bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomized double-blind placebo-controlled trial of primary maintenance vigil immunotherapy (VITAL study) in stage III/IV ovarian cancer: Efficacy assessment in BRCA1/2-wt patients.
Authors: Rocconi Rodney Paul , Grosen Elizabeth A. , Ghamande Sharad A. , Chan John K. , Barve Minal A. , Oh Jonathan , Tewari Devansu , Morris Peter C. , Stevens Erin E. , Bottsford-Miller Justin N. , Tang Min , Aaron Phylicia , Wallraven Gladice , Bognar Ernest , Manning Luisa , Nemunaitis John J. , Slomovitz Brian M. , Herzog Thomas J , Monk Bradley J. , Coleman Robert L. ,   Vigil Team
Published: May 2020

6017

Background: Vigil is an autologous tumor cell vaccine constructed from autologous harvested tumor tissue transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin thereby creating TGFβ expression control. Methods: A randomized double-blind placebo-controlled trial of Vigil vs. placebo was performed in advanced stage frontline OC patients. Relapse-free survival (RFS) and safety were endpoints. Patients who achieved complete clinical response were randomized [1:1 to placebo (control group, CG) or Vigil (Vigil group, VG)] after completion of frontline surgery and chemotherapy. All patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses. Results: Ninety-two patients were randomized with 91 patients in the per-protocol population (PP), (VG n=46; CG n=45). 62 patients were tested for BRCA1/2 status. VG showed no added overall toxicity compared to CG and no grade 4/5 toxicities were observed. Grade 2/3 toxic events were observed in 18% of CG patients (most common bone pain, fatigue) compared to 8% of VG patients (most common nausea, musculoskeletal pain). From time of randomization median RFS for all 91 patients was favorable in the VG (HR 0.69, one-sided p 0.088).Stratified by BRCA status, an advantage in RFS was seen in the BRCA1/2-wt patients in VG (19.4 mo) compared to CG (8 mo) (HR 0.51, 90% CI 0.26 – 1.01, one-sided p 0.050) from time of randomization and HR of 0.49 (90% CI 0.25 – 0.97, one-sided p 0.038) from time of surgery. Median time from surgery to randomization was 208.5 days (6.9 mo) in VG vs. 200 days (6.6 mo) in CG. 37.5% BRCA1/2-wt Vigil treated patients relapsed compared to 71% of placebo at time of data snap for analysis (HR 0.51, one-sided p 0.05), (median follow-up of 34.3 mo for all n=91 subjects). Germline and somatic BRCA1/2 molecular testing via central third party is underway on all 91 patients under continued blinded conditions to validate activity in BRCA1/2-wt. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed RFS clinical benefit, particularly in BRCA1/2-wt disease. Clinical trial information: NCT02346747. [Table: see text]
Gastric-type adenocarcinoma of the cervix: Genomic drivers and clinical outcomes.
Authors: Sassine Dib , Straubhar Alli M. , Aghajanian Carol , Alektiar Kaled M. , Broach Vance , Cadoo Karen Anne , Jewell Elizabeth Lin , Kyi Chrisann , Leitao Mario M. , Mueller Jennifer Jean , Murali Rajmohan , O'Cearbhaill Roisin Eilish , Park Kay J. , Sonoda Yukio , Weigelt Britta , Zamarin Dmitriy , Abu-Rustum Nadeem , Friedman Claire Frances
Published: May 2020

6030

Background: Cervical Gastric-type adenocarcinoma (CGA) is a non-HPV-associated adenocarcinoma, comprising 10% of all cervical adenocarcinomas (Park et al, 2019). The optimal management approach is unclear, given that most data in advanced cervical cancer is driven by HPV-positive disease. We summarize our experience with this rare tumor type at a large cancer center. Methods: A retrospective review was performed for all women diagnosed with CGA 6/1/2002- 7/1/2019. Patients who did not follow up after a single visit were excluded. Kaplan-Meier survival analysis was performed to determine progression-free survival (PFS) and overall survival (OS) from date of diagnosis. Tumors from a subset of patients were subjected to MSK-IMPACT targeted sequencing and analysis (Zehir et al, 2017). Results: A total of 68 women were identified; 47 met inclusion criteria. The median age at diagnosis was 52 years (range 27-83). The majority of patients were white (70%), an additional 19% were Asian. The majority of patients (60%, n=28) presented with advanced disease (FIGO 2018, stage II-IV), while 40% (n=19) were Stage I. Of note, 26% (n=12) had positive pelvic lymph nodes and 13% (n=6) had ovarian metastases at time of surgical resection. For upfront treatment: 13% (n=6) had surgery alone of whom 83% had stage 1 disease, 36% (n=17) had surgery followed by adjuvant therapy, 30% (n =14) received definitive chemo-radiation (CRT). All patients with stage IV disease 15% (n=7) received chemotherapy alone. At completion of primary treatment, 19% (n=9) of patients had persistent disease. In patients who received CCRT, 65% (n=22) recurred, the majority (64%) within 12 months of completion of upfront therapy. Pelvic recurrence was the most common site (n=14, 64%). With a median follow up time of 30 months (range 1-159), the median PFS for Stage I was 34.4 months, compared to 17.5 months in patients with Stage II-IV disease (p= 0.29). Of the 24 patients that had MSK-IMPACT, the most common mutation was TP53 (n=16, 64%) followed by mutations in the RAS pathway (n=8, 33%), PIK3CA (n=3, 12.5%), STK11 (n=3, 12.5%), and ERBB2 alterations (n=2, 8.3 %). 2 (8.3%) women enrolled on a clinical trial based on their NGS results, one targeting ERBB2 and one targeting PIK3CA. Conclusions: Consistent with prior published literature, CGA is an aggressive form of cervical cancer with poor median OS in the advanced setting. With universal HPV vaccination, HPV negative cervical cancer will represent a larger percentage of newly diagnosed cancers and further research is needed to identify the optimal management approach.
Phase I study to assess the safety, tolerability, pharmacokinetics/pharmacodynamics and preliminary efficacy of SC10914 in patients with advanced solid tumors.
Authors: Gong Jifang , Tang Jinhai , Yin Yongmei , Ye Dingwei , Zhang Jian , Zheng Hong , Gao Yunong , Jang Haoyuan , Chen Xiao , Zhang Zhe , Shen Lin
Published: May 2020

6047

Background: SC10914 is a highly selective inhibitor of PARP enzymes, including PARP1 and PARP2. SC10914 has a similar structure with olaparib. We conducted a phase I study to assess the safety, tolerability, PK/PD and preliminary efficacy of SC10914 in patients with advanced solid tumors. Methods: This is a phase I dose-escalation study with 3+3 design, we enrolled patients at 4 sites in China. Eligible patients were diagnosed with advanced solid malignancies who are refractory to standard therapies or for which no standard therapy exists; had measurable disease; had adequate organ function. Patients received SC10914 daily at ten escalating doses from 30 mg QD to 500 mg TID in a 28-day cycle. We obtained blood for PK and CA125 assessments. Toxic effects were assessed by CTCAE 4.03 criteria and tumour responses ascribed by RECIST 1.1 and CA125 was assessed by GCIG criteria. Results: As of January 2020, 52 patients were enrolled, of which 14 were males and 38 were females. Ten doses were escalated to 500mg TID, and no DLT was observed, and MTD was not obtained. The incidence of grade 3/4 AEs and SAEs that were related to SC10914 were 34.6% (18/52) and 13.5% (7/52). Grade 3/4 adverse reaction happened in at least two patients were anaemia/reduced hemoglobin (10/52, 19.2%), decreased WBC count (5/52, 9.6%), neutropenia (3/52, 5.8%), thrombocytopenia (2/52, 3.8%), and decreased lymphocyte count (2/52, 3.8%). A total of 17 gBRCAm evaluable ovarian cancer patients were enrolled, 6 of them had PR, the ORR was 35.3% (6/17). 10 gBRCAm ovarian cancer patients were enrolled in TID groups (including 2 patients who received BID doses at the beginning and changed to 300 mg TID dose after several cycles of treatment), 5 of them had PR, the ORR was 50% (5/10). The ORR of 400 mg TID group was 66.7%(4/6). PK data showed that the exposure of SC10914 was increased with dose increasing at the dose of 30 mg to 250 mg. The half-life of SC10914 was about 2-5 hours. Conclusions: SC10914 was safe in patients with advanced solid tumors. The main toxicity was blood-related adverse reactions. SC10914 was effective in gBRCAm ovarian cancer patients. 400 mg TID might be RP2D. Clinical trial information: NCT02940132.
Anlotinib in patients with recurrent platinum-resistant or refractory ovarian carcinoma: A prospective, single-arm, single-center, phase II clinical study.
Authors: Shan Boer , Shen Wenbin , Wang Huaying
Published: May 2020

6061

Background: Recurrent platinum-resistant or refractory ovarian carcinoma is difficult to treat, and how to improve the treatment effect of these patients is still an urgent problem to solve. Anlotinib is a new multi-target tyrosine kinase inhibitor and its anti-tumor vascular targets include VEGFR, PDGFR and FGFR. Previous researches have shown clinical antitumor activity of anlotinib in various cancers, including the phase I study on gynecologic tumor. This phase II study (ChiCTR2000029654) aims to further evaluate the safety and efficacy of anlotinib in patients with recurrent or refractory ovarian carcinoma. Methods: Patients who have previously received second-line or more chemotherapy, with histopathologically confirmed ovarian high-grade serous gonadal carcinoma (including salpingocarcinoma and peritoneal carcinoma), ECOG 0-2 were considered eligible for enrollment. Anlotinib was administered orally (12 mg qd, d1-14; 21 days per cycle) till disease progression, death or intolerant toxicity. Therapeutic effects are evaluated every 6 weeks. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety and quality of life (QOL). Results: Between 2019 March to 2020 January, 15 patients (female) with FIGO histopathological stage IA(6.7%), IIIA (73.3%), IIIC (6.7%) and IV (13.3%) were enrolled and 14 patients were evaluable with a median age of 59 years (range: 47-69). The mean follow-up period is 3.5 months (95% CI: 2.1-4.8). Therapeutic evaluation showed the incidence of partial response, stable disease and progression disease was 14.3%, 57.1% and 28.6% respectively, yielding the ORR of 14.3% (2/14; 95% CI: 1.8%-42.8%) and the DCR of 71.4% (10/14; 95% CI: 41.9%-91.6%). The median PFS was not reached. Most of the occurring AEs were grade 1, including hypertention (57.1%), fatigue (50.0%), hand-foot syndrome (35.7%), hoarseness (14.3%), diarrhea (7.1%), gum-pain (7.1%), decrease in leukocyte count (6.7%) and urine protein (7.1%). Only cancer pain (7.1%) was grade 2. No high grade AE was observed in these 14 patients. Neither unexpected safety signals nor treatment related death occurred. Conclusions: Anlotinib showed a promising efficacy with a favourable toxicity profile for patients with recurrent platinum-resistant or refractory ovarian carcinoma. And we will report more results ahout anlotinib in the future. Clinical trial information: ChiCTR2000029654.
Patterns of progression and subsequent management of patients with BRCA1/2 mutated platinum-sensitive recurrent epithelial ovarian cancer (EOC) progressing on olaparib versus placebo: the SOLO2/ENGOT Ov-21 trial (NCT01874353).
Authors: Frenel Jean-Sebastien , Kim Jae-Weon , Berton Dominique , Asher Rebecca , Vidal Laura , Pautier Patricia , Ledermann Jonathan A. , Penson Richard T. , Oza Amit M. , Korach Jacob , Huzarski Tomasz , Pignata Sandro , Colombo Nicoletta , Park-Simon Tjoung-Won , Tamura Kenji , Sonke Gabe S. , Lowe Elizabeth S. , Freimund Alison E. , Lee Chee Khoon , Pujade-Lauraine Eric
Published: May 2020

6070

Background: Olaparib maintenance is a standard treatment of BRCA1/2 mutated platinum-sensitive recurrent EOC. Despite improvement in PFS, olaparib (O) resistance often occurs and the optimal management of post-olaparib progression remains undefined. Methods: Data of patients who participated in the SOLO-2 trial and progressed were analyzed. Primary objective was to depict the patterns of progression of patients treated with O compared to placebo (P). Secondary objectives include description of post-progression treatments. Results: 106/195 (54%) and 80/99 (81%) patients had a RECIST progression in the O and P arms respectively. As permitted in the protocol, 37 (35%) pts continued O despite a RECIST progression and 10 remained on treatment at the date of data base cut-off of the primary endpoint. Median duration of O post progression was 3.2 months (range: 1 to 19.4). In the placebo arm, only 20% of the patients with progressive disease continued placebo during a median of 1.6 months (range:1.1 to 16.1). Patterns of sites of progressive disease were similar in the O and P arms respectively in terms of liver (21% vs 18%), lung (4% vs 3%), lymph node (20% vs 16%) peritoneal (48% vs 32%) or brain metastases (0% vs 2%). Number of sites of relapsing disease were similar in the O and P arm respectively (1 (68% vs 64), ≥2 (32% vs 36%). A total of 54 (51%) patients in the O arm and 42 (53%) in the P arm received subsequent platinum-based therapy. In both arms, 8% received bevacizumab and 6% received no further treatment. Median PFS with first post-study platinum-based and non platinum-based therapy were 7.1 months and 5.6 months respectively. In the P arm, 18 (23) patients received PARP inhibitors following the first subsequent chemotherapy. Conclusions: Patterns of disease progression and subsequent chemotherapy were similar in patients receiving O or P in the SOLO2 trial. Instead of switching to chemotherapy, continuing O at the time of RECIST progression was an option for 35% of the patients. Clinical trial information: NCT01874353.
Methylated DNA markers for plasma detection of ovarian cancer: Discovery, validation, and clinical feasibility.
Authors: Bakkum-Gamez Jamie Nadine , Marinelli Lisa , Ahlquist David A. , Slettedahl Seth , Mahoney Douglas W. , Taylor William R. , Burger Kelli , Berger Calise K. , Doering Karen A , Lemens Maureen , Shridhar Viji , Allawi Hatim T. , Berg Hannah , Giakoumopoulos Maria , Kaiser Michael W. , Schoolmeester J. Kenneth , Kerr Sarah , Sherman Mark E. , Kisiel John B.
Published: May 2020

6072

Background: Effective screening tests for ovarian cancer (OC) are lacking; most cases present at advanced stage and portend poor prognosis. DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. In DNA extracted from tissues, we first discovered, then validated discriminant methylated DNA marker (MDM) candidates for OC and subsequently tested independent plasma from women with and without OC. Methods: For discovery, DNA from 67 frozen tissues (18 high grade serous (HGS), 18 endometrioid, 15 clear cell (CC), 6 mucinous OCs; 10 benign fallopian tube epithelium (FT); and 19 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with OC. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent FFPE tissues from OCs (36 HGS, 22 endometrioid, 21 CC, and 14 mucinous) and 29 FT. Top performing MDMs in tissue were tested using long-probe quantitative amplified signal assays in independent pre-treatment plasma samples from women newly-diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated. Results: After RRBS discovery and biological validation, 33 MDMs showed marked methylation fold changes (10 to > 1000) across all OC histologies vs FT. The top 11 MDMs ( GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, DSCR6, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (76 (84%) HGS) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95%CI 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86 - 0.96)). Among HGS, the panel correctly identified 83%, including 5/6 stage I/II, and the majority of other subtypes (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded outstanding candidate MDMs for OC that performed with promisingly high sensitivity and specificity in plasma. Larger plasma-based OC MDM testing studies, with larger numbers of non-HGS histologies are warranted. [Table: see text]
PFS by blinded independent central review (BICR) in the VELIA trial of veliparib (V) plus carboplatin/paclitaxel (CP) and as monotherapy in newly diagnosed patients (pts) with high-grade serous ovarian cancer (HGSC).
Authors: Aghajanian Carol , Bookman Michael A. , Fleming Gini F. , Brady Mark F. , Swisher Elizabeth M. , Steffensen Karina Dahl , Friedlander Michael , Okamoto Aikou , Moore Kathleen N. , Sullivan Danielle Marie , Fallstrom Mathias , Dinh Minh , Ratajczak Christine , Coleman Robert L.
Published: May 2020

6077

Background: The phase III VELIA trial (NCT02470585) demonstrated statistically significant improvement in PFS per investigator (INV) for V added to CP and continued as maintenance (CPV-V) vs. CP alone in pts with newly diagnosed HGSC in the BRCA mutated ( BRCAm), homologous recombination deficient (HRD), and whole populations. Here we present pre-specified analyses of PFS per BICR. Methods: Pts with Stage III-IV HGSC received V or Placebo (PL) with CP (6 cycles) and as maintenance (30 additional cycles). Primary analysis of PFS by INV compared CPV-V to CP alone in the BRCAm, HRD, and whole populations. Exploratory analyses of PFS in BRCA wildtype (wt) and non-HRD HGSC were performed. Radiologic tumor assessments were also prospectively submitted to an independent central reviewer for blinded assessment per RECIST v 1.1. PFS per BICR and rates of concordance between INV and BICR for determination of disease progression were analyzed. Safety data from the primary analysis were previously reported. Results: 1140 total pts were enrolled (CPV-V 382; CP 375). In the whole population, 26% of HGSCs were BRCAm and 55% were HRD. Concordance rates between INV and BICR were 68-85% by arm for each population. Analyses of PFS per BICR and per INV were consistent (Table). PFS was prolonged in the CPV-V vs. CP arm in all primary and exploratory populations assessed. Conclusions: Analyses of PFS per BICR supported the primary analysis of PFS per INV in the BRCAm, HRD, and whole populations, as well as exploratory BRCAwt and non-HRD populations. Median PFS per BICR was longer compared to PFS per INV assessments in all populations and in both arms. These findings support the reliability of PFS by INV in ovarian cancer trials. Alternate strategies like audits may be appropriate to support PFS by INV with less time and expense than full BICR. Clinical trial information: NCT02470585. [Table: see text]
Lenvatinib (LEN) plus pembrolizumab (PEMBRO) for early-line treatment of advanced/recurrent endometrial cancer (EC).
Authors: Makker Vicky , Taylor Matthew H. , Aghajanian Carol , Oaknin Ana , Mier James , Cohn Allen Lee , Romeo Margarita , Bratos Raquel , Brose Marcia S. , DiSimone Christopher , Messing Mark , Dutta Lea , Ren Min , Schmidt Emmett V. , Orlowski Robert , McKenzie Jodi Alicia , Gillis Kathryn , Casado Herraez Antonio
Published: May 2020

6083

Background: As part of an ongoing phase Ib/II study (NCT02501096) in patients (pts) with selected solid tumors, LEN (20 mg PO QD) + PEMBRO (200 mg IV Q3W) displayed substantial and durable antitumor activity in advanced EC. In previously treated EC that was not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR; n=94 pts), the objective response rate (ORR) by independent imaging review (IIR) per RECIST 1.1 was 38.3% (95% CI 28.5–48.9). In this post hoc analysis, we assessed 2 subgroups of pts with previously treated, advanced, non MSI-H or dMMR EC who received LEN + PEMBRO in an early-treatment setting. Methods: Pts were examined in 2 subgroups: (1) Pts with only 1 prior line of cytotoxic therapy regardless of surgical stage or setting (adjuvant treatment for local-regional disease or treatment for metastatic disease); and (2) pts from subgroup 1 with local-regional disease at diagnosis who received only adjuvant cytotoxic therapy. There were no restrictions on prior hormonal or chemoradiation therapies in either subgroup. Tumor responses were assessed by IIR per RECIST 1.1. Results: Subgroup 1 included 63 pts and subgroup 2 had 21 pts. ORR (95% CI) was 41.3% (29.0–54.4) for subgroup 1 and 57.1% (34.0–78.2) for subgroup 2. Additional efficacy outcomes are summarized in the table. In subgroup 1, treatment-related adverse events (TRAEs) occurred in 62 (98%) pts (42 [67%] ≥ grade 3). TRAEs led to study-drug interruption of one or both drugs in 43 (68%) pts and dose reductions of LEN in 42 (67%) pts; 12 (19%) pts discontinued one or both drugs due to a TRAE. Serious TRAEs occurred in 18 (29%) pts and 2 (3%) pts died from a TRAE. The safety profile for subgroup 2 was generally similar to the profile for subgroup 1. Conclusions: The efficacy of LEN + PEMBRO for early-line treatment of advanced non MSI-H or dMMR EC appears promising. No new safety signals have emerged. A phase III study of LEN + PEMBRO vs paclitaxel + carboplatin for first-line treatment in advanced or recurrent EC is underway. Clinical trial information: NCT02501096. [Table: see text]
Results of a randomized phase III study of dysphagia-optimized intensity modulated radiotherapy (Do-IMRT) versus standard IMRT (S-IMRT) in head and neck cancer.
Authors: Nutting Christopher , Rooney Keith , Foran Bernadette , Pettit Laura , Beasley Matthew , Finneran Laura , Roe Justin , Tyler Justine , Roques Tom , Cook Audrey , Petkar Imran , Bhide Shree , Srinivasan Devraj , Boon Cheng , De Winton Emma , Frogley Robert , Mertens Kathrin , Emson Marie , Hall Emma ,   on behalf of the DARS Investigators
Published: May 2020

6508

Background: Most newly diagnosed oro- & hypopharngeal cancers (OPC, HPC) are treated with (chemo)RT with curative intent but at the consequence of adverse effects on quality of life. CRUK/14/014 investigated if using Do-IMRT to reduce RT dose to the dysphagia/aspiration related structures (DARS) improved swallowing function compared to S-IMRT. Methods: Patients with T1-4, N0-3, M0 OPC/HPC were randomised 1:1 to S-IMRT (65 Gray (Gy)/30 fractions (f) to primary & nodal tumour; 54Gy/30f to remaining pharyngeal subsite & nodal areas at risk of microscopic disease) or Do-IMRT. The volume of the superior & middle pharyngeal constrictor muscle (PCM) (OPC) or inferior PCM (HPC) lying outside the high-dose target volume was set a mandatory mean dose constraint in Do-IMRT. Treatment allocation was by minimisation balanced by centre, use of induction/concomitant chemotherapy, tumour site & AJCC stage. Primary endpoint was mean MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after RT with 102 patients needed to detect a 10 point improvement (assuming S-IMRT score of 72, standard deviation (SD) 13.8; 90% power, 2-sided 5% alpha). Patients were blind to treatment allocation. Secondary endpoints included local control. Results: 112 patients (56 S-IMRT, 56 Do-IMRT) were randomised from 22 UK centres from 06/2016 to 04/2018. Mean age was 57 years; 80% were male; 97% had OPC; 90% had AJCC stage 3&4 disease; 86% had concomitant chemotherapy only, 4% induction & concomitant and 10% no chemotherapy. 111/112 had RT doses as prescribed (1 patient died before RT). Median of the mean inferior PCM dose was S-IMRT 49.8Gy (IQR 47.1-52.4) vs. Do-IMRT 28.4Gy (21.3–37.4), p < 0.0001; superior & middle PCM dose was S-IMRT 57.2Gy (56.3–58.3) vs. Do-IMRT 49.7Gy (49.4–49.9), p < 0.0001. Do-IMRT had significantly higher MDADI scores: S-IMRT 70.3 (SD 17.3) vs. Do-IMRT 77.7 (16.1), p = 0.016. 3 local recurrences (1 S-IMRT, 2 Do-IMRT) have been reported. Conclusions: Do-IMRT reduced RT dose to the DARS and improved patient reported swallowing function compared with S-IMRT. This is the first randomised study to demonstrate functional benefit of swallow-sparing IMRT in OPC. Clinical trial information: 25458988 .
Plasma-based tumor mutational burden (bTMB) as predictor for survival in phase III EAGLE study: Durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum failure.
Authors: Li Weimin , Wildsmith Sophie , Ye Jiabu , Si Han , Morsli Nassim , He Philip , Shetty Jagdish , Yovine Alejandro Javier , Holoweckyj Nicholas , Raja Rajiv , Real Katia , Scorer Paul , Hembrough Todd , Walker Jill , Zhang Qu , Mesia Ricard , Haddad Robert I. , Licitra Lisa F. , Ferris Robert L.
Published: May 2020

6511

Background: In NSCLC, bTMB assessed from circulating tumor DNA shows promise as a predictive survival biomarker for immunotherapy, but its value in R/M HNSCC is uncertain. We evaluated bTMB as a predictor of survival in R/M HNSCC. Methods: EAGLE (NCT02369874) was a randomized, open-label, phase 3 trial evaluating D (anti-PD-L1), or D+T (anti-CTLA-4), vs CT in R/M HNSCC. Patients (pts) with disease progression after platinum-based CT were randomized (1:1:1) to D (10 mg/kg intravenous [IV] every 2 weeks [Q2W]), D (20 mg/kg IV Q4W) + T (1 mg/kg IV Q4W for up to 4 doses, followed by D at 10 mg/kg Q2W) or CT. bTMB was assessed in pretreatment plasma samples using the Guardant Health OMNI platform. Association of somatic loss of function mutations with OS was assessed. Results: 736 intent-to-treat pts were randomized; 247 were evaluable for bTMB (BEP). bTMB expression was not linked to HPV status, PD-L1 status, age, gender, tumor location, or ECOG PS. Smoking and progression within 6 months on multi-modality CT in localized disease trended with higher bTMB. OS and PFS HRs were significantly improved for D or D+T vs CT in pts with high bTMB (≥16 mut/Mb) vs low (<16 mut/Mb; Table). The benefit of D or D+T vs CT in pts with high bTMB generally improved with increasing cutoff. 74 pts (27 D, 20 D+T, 27 CT pts) were bTMB high. 18-month OS rates were higher for D+T (22%; 95% CI 7%–42%) and D (33%; 95% CI 17%–51%) vs CT (0%; 95% CI 0%–0%) in pts with high bTMB. Pts with mutations in KMT2D, a HNSCC tumor suppressor gene, showed improved OS for D+T vs CT (HR 0.39; 95% CI 0.18–0.85). A trend of improved OS for D+T vs CT (HR 0.19; 95% CI 0.03–1.03) was also seen in pts with ATM mutations. Conclusions: This is the first retrospective analysis of a phase 3 trial to show bTMB may be predictive of outcomes for checkpoint inhibitors in R/M HNSCC. In pts with high bTMB, D or D+T improved OS hazards by at least 60%, vs CT at cutoffs ≥16 mut/Mb. Validation of bTMB as a predictive biomarker is ongoing. Clinical trial information: NCT02369874 . [Table: see text]
Combination of monalizumab and cetuximab in recurrent or metastatic head and neck cancer patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors.
Authors: Cohen Roger B. , Bauman Jessica Ruth , Salas Sebastien , Colevas A. Dimitrios , Even Caroline , Cupissol Didier , Posner Marshall R. , Lefebvre Gautier , Saada-Bouzid Esma , Bernadach Maureen , Seiwert Tanguy Y. , Pearson Alexander T. , Calmels Franceline , Zerbib Robert , Andre Pascale , Rotolo Federico , Boyer-chammard Agnès , Fayette Jerome
Published: May 2020

6516

Background: Monalizumab is a first-in-class immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), which is expressed on subsets of Natural Killer (NK), gd T and tumor-infiltrating CD8+T cells. NKG2A blockade promotes innate anti-tumor immunity mediated by NK and CD8+T cells and enhances NK cell antibody-dependent cell-mediated cytotoxicity induced by cetuximab. In a Phase I study, the combination of monalizumab and cetuximab was well tolerated. In an initial expansion cohort 1 of 40 patients (pts) who had progressed after platinum-based therapy, we reported an overall response rate (ORR) of 27.5%, a 4.5 month median PFS and an 8.5 month median OS. In a subset of patients (n=18) previously treated with PD-(L)1 inhibitors (IO), corresponding results were 17%, 5.1, and 14.1 months, respectively (ESMO 2019). Here we present data from a second expansion cohort 2 (n=40) conducted specifically in the post-IO setting to independently confirm the cohort 1 results. Methods: Eligible patients had R/M SCCHN previously treated with platinum and a PD-(L)1 inhibitor. Pts received monalizumab 750 mg q2weeks and cetuximab according to the label until progression or toxicity. Cohort 2 was designed as a confirmatory multicenter single arm phase II study, with a pre-planned total of 40 patients. The primary endpoint was ORR assessed per RECIST 1.1. Results: As of January 31, 2020, 40 pts have been treated in cohort 2. Median follow-up is 7.3 months (range, 1.9-13.6+). Eight (8) pts have a confirmed partial response (PR); ORR is 20% [95% confidence interval: 11-35]. Median time to response is 1.6 months [1.6-5.3]. At the time of data analysis, 3 pts were still in PR and 3 pts had stable disease continue on treatment. PFS and OS are still immature. Conclusions: In pts previously treated with platinum and PD-(L)1 inhibitors, the combination of monalizumab and cetuximab demonstrated promising activity. The second extension cohort confirmed prospectively the ORR reported in cohort 1. A randomized phase III trial of monalizumab and cetuximab is planned in this platinum and IO-pretreated SCCHN population. Clinical trial information: NCT02643550 .
Network-meta-analysis of chemotherapy in nasopharyngeal carcinoma (MAC-NPC): An update on 8,221 patients.
Authors: Petit Claire , Lee Anne WM , Carmel Alexandra , Ng Wai Tong , Ma Jun , Chan Anthony TC , Hong Ruey-Long , Chen Ming-Yuan , Chen Lei , Zhu Guopei , Li Wen-Fei , Poh Sharon , Ngan Roger , Mai Hai-Qiang , Huang Pei-Yu , Zhang Li , Fountzilas George , Bourhis Jean , Pignon Jean-Pierre , Blanchard Pierre
Published: May 2020

6523

Background: Based on an individual patient data (IPD) network meta-analysis (NMA) of 20 randomized trials and 5,144 patients (pts), the MAC-NPC collaborative group has shown that the addition of adjuvant chemotherapy (AC) to chemo-radiotherapy (CRT) achieved the highest survival benefit in nasopharyngeal carcinoma (NPC; Ribassin-Majed JCO 2017). Here, we updated the meta-analysis with the addition of 8 trials. Methods: Trials of Radiotherapy (RT) with or without chemotherapy (CT) in patients with non-metastatic NPC were identified and updated IPD obtained. Both Western and Chinese medical literatures were searched. Overall Survival (OS) was the main endpoint. Fixed and random-effects frequentist NMA models were applied, network heterogeneity and consistency were evaluated. P-score was used to rank the treatments. R software - netmeta package was used to perform the analyses. Treatments were grouped in the following categories: RT alone (RT), induction chemotherapy followed by RT (IC-RT), induction chemotherapy without taxanes followed by concomitant chemoradiotherapy (ICtax(-)-CRT), induction chemotherapy with taxanes followed by concomitant chemoradiotherapy (ICtax(+)-CRT), concomitant chemoradiotherapy (CRT), concomitant chemoradiotherapy followed by adjuvant chemotherapy (CRT-AC) and RT followed by adjuvant chemotherapy (RT-AC). Results: Overall 28 trials and 8,214 pts were included. Median follow-up was 7.2 years. There was no heterogeneity in the NMA. There was inconsistency in the main analysis, which disappeared after the exclusion of 2 outlier trials. ICtax(+)-CRT ranked the best treatment for OS with a P-Score of 91%. Hazard ratio [HR, 95% Confidence Interval] for ICtax(+)-CRT was 0.75 [0.59-0.96] compared to CRT and 0.92 [0.69-1.24] compared to CRT-AC (second best treatment in raking with a P-Score of 85%; see league table below). When the 2 types of IC were merged, CRT-AC ranked the first followed by IC-CRT with P-Scores of 93% and 86% respectively, with a HR of 0.97 [0.84-1.14] for CRT-AC vs. IC-CRT. Conclusions: This IPD NMA of the treatment of locally advanced NPC demonstrates that the addition of IC or AC to CRT improves disease control probability and survival over CRT alone. Data on progression-free survival, locoregional and distant control will be presented at the meeting. [Table: see text]
Association between calcitonin and efficacy of anlotinib in medullary thyroid carcinoma: An analysis based on the ALTER01031 trial.
Authors: Gao Ming , Chi Yihebali , Tang Pingzhang , Xu Zhengang , Zheng Xiangqian , Li Dapeng , Chen Xiaohong , Ge Minghua , Zhang Yuan , Guo Zhuming , Wang Jun , Chen Jie , Zhang Jiewu , Cheng Ying , Li Zhendong , Liu Hui , Qin Jianwu , Zhu Jingqiang , Cheng Ruochuan
Published: May 2020

6526

Background: Calcitonin (Ct) is the most important biomarker for medullary thyroid carcinoma (MTC). In a randomized, placebo-controlled phase IIb trial (ALTER01031, NCT02586350) for MTC, anlotinib exhibited a strong capability not only in PFS prolongation but also in decreasing Ct level. This subanalysis explored the relationship between Ct level and anlotinib efficacy in this trial. Methods: Serum Ct of patients (pts) were tested at baseline and on week 6 (after 2 treatment cycles). Correlation between changes in Ct level and changes in target lesion diameters was explored. The influence of baseline Ct level on median PFS for anlotinib treated pts was estimated. Finally, pts in anlotinib arm were divided into two subgroups based on the percentage decline of Ct levels (> 50% vs. ≤50%) at week 6. Median PFS (mPFS), median OS (mOS) and objective response rate (ORR) of two groups were compared. Results: 86 of 91 enrolled pts (58 in anlotinib arm and 28 in placebo arm) were recorded their serum Ct levels at baseline and no significant difference was observed between two arms (7990.0 ng/L vs. 10891.5 ng/L, P = 0.192). After 2 treatment cycles, the Ct level decreased to 4597.5 ng/L in anlotinib arm (n = 50) while increased slightly in placebo arm (12640.0 ng/L, n = 24, P = 0.006). For 49 pts in anlotinib arm who had complete assessments at baseline and week 6, roughly linear relationship was observed between Ct levels (X-axis) and target lesion diameters (Y-axis) in percent changes from baseline to week 6 (y = 0.175x – 0.049; r = 0.352, P = 0.016, excluding 3 outliers). Pts with less baseline Ct level (≤ median value vs. > median value) did not show more PFS benefit (17.7 vs. 22.4 months, P = 0.802). However, after 2 treatment cycles, a trend of better survival and higher response was observed in pts with high percentage decline of Ct level (> 50%, n = 25) than those with low percentage decline (≤50%, n =25) although without statistical difference (data presented in the table below). Conclusions: In ALTER01031, anlotinib showed a strong capability in rapidly decreasing serum Ct. Lower baseline Ct level does not mean better prognosis while a rapid Ct decrease may predict improved survival and treatment response to MTC pts received anlotinib. Clinical trial information: NCT02586350 . [Table: see text]
A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients.
Authors: van Boxtel Wim , Uijen Maike , Driessen Chantal , Pegge Sjoert , Willems Stefan M. , Jonker Marianne , Dijkema Tim , van Engen - van Grunsven Ilse , Van Herpen Carla M.L.-
Published: May 2020

6529

A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients. Background: Because c-MET and VEGFR are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in recurrent/metastatic (R/M) SGC pts. Methods: A single center, single arm, phase II study was conducted. Immunohistochemical c-MET positive (H-score ≥10) R/M SGC pts were included in 3 cohorts: adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), and other SGCs. Objective growth or complaints due to the disease were required before inclusion in the ACC and other SGC cohort. No prior systemic treatments were required. Pts started 60 mg cabozantinib tablets OD. Primary endpoint was the objective response rate (ORR). A Simon two-stage design was used. In case of ≥1 objective response in the first 9 pts/cohort, 8 additional pts would be included in the cohort. Results: In total 25 pts were included from Sep. 2018 until premature closure due to severe toxicity in Nov. 2019. Median age was 56 years (range 49-72), prior treatments included: primary tumor resection ( n=19), radiotherapy ≥50Gy ( n=24), systemic therapy ( n=10; adjuvant in 2 pts, palliative in 8 pts). Six pts had grade 3 ( n=4), grade 4 ( n=1), or grade 5 ( n=1) wound/fistula complications, occurring at a median of 7.2 mths on cabozantinib (range 2.1-12.8). This resulted in a severe wound complication rate of 32% in 19 pts on treatment for ≥2 mths. Remarkably, 4 out of 6 pts developed this complication in the area exposed to high-dose Rx; 2/4 had a pre-existing fistula in this area. Median interval between Rx and start of cabozantinib was 71.3 mths (range 10.6-94.7). Other grade ≥3 adverse events in >1 pt were: hypertension (5 pts), diarrhoea (2 pts) and dehydration (2 pts). Current median follow-up is 6.8 mths. The ORR was 6% (1/17 pts) in the ACC cohort, 20% (1/5 pts) in the SDC cohort, and 0% (0/3 pts) in other SGC pts; median PFS is 12.6 mths (95% CI 6.8 – 18.4 mths), 9.0 mths (insufficient events for 95% CI), and 6.9 mths (95% CI 0 – 15.2 mths), respectively. Median OS is not reached in any cohort. Conclusions: This phase II study on cabozantinib in R/M SGC pts demonstrated severe wound and fistula complications in 32% of pts on treatment for ≥2 mths, mostly (4/6 pts) within the radiotherapy field. Because of this toxicity the study was closed prematurely. Furthermore, cabozantinib showed minimal clinical activity in SGC pts. Research funding: Ipsen Pharmaceuticals Clinical trial information: NCT03729297 .
A phase I/Ib study of lenvatinib and cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Dunn Lara , Ho Alan Loh , Eng Juliana , Michel Loren S. , Fetten James Vincent , Warner Elizabeth , Kriplani Anuja , Zhi Wanqing Iris , Ng Kenneth K. , Haque Sofia , Pfister David G. , Sherman Eric Jeffrey
Published: May 2020

6541

Background: Despite overexpression of EGFR in HNSCC, cetuximab monotherapy has limited benefit. Fibroblast growth factor receptor (FGFR) signaling is a known resistance mechanism to EGFR inhibition. Lenvatinib is a multi-targeted receptor tyrosine kinase inhibitor (RTKI) and has unique activity against FGFR 1,2,3, and 4. We are evaluating inhibition of EGFR and RTKs including FGFR through the combination of cetuximab and lenvatinib in patients (pts) with R/M HNSCC. Methods: In this phase I/Ib, single-institution study, pts with measurable disease per RECIST v1.1 that is incurable with surgery and radiation are eligible regardless of prior cetuximab therapy. The dose de-escalation phase included pts with HNSCC and cutaneous squamous cell carcinoma (cSCC) treated with standard cetuximab dosing and lenvatinib in 3 potential dose levels (DL): (0) 24mg, (-1) 20mg, (-2) 14mg oral daily in a standard 3+3 design. The primary objective was to determine the MTD of lenvatinib in combination with cetuximab. The expansion phase included an additional 5 pts with HNSCC treated at the MTD. Exploratory endpoints include ORR and PFS in HNSCC pts treated at the MTD. Results: 12 evaluable pts were treated on the dose de-escalation phase. There were no DLTs on DL 0; however, 3/6 pts were removed immediately following the 28-day DLT period due to toxicity that included extensive thrombotic events and athlerosclerotic disease. On DL -1, 0/6 pts (5 HNSCC/1 cSCC) had a DLT establishing lenvatinib 20mg daily as the MTD. 7 pts were enrolled onto the expansion phase; 4 are currently evaluable for response and 2 are unevaluable because of withdrawal due to a cetuximab reaction and required surgery. Of the 9 evaluable HNSCC pts treated with lenvatinib 20mg daily, 6 pts had a PR with a 67% ORR. For the 8 pts who have completed treatment, the median PFS is 3.6 months (range 1.6-10.4). Grade 3 AEs regardless of attribution included hypertension (3), oral mucositis (3) and oral cavity fistula (1). The most common AEs were acneiform rash (7), fatigue (6), and hypertension/hypothyroidism/oral mucositis (5 each). Conclusions: The MTD of lenvatinib 20mg daily with cetuximab appears to be active in R/M HSNCC with an impressive preliminary ORR, warranting further evaluation of the efficacy of this combination. Clinical trial information: NCT03524326 .
Radiomic response evaluation of recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC) patients receiving pembrolizumab on KEYNOTE-012 study.
Authors: Taylor Kirsty , Kazmierski Michal , Billfalk-Kelly Astrid , Khodakarami Farnoosh , Driscoll Brandon , Wang Lisa , Bratman Scott Victor , Haibe-Kains Benjamin , Siu Lillian L.
Published: May 2020

6545

Background: Immunotherapy has become a standard of care in the treatment of R/M HNSCC, however only a subset of patients respond, highlighting the need for predictive and prognostic biomarkers. Radiomics is a non-invasive method to quantitatively analyze tumors through conventional imaging. Methods: The pre-treatment and first-on-treatment (after 8 weeks) computed tomography (CT) scans from 132 R/M HNSCC patients treated with single-agent Pembrolizumab (10mg/kg Q2W or 200mg Q3W IV) on the KEYNOTE-012 study were analyzed. Identified target lesions, per RECIST 1.1, were manually contoured, and radiomic features from the tumor and peritumoral region (3 mm expansion of the tumor) were extracted using PyRadiomics. All combinations of image filters and feature classes, not including shape descriptors of peritumoral region, were extracted. Feature space dimensionality was reduced by clustering features (hierarchical clustering using Pearson-based distance and complete linkage) and selecting the medoid of each cluster. Correlation with lesion-level response (LLR) at first-on-treatment CT and overall response (OR) was evaluated using concordance index (CI) with Benjamini-Hochberg multiple testing correction. Results: A total of 406 lesions were included (45 head & neck (HN), 207 lung, 57 liver, 86 lymph nodes (LN), 11 other). 3562 features were extracted from pre-treatment scans (2246 tumor, 1316 peritumor). Considering all lesion sites collectively, 27 of 110 feature clusters were significantly correlated with LLR (false discovery rate (FDR) < 0.05) but not with best overall RECIST response per patient on study. However, when grouped by organ, a number of feature cluster medoids were significantly associated (FDR < 0.05) with LLR (HN: 1, lung: 28, liver: 8, LN: 1) and OR (liver: 18). Feature clusters predictive of LLR and OR included descriptors of both tumor-specific and tumor/peritumoral gray-level intensity and texture (e.g. 74% tumor and 26% peritumoral features in clusters significantly associated with OR in liver). Conclusions: Tumor and peritumoral radiomic features at baseline correlate with LLR and OR to immunotherapy in R/M HNSCC. Despite significant heterogeneity in lesion site, both global and site-specific significant feature clusters could be identified.
Exome scale liquid biopsy characterization of putative neoantigens and genomic biomarkers pre- and post anti-PD-1 therapy in squamous cell carcinoma of the head and neck.
Authors: Abbott Charles , Bedi Nikita , Zhang Simo V , Li Robin , Pyke Rachel , Levy Eric , Chernock Rebecca , Mansour Mena , Sunwoo John B. , Colevas A. Dimitrios , Chen Richard , Boyle Sean Michael
Published: May 2020

6557

Background: The reduced scope, and number of genes profiled by typical liquid biopsy panels can result in missed biomarkers including neoantigens, which may change with treatment, as well as potentially undetected resistance mechanisms and pathways beyond the scope of targets typically captured by panels. To address these limitations, we used a whole-exome scale liquid biopsy monitoring platform, NeXT Liquid Biopsy, to analyze head and neck squamous cell carcinoma (HNSCC) patients that have received anti-PD1 therapy. Presently, we sought to (1) monitor neoantigen changes in cfDNA as a complement to tumor biopsy-derived neoantigens, (2) compare the impact of tumor escape mechanisms, including HLA-LOH, on neoantigens identified in tissue and cfDNA and (3) to identify novel biological signatures that combine information from both solid tumor and liquid biopsies. Methods: Pre- and post-intervention matched normal, tumor and plasma samples were collected from a cohort of 12 patients with HNSCC. Following baseline sample collection all patients received a single dose of nivolumab, followed by resection approximately one month later when feasible, or a second biopsy where resection was impractical. Solid tumor and matched normal samples were profiled using ImmunoID NeXT, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale somatic variants were identified in cfDNA from plasma samples using the NeXT Liquid Biopsy platform. Data from these two platforms were compared with corresponding clinical findings. Results: Concordant somatic events were detected between plasma and tumor at pre- and post-treatment timepoints. Neoantigens predicted to arise from these somatic events were reduced in solid tumor post-treatment, but increased in cfDNA, when compared to pre-treatment timepoints. HLA LOH was identified in a number of subjects, likely resulting in reduced neoepitope presentation in those cases. Immune cell infiltration increased in the tumor following treatment, with no changes to the CD8+/Treg cell ratio, suggesting consistent immunoregulation. Conclusions: Exome-wide neoantigen burden was reliably predicted from cfDNA, providing additional insight complementing data from solid tumor. Analyzing HLA LOH, and neoantigen burden from both solid and liquid biopsies together over the course of treatment creates a more comprehensive profile of therapeutic response and resistance mechanisms in HNSCC patients missed with typical liquid biopsy panels.