the non-survivor group at 2-weeks post infusion. However, as immunotherapy proceeded, 2-year survivors displayed significant increases in multiple lymphocyte module associated transcripts. These immune correlates were associated with increased IFN-γ and decreased myeloid chemokine concentrations in peripheral sera during immunotherapy in 2-year survivors. Longitudinal immunophenotyping of patient PBMCs at serial timepoints showed that 2-year survivors displayed significant decreased amounts of monocytic myeloid-derived suppressor cells (mMDSCs), compared to non-survivors after chemotherapy, which subsequently determined successful CTL immunotherapy survival benefit. Conclusions: This is the first report in human cancer patients that successful adoptive T cell immunotherapy correlates with lower mMDSCs following chemotherapeutic preconditioning. We have also identified potential prognostic immune biomarkers that effectively predicts efficacy of CTL immunotherapy, following upfront combination chemotherapy, and thus survival. Lymphodepletion with chemotherapy appears to be vital for adoptive T cell therapy efficacy.
Intact APM and PD-1:PD-L1 pathway upregulation in HIV-infected head and neck cancer patients.
Authors: Pai Sara I. , Lee J. Jack , Carey Thomas E. , Westra William H. , Ferrone Soldano , Moore Charles , Shin Dong Moon , Ferris Robert L.
Published: September 2018

6058

Background: HIV-infected individuals have a higher incidence of oral infection with human papillomavirus (HPV) and possibly a higher incidence of head and neck cancer (HNC). Whether this observation reflects defects in the ability of this Òimmune-compromisedÓ patient population to mount sufficient tumor specific immune responses and/or reflects activation of immune escape mechanisms is not known. To address this question, we investigated the expression of HLA class I antigen processing machinery (APM) components and PD-1:PD-L1 pathway activation in HIV(+) HNC patients. Methods: 62 HIV(+) HNC patients diagnosed between 1991-2011 from five tertiary care referral centers in the United States and matched HIV(-) HNC controls were identified. HLA class I APM component, PD-1, and PD-Ll expression were analyzed by immunohistochemical staining. Clinical data was abstracted from the medical records. Results: 44 of 62 (71%) HIV(+) HNC cases were matched based on gender, age ( < 10 years), and anatomic sub-site to HIV(-) HNC patients. There was no significant difference between the cases and controls in HLA-A, HLA-B/C, LMP2, and TAP1, as well as PD-1 and PD-L1 expression. Overall, 62% of all subjects had high PD-1 expression and 82% of the subjects expressed PD-L1. HLA-A, HLA-B/C, and LMP2 expression was significantly correlated with moderate to high PD-1 expression in the HIV(+) HNC cases (p = 0.004, p = 0.026, and p = 0.006, respectively) but not in the HIV(-) controls. Similarly, HLA-A expression was also significantly associated with PD-L1 expression only in the HIV(+) HNC cases (p = 0.029). Conclusions: No defects were detected in the expression of the HLA class I APM components tested. PD-1:PD-L1 pathway was found to be upregulated in both HIV(+) and HIV(-) HNC patients. Our data suggest that recently approved anti-PD-1 immunotherapy should not exclude HIV(+) patients.
Optima: A phase II dose and volume de-escalation trial for high- and low-risk HPV+ oropharynx cancers.
Authors: Melotek James , Seiwert Tanguy Y. , Blair Elizabeth A. , Karrison Theodore G. , Agrawal Nishant , Portugal Louis , Gooi Zhen , Stenson Kerstin , Brisson Ryan J. , Arshad Saba , Dekker Allison , Kochanny Sara , Saloura Vassiliki , Spiotto Michael T. , Villaflor Victoria Meucci , Haraf Daniel J. , Vokes Everett E.
Published: September 2018

6066

Background: In this prospective phase II de-escalation study, we used induction chemotherapy to identify favorable HPV+ oropharyngeal cancer (OPC) pts, including those with high-risk tumors, and applied significantly lower radiation or chemoradiation doses than previously reported. Methods: Pts with HPV+ OPC were classified as low-risk (≤T3, ≤N2B, ≤10 PYH) or high-risk (T4 or ≥N2C or > 10 PYH). Pts received 3 cycles of carboplatin (AUC 6, D1) and nab-paclitaxel (100 mg/m2, D1/8/15). 1) Low-risk pts with ≥50% response received low-dose radiotherapy alone to 50Gy (RT50). 2) Low-risk pts with 30-50% response OR high-risk pts with ≥50% response received low-dose chemoradiotherapy to 45Gy (CRT45). 3) All other ( = poor response) pts received regular-dose CRT (CRT75). All pts also received de-escalated RT volumes limited to the first echelon of uninvolved nodes. CRT consisted of paclitaxel, 5-FU, hydroxyurea, and 1.5Gy twice daily RT every other week. Primary site biopsy and neck dissection were performed only after de-escalated treatment (RT50, CRT45) for pathologic confirmation. The primary endpoint was 2-year PFS. Secondary endpoints included pathologic complete response (pCR) rate and toxicity. Results: 62 pts were enrolled. 28 pts (45.2%) were low-risk and 34 pts (54.8%) were high-risk. 71.4% of low-risk pts received RT50 and 21.4% received CRT45. 70.6% of high-risk pts received CRT45. The pCR rate was 94.4% after RT50 and 92.3% after CRT45. Median follow-up is 1 year. The 2-year PFS and OS were both 100% for low-risk pts, and 91.6% and 97.0% for high-risk pts. Significant decrease in the rates of grade ≥3 mucositis (15.8% RT50, 46.4% CRT45, 60.0% CRT75, p = .033) and grade ≥3 dermatitis (0% RT50, 21.4% CRT45, 30.0% CRT75, p = .056) were observed. PEG-tube dependency was improved at 3 months (0% RT50, 14.8% CRT45, 70.0% CRT75, p < .001) and 6 months (0% RT50, 3.7% CRT45, 20.0% CRT75, p = .066) post-treatment. Conclusions: Favorable response to induction chemotherapy appears to be a powerful biomarker for dose and volume de-escalation with 50Gy RT or 45Gy CRT. Outstanding survival and high pCR rates suggest that completion neck dissection may not be necessary. Toxicity and functional outcomes are significantly improved. Clinical trial information: NCT02258659.
Prognostic factors associated with benefit to post-operative chemotherapy: A National Cancer Data Base analysis.
Authors: Geiger Jessica Lyn , Woody Neil McIver , Reddy Chandana A. , Koyfman Shlomo A. , Joshi Nikhil Purushottam , Bodmann Joanna , Harr Bridgett Ann , Ives Denise I. , Ferrini Jodi , Burkey Brian , Scharpf Joseph , Lamarre Eric , Prendes Brandon , Lorenz Robert , Adelstein David J.
Published: September 2018

6072

Background: Addition of chemotherapy to adjuvant radiation (RT) confers an OS benefit and is recommended in HNSCC patients with nodal extracapsular extension (ECE) and positive surgical margins based on pooled data. The purpose of this study is to retrospectively evaluate a larger patient data set in an attempt to confirm this observation and to assess current patterns of practice. Methods: The National Cancer Data Base (NCDB) was queried to identify patients with HNSCC who were treated with primary definitive surgery followed by adjuvant RT between 2004 and 2012. For patients treated with surgery and post-operative RT with or without chemotherapy, the effect of the systemic therapy on OS was explored using multivariable Cox proportional hazards modeling and stratified by patient and disease factors. Results: 6,351 patients were identified meeting study criteria; 3157 patients (49.7%) received adjuvant RT alone, and 3194 patients (50.3%) received adjuvant chemoradiotherapy (CRT). An increase in chemotherapy usage was observed over time (6% of patients in 2004; 16% in 2012). No difference was seen in OS by use of CRT (median OS 8.3 years in patients without CRT vs. 9.4 years in patients with CRT, p = 0.0893). On multivariate analysis OS was improved in younger patients, patients with less co-morbidity, oropharynx, lower T and lower N. OS was also improved in patients given chemotherapy if either ECE or positive surgical margins were present (HR 1.166, p = 0.0438) but not in those with negative surgical margins and no ECE (HR 1.037, p = 0.5888). Nonetheless, chemotherapy was given to 38% of post-operative patients without these risk factors and not given to 35% of patients with risk factors. Conclusions: This NCDB analysis confirms an OS benefit with addition of chemotherapy to post-operative RT in HNSCC patients with ECE or positive surgical margins but not in patients without these risk factors, consistent with current guidelines. National practice patterns, however, do not mirror these recommendations. These results are subject to limitations of retrospective analysis of a large database and further studies are needed to better elucidate high risk factors benefiting from intensifying adjuvant therapy.
Targeted therapy for advanced salivary cancer with HER2 or hedgehog alterations: Interim data from MyPathway.
Authors: Kurzrock Razelle , Meric-Bernstam Funda , Hurwitz Herbert , Hainsworth John D. , Spigel David R. , Bose Ron , Swanton Charles , Burris Howard A. , Sweeney Christopher , Yoo Bongin , Beattie Mary Stanley , Patel Rajesh , Schulze Katja , Lam Elaine Tat
Published: September 2018

6086

Background: Salivary gland cancers comprise <1% of cancers. Advanced cases have a 40% 5-year survival rate. Due to their rarity, no standard treatment guidelines exist. However, salivary duct carcinomas have morphological and gene expression profiles similar to breast cancers, and 20–40% of this subset have HER2 alterations. MyPathway (NCT02091141) is an ongoing, phase 2, multi-basket study evaluating the efficacy of targeted treatments in nonindicated tumor types with alterations in the HER2, BRAF, Hedgehog (Hh), or EGFR pathways. We present interim data for patients with salivary cancer. Methods: Patients had advanced salivary cancer with HER2 (amplification, overexpression, and/or mutation) or Hh (SMO or PTCH-1) alterations, locally assessed by gene sequencing, FISH, or IHC, as applicable. Patients received standard doses of pertuzumab + trastuzumab or vismodegib, respectively, until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed objective response rate (ORR) by RECIST v1.1. Results: As of Nov 30, 2016, 8 patients had been treated for salivary cancer, all carcinomas (7 had HER2 alterations; 1 had an Hh alteration). One HER2 patient without a post-baseline tumor assessment by data cut-off was not evaluable for efficacy. Characteristics and outcomes are shown (Table). Of 6 patients with a complete response (CR) or partial response (PR), 5 patients were still receiving study treatment by the data cut-off, with a median time on treatment of 4.6 months (range 1.4–12.5). There were no new safety signals. Conclusions: Six of 7 patients (86%) with advanced salivary carcinoma achieved CR or PR by targeting HER2 (n=5) or Hh (n=1) alterations. These promising results merit study of these treatments in additional patients. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
Primary outcomes analysis of a multicenter randomized controlled trial of an interactive decision tool for patients with breast cancer.
Authors: Hawley Sarah T. , An Lawrence C. , Li Yun , Resnicow Ken , Morrow Monica , Jagsi Reshma , Katz Steven J.
Published: September 2018

6500

Background: High quality treatment decisions require that patients are well informed about treatment and that their values are considered. Yet studies show that patient knowledge about breast cancer treatment trade-offs is low and appraisal of decision-making is not optimal. Methods: We conducted a randomized controlled trial (RCT) of a tailored, comprehensive (locoregional and systemic treatment) and interactive decision tool (iCanDecide), compared with static online information. 537 newly diagnosed, early stage breast cancer patients were enrolled at the first visit in 22 surgical practices. Participants were surveyed 5 weeks (N = 496; RR 92%) post enrollment after locoregional treatment decision-making. The primary outcome was a high quality decision, including two components: high knowledge about treatment options and a values concordant treatment decision. The main secondary outcome was preparation for decision making. We evaluated the distribution of participants in each arm, and conducted logistic regression modeling to assess the association between the intervention and the outcomes controlling for patient characteristics and strength of treatment preference at enrollment. Results: Significantly more intervention than control patients had high knowledge (60% vs. 42%, p < 0.001), although the majority of both groups reported values concordant treatment (~84%). Intervention patients also reported feeling prepared for decision making significantly more often than controls (45% vs. 32%, P < 0.01). Patients randomized to the interactive intervention had higher knowledge (OR: 2.2; 95% CI 1.2-4.0) and preparation for decision making (OR: 1.5; 95% CI 1.1-1.4), even after adjusting for age, education, race, stage and clinical site. Conclusions: In this large RCT, a tailored, interactive treatment decision tool for breast cancer improved knowledge and prepared patients for complicated decision making, more than access to static online information. Future work to further integrate such tools into the clinical workflow is needed. Clinical trial information: NCT01840163.
Comparison of reporting phase I trial results in ClinicalTrials.gov and matched publications.
Authors: Shepshelovich Daniel , Goldvaser Hadar , Wang Lisa , Abdul Razak Albiruni Ryan , Bedard Philippe L.
Published: September 2018

6514

Background: The 2007 Food and Drug Administration (FDA) Amendments Act mandated reporting of results of clinical trials in ClinicalTrials.gov, a large public registry, within 12 months of completion. We compared results reported for phase I trials in ClinicalTrials.gov and matched primary publications. Methods: The ClinicalTrials.Gov database was searched for completed adult phase I cancer trials with reported results. Only trials with dose escalation of systemically administered medications were included. PubMed was searched for matching primary publications, defined as identical intervention, number of arms and enrolled subjects, published prior to November 1, 2016. Results reported in the primary publication were compared with the ClinicalTrials.gov database using a 28-point score (2 = complete agreement; 1 = partial agreement; 0 = no mention) for 14-items related to study design (4 items), outcome measures (4 items) and safety profile (6 items). The ClinicalTrials.gov database was used as the reference for results reporting. Linear regression was used to identify factors associated with incomplete reporting. Results: After a review of 583 trials in ClinicalTrials.gov, 163 matching primary publications were identified, comprising 95 (58%) phase I and 68 (42%) phase I/II trials. Publications reported outcomes that did not appear in ClinicalTrials.gov in 25% of trials. Outcomes were omitted or downgraded in publications in 39% of trials. The overall median reporting score was 23/28 (interquartile range 21-25). Items that were incompletely reported in publications were: inclusion criteria (29%), primary outcome definition (26%), secondary outcome definitions (53%), adverse events (71%), serious adverse events (80%) and dates of study start and database lock (91%). Phase I (p < 0.001) and multicenter trials (p = 0.002) were associated with higher reporting scores than phase I/II and single center trials. Conclusions: Reported results in primary publications for early phase cancer trials are frequently inconsistent or incomplete compared with ClinicalTrials.gov entries. ClinicaTrials.gov may provide a more comprehensive overview of safety data from new cancer drug trials.
Factors influencing prostate cancer treatment decisions for African American (AA) and Caucasian (CA) men.
Authors: Gordon Brittaney-Belle Elizabeth , Basak Ramsankar , Usinger Deborah S , Godley Paul Alphonso , Chen Ronald C.
Published: September 2018

6517

Background: Prostate cancer causes a disproportionate burden to AA men, and AA men are less likely than CA men to receive aggressive treatment. This is the first study to examine factors influencing treatment decision-making of AA vs. CA men in a population-based cohort. Methods: 1171 men were enrolled soon after diagnosis and before treatment through Rapid Case Ascertainment of the North Carolina state cancer registry. Researchers asked patients regarding their priorities in treatment decision-making and information sources. Differences in AA and CA men were compared using the chi-square test. Results: The most important factor for both AA and CA men was curing cancer, and preserving QOL was second most important. However, AA men were more concerned about additional factors including impact on daily activities (74% very important AA vs 58% CA for intermediate/high risk disease), recovery time (81% vs 50%), cost (66% vs 32%) and treatment time (76% vs 39%) (p < .001 for each item). The most important source of information impacting treatment decisions for CA men were physician recommendations (61%), personal research (32%) and family/friend opinion (7%); for AA men, the corresponding numbers were 50%, 32% and 19%. Conclusions: AA and CA men with prostate cancer are both concerned about curing cancer, but AA men are more likely to consider multiple other social and personal factors as important in their decision-making process. Improved understanding of these differences may provide opportunities to address racial disparities in prostate cancer. [Table: see text]
Assessment of actionability of cancer genomic testing panels based on a structured clinical trial knowledge base.
Authors: Levy Mia Alyce , Micheel Christine , Jain Neha , Mittendorf Kathleen F
Published: September 2018

6533

Background: Today’s oncologist is responsible for choosing appropriate cancer genomics tests to inform patient treatment from multiple available platforms, weighing cost, availability, sensitivity and specificity, and clinical actionability. Knowledge-driven clinical decision support tools can assist clinicians in choosing the panel that is most informative in a given clinical space. Methods: Using a queryable knowledgebase of >1800 active clinical trials containing structured eligibility criteria curations for diagnosis and genomic alterations, we compared two CLIA-regulated genomic panels for clinical actionability over the landscape of solid, breast, and lung cancer clinical trials. Results: The larger panel (73 genes) was more actionable than the smaller panel (62 genes) in the breast cancer (10x more trials returned) and solid tumor (2.7x more trials returned) clinical trial space, while the smaller panel returned 1.2x more trials in the lung cancer space (see table). Conclusions: This analysis demonstrates that patient diagnosis has a significant effect on the potential clinical actionability of a given genomic panel. Further, this analysis demonstrates the clinical utility of knowledge-driven clinical decision support tools for test selection, especially given the often-limited tumor sample available, cost of genomic panel testing, and continuously shifting trial landscape. [Table: see text]