Safety and efficacy of durvalumab following multimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Two-year follow-up results from Big Ten Cancer Research Consortium study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 404-404 ◽  
Author(s):  
Hirva Mamdani ◽  
Bryan J. Schneider ◽  
Pashtoon Murtaza Kasi ◽  
Laith I. Abushahin ◽  
Thomas J. Birdas ◽  
...  
Keyword(s):  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Predictive Biomarkers ◽  
R0 Resection ◽  
Trimodality Therapy ◽  
Surgical Specimen ◽  
Safety And Efficacy ◽  
Grade 3

404 Background: Concurrent chemoradiation(CRT) followed by esophagectomy is a standard of care for locally advanced esophageal(LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients(pts) experience disease relapse within the 1st yr after treatment(tx) completion. No adjuvant tx has been shown to improve survival in these pts. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown radiation +/- chemotherapy upregulate PD-1/PD-L1 pathway. Methods: We conducted a phase II trial evaluating safety and efficacy of durvalumab(durva) in pts with LA-EAC and GEJ adenocarcinoma who have residual disease in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: 24 pts were enrolled from 4/2016-1/2018(median age: 60yrs (range, 43-70). 18 received carbo/paclitaxel and 6 received cis/5-FU concurrently with radiation. Staging at diagnosis: T2N0(n = 3, 12.5%), T2N2(n = 3, 12.5%),T3N0(n = 6, 25%), T3N1(n = 6, 25%), T3N2(n = 4, 17%), T3N3(n = 1, 4%), T3Nx(n = 1, 4%).19 pts(79%) had positive lymph nodes(LNs) at the time of surgery following CRT. 12 pts completed 1yr of tx, 12 came off tx because of relapse(6), AEs(5), and consent withdrawal(1). Most common AEs were fatigue(n = 8, 33.3%) and nausea(n = 6, 25%). 3pts (12.5%) developed grade 3 irAEs: pneumonitis(1), hepatitis(1), colitis(1). At median follow up of 21.9mo(range, 1.7-23.9mo), 11 pts have relapsed: 9 distant and 2 locoregional. Two of 3 pts with grade 3 irAEs are alive and disease free at 17 and 23 mo respectively. 1-yr RFS and OS were 79.2% and 95.5%, respectively. RFS at 26 mo was 20.6%. Overall mOS and mOS after relapse were 28.1mo(range, 22.9-28.1) and 11.1 mo(range, 0.1-11.3mo) respectively. The study was expanded to enroll 14 additional pts who are currently undergoing tx. Conclusions: Adjuvant durvalumab following trimodality therapy for LA-EAC and GEJ adenocarcinoma is safe with improvement in 1-yr RFS to 79.2% compared to historical rate of 50%. RFS was 20.6% at 26 months. Evaluation of predictive biomarkers of RFS with durva is underway. Clinical trial information: NCT02639065.

Safety and efficacy of durvalumab following multimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Results from Big Ten Cancer Research Consortium study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4058-4058 ◽  
Author(s):  
Hirva Mamdani ◽  
Bryan J. Schneider ◽  
Laith I. Abushahin ◽  
Thomas J Birdas ◽  
Kenneth Kesler ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Median Number ◽  
R0 Resection ◽  
Big Ten ◽  
Trimodality Therapy ◽  
Surgical Specimen ◽  
Safety And Efficacy ◽  
Distant Relapse

4058 Background: Concurrent chemoradiation (CRT) followed by esophagectomy is a standard of care for locally advanced esophageal (LA-EAC) and GEJ adenocarcinoma. Approximately 50% of patients (pts) experience disease relapse within the 1st yr after treatment(tx) completion. No adjuvant tx has been shown to improve survival in these pts. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown upregulation of PD-1/PD-L1 pathway with RT +/- chemotherapy. Methods: We conducted a phase II trial evaluating safety and efficacy of durvalumab (durva), a monoclonal antibody against PD-L1, in pts with LA-EAC and GEJ adenocarcinoma who have viable tumor in surgical specimen after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1yr. Results: 24 pts were enrolled from 4/2016-1/2018 (median age: 60yrs (range, 43-70). 18 received carbo/paclitaxel and 6 received cis/5-FU concurrently with radiation. Staging at diagnosis: T2N0 (n=3, 12.5%), T2N2 (n=3, 12.5%),T3N0 (n=6, 25%), T3N1 (n=6, 25%), T3N2 (n=4, 17%), T3N3 (n=1, 4%), T3Nx (n=1, 4%).19 pts (79%) had positive lymph nodes (LNs) at the time of surgery following CRT. 12 pts completed 1yr of tx, 12 came off tx before 1yr because of relapse(6), AEs(5), and consent withdrawal (1). Median number of tx cycles was 12.5 (range, 2-13). Most common AEs were fatigue (n=8, 33.3%) and nausea (n=6, 25%). 3pts (12.5%) developed grade 3 irAEs: pneumonitis (1), hepatitis (1), colitis (1). At median follow up of 14.5 mo (range, 1.7-24mo), 17 are disease free (including 5 who came off tx before 1yr). 7pts (29%) have relapsed (3 alive, 4 died). 6/7pts had distant relapse (lung, brain, bone, cervical LNs) and 1 had locoregional relapse. 1-yr RFS and OS were 79.2% and 95.5%, respectively. 2-yr OS was 59.2%. RFS probability at 26 mo was 67.9%. Median survival after relapse was 11.1 mo (range, 0.1-11.3mo). Conclusions: Adjuvant durvalumab following trimodality therapy for LA-EAC and GEJ adenocarcinoma was safe and feasible with improvement in 1-yr RFS to 79.2% compared to historical rate of 50%. OS results are encouraging in this high risk pt population. Clinical trial information: NCT02639065.

Safety and efficacy of durvalumab following trimodality therapy for locally advanced esophageal and GEJ adenocarcinoma: Early efficacy results from Big Ten Cancer Research Consortium study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 5-5 ◽  
Author(s):  
Hirva Mamdani ◽  
Bryan J. Schneider ◽  
Laith I. Abushahin ◽  
Thomas J Birdas ◽  
Kenneth Kesler ◽  
...  
Keyword(s):  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Primary Objective ◽  
R0 Resection ◽  
Big Ten ◽  
Trimodality Therapy ◽  
Safety And Efficacy ◽  
Research Consortium

5 Background: The standard of care for locally advanced esophageal adenocarcinoma(LA-EAC) is concurrent chemoradiation (CRT) followed by esophagectomy. Approximately 30% of patients (pts) achieve complete pathologic response (pCR) with this approach. The risk of relapse in the remaining 70% of pts is high, with 1-yr relapse free survival (RFS) of 50%. No adjuvant therapies have been shown to improve survival. Immune checkpoint inhibitors have activity in metastatic PD-L1 positive EAC. Preclinical studies have shown upregulation of PD-1 pathway with radiation +/- chemotherapy. Methods: We conducted a phase II study evaluating safety and efficacy of durvalumab (durva), a monoclonal antibody against PD-L1, in pts with LA-EAC and GE junction (GEJ) adenocarcinoma who do not achieve pCR after neoadjuvant CRT and R0 resection. Pts received durva 1500mg IV every 4 weeks for up to 1 yr after surgery. Primary objective was 1-yr RFS. Secondary objectives were incidence and severity of treatment related adverse events (AEs). Results: Twenty-four pts were enrolled from Apr 2016 to Jan 2018 (median age: 60yrs (range, 43-74)). Fourteen pts had GEJ adenocarcinoma and 10 had distal EAC. Eighteen received carboplatin/paclitaxel and six received cisplatin/5-FU concurrently with 50-50.4Gy radiation. Nineteen pts (79%) had positive lymph nodes at the time of surgery after neoadjuvant CRT, including three (12.5%) with N3, nine (37.5%) with N2, and seven (29%) with N1 disease. Among N0 pts, two had T3N0, one had T2N0, and two had T1N0 disease. At median follow-up of 11.7 mo (range 1.7-23.9 mo), seven pts (29%) have relapsed (five alive, two died); 17(67%) are disease free (six on treatment, seven completed treatment, three off-treatment); 1-yr and projected 26 mo RFS are 78.6% and 62.9%, respectively. Five pts (20.8%) developed grade 3 AEs: diarrhea (n = 1), hepatitis (n = 1), encephalopathy (n = 1), hyperglycemia (n = 1), hypoglycemia (n = 1). Most common grade 1 and 2 AEs were fatigue (33.3%), nausea (25.0%), and cough (20.8%). Conclusions: Adjuvant durva in pts with residual disease following trimodality therapy for EAC and GEJ adenocarcinoma is safe and feasible with 1-yr RFS of 78.6% compared to historical rate of 50%. Clinical trial information: NCT02639065.

BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC)—Initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1023-1023
Author(s):  
Peter Schmid ◽  
Seock-Ah Im ◽  
Anne Armstrong ◽  
Yeon Hee Park ◽  
Wei-Pang Chung ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Safety And Efficacy ◽  
Grade 3 ◽  
The Impact ◽  
Initial Results

1023 Background: Chemotherapy with immune checkpoint inhibitors can improve outcomes vs chemotherapy alone in patients (pts) with metastatic TNBC; however, many still have poor clinical outcomes. BEGONIA is an ongoing 2 part, multicenter, multiarm, open-label platform study evaluating safety and efficacy of D (anti–PD-L1)+P and D±P combined with novel therapies as first-line (1L) treatment for metastatic TNBC (NCT03742102). We report initial results from Part 1 of Arm 1, D+P, and Arm 6, D+T-DXd, an antibody-drug conjugate comprising an anti-HER2 antibody, tetrapeptide-based cleavable linker, and topoisomerase I inhibitor payload. Methods: Eligible pts had untreated unresectable locally advanced or metastatic TNBC. Pts with HER2-low–expressing tumors (IHC 2+/ISH–, IHC 1+/ISH–, or IHC 1+/ISH untested) per local testing were assigned to the D+T-DXd arm. Pts received D (1500 mg IV Q4W)+P (90 mg/m2 IV Day 1, 8, 15 Q4W) in Arm 1 and D (1120 mg IV)+T-DXd (5.4 mg/kg IV) Q3W in Arm 6, until progression or unacceptable toxicity. Primary objectives are safety and tolerability. Secondary endpoints include objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS). Tumors were assessed Q8W (D+P) or Q6W (D+T-DXd). The first 6 pts treated with D+T-DXd were evaluated for dose-limiting toxicities (DLTs), with additional pts enrolled if D+T-DXd was tolerated. Study arms are noncomparable due to differing eligibility criteria, treatments, and data maturity. Results: Arm 1 D+P (data cutoff Sep 2020): 23 pts received D+P (7 ongoing); 2 discontinued D+P due to AEs. Median follow-up time was 16.6 (range 8.5–19.8) mos. Any Grade 3/4 AEs and SAEs were experienced by 10 (44%) and 1 (4%) pts, respectively. D dose was delayed for 7 (30%) pts. Confirmed ORR was 13/23 (57%) with 54% of those remaining in response at 12 mos (median DoR not reached). Median PFS was 7.3 (95% CI 5.4–13.8) mos in the D+P arm. Arm 6 D+T-DXd (data cutoff Nov 2020): 11 pts received D+T-DXd to date (all ongoing). Median follow-up time was 2.3 (0–6) mos. Any Grade 3/4 AEs and SAEs were experienced by 4 (36%) and 1 (9%) pts, respectively. Pts who received D+T-DXd had no DLTs and 1 had a Grade 1 troponin increase. D dose was delayed and T-DXd dose reduced for 2 (18%) pts each. Confirmed ORR was 4/4 (100%; only 4 pts had the opportunity to complete 2 on-treatment disease assessments) with all 4 remaining in response at data cutoff (median DoR not reached). Conclusions: D+P demonstrated a tolerable safety profile and response rate as expected for a 1L TNBC IO/taxane combination. D+T-DXd showed promising early safety and efficacy in 1L HER2-low–expressing TNBC; pt evaluation and enrollment for D+T-DXd are ongoing. D+T-DXd data will be updated and the impact of PD-L1 expression in both arms will be examined. Clinical trial information: NCT03742102 .

scholarly journals Carbon ion radiotherapy for prostate cancer with bladder invasion

BMC Urology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuhei Miyasaka ◽  
Hidemasa Kawamura ◽  
Hiro Sato ◽  
Nobuteru Kubo ◽  
Tatsuji Mizukami ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Locally Advanced ◽  
Therapeutic Benefit ◽  
Carbon Ion Radiotherapy ◽  
Safety And Efficacy ◽  
Carbon Ion ◽  
Grade 3 ◽  
Bladder Invasion

Abstract Background The optimal management of clinical T4 (cT4) prostate cancer (PC) is still uncertain. At our institution, carbon ion radiotherapy (CIRT) for nonmetastatic PC, including tumors invading the bladder, has been performed since 2010. Since carbon ion beams provide a sharp dose distribution with minimal penumbra and have biological advantages over photon radiotherapy, CIRT may provide a therapeutic benefit for PC with bladder invasion. Hence, we evaluated CIRT for PC with bladder invasion in terms of the safety and efficacy. Methods Between March 2010 and December 2016, a total of 1337 patients with nonmetastatic PC received CIRT at a total dose of 57.6 Gy (RBE) in 16 fractions over 4 weeks. Among them, seven patients who had locally advanced PC with bladder invasion were identified. Long-term androgen-deprivation therapy (ADT) was also administered to these patients. Adverse events were graded according to the Common Terminology Criteria for Adverse Event version 5.0. Results At the completion of our study, all the patients with cT4 PC were alive with a median follow-up period of 78 months. Grade 2 acute urinary disorders were observed in only one patient. Regarding late toxicities, only one patient developed grade 2 hematuria and urinary urgency. There was no grade 3 or worse toxicity, and gastrointestinal toxicity was not observed. Six (85.7%) patients had no recurrence or metastasis. One patient had biochemical and local failures 42 and 45 months after CIRT, respectively. However, the recurrent disease has been well controlled by salvage ADT. Conclusions Seven patients with locally advanced PC invading the bladder treated with CIRT were evaluated. Our findings seem to suggest positive safety and efficacy profiles for CIRT.

scholarly journals Role of interstitial brachytherpy using template (mupit) in locally advanced carcinoma cervix

2016 ◽  
Author(s):  
Ashish Bhange ◽  
Abhishek Gulia ◽  
Anirudh Punnakal ◽  
Anil Kumar Anand ◽  
Anil Kumar Bansal ◽  
...  
Keyword(s):  
Local Control ◽  
Residual Disease ◽  
Locally Advanced ◽  
Concurrent Chemotherapy ◽  
Interstitial Brachytherapy ◽  
Carcinoma Cervix ◽  
Advanced Carcinoma ◽  
Needle Position ◽  
Grade 3

Introduction: Locally advanced carcinoma cervix includes stages IIB, IIIA, IIIB and IVA. Interstitial brachytherapy has the potential to deliver adequate dose to lateral parametrium and to vagina. Hence, it is preferable in cases with distorted anatomy, extensive (lower) vaginal wall involvement, bulky residual disease post EBRT and parametrium involvement upto lateral pelvic wall. Aim and Objective: To determine clinical outcome and complications (acute and chronic) in locally advanced carcinoma cervix, treated with interstitial brachytherapy using template (MUPIT - Martinez universal perineal interstitial template). Materials and Methods: This study is a retrospective analysis of 37 cases of locally advanced carcinoma cervix (stage IIB-2, IIIB-30, IVA-5), treated with EBRT (dose-median 45Gy/25#) ± concurrent chemotherapy (CCT) - Inj. Cisplatin/Inj Carboplatin, followed by interstitial brachytherapy using MUPIT from December 2009 to June 2015. Initial treatment with EBRT ± CCT was followed by intertstitial brachytherapy. Under spinal anaesthesia and epidural analgesia, MUPIT application was done. Straight and divergent needles (median 26, range 19-29) were inserted to cover parametrium adequately. Needle position was verified with planning CT scan and Brachytherapy planning was done. Dose was normalized to 5 mm box surface from outermost needle with optimization of dose to OAR (Bladder, Rectum and Sigmoid colon). Prescription dose –25Gy in 5#. Treatment was delivered by Microselectron HDR using Ir192 source. Treatment fractions were delivered twice daily with min 6 Hrs. gap in-between fractions. Results: The median duration of follow-up was 25 months. Local control was achieved in 28 patients with residual disease in 7 patients and local recurrence in 2 patients. 10 patients had acute lower GI toxicity {Grade1 (n=6), Grade 2 (n=4)}, 2 patients had acute Grade 1 bladder toxicity. 1 patient had grade 3 and 1 patient had grade 4 chronic bladder toxicity. Chronic rectal toxicity was seen in 10 patients {Grade 2 (n=4), Grade 3 (n=4), Grade 4 (n=2)}. Conclusion: Local control was achieved in 28/37 patients (75.6%) and overall survival rate of 81.1% at median follow up of 25 months in patients with locally advanced carcinoma cervix and unfavorable prognostic factors.

scholarly journals A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Hirva Mamdani ◽  
Bryan Schneider ◽  
Susan M. Perkins ◽  
Heather N. Burney ◽  
Pashtoon Murtaza Kasi ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Phase Ii ◽  
Residual Disease ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
M2 Macrophages ◽  
Activated T Cells ◽  
Trimodality Therapy ◽  
Surgical Specimen

BackgroundMost patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients.MethodsWe conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population.ResultsThirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56–84%) with median RFS of 21 months (95% CI, 14–40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05–0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15–0.93, p = 0.0351, respectively).ConclusionsAdjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.

A single-arm, phase II feasibility study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 96-96
Author(s):  
M. Ryu ◽  
Y. Choi ◽  
B. Kim ◽  
Y. Park ◽  
H. Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Advanced Gastric Cancer ◽  
Residual Disease ◽  
Gastroesophageal Junction ◽  
Locally Advanced ◽  
Phase Iii ◽  
R0 Resection ◽  
Locally Advanced Gastric Cancer ◽  
Grade 3

96 Background: The aim of this study was to evaluate feasibility and safety of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy in patients with potentially resectable adenocarcinoma of stomach or gastroesophageal junction. Methods: Forty-one patients with clinical stage T3-4N0M0 or T2-4N+M0 determined by CT, endoscopic ultrasonography, and laparoscopy were enrolled between DEC 2008 and MAR 2010. Gastrectomy with D2 lymph node dissection was conducted after 3 cycles of DOS chemotherapy. DOS chemotherapy consists of docetaxel 50 mg/m2 iv (day1), oxaliplatin 100 mg/m2 iv (day1), and S-1 40 mg/m2 po bid (days1-14) at 3 weeks interval. After curative gastrectomy, the patients were given 1 year of adjuvant chemotherapy with S-1 (40 mg/m2 D1-28, every 6 weeks). Results: All patients finished the planned neoadjuvant chemotherapy. Twenty-three (56%) patients achieved a partial response, and the remaining 18 patients had stable disease by CT scan after 3 cycles of DOS chemotherapy. No disease progression was observed during the neoadjuvant chemotherapy. A median 4.7 weeks (range, 4.0-7.6) after the start of the 3rd cycle of DOS chemotherapy, 39 (95%) patients underwent R0 resection with no pathologic residual disease in 4 (10%) patients. Hematologic toxicities were common including grade 4 neutropenia (32%), grade 3 thrombocytopenia (17%), and febrile neutropenia (10%). However, hematologic toxicities were generally transient and manageable. There were no grade 3 or 4 non-hematologic toxicities with frequency > 5% of patients. With all toxicities taken together, 21 (51%) patients experienced grade 3 or 4 toxicities (except grade 3 neutropenia). There was no treatment-related death, and surgical complications included only mild wound problem in 4 (10%) patients. Conclusions: In this study, neoadjuvant DOS chemotherapy could induce a sufficient down-staging and R0 resection of locally advanced gastric cancer with mild and manageable toxicities. A phase III randomized trial is planned for evaluating the benefit of neoadjuvant DOS chemotherapy in patients with locally advanced gastric cancer. [Table: see text]

Multicenter phase II study combining panitumumab with chemoradiation followed by surgery for patients with operable esophageal cancer (PACT-study).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4094-4094 ◽  
Author(s):  
Sil Kordes ◽  
Dirk Richel ◽  
Mark I. van Berge Henegouwen ◽  
Maarten C. Hulshof ◽  
Sybren L. Meijer ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Residual Disease ◽  
Growth Factor Receptor ◽  
Postoperative Mortality ◽  
Esophageal Reconstruction ◽  
Resected Specimen ◽  
R0 Resection ◽  
Surgical Specimen ◽  
Consistent Finding ◽  
Grade 3

4094 Background: A consistent finding in many studies in patients with operable esophageal and gastro-esophageal junction cancer is that response to preoperative therapy, particularly the absence of residual disease in the surgical specimen, is an indicator of better disease-free and overall survival. One of the potential strategies to improve these local effects of preoperative chemoradiation (CRT) is the concurrent inhibition of the epidermal growth factor receptor (EGFR). Therefore in our trial we evaluated the pathologic response of panitumumab in combination with neoadjuvant CRT as first line treatment of operable adenocarcinomas or squamous cell carcinomas of the esophagus. Methods: Patients with resectable cT1N1M0 or cT2-3N0-2M0 tumors received preoperative CRT consisting of 3 administrations of panitumumab (6mg/kg) in weeks 1-3-5, weekly administrations of carboplatin (AUC = 2) and paclitaxel (50 mg·m2) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week) followed by surgery. The primary endpoint was the percentage of pathologic complete responses (pCR). Results: From January 2010 till December 2011, 91 patients were enrolled. 3 patients were not resected due to the development of metastatic disease during CRT. Results of all patients will be presented at ASCO. The majority of the 74 patients operated thus far had T3 (85%) and node positive (77%) tumors. 21.6% reached pCR and 13.5% had less than 10% viable tumor cells in the resected specimen. R0-resection was achieved in 98.6%. There were 58 patients with adenocarcinoma and 11 patients with squamous cell carcinoma. The pCR of these patients were 15.5% and 45.5%, respectively. Main grade 3 toxicities were esophagitis, fatigue, rash and anorexia. 1 postoperative death occurred due to ischemia of the esophageal reconstruction. Conclusions: The addition of panitumumab to chemoradiotherapy with carboplatin and paclitaxel was feasible without increasing postoperative mortality, but did not improve the rate of pathologic complete responses compared to historical data.

Oxaliplatin, irinotecan, and PK-adjusted 5-fluorouracil within a multidisciplinary approach in patients with locally advanced pancreatic cancer (LAPC): Preliminary results.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 356-356
Author(s):  
Patricia Martin Romano ◽  
Azucena Aldaz ◽  
Ana Chopitea ◽  
Fernando Pardo ◽  
Leire Arbea ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Area Under The Curve ◽  
Therapeutic Index ◽  
Pathological Response ◽  
R0 Resection ◽  
Borderline Resectable ◽  
Optimal Sequence ◽  
Grade 3

356 Background: Neoadjuvant therapy is an increasingly used approach in LAPC patients (pts) but the optimal sequence remains to be defined. We evaluated the feasibility and efficacy of induction chemotherapy (ICT) with pharmacokinetic (PK) monitoring, chemo-radiotherapy (CRT) and surgery. Methods: Borderline resectable and unresectable LAPC pts with EUS stages T3-4/N+ were included. Pts were planned to receive 4 cycles of biweekly ICT with Oxalipatin (85mg/m²), Leucovorin (400mg/m²), Irinotecan (150mg/m²) and 5-FU (initial dose of 3200mg/m² in 46h and then tailored according to PK monitoring to reach an area under the curve (AUC) between 25-30 mg·h·L-1.) After ICT, pts with no progressive disease received CRT (50.4 Gy, daily concurrent Capecitabine and weekly Oxaliplatin). Surgery was planned 4 to 6 weeks after the completion of CRT. Pathological response was graded according to the CAP classification. Toxicity was recorded according to the NCI-CTCAE 4.0. Results: From November 2011 to February 2013, 13 LAPC treatment-naïve (M/F: 11/2) pts were enrolled (T4; 30.8%, N+; 61.5%, 8 borderline resectable, 5 unresectable due to celiac abutment (2 pts), SMA and celiac encasement (1 pt), unreconstructible SMV and portal occlusion (2 pts). Median age was 63. During ICT, 5- FU dose had to be increased from baseline in 30.7% pts. Grade 3-4 ICT-related toxicities were neutropenia (6 pts) and diarrhea (1 pt). During CRT, grade 3 toxicity included neutropenia (2 pts), thrombocytopenia (1 pt), diarrhea (1 pt), asthenia (1 pt) and mucositis (1 pt); three pts required hospital admission in hospital. Twelve pts completed the whole neoadjuvant program. Ten pts proceeded to surgery with an R0 resection rate of 76.9%. Pathological response was CAP 0 (no viable cells) and CAP 1 (small groups of cancer cells) in 20% and 50% of pts, respectively; ypT0 and ypN0 rates were 20 and 60%. After a median follow-up of 12 months, the 12-month actuarial median PFS and OS were 80% and 75%, respectively. Conclusions: This neoadjuvant strategy seems feasible and promising although a longer follow-up is required. 5-FU PK modulation may contribute to a better therapeutic index.

Predictive biomarkers of ipilimumab toxicity in metastatic melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9559-9559 ◽  
Author(s):  
Michael Gowen ◽  
Jeremy Tchack ◽  
Hua Zhou ◽  
Keith Michael Giles ◽  
Scott Paschke ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Metabolic Pathways ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Test Results ◽  
Human Proteins ◽  
Pre Treatment ◽  
Grade 3 ◽  
Severe Grade

9559 Background: There are no predictive biomarkers of ipilimumab (IPI) toxicity. Of metastatic melanoma (MM) patients (pts) receiving IPI (3mg/kg), 35% require systemic therapies to treat immune-related adverse events (irAEs) and 20% must terminate treatment (Horvat et al., JCO 2015). Here we tested the hypothesis that a pre-existing autoantibody (autoAb) profile is predictive of IPI irAEs. Methods: We measured autoAb levels in pre- and post-treatment sera from mm pts who received IPI (3mg/kg) monotherapy on a proteome microarray containing ~20,000 unique full-length human proteins (HuProt array, CDI Laboratories). Clinical data were prospectively collected with protocol-driven follow-up. IrAEs were categorized by CTCAE guidelines as none (grade 0), mild (grade 1-2), or severe (grade 3-4). AutoAb levels were standardized using median quantile normalization and considered positive hits if > 2-SD above the peak array signal and differed by ≥2 fold with p < 0.05 between toxicity groups (Non-parametric Analysis/Wilcox test). Results: Seventy-eight sera from 37 mm pts were analyzed. Antibodies against CTLA-4 were significantly elevated post IPI treatment (p < 0.0001), validating the assay. The pre-treatment levels of 190 IgG autoAbs were significantly different in pts who experienced irAEs (n = 28) compared to those with no irAEs (n = 9). Comparison of severe irAE (n = 9) and no irAE (n = 9) groups revealed 129 IgG autoAbs that significantly differed in pre-treatment sera. Localization and pathway analysis (UniProt, KEGG, Reactome) showed 81/190 (43%) of the autoAbs targeted nuclear and mitochondrial antigens and were enriched in metabolic pathways (p = 0.015). AutoAbs associated with irAEs did not correlate with treatment response. Conclusions: AutoAbs to antigens enriched in metabolic pathways prior to treatment may predict IPI-induced toxicity in MM. The subcellular localization of targeted antigens could explain the autoimmune toxicities associated with IPI. Studies in larger cohorts and in pts receiving other checkpoint inhibitors and/or combination therapies are essential to determine the validity of the data. If validated, our results would support the discovery of the first toxicity predictor in cancer immunotherapy.

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