Clinical outcomes in pancreatic adenocarcinoma (PAC) associated with a known BRCA mutation.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 268-268 ◽  
Author(s):  
M. A. Lowery ◽  
Z. K. Stadler ◽  
E. Ludwig ◽  
E. Salo-Mullen ◽  
D. R. D'Adamo ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Germ Line ◽  
Advanced Disease ◽  
Brca Mutation ◽  
Brca1 Mutation ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Genetic Mutation ◽  
Platinum Based Chemotherapy ◽  
Increased Risk

268 Background: BRCA1 and -2 germ-line mutations are associated with increased risk of PAC; approximately 5% of all cases of PAC are estimated to be due to an inherited genetic mutation (Lynch, HT, et al. Pancreatology, 2001;1(5):466-471). Other BRCA-associated cancers have demonstrated increased sensitivity to platinum chemotherapy and PARP inhibitors (PARPi) with improved clinical outcomes compared to sporadic cases (J Clin Oncol, 2008 Dec 1;26(34):5530-6). Outcomes in BRCA-associated pancreatic cancer are unknown. Methods: Patients with a known BRCA1 or -2 mutation and a diagnosis of PAC were retrospectively identified from the MSKCC Familial Pancreas Cancer Registry and via institutional database review. Outcomes and clinical characteristics were reviewed. 7 patients (1 male) with BRCA2 mutation and PAC, 4 patients (1 male) with BRCA1 mutation and PAC, were identified. Two further cases of BRCA mutation and cholangiocarcinoma were identified. Results: See Table for patient demographics. Treatment for advanced disease included a PARP inhibitor (PARPi) in 2 cases; both pts had a radiologic partial response (PR) to therapy. Five patients received platinum-based chemotherapy for advanced disease, 4 of whom had a PR. Median survival for all patients was 27.6 months. Conclusions: The use of platinum- containing chemotherapy, radiation therapy, and PARPi to target the BRCA-associated defective DNA repair mechanism is deserving of further investigation in these patients. PARPi have demonstrated promising efficacy in patients with BRCA-mutated breast and ovarian cancer and are undergoing prospective evaluation in PAC. Genetic testing in patients presenting with a personal history or strong family history of BRCA associated cancers may help to guide choice of therapy. [Table: see text] No significant financial relationships to disclose.

Maintenance olaparib plus bevacizumab (bev) after platinum-based chemotherapy plus bev in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC): Efficacy by BRCA1 or BRCA2 mutation in the phase III PAOLA-1 trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6039-6039
Author(s):  
Domenica Lorusso ◽  
Jean-Pierre Lotz ◽  
Philipp Harter ◽  
Claire Cropet ◽  
Maria Jesus Rubio Pérez ◽  
...  
Keyword(s):  
Brca Mutation ◽  
Brca1 Mutation ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Phase Iii ◽  
Primary Data ◽  
High Grade ◽  
Newly Diagnosed ◽  
First Line ◽  
Platinum Based Chemotherapy

6039 Background: In PAOLA-1/ENGOT-ov25 (NCT02477644), adding the PARP inhibitor olaparib to maintenance bev after first-line platinum-based chemotherapy plus bev led to a statistically significant progression-free survival (PFS) benefit in pts with advanced HGOC (HR 0.59; 95% CI 0.49–0.72) (Ray-Coquard et al. 2019). Retrospective subgroup analysis in GOG-0218 (Norquist et al. 2018) suggested BRCA mutation (BRCAm) status did not significantly impact the PFS benefit provided by bev. We explored the efficacy of olaparib plus bev by BRCA1 mutation ( BRCA1m) or BRCA2 mutation ( BRCA2m) in PAOLA-1. Methods: PAOLA-1 is a randomized, double-blind, Phase III trial in pts with newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer receiving platinum-based chemotherapy plus bev then maintenance bev. Pts unrestricted by surgical outcome or BRCAm status and in response to first-line therapy were randomized to maintenance olaparib tablets (300 mg bid for up to 24 months) plus bev (15 mg/kg q3w for up to 15 months in total) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. Investigator-assessed PFS (modified RECIST v1.1) by BRCAm was a predefined analysis. Results: Of 806 randomized pts, 160 (20%) had tumor BRCA1m, 76 (9%) had tumor BRCA2m and 1 (<1%) had both. Median PFS follow-up was 24.1 and 27.4 months in BRCA1m and BRCA2m pts, respectively. At primary data cutoff, PFS was prolonged with olaparib plus bev versus placebo plus bev in BRCA1m pts and BRCA2m pts (Table). The percentage of BRCA1m pts who received olaparib plus bev and were progression-free at 1 and 2 years was 95% and 73% (vs. 70% and 29% for placebo plus bev) and for BRCA2m pts was 89% and 84% (vs. 84% and 53%) (Kaplan-Meier estimates). Conclusions: In PAOLA-1, maintenance olaparib plus bev provided a significant PFS benefit versus placebo plus bev in all pts analysed, regardless of whether they had BRCA1m or BRCA2m. The median PFS in the control arm suggests a role for bev in this subgroup and the hazard ratio versus an active control arm shows the value of adding maintenance olaparib to bev. Clinical trial information: NCT02477644. [Table: see text]

Predictors of clinical outcomes in patients undergoing curative treatment for esophageal or gastroesophageal junction adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16067-e16067
Author(s):  
Tara Magge ◽  
Robert Van Haren ◽  
Sandra Lynne Starnes ◽  
Gregory Wilson ◽  
Sameer H. Patel ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Gastroesophageal Junction ◽  
Neoadjuvant Treatment ◽  
Curative Treatment ◽  
Considerable Proportion ◽  
Curative Intent ◽  
Predictors Of Recurrence ◽  
Platinum Based Chemotherapy ◽  
Increased Risk ◽  
Ecog Ps

e16067 Background: Management of locally advanced esophageal and gastroesophageal junction (E/GEJ) adenocarcinoma is typically managed with neoadjuvant treatment followed by surgery. Clinical outcomes remain suboptimal and a considerable proportion of patients develop recurrence. However, prognostic and predictive factors are not well-defined. We thus aimed to identify any factors that were associated with disease recurrence and decreased overall survival (OS) among patients with E/GEJ adenocarcinoma treated with curative intent. Methods: A retrospective study spanning 2011-2020 was performed, which identified 56 patients who underwent esophagectomy for E/GEJ adenocarcinoma at the University of Cincinnati. Data on baseline demographic and clinical characteristics, treatment details, pathologic outcomes, recurrence patterns, and survival were extracted from the electronic medical record. Predictors of recurrence and OS, using multivariable logistic regression and Cox proportional hazards analyses, respectively, were identified using all potential predictors and parsimonious modeling. The study was approved by the UC IRB; statistical analyses were performed using SAS 9.2; 95% confidence intervals and two-sided p-values were calculated. Results: Of the 56 patients included, 50 (89%) were White and 6 (11%) were Black; 46 (82%) were male and 48 (85%) were current or former smokers. Tumor location was E in 37 (66%) and GEJ in 19 (34%) patients; 30 (64%) had cT3 or cT4 tumors and 27 (55%) had node-positive disease. Neoadjuvant treatment included platinum-based chemotherapy for 43 (77%) and radiation for 40 (71%) patients; all patients underwent esophagectomy. Median OS for the entire cohort was 4.2 (95% CI 1.8-NR) years and 23(41%) had recurrence after resection. Multivariable modeling showed body mass index (BMI) < 25 (OR vs. BMI ≥ 25: 5.41, 95% CI 1.4-20.4, p = 0.01) to be associated with recurrence; a higher pathologic T stage showed a trend toward increased risk (pT stages 1, 2, and 3 patients (vs. pT 0) were 0.2, 1.1, and 2.5 times more likely to have recurrent disease, respectively. OS was inferior for patients with recurrence (HR for death, vs. no recurrence: 5.42, 95% CI 2.1-13.8, p < 0.001) and a baseline ECOG PS ≥2 (HR vs. ECOG PS < 2: 2.36, 95% CI 0.87-6.4, p = 0.09). Conclusions: In this dataset of patients with E/GEJ adenocarcinoma treated with curative-intent resection, baseline clinical parameters of lower BMI and worse ECOG PS (rather than disease characteristics such as T and N stage) were the main predictors of recurrence and decreased OS. These findings suggest that improving clinical outcomes may at least partly depend on prehabilitation targeting nutrition and physical therapy for patients undergoing curative treatment for E/GEJ adenocarcinoma.

scholarly journals Dramatic response of FOLFIRINOX regimen in a collision pancreatic adenocarcinoma patient with a germline BRCA2 mutation: a case report

2019 ◽  
Vol 49 (11) ◽  
pp. 1049-1054 ◽  
Author(s):  
Hideki Shimmura ◽  
Hidekazu Kuramochi ◽  
Norie Jibiki ◽  
Satoshi Katagiri ◽  
Takayoshi Nishino ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Ductal Carcinoma ◽  
Past History ◽  
Brca Mutation ◽  
Primary Tumour ◽  
Brca2 Mutation ◽  
Breast Tumour ◽  
Metastatic Tumour ◽  
Brca1 And Brca2 ◽  
Platinum Based Chemotherapy

Abstract Germline BRCA1 and BRCA2 mutations are the most common gene mutations in familial pancreatic adenocarcinoma. Several reports have demonstrated the utility of platinum-based chemotherapy for treating cancer patients who harbour a BRCA mutation. Here we discuss a 47-year-old Japanese female with no relevant past history who presented with epigastralgia and fever in September 2016. A computed tomography scan revealed a low-density, low-enhanced tumour 15 mm in diameter in the head of the pancreas. The pathological diagnosis was a ductal pancreatic carcinoma. A 6 mm low-enhanced metastatic tumour was also detected in segment 4 of the liver. Because she had early onset of the disease and a family history—her mother died of pancreatic adenocarcinoma at age 48—we considered a diagnosis of familial pancreatic adenocarcinoma. She received modified FOLFIRINOX. Two months after starting chemotherapy, she was diagnosed with an invasive ductal carcinoma in the right breast. FOLFIRINOX was continued for 8 cycles (4 months); the primary pancreatic adenocarcinoma shrank and the liver metastatic foci disappeared, but the size of the breast tumour increased. Total right breast excision and sentinel lymph node dissection were performed. FOLFIRINOX was continued and after 12 cycles (6 months), both her pancreatic adenocarcinoma and liver metastasis were no longer visible using imaging. Pancreatoduodenectomy was performed and the primary tumour had shrunk to 2.5 mm. Genetic testing revealed a germline BRCA2 mutation. The FOLFIRINOX regimen showed dramatic effects on the collision pancreatic but not on the breast cancer.

scholarly journals PARP Inhibitor Olaparib Use in a BRCA1-Positive Patient With Metastatic Triple-Negative Breast Cancer, Without the Initial Use of Platinum-Based Chemotherapy, Showing Significant Rapid Near Resolution of Large Liver Metastasis While Patient Experienced Gout-Like Symptoms

2019 ◽  
Vol 7 ◽  
pp. 232470961986498 ◽  
Author(s):  
Trevanne Matthews Hew ◽  
Lara Zuberi
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Management Options ◽  
Federal Drug Administration ◽  
Platinum Based Chemotherapy ◽  
Metastatic Setting

Triple-negative breast cancer (TNBC) accounts for 20% of breast cancers diagnosed worldwide. This subtype of breast cancer tends to behave more aggressively, and unlike other breast cancer subtypes, there are no standard targeted treatments for most patients. However, up to 20% of patients with TNBC harbor a breast cancer gene (BRCA) mutation, particularly in BRCA1. For patients who carry this gene mutation, this opens the door for new management options by the use of newer agents such as polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the metastatic setting. Given that this is uncommon and that PARP inhibitors have only recently received Federal Drug Administration approval, the experience with these drugs is relatively new. In this article, we present a case of a patient treated in this setting with olaparib who developed an unanticipated side effect as a result of the high efficacy of the drug.

An exploratory study to determine if BRCA1 and BRCA2 mutation carriers have higher risk of cardiac toxicity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1585-1585 ◽  
Author(s):  
Roohi Ismail-Khan ◽  
Monique Sajjad ◽  
Weihong Sun ◽  
Hatem Hussein Soliman ◽  
Hyo S. Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
General Population ◽  
Exploratory Study ◽  
Online Survey ◽  
Cardiac Toxicity ◽  
Brca Mutation ◽  
Brca2 Mutation ◽  
Mutation Carriers ◽  
Increased Risk ◽  
Brca Mutation Carriers

1585 Background: Anthracycline related cardiac toxicity (CT) is a concern in treating women with breast cancer. The prevalence of heart failure (HF) affects 2% of the population, less so in women. Patients receiving anthracycline based therapy (ABT) have a dose-dependent risk of reduction in ejection fraction. Recent work by Dr. Verma suggests that BRCA-deficient mice manifest increased levels of cardiac failure. We sought to explore the risk for CT and evaluate the association between ABT and HF in female BRCA mutation carriers. Methods: An online survey was developed to collect information about breast cancer treatment (including HF) in BRCA mutation carriers through the national BRCA patient advocacy organization FORCE via their 2011 conference and their website as well as the Moffitt-based Inherited Cancer Registry (ICARE). The prevalence of CT and HF was calculated in both BRCA 1 and 2 breast cancer patients and compared to general population risks. Data from those that received ABT was compared to published HF rates from ABT. Results: Our sample included 227 BRCA1 carriers and 164 BRCA2 carriers in whom 6.4% reported cardiac toxicity (i.e., either HF and/or CT). This included similar proportions in BRCA1 vs BRCA2 carriers (i.e., 6.6% and 6.1%, respectively). These proportions are significantly higher than the published rate of 2% (all p-values < 0.001). Specifically regarding ABT, 112 mutation carriers had doxorubicin (Adriamycin) for treatment of whom 8% reported HF, similar to the 11 who had Epirubicin (11 patients), of whom 9% reported HF. Conclusions: Our data suggests that BRCA mutation carriers may have an increased risk of CT compared to the general population. In particular, women with BRCA mutations treated with ABT also appear to have a higher risk of developing CT and/or HF. This exploratory study provides the basis upon which larger retrospective and prospective studies are currently being planned. The high percentage of CT observed in this study requires confirmation as they could inform recommendation for cardiac screening and review of the current standard for ABT use in this population.

Germline BRCA1 mutations and pancreatic adenocarcinoma: A literature review.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15716-e15716
Author(s):  
Ahmad Al-Taee ◽  
Ammara Gill ◽  
Suzanne M. Mahon ◽  
Bassel Jallad
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Brca Mutation ◽  
Brca1 Mutation ◽  
Brca2 Mutation ◽  
The United States ◽  
Prior History ◽  
Cancer Predisposition Syndrome ◽  
Brca1 Mutations ◽  
Number Of Patients ◽  
Pubmed Database

e15716 Abstract Background: Pancreatic adenocarcinoma (PAC) is the fourth leading cause of cancer-related deaths in the United States. Although the vast majority of cases are sporadic, up to 10% of cases are related to a hereditary cancer predisposition syndrome, the most common of which is germline BRCA mutation. Although BRCA2 mutation has been well described in the literature, data on BRCA1 mutation-associated PAC is limited. This work aims at reviewing the literature on BRCA1 mutation-associated PAC and discussing the relevant findings. Methods: We have searched the Pubmed database for articles using the search terms “pancreatic”, “BRCA”, BRCA1”, “adenocarcinoma” or any combination of these keywords. Data about epidemiology, staging, prior history of other tumors, and management were collected. Systematic data extraction and assessments of quality were carried out by two reviewers, and good agreement was found. Results: A total of 13 studies were selected for review and included a total of 149 patients. The prevalence rate of PAC among patients with germline BRCA1 mutations ranged between 0.002% and 0.03%. Moreover, the prevalence of BRCA1 mutations in patients with BRCA-related PAC was found to be between 27% and 30%. Of note, PAC was diagnosed as the first tumor in 74% of patients with BRCA1-related PAC. The most common stage at diagnosis was stage 4 (56%) followed by stage 2 (22%). Conclusions: Germline BRCA1 mutation-associated PAC is an under-recognized entity when compared to BRCA2 mutations. Given the incredibly poor prognosis and the growing interest in targeted therapies, physicians need to be familiar with BRCA1 mutations as a possible etiology of PAC. A significant number of patients with BRCA1 mutation-associated PAC were diagnosed with PAC as the first tumor. Therefore, upper gastrointestinal screening should be considered in patients with germline BRCA1 mutations.

Contralateral Breast Cancer in BRCA1 and BRCA2 Mutation Carriers

2004 ◽  
Vol 22 (12) ◽  
pp. 2328-2335 ◽  
Author(s):  
Kelly Metcalfe ◽  
Henry T. Lynch ◽  
Parviz Ghadirian ◽  
Nadine Tung ◽  
Ivo Olivotto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Contralateral Breast Cancer ◽  
Brca Mutation ◽  
Brca1 Mutation ◽  
Brca2 Mutation ◽  
Contralateral Breast ◽  
Second Primary ◽  
Brca1 And Brca2 ◽  
Breast Cancer Death ◽  
Actuarial Risk

Purpose To estimate the risk of contralateral breast cancer in BRCA1 and BRCA2 carriers after diagnosis and to determine which factors are predictive of the risk of a second primary breast cancer. Patients and Methods Patients included 491 women with stage I or stage II breast cancer, for whom a BRCA1 or BRCA2 mutation had been identified in the family. Patients were followed from the initial diagnosis of cancer until contralateral mastectomy, contralateral breast cancer, death, or last follow-up. Results The actuarial risk of contralateral breast cancer was 29.5% at 10 years. Factors that were predictive of a reduced risk were the presence of a BRCA2 mutation (v BRCA1 mutation; hazard ratio [HR], 0.73; 95% CI, 0.47 to 1.15); age 50 years or older at first diagnosis (v ≤ 49 years; HR, 0.63; 95% CI, 0.36 to 1.10); use of tamoxifen (HR, 0.59; 95% CI, 0.35 to 1.01); and history of oophorectomy (HR, 0.44; 95% CI, 0.21 to 0.91). The effect of oophorectomy was particularly strong in women first diagnosed prior to age 49 years (HR, 0.24; 95% CI, 0.07 to 0.77). For women who did not have an oophorectomy or take tamoxifen, the 10-year risk of contralateral cancer was 43.4% for BRCA1 carriers and 34.6% for BRCA2 carriers. Conclusion The risk of contralateral breast cancer in women with a BRCA mutation is approximately 40% at 10 years, and is reduced in women who take tamoxifen or who undergo an oophorectomy.

scholarly journals Aromatase Inhibitors and Contralateral Breast Cancer in BRCA Mutation Carriers: A long-term Follow-up

2021 ◽  
Author(s):  
Maryam Nemati Shafaee ◽  
Kristina Goutsouliak ◽  
Heather Lin ◽  
Therese B Bevers ◽  
Angelica Gutierrez-Barrera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitors ◽  
Prophylactic Mastectomy ◽  
Brca Mutation ◽  
Brca1 Mutation ◽  
Brca2 Mutation ◽  
Mutation Status ◽  
Mutation Carriers ◽  
Brca Mutation Carriers

Abstract Background: Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown. Methods: This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004-2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow up was 11.5 years. Risk of CBC was evaluated as time to event. Results: 935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs %6.5 (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p=0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC. Conclusions: This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts.

scholarly journals Endometrial Cancer Risk in Women with Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study

2021 ◽  
Author(s):  
Marthe M de Jonge ◽  
Cornelis D de Kroon ◽  
Denise J Jenner ◽  
Jan Oosting ◽  
Joanne A de Hullu ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cohort Study ◽  
General Population ◽  
Cox Regression ◽  
Statistical Tests ◽  
Brca1 Mutation ◽  
Brca2 Mutation ◽  
Mutation Carriers ◽  
Increased Risk

Abstract Background Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain, therefore we assessed this in a large Dutch nationwide cohort study. Methods 5,980 BRCA1/2 (3,788 BRCA1, 2,151 gBRCA2, 41 both BRCA1/BRCA2) and 8,451 non-BRCA1/2 mutation carriers were selected from the HEBON-cohort. Follow-up started at date of nationwide PALGA coverage (January 1, 1989) or at the age of 25 years (whichever came last), and ended at date of EC diagnosis, last follow-up or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared to: 1) general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were two-sided. Results Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119,296 and 160,841 person-years, respectively (SIR = 2.83, 95% confidence interval (CI) = 2.18–3.65; and HR = 2.37, 95% CI = 1.53–3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61–4.72; HR = 2.91, 95% CI = 1.83–4.66), serous-like EC (SIR: 12.64, 95% CI = 7.62–20.96; HR = 10.48, 95% CI = 2.95–37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80–3.83; HR = 2.01, 95% CI = 1.18–3.45) and TP53-mutated EC (HR = 15.71, 95% CI = 4.62–53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01–2.87), and serous-like EC risks (SIR = 5.11, 95% CI = 1.92–13.63) were increased when compared to the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%). Conclusions BRCA1/2 mutation carriers have a 2- to 3-fold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.

Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: A phase II study of cediranib in combination with olaparib in advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9065-9065 ◽  
Author(s):  
Joseph W. Kim ◽  
Navid Hafez ◽  
Hatem Hussein Soliman ◽  
Siqing Fu ◽  
Shumei Kato ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Platinum Based Chemotherapy

9065 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumors carrying a germline BRCA mutation. We therefore tested the anti-tumor activity of cediranib and olaparib combination in patients (pts) with advanced solid tumors. Here, we report the data from the SCLC cohort. Methods: This multi-institutional, two-stage, phase 2 study enrolled pts with metastatic SCLC previously treated with a minimum of one prior line of platinum-based chemotherapy in advanced setting. Patients were treated with cediranib 30mg po daily plus olaparib 200mg po BID until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Baseline tumor biopsies were obtained for biomarker analyses. Results: Baseline characteristics of the 25 pts enrolled are summarized below. The overall ORR rate was 28% (95% CI: 0.104,0.456). Median duration of response was 3.8 months (mos). Six of 8 pts had an objective response lasting longer than 3 mos up to 10.3 months. Disease control rate (# of pts with CR, PR or SD / # evaluable pts) was 88% (95% CI: 0.75,1.01). Median progression free survival was 4.1 mos (95% CI: 2.3, 6.2). Median OS was 5.5 mos (95% CI: 3.4, NA). Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 14 of 25 (56%). G3/4 AEs occurring in > 10% of pts were hypertension (21%), fatigue (17%) and weight loss (13%). Conclusions: The cediranib/olaparib combination resulted in promising clinical activity with ORR of 28% in biomarker-unselected pts with platinum-pretreated SCLC. The regimen required prompt initiation of antihypertensives, but AEs were overall manageable. Analyses of mutation status in homologous recombination DNA repair genes are going and will be correlated with clinical activity. Clinical trial information: NCT02498613. [Table: see text]

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