Prior Chemotherapeutic Regimens Research Articles

Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) in Locally Advanced or Metastatic Breast Cancer: Prospective Cohort Study.

Eribulin, a halichondrin-class microtubule dynamics inhibitor, is a preferred treatment option for patients with advanced breast cancer who have been pretreated with an anthracycline and a taxane. Peripheral neuropathy (PN) is a common side effect of chemotherapies for breast cancer and other tumors. The Incidence and Resolution of Eribulin-Induced Peripheral Neuropathy (IRENE) noninterventional postauthorization safety study assessed the incidence and severity of PN in patients with breast cancer treated with eribulin. IRENE is an ongoing observational, single-arm, prospective, multicenter, cohort study. Adult patients (≥18 years of age) with locally advanced or metastatic breast cancer and disease progression after 1-2 prior chemotherapeutic regimen(s) for advanced disease were treated with eribulin. Patients with eribulin-induced PN (new-onset PN or worsening of preexisting PN) were monitored until death or resolution of PN. Primary endpoints included the incidence, severity, and time to resolution of eribulin-induced PN. Secondary endpoints included time to disease progression and safety. In this interim analysis (data cutoff date: July 1, 2019), 67 (32.4%) patients experienced any grade eribulin-induced PN, and 12 (5.8%) patients experienced grade ≥3 eribulin-induced PN. Median time to resolution of eribulin-induced PN was not reached. Median time to disease progression was 4.6 months (95% CI, 4.0-6.5). Treatment-emergent adverse events (TEAEs) occurred in 195 (93.8%) patients and serious TEAEs occurred in 107 (51.4%) patients. The rates of any grade and grade ≥3 eribulin-induced PN observed in this real-world study were consistent with those observed in phase III randomized clinical trials. No new safety findings were observed.

Overall survival data from a 3-arm, randomized, open-label, phase 2 study of relacorilant, a selective glucocorticoid receptor modulator, combined with nab-paclitaxel in patients with recurrent platinum-resistant ovarian cancer.

LBA5503 Background: Cortisol contributes to chemotherapy resistance by suppressing apoptotic pathways that cytotoxic agents utilize. Preclinical and clinical data indicate that glucocorticoid receptor (GR) modulation with relacorilant (RELA) reverses the anti-apoptotic effects of cortisol and restores the efficacy of cytotoxic agents. We report overall survival (OS) results from a randomized, controlled phase 2 study of RELA + nab-paclitaxel (NP) compared to NP only in patients with ovarian cancer (NCT03776812). The primary analysis showed improved progression-free survival (PFS) and a favorable safety profile with intermittent RELA + NP vs NP only, despite overrepresentation of primary platinum-refractory patients in the intermittent RELA + NP (n = 7) vs the NP-only arm (n = 1). Methods: A phase 2, open-label, randomized, 3-arm study of 2 RELA dosing schedules + NP compared with NP only was performed. 178 women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer or ovarian carcinosarcoma with ≤4 prior chemotherapeutic regimens were enrolled. Patients were randomized 1:1:1 to: a) NP (80 mg/m2) + intermittent RELA (150 mg QD the day before, of, and after NP) (n = 60); b) NP (80 mg/m2) + continuous RELA (100 mg QD) (n = 58); or c) NP only (100 mg/m2) (n = 60). NP was administered on days 1, 8, and 15 of each 28-day cycle. The primary endpoint was PFS; OS was a secondary endpoint. OS data for the intermittent and continuous arms were compared to NP only using a 2-sided log-rank test, stratified by presence of ascites and relapse within 6 months on previous taxane, at a 0.05 level of significance without multiplicity adjustment. Results: At the pre-defined OS analysis (128 OS events), hazard ratios (HRs) were 0.67 (95% CI [0.43, 1.03], P= 0.066) and 0.85 (95% CI [0.56, 1.29], P= 0.447) for intermittent and continuous RELA + NP vs NP only. Median OS was 13.9 (95% CI [11.1, 18.4]), 11.3 (95% CI [7.5, 16.4]), and 12.2 (95% CI [7.7, 15.3]) months in the intermittent RELA + NP, continuous RELA + NP, and NP-only arms. In the subgroup of patients without primary platinum-refractory disease, a statistically significant improvement in OS was observed with HR 0.63 (95% CI [0.39, 0.99], P= 0.045) and median OS of 13.9 (95% CI [11.1, 18.4]) vs 12.2 (95% CI [7.7, 15.3]) months for intermittent RELA + NP vs NP only. Conclusions: In addition to the improved PFS and DOR observed at the primary analysis, the OS analysis confirmed the survival benefit of intermittent RELA + NP compared to NP only, particularly in patients who were not primary platinum refractory. A phase 3 trial evaluating intermittent RELA + NP vs investigator’s choice of chemotherapy in patients without primary platinum-refractory disease is ongoing (NCT05257408). Clinical trial information: NCT03776812.

Real-world clinical effectiveness of eribulin in metastatic breast cancer patients with visceral metastases in the United States.

e13058 Background: Eribulin mesylate was approved in the United States (US) in 2010 for the treatment of metastatic breast cancer (mBC) after at least two prior chemotherapeutic regimens, which should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Visceral metastases, including those to the lung and brain, have been identified as poor prognostic features for patients with mBC. The objective of this analysis was to assess the real-world clinical effectiveness of eribulin in mBC patients with visceral metastases when treated in accordance with the US label. Methods: Patients with mBC initiating eribulin consistent with the US label between 2011-2017 were identified through a retrospective, multi-site chart review study conducted in US oncology practices. De-identified, patient-level demographics, clinical characteristics, treatment patterns, and outcomes were entered into an electronic case report form by the patients’ treating physicians. Sites of metastases at initiation of eribulin were indicated by providers. Clinical outcomes assessed included best overall response to eribulin as recorded in the patient’s chart, progression-free survival (PFS), and overall survival (OS). The proportion of patients with either a complete or partial response as their best overall response was calculated. PFS and OS were calculated by the Kaplan-Meier method from the initiation of eribulin for all patients with visceral metastases and subsets reporting lung or brain metastases site, respectively. Results: The analysis included 470 patients with visceral metastases, including 342 with lung metastases and 22 with brain metastases at the time of eribulin initiation. Eribulin was third-line therapy for approximately three quarters of patients in these subgroups, and the remainder received eribulin in fourth line or later. Mean age was 59 years in general (59 and 54 years in those with lung and brain metastases, respectively). Over half of patients (53.6%) had either a complete or partial response to eribulin. Median PFS was estimated at 6.0 months, and median OS was estimated at 10.5 months. Results for the subgroups of patients with lung and brain metastases are shown in the table. Conclusions: The results of this retrospective analysis affirm clinical effectiveness of eribulin in mBC patients with visceral metastases, when used consistent with the US label.[Table: see text]

Prolonged Survival in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressed Metastatic Breast Cancer after Targeted Therapy is Dominantly Contributed by Luminal-Human Epidermal Growth Factor Receptor-2 Population

The prognosis of patients with human epidermal growth factor receptor-2 (HER2)-overexpressed metastatic breast cancer (MBC) has improved drastically following the development of anti-HER2 therapies. We question what factors are involved in the improved outcome by the treatment. One hundred and two MBC patients who received chemotherapy were classified into groups according to breast cancer subtype: luminal/HER2-negative (n = 50), HER2 (n = 26), and triple-negative subtypes (n = 26). Clinicopathologic features and clinical outcomes of the groups were compared. Disease-free intervals in the triple-negative group were significantly shorter than those in the other two groups. Age, tumor grade, the number of disease sites, and prior chemotherapeutic regimens did not differ among the groups. As a result, median overall survival was significantly longer in the HER2 and luminal/HER2-negative groups than in the triple-negative group (114, 68, and 18 months, respectively, p < 0.001). To determine key factors underlying favorable outcomes of the HER2 group, the HER2 group was further divided into two subgroups, luminal-HER2 and non-luminal-HER2 groups, according to their hormone receptor status, and clinical outcomes were compared. Median overall survival from the time of diagnosis of MBC in the luminal-HER2 group was significantly longer than that in the non-luminal-HER2 group (not reached and 39 months, respectively, p = 0.048), and was as favorable as shown in the luminal/HER2-negative group. In conclusion, the prognosis and survival of patients with HER2-overexpression receiving anti-HER2 therapy improved considerably in the luminal-HER2, but not in the non-luminal-HER2 group.

Abstract P3-09-03: A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes (KELLY study)

Abstract BACKGROUND: Studies of checkpoint inhibitor monotherapy have shown only modest activity in hormone receptor (HR)-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) metastatic breast cancer (MBC). However, pembrolizumab (P) added to standard neoadjuvant therapy significantly improved the estimated pathologic complete response rate in HR+/HER2- early breast cancer in the I-SPY-2 trial. The KELLY trial aimed to evaluate the efficacy and safety of P in combination with eribulin (E) in anthracycline- and taxane-pretreated patients (pts) with HR+/HER2- inoperable locally recurrent or MBC irrespective of programmed death-ligand 1 (PD-L1) status. METHODS: This is an open-label, single-arm, multicenter phase IIA clinical trial (ClinicalTrials.gov identifier: NCT03222856). Eligible pts had HR+/HER2- inoperable locally recurrent or MBC, who were previously treated with endocrine therapy and at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease, and with prior anthracycline/taxane exposure either in the early or metastatic setting. Pts received E 1.23 mg/m2 intravenously (IV) on days 1 and 8 with P 200 mg fixed dose IV on day 1 of a 21-day cycle until unacceptable toxicity or disease progression. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety and tolerability of the combination. Exploratory objectives included: (1) the analysis of PFS and ORR based on immune-related RECIST (irRECIST) and (2) the associations of PFS and OS to CBR/ORR, prior exposure to CDK4/6, mTOR, or PI3K inhibitors, PD-L1 status, tumor-infiltrating lymphocytes (TILs), gene signatures, mutational load, and circulating tumor cells. RESULTS: Between January 2018 and October 2018, 44 pts were enrolled in the study. The median age was 54.1 years (range: 46-60.5 years), 70.5% were ECOG 0, 90.1% had visceral disease (86.4% with liver metastases), and 54% with ≥3 involved organ sites. The median number of prior endocrine therapies was two (range: 1-6) and 52.3% of patients had previously received two chemotherapeutic regimens for treatment of locally recurrent and/or MBC. With a median follow-up of 6.64 months (mo.) (range: 1-14.2 mo.), E and P combination met primary endpoint (CBR 53.7%, 95%CI: 36.9-67.3%). ORR and median PFS were 36.4% (95%CI: 22.8-52.3%) and 6.03 mo. (95%CI: 3.7-8.4 mo.), respectively. All-cause adverse events occurred in 100% of pts (G3-4, 56.8%), without treatment-related deaths. ORR and median PFS based on irRECIST were 36.4% (95%CI: 22.8-52.3%) and 6.1 mo. (95%CI: 4.2-8.5 mo.), respectively. OS data are immature (13 deaths, 29.5%). A significant difference in median PFS has been observed between pts with and without clinical benefit (8.5 Vs. 2.2 mo., p&amp;lt;0.001) and responders compared with non-responders (8.3 Vs. 3.4 mo., p=0.024). Previous exposure to CDK4/6, mTOR, or PI3K inhibitors was not associated with differences in PFS (TABLE 1). Updated data, including results about PD-L1 status and TILs will be presented. CONCLUSIONS: E plus P was a safe and active regimen for pts with previously treated HR+/HER2- locally recurrent or MBC that merits further investigation. Exploratory biomarker analysis is pending. TABLE 1Prior treatmentNEvents (%)Median PFS, mo. (95%CI)p-valueCDK4/6 inhibitorsNo2316 (69.2)6 (3.7-10.4)0.832Yes2115 (71.4)6.1 (2.5-NA)mTOR or PI3K inhibitorsNo2620 (76.9)6 (3.7-8.47)0.727Yes1811 (61.1)6 (2.5-NA) Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Esther Holgado, Giuseppe Curigliano, Elena López Miranda, José Luis Alonso-Romero, Begoña Bermejo, Lourdes Calvo, Vicente Carañana, Susana de la Cruz Sánchez, María Gión Cortés, Raúl Márquez Vázquez, Aleix Prat, Manuel Ruiz Borrego, Miguel Sampayo, Miguel Àngel Seguí, Jesus Soberino, Andrea Malfettone, Peter Schmid, Javier Cortés. A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes (KELLY study) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-03.

Third Line Eribulin for Triple-negative Metastatic Breast Ductal Carcinoma Resulting in Extended Progression-free Survival of 57 Months

Eribulin is a non-taxane microtubule inhibitor approved for the treatment of metastatic breast carcinoma after two prior chemotherapeutic regimens. We report a patient with extended progression-free survival (PFS) of more than 57 months with metastatic breast carcinoma treated with eribulin in the third-line setting. A 48-year-old lady was diagnosed with stage IIA (pT2N0M0), high grade, triple-negative, invasive ductal carcinoma (IDC) of the left breast on core needle biopsy. She underwent neoadjuvant chemotherapy with adriamycin, and cyclophosphamide followed by a negative sentinel lymph node (SLN) biopsy. Subsequent mastectomy and axillary lymph node dissection revealed a 2.5 cm, high grade, triple-negative IDC with three additional lymph nodes negative for metastatic carcinoma, consistent with the initial diagnosis. Eight months into the surveillance program, the patient developed a 2.8 cm right lower lobe (RLL) lung mass with standard uptake value (SUV) of 27 on positron emission tomography-computed tomography (PET/CT). Core needle biopsy of the lung lesion revealed sheets of poorly differentiated carcinoma, immunophenotypically compatible with the initial diagnosis of breast pathology. She then commenced single-agent paclitaxel in the 1st line metastatic setting with a significant decrease in RLL lung mass to less than 1 cm with an SUV of 1.7 noted. The patient developed progression after seven months and started 2nd line gemcitabine noting initial improvement and subsequent stable disease for a period of 12 months. Eventual progression of RLL lung nodule measuring 2.1 cm with SUV of 10 noted. Initiated 3rd line eribulin with a notable response on imaging studies within three months and with no evidence of disease (NED) on scans over the subsequent 57 months. Eribulin related mild neuropathy superimposed on previous paclitaxel associated grade 2 neuropathy required a 20% eribulin dose reduction. The patient is currently clinically and radiographically stable with plateaued serum tumor markers. Our patient has shown excellent response and tolerance to eribulin with PFS of over 57 months (nineteen times the norm) which is rare.

The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Blinatumomab/Lenalidomide in Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase I California Cancer Consortium Study of Safety, Efficacy and Immune Correlative Analysis

Blinatumomab/Lenalidomide in Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase I California Cancer Consortium Study of Safety, Efficacy and Immune Correlative Analysis

P1.01-135 Salvage Chemotherapy After Immunotherapy Failure in Non-Small-Cell Lung Cancer Patients

Objective response rate (ORR) to salvage chemotherapy (sCT) in non-small-cell lung cancer (NSCLC) patients failing upfront platinum-based doublets is limited (≈5-15%). Recently, unexpected favorable outcomes have been reported for sCT upon progression to immune checkpoint inhibitors (ICIs) as compared to historical data, with ORR observed in up to 53% and 27% in Asian and Caucasian patients respectively. Few data are available regarding prior response to ICIs and sCT performance, especially in Caucasian patients. All consecutive patients with advanced NSCLC who started ICIs at our institution from Apr 2013 to Dec 2018 were retrospectively reviewed. Patients who underwent sCT after progression to ICIs and had at least one radiological response assessment were included. ORR was calculated as the percentage of complete or partial responses according to RECIST 1.1 as best response. Survivals were estimated with Kaplan-Meier method. Correlation was assessed using Spearman’s test. Out of 283 patients included, 43 received sCT after ICIs. Among them, 29 (67%) had adenocarcinoma and 14 (37%) squamous cell carcinoma. 11 (26%) patients received sCT as second line therapy and 32 (74%) as third or more advanced treatment. sCT regimens included platinum based doublets (14; 32.5%), docetaxel or paclitaxel (20; 46.5%), and other monotherapies such as gemcitabine or vinorelbine (9; 21%). ORR to sCT was 30%. Median progression free survival and overall survival were 3.6 and 8.4 months, respectively. All patients receiving taxanes as sCT had already been treated with platinum based therapy and their ORR to sCT was 40%. ORR to upfront chemotherapy was 50%, while ORR to the last chemotherapeutic regimen prior to ICIs was 35%. ORR to sCT in pretreated patients was non-inferior to that observed in chemo-naïve ones (31% and 27%, respectively). High ORR (25%) was observed even in patients receiving sCT beyond third line. Neither response to ICIs (P=0.36) nor to prior chemotherapeutic regimens (P>0.05) were associated to the likelihood of achieving tumor response to sCT. We provide further evidence that NSCLC patients progressing to ICIs might still benefit from sCT even if heavily pretreated, regardless of sensitivity to ICIs or previous chemotherapy regimens. Further investigations are needed for uncovering bases of increased sensitivity to genotoxic agents in patients with innate or acquired resistance to ICIs and exploiting optimal treatment sequence.

OXALIPLATIN RE-INTRODUCTION THERAPY AMONG PATIENTS WITH ADVANCE STAGE COLORECTAL CANCER

Background: : Retreating with prior chemotherapeutic regimens is a possible option for palliative treatment for patients with advanced stage colorectal cancer (CRC). Objective: This study aimed to examine the feasibility and clinical outcomes of oxaliplatin re-introduction therapy.&#x0D; Methods: The present study was a prospective case series of patients with advanced stage colorectal adenocarcinoma who were previously treated and re-treated with oxaliplatin combination therapy at Phramongkutklao Hospital between April 1st, 2011 and March 30th, 2014. Treatment regimens are described below. First, FOLFOX4 (14-day cycles of oxaliplatin 85 mg/m2, folinic acid 200 mg/m2) was given days 1-2 plus fluorouracil 400 mg/m2 (bolus) and 600 mg/m2 (continuous 22 hours infusion). Second, modificd FOLFOX6 (oxaliplatin 85 mg/m2) was given day I with calcium folinate 400 mg/m2 as a 2-hour infusion followed by bolus 5-fluorouracil 400 mg/m2 and a 46-hour infusion of 5-fluorouracil 2,400 mg/m2). Similarly, XELOX (130 mg/m2 intravenous oxaliplatin) was provided for 2 hours day 1 plus oral capecitabine 1,000 mg m2 twice daily for 2 weeks from day 1. Treatment was continued until disease progression (PD), intolerability to therapy, poor performance status, withdrawal of consent or death occurred. Authors evaluated tolerability, feasibility, types and rate of untoward medical occurrences due to adverse reactions of PD.&#x0D; Results: Thirteen patients with CRC were recruited in the study. The median cycles (range) of receiving oxaliplatin-based chemotherapy before re-introduction therapy was 8 (3-15) cycles. The median age (range) was 50 (27-78) years. Etiologies of treatment cessation were recorded by number of patients as follows: tumor progression (6), lost to follow-up (1), refused to receive further treatment (1), allergic reaction (2) and physical deterioration (2). Eflicacy of the treatment was assessed in 10 of 13 patients. Of 10 patients, 2 developed drug allergies and 1 was lost to follow-up. Six patients (60%) had PD while 4 patients (40%) had stabilized disease measured by the Response Evaluation Criteria in Solid Tumors (RECIST).&#x0D; Conclusion: Reintroducing oxaliplatin combination chemotherapy is one of the treatments in advanced stage CRC. In this study, physical deterioration and tumor progression were the main etiologies of treatment cessation.

Apatinib for chemotherapy-refractory extensive-stage SCLC: a retrospective study.

There is no standard treatment strategy for patients with extensive-stage small cell lung cancer (SCLC) who have failed two or more prior chemotherapeutic regimens. In this study, we retrospectively evaluated the efficacy and safety of apatinib in patients with extensive-stage SCLC after failure of more than second-line chemotherapy. A study group comprised of 22 patients with extensive-stage SCLC after failure of more than two prior chemotherapeutic regimens was given apatinib orally at an initial dose of 500mg daily until disease progression or unacceptable toxicity. This study was analyzed according to the National Cancer Institute Common Toxicity Criteria for adverse events (AEs) and Response Evaluation Criteria in Solid Tumors (RECIST) for response assessment. Between August 30, 2015, and May 26, 2017, 22 patients were enrolled for evaluating the efficacy and safety of apatinib. Among them, 12/22 (54.5%) underwent dose reduction during treatment. Up to July 31, 2018, the median progression-free survival rate was 135.0 days [95% confidence interval (CI) 63.8-206.2]. According to the RECIST criteria, the disease control rate (DCR) was 86.4%, 19/22 [comprised of partial response (PR) 18.2%, 4/22; and stable disease (SD) 68.2%, 15/22 patients]. The most frequent AEs were hand-foot syndrome (45.5%, 10/22), secondary hypertension (45.5%, 10/22) and fatigue (40.9%, 9/22). The primary grade 3 or 4 toxicities were hypertension (22.7%, 5/22), hand-foot syndrome (13.6%, 3/22), and proteinuria (9.1%, 2/22). Apatinib exhibits modest activity and acceptable toxicity for patients with heavily pretreated extensive-stage SCLC.

Abstract PD6-13: Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer

Abstract Background: Eribulin mesylate (ERI), a nontaxane microtubule inhibitor with effects on tumor biology (increased vascular perfusion, reversal of epithelial to mesenchymal transition), is approved as a monotherapy for the treatment of patients (pts) with metastatic breast cancer who received ≥2 prior chemotherapeutic regimens for metastatic disease. In a pooled analysis, ERI significantly prolonged OS compared with capecitabine or treatment of physician's choice in pts with metastatic triple-negative breast cancer (mTNBC; 12.9 vs 8.2 mo, n=428). Pembrolizumab (PEM) is a human programmed death (PD) receptor-1–blocking antibody approved for the treatment of several advanced cancers. In a phase (Ph) 2 study in mTNBC, PEM monotherapy as first-line therapy demonstrated ORR, 23%; median PFS, 2.1 mo [95% CI 2.0-3.9], and in pts pretreated with ≥1 prior chemotherapy demonstrated ORR, 5%; median OS, 8.9 mo [95% CI 7.2-11.2]). Methods:This open-label Ph 1b/2 trial enrolled pts (aged ≥18 yrs; ECOG PS ≤1) with mTNBC treated with ≤2 prior lines of chemotherapy for metastatic disease. Ph 1b included a safety cohort of ≥6 pts who received intravenous (IV) ERI 1.4 mg/m2 on day (d) 1 and d8 and IV PEM 200 mg on d1 of a 21-d cycle. In Ph 2, pts were enrolled based on prior chemotherapy in the metastatic setting [0 vs 1–2 lines]. Primary endpoints: safety, tolerability (Ph 1b), and ORR (Ph 2); secondary endpoints: PFS, OS, and efficacy in PD-L1+ pts. Results: We report data from 82 of 104 enrolled pts (data cut-off Nov 1, 2016).The RP2D was ERI 1.4 mg/m2 on d1 and d8 and PEM 200 mg on d1 of a 21-d cycle. Most common treatment-emergent adverse events (TEAEs) were fatigue (73.2%), nausea (51.2%), peripheral sensory neuropathy (46.3%), alopecia (43.9%), and pyrexia (36.6%). Most common Grade (G) 3 or 4 TEAEs related to ERI: neutropenia (29.3%), peripheral neuropathy (8.5%), and asthenia/fatigue (7.3%). G3/4 immune-related TEAEs related to PEM: 19.5% of pts. TEAEs that led to drug withdrawal/dose reduction: 18.3%/28.0% of pts. G5 events: 3 pts (respiratory failure, pleural effusion, and multiple organ failure; none related to study drug). Response was irrespective of PD-L1 status (Table1). Results of the final analysis will be available for presentation. Overall (n=82)No prior chemotherapy in metastatic setting (n=48)1-2 Prior lines of chemotherapy in metastatic setting (n=34)PD-L1+ (n=35)PD-L1- (n=36)ORR, n (%) [95% CIa]21 (25.6) [16.8, 35.4]12 (25.0) [14.0, 37.8]9 (26.5) [13.3, 41.8]9 (25.7) [12.9, 40.8]9 (25.0) [12.5, 39.8]CBRb, n (%)25 (30.5)13 (27.1)12 (35.3)10 (28.6)12 (33.3)DCRc, n (%)46 (56.1)28 (58.3)18 (52.9)19 (54.3)21 (58.3)Median PFS, mo [95% CI]4.1 [2.3-4.8]4.1 [2.2-4.9]3.9 [2.1-6.3]4.1 [2.1-4.8]4.1 [2.3-6.3]Median OS, mo [95% CI]NE [17.7-NE]17.7 [13.7-NE]NE [13.1-NE]----a Credible interval from Bayesian analysis; b clinical benefit rate = CR+PR+SD; c disease control rate = CR+PR+SD ≥24 weeks. NE, not estimable. Conclusions: ERI+PEM was well tolerated and demonstrated activity in pts with mTNBC. The combination resulted in improved ORR, with longer PFS, OS, and comparable TEAEs to those observed with either treatment as monotherapy. Further exploration of this combination is warranted. Citation Format: Tolaney SM, Kalinsky K, Kaklamani V, Savulsky C, Olivo M, Aktan G, Kaufman PA, Xing D, Almonte A, Misir S, Karantza V, Diab S. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-13.

Abstract P6-14-05: Phase 2 study evaluating the efficacy and safety of eribulin mesylate administered biweekly for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer

Abstract Background: Eribulin mesylate, a microtubule inhibitor, is approved in the US for the treatment of patients (pts) with metastatic breast cancer (MBC) who have previously received at least 2 chemotherapeutic regimens for the treatment of metastatic disease, including an anthracycline and a taxane. The recommended dose is 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) on day (D) 1 and D8 of a 21-D cycle. However, this schedule can result in dose delays and reductions due to myelosuppression. A dosing regimen of eribulin (1.4 mg/m2) administered intravenously (IV) biweekly (Q2W; on D1 and D15) in 28-D cycles was evaluated with the intent of improving eribulin's safety profile without compromising efficacy. Methods: Female pts with human epidermal growth factor receptor (HER)2-negative MBC, who had received 2-5 prior chemotherapy regimens and had ECOG PS ≤2 were enrolled in 12 sites in the US. Prophylactic granulocyte colony-stimulating factor (G-CSF) was not allowed. If neutropenia occurred, growth factors were used during eribulin treatment at the physician's discretion. Primary endpoints were objective response rate (ORR) and disease control rate (DCR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), dose intensity (measured by feasibility rate), safety and tolerability. Results: Median age of the 58 enrolled pts was 64 yrs (range: 38-85). The majority of pts (93%) had ECOG PS ≤1, and 12% of pts had triple-negative MBC. Number of prior chemotherapeutic regimens: 2 (17% of patients), 3 (24%), 4 (27%), and 5 (31%). 76% Of pts had visceral disease and 86% had previous taxane therapy. ORR (95% confidence interval [CI]) was 12% (5-24), DCR (CR+PR+SD) was 65% (95% CI: 51-77), and CBR (CR+PR+SD ≥23 weeks) was 30% (95% CI: 18-43) [n=57]. Median PFS (95% CI) was 3.6 mo (2.9-4.1). Median OS (95% CI) was 13.2 mo (10.6-not estimable). 6-Month and 12-month OS rates were 84% and 54%, respectively. Dose intensity measured by the feasibility rate (defined as the percentage of pts completing the first 2 and 4 cycles without a dose delay &amp;gt;5 days or dose reduction due to an adverse event [AE]) was 70% and 46%, respectively. The most frequent AEs (all grades) were neutropenia (69%), fatigue (48%), alopecia (45%), and constipation (36%). 22% Of pts had grade (G) 1 alopecia and 22% of pts had G2 alopecia. 72% Of pts had G3/4 AEs: neutropenia, 57%, and peripheral neuropathy, 12%. G3 peripheral sensory neuropathy occurred in 9% of pts, with no G4 incidence. There were 2 deaths (1 sepsis, 1 acute respiratory failure), which were considered not related to treatment. 50% (29/58) Of all patients received at least 1 dose of growth factor and 70% (28/40) of patients with neutropenia received growth-factor support. Conclusions: Tumor response rates and OS of this treatment schedule in a heavily pretreated patient population were similar compared to previously reported phase 3 studies of eribulin. The toxicities associated with biweekly eribulin were manageable. Citation Format: Smith II J, Irwin A, Jensen L, Tedesco K, Misir S, Zhu W, Almonte A, He Y, Olivo M, O'Shaughnessy J. Phase 2 study evaluating the efficacy and safety of eribulin mesylate administered biweekly for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-14-05.

Efficacy of combination chemotherapy using irinotecan and nedaplatin for patients with recurrent and refractory endometrial carcinomas: preliminary analysis and literature review

We aimed to retrospectively evaluate the efficacy and toxicity of an irinotecan hydrochloride (CPT) and nedaplatin (N) combination therapy for recurrent and refractory endometrial carcinoma, administered based on UGT1A1 genotype. Between 2009 and 2017, 21 patients who received CPT-N therapy for recurrent endometrial carcinoma as second- or third-line chemotherapy at our hospital were identified. The CPT-N regimen included 40-70mg/m2 of CPT-11 on days 1, 8, and 15, and 50mg/m2 of nedaplatin on day 1, q4 weeks. The median patient age was 63years. The number of prior chemotherapeutic regimens ranged from 1 to 2. Two patients had prior pelvic irradiation. The response rate [ratio of complete remission (CR) to partial remission (PR)] of CPT-N therapy was 3 of 21 (14.3%), and clinical benefit rate (CBR) [the combined percentages of CR, PR, and stable disease (SD)] was 9 of 21 (42.8%). Toxicities included grade 3 neutropenia [4 (19.0%) cases], grade 3 febrile neutropenia [2 (9.5%) cases], and grade 3 diarrhea [3 (14.3%) cases]; all resolved with conservative treatment. Patients with a wild-type UGT1A1 status received higher doses of CPT-11 (p = 0.048) and had similar RR and CBR compared to those with a UGT1A1*6 and *28 status. There were no significant differences in frequencies of hematological or non-hematological toxicities, regardless of UGT1A1 status. The CPT-N regimen for recurrent and refractory endometrial carcinoma had tolerable side effects and significant efficacy. This regimen is a viable treatment option for endometrial carcinoma.

MA 07.11 A Phase II Study of Trastuzumab Emtansine in HER2-positive Non-Small-Cell-Lung Cancer

Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with vinca-alkaloid, has been approved for clinical use in HER2-positive breast cancer. HER2-alterations are detected even in non-small-cell lung cancer (NSCLC). We have launched a phase II trial of T-DM1 monotherapy for patients with HER2-positive lung cancer. Eligible patients had pathologically diagnosed NSCLC with documented HER2-positivity (immunohistochemistry [IHC] 3+, both IHC 2+ and fluorescence in situ hybridization [FISH] +, or exon 20 insertion mutation) and were previously treated with standard chemotherapy. Thirty patients would receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate (ORR) per RECIST v1.1. This study was early terminated due to the limited efficacy, leading that only 16 patients were registered. The demographics of the 15 evaluable patients were as follows: age (median; 67, range: 45-77), sex (male; 47%), performance status (0-1; 80%), histology (non-squamous; 100%), HER2 status (IHC3+; 33%, IHC2+/FISH; 20%, and mutation; 47%) and number of prior chemotherapeutic regimens (median; 4, range: 1-7). Of 15 patients, one, who possessed HER2 mutation achieved a partial response, resulting in ORR of 6.7%. None of the 15 patients experienced treatment-related deaths. Survival data would be presented at the meeting. T-DM1 has a limited efficacy for HER2-positive NSCLCs in our cohort. Additional molecular approaches are warranted for the precision medicine in HER2-positive tumors. UMIN registration number 000019446.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study

BackgroundThe primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. MethodsPatients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. ResultsForty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2–25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. ConclusionIn this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity.

Safety and tolerability of eribulin mesylate in patients with pretreated metastatic breast cancer.

The safety and tolerability of eribulin mesylate for the treatment of metastatic breast cancer (MBC) are examined. This retrospective analysis used pooled safety and tolerability data from three Phase II trials and one Phase III trial of eribulin in patients with MBC. In these studies, patients with pretreated MBC received eribulin mesylate 1.4 mg/m(2) as a two- to five-minute i.v. infusion on days 1 and 8 of a 21-day cycle. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events, version 3.0. Across the four trials, 908 patients received eribulin and were assessed for safety. Aside from anthracyclines and taxanes, the most common prior chemotherapy agents were capecitabine, vinorelbine, and gemcitabine. Patients had received a mean of 3.7 (range, 1-11) prior chemotherapeutic regimens. Dose delays, reductions, and interruptions due to treatment-emergent adverse events occurred in 35.0%, 17.3%, and 2.9% of patients, respectively. Treatment was discontinued in 12.3% of patients due to adverse events, regardless of whether the adverse event was considered treatment related. The most common grade 3 or 4 treatment-related adverse events were neutropenia (52.4%) and leukopenia (19.3%). Serious adverse events occurred in 26.1% of patients, with the most common being febrile neutropenia (3.6%) and pyrexia (2.3%). Peripheral neuropathy was seen in 30.6% of patients, with 6.6% experiencing grade 3 or 4 reactions. Despite heavy pretreatment with anthracyclines, taxanes, and capecitabine, eribulin was well tolerated in this pooled analysis of patients with MBC.

A Pilot Study of Peripheral Blood Hematopoietic Stem Cells Mobilization with the Combination of Bortezomib and G-CSF in Multiple Myeloma and Non-Hodgkin's Lymphoma Patients.

Background: Bortezomib has become an integral part of front-line therapy of multiple myeloma in a large majority of patients. There are preliminary reports which show that addition of bortezomib can augment the peripheral blood CD34 count during stem cell mobilization. In this single center prospective trial we added bortezomib to G-CSF to evaluate the effects of bortezomib on peripheral CD34 counts and collection.Methods: Patients aged 18-70 years with diagnosis of multiple myeloma (MM) or non-hodgkin's lymphoma (NHL) who were eligible for autologous stem cell transplantation (ASCT) and had received no more than three prior chemotherapeutic regimens were eligible for the study. Patients were enrolled in two groups. Group A (N=3) received G-CSF 16mcg/kg for 5 days and proceeded to stem cell collection on D5 and then received bortezomib 1.3mg/m2 on D5 after stem cell collection and G-CSF 16mcg/kg on D6, 7, 8 and repeat stem cell collection on D6, 7, 8 till the goal was achieved. Group B (N=17) received G-CSF 16mg/kg on D1-5 and received bortezomib 1.3mg/m2 on D4 and proceeded to stem cell collection on D5. If the patient was not able to collect the predefined goal CD34, G-CSF was continued on D 6, 7, 8 and a second dose of bortezomib 1.3mg/m2 was given on D7. Mobilization procedure was stopped once the predefined goal CD34 collection (4 x 106/kg for MM and 2 x 106/kg for NHL) had been collected.Primary objectives of the study was to determine if addition of bortezomib to G-CSF will result in an increase in PBSCs by > 2-fold and to achieve median neutrophil engraftment 12 days post ASCT. Secondary objectiveswere to evaluate the collected product for co-mobilization of lymphoma or myeloma cells and to determine if the use of bortezomib increases the mobilization of immune-stimulatory Dendritic cell (DC) -1 subsets.Results: A total of 23 patients were enrolled and 20 were evaluable for the results. Only one patient with NHL was enrolled and rest had MM. Median age of pts was 57 years, M/F 8/12, median number of previous chemotherapy regimens was 1 (range 1-3).The median peripheral blood CD34 count pre and post bortezomib in all patients were 28.8 x 106/kg and 37 x 106/kg respectively. All three patients in group A had drop in peripheral blood CD34 counts on D6 post bortezomib as they had undergone stem cell collection on day 5. In part B (N=17), 15 patients had increase in peripheral blood CD 34+ve cell counts with 4 patients achieved doubling while 11 pts had less than doubling of peripheral blood CD34 count after receiving bortezomib. Two patients had minimal drop in the peripheral blood CD34 counts post bortezomib. Median number of CD34 cells collected in15 patients (part B) were 5.06 x 106 CD34 cells/kg (range 4-15.1). 18 patients proceeded to ASCT and median time to neutrophil engraftment (ANC ≥500/cumm) post transplant was 12 days (range 11-16) and platelet engraftment (Plt count ≥ 20,000/cumm) was 18 days (range 15-27). There was no significant change in DC1/DC2 ratio in both groups following treatment with bortezomib and G-CSF (Figure 1).In group A all three patients collected goal CD34 count on day 5 and 2/3 patients collected >4 x106 CD34 cells/kg on D6 post bortezomib and1/3 patients collected 2.6 x 106 on D6 post bortezomib. In group B (n=17), 2 patients were unable to collect because of low CD34 counts on D4 and D5, 11 pts collected the goal in one day (D 5) and 4 pts required two days of apheresis (D 5 and 6). None of the patients received D7 bortezomib.Conclusion: Use of bortezomib during autologous stem cell collection was safe and well tolerated. Majority of patients had increase in peripheral blood CD34 counts post bortezomib administration on D4. Future trials should explore bortezomib as an alternate strategy to chemo-mobilization in combination with growth factors. [Display omitted] [Display omitted] DisclosuresOff Label Use: Bortezomib for stem cell mobilization. Lum:Karyopharm Therapeutics Inc: Equity Ownership; Transtarget.Inc: Equity Ownership. Deol:Bristol meyer squibb: Research Funding. Abidi:celgene: Speakers Bureau; Millenium: Research Funding.

Phase I study of intraperitoneal IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer administered in combination with pegylated liposomal doxorubicin in recurrent or persistent epithelial ovarian, Fallopian tube, or primary peritoneal cancer patients: An NRG/GOG study.

5541 Background: EGEN-001 is an immunotherapeutic agent that comprises a human IL-12 plasmid that encodes for functional IL-12 and a synthetic DNA delivery system polyethyleneglycol-polyethyleneimine-cholesterol that facilitates plasmid delivery into cells. Ip injection of EGEN-001 is associated with increases in IL-12 levels and its downstream cytokines in the tumor environment without a significant increase in systemic circulation. The study’s purpose was to assess safety and efficacy of escalating doses of EGEN-001 with pegylated liposomal doxorubicin (PLD) in recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC) patients. Methods: Patient eligibility criteria: Females age ≥ 18 years with persistent or recurrent EOC. Patients were not required to have measurable disease and could have a biochemical recurrence; must have had one prior platinum-based chemotherapeutic regimen and up to two additional cytotoxic regimens; have adequate organ function. The trial was a ...

Eribulin treatment patterns in patients with and without prior anthracycline use.

292 Background: Eribulin mesylate is indicated for patients with metastatic breast cancer after treatment with ≥2 prior chemotherapeutic regimens for metastatic disease. Prior therapy should have included an anthracycline and a taxane. Evidence examining the effects of prior exposure to anthracyclines on eribulin therapy is limited. The purpose of this study was to compare demographic characteristics and treatment patterns for anthracycline-experienced patients vs. anthracycline-naïve patients treated with eribulin. Methods: A retrospective analysis using electronic medical record (EMR) data from 1/1/08 to 3/1/14 was conducted. Chemotherapy drugs were identified by the treatment name field in the EMR. Index date was defined as the first eribulin treatment. Patients with ≥2 eribulin administrations, continuous eligibility including a 6 month pre-period prior to the index date, and no treatment gaps more than 6 months were included. Patients were stratified into an anthracycline experienced cohort (treated prior to eribulin therapy) or without anthracycline cohort (never treated with this drug class prior to eribulin therapy). Demographics (gender, age, receptor status) and treatment characteristics (number and days of eribulin therapy) were compared between the cohorts. Results: 190 patients received eribulin; 46 (24%) with prior anthracycline use, 144 (76%) without. The majority of patients were female (87% for prior anthracycline, 97% without), and the average age of both groups was 59 yrs. Most patients were HR+/HER2- (56% overall; 70% for prior anthracycline, 51% for without), followed by TNBC (29% overall; 24% prior anthracycline, 31% without). Some patients had been treated previously with trastuzumab (15% overall; 7% for prior anthracycline, 17% for without). The number of eribulin administrations did not differ significantly between cohorts (8.2 administrations for anthracycline vs. 9.6 without, p=0.268). Likewise the number of days of therapy did not differ significantly (88.1 days for prior anthracycline vs. 104 without, p=0.369). Conclusions: There was no significant difference detected for prior anthracycline use impacting the number of eribulin administrations or days of therapy.