Fleming, Gini F.

5579 Background: Adavosertib (AZD-1775) is a potent small molecule inhibitor of Wee-1, currently in clinical development. In a double-blind, placebo-controlled, phase 2 trial (NCT02151292), adavosertib and gemcitabine significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with recurrent platinum-resistant or platinum-refractory high grade serous ovarian cancer (HGSOV) compared to gemcitabine alone. We investigated whether plasma and intra-tumoral adavosertib concentrations correlated with survival in these patients. Methods: Adavosertib was administered orally on Days 1, 2, 8, 9, 15 and 16 at 175 mg per day, and gemcitabine was administered on Days 1, 8 and 15 at 1000 mg/m2 every 28 days. Serial blood samples were collected on Day 1 of cycle 1 after adavosertib administration. Tumor biopsies were taken 1-2 weeks after initiation of study treatments. Plasma and tumor adavosertib concentrations were determined using validated HPLC-MS/MS. Patients were divided into groups with plasma or tumor adavosertib concentrations above or below the biologically active concentration (BAC) of 125 ng/ml (Leijen et al, J Clin Onco 2016). Survival was described using the Kaplan-Meier method. Results: Among 61 HGSOV patients who received adavosertib, plasma samples were available in 47, and tumor samples were available in 31 patients. Among 25 non-HGSOV patients (exploratory cohort), plasma and tumor samples were available in 21 and 17 patients respectively. The mean maximum adavosertib concentration (Cmax) was 355.3 ± 120.9 ng/ml and 358.6 ± 117.9 ng/ml respectively. Cmax was above BAC in all patients. The mean tumor adavosertib concentration was 609.2 ± 1129.2 ng/ml (range: 0.47 – 5501 ng/ml) for HGSOV patients, and 964.2 ± 1611.2 ng/ml (range: 0.22 – 6116 ng/ml) for non-HGSOV patients. There was no correlation between Cmax and tumor adavosertib concentrations. In HGSOV, the median PFS was 5.8 months for patients with tumor concentrations above BAC, and 3.5 months for those with tumor concentrations below BAC (Hazard ratio (HR): 0.46, 95% confidence interval: 0.19 – 1.14, p = 0.06). No difference in PFS was seen in non-HGSOV patients according to tumor adavosertib concentration. Tumor adavosertib concentration did not correlate with OS. Conclusions: Although Cmax was above BAC in all patients, there was a high variability in tumor adavosertib concentrations. In HGSOV, higher tumor adavosertib concentration was associated with a trend towards improved PFS, but not OS. Our results indicate that the current adavosertib dosing regimen may not produce the desired concentrations in tumors for some patients, and further optimization may be needed.

5553 Background: In patients with high-grade ovarian cancer in first-line setting, predictive factors of bevacizumab efficacy are needed, for selecting patients. In ICON-7 trial, a poor tumor intrisic chemosensitivity (defined by unfavorable modeled CA-125 kinetic ELIMination rate constant KELIM) was a predictive biomarker. Among patients with high-risk diseases, only those with unfavorable KELIM had survival benefit from bevacizumab (mOS: 29.7 vs 20.6 months, HR = 0.78)(Colomban. JNCI CS 2020). The objective was to perform an external validation in GOG-0218 trial (NCT00262847). Methods: In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel +/- concurrent bevacizumab/placebo followed by a 15 month maintenance. Patient KELIM values were estimated with longitudinal CA-125 kinetics during the first 100 chemotherapy days. The association between KELIM score (categorized as favorable ≥ 1, or unfavorable < 1) and efficacy of bevacizumab (bevacizumab-concurrent + maintenance, vs placebo) for PFS and OS was assessed using univariate/multivariate analyses, in a Training set with 2/3 patients managed the investigators, and then a Validation set with all patients, managed by NGR-GOG. Results: KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. In both sets, the patients with unfavorable KELIM derived benefit from bevacizumab compared to placebo (Training: PFS, HR = 0.65 [0.54-0.80]; OS, HR = 0.80 [0.65-0.99]; Validation: PFS, HR = 0.69 [0.59-0.82]; OS, HR = 0.87 [0.73-1.03]), whilst those with favorable KELIM had no benefit from bevacizumab (Training: PFS, HR = 0.96 [0.75-1.23]; OS, HR = 1.05 [0.80-1.37]; Validation, PFS, HR = 0.96 [0.79-1.17]; OS HR = 1.11 [0.89-1.84]). The highest benefit was observed in patients with high-risk diseases (stage IV or sub-optimally resected stage III) characterized by unfavorable KELIM, for PFS (Learning (n = 276): mPFS: 9.0 vs 5.2 months, HR = 0.61 [0.48-0.78]; Validation (n = 433): mPFS: 9.1 vs 5.6 months, HR = 0.64 [0.53-0.78]), and for OS (Learning (n = 278): mOS: 38.9 vs 27.9 months, HR = 0.72 [0.56-0.93], Validation set (n = 438): mOS: 35.1 vs 29.1 months, HR = 0.79 [0.65-0.97]). Conclusions: This validation analysis of GOG-0218 trial confirms the outcomes of ICON-7 trial about the association between poor tumor chemosensitivity and benefit from concurrent + maintenance bevacizumab, suggesting that bevacizumab is mainly effective in patients with poorly chemosensitive diseases. No benefit was found in patients with favorable KELIM. The patients who derived the highest benefit from bevacizumab in PFS and OS (OS absolute benefit ̃ 6 to 9 months) were those with high-risk diseases (stage IV, or incompletely resected stage III) associated with an unfavorable KELIM score (calculator on https://www.biomarker-kinetics.org/CA-125).

Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

Abstract BACKGROUND: Patients with ROC have limited treatment options in later lines of therapy, as many become platinum-resistant or -ineligible. Poly(ADP-ribose) polymerase inhibitor (PARPi) treatment is one option, however these agents are currently not approved for BRCAwt patients in the treatment setting. Niraparib, a PARPi, has demonstrated increased progression-free survival vs placebo as maintenance therapy for platinum-responsive ROC. Niraparib was effective regardless of BRCAmut or homologous recombination deficiency (HRD) status, although an increased treatment effect was observed in the HRDpos population. QUADRA (NCT02354586) evaluated niraparib treatment in heavily pretreated ROC patients, regardless of BRCAmut or HRD status, platinum sensitivity, or prior PARPi use. METHODS: Eligible patients had grade 2-3 serous ROC, ≥3 prior chemotherapy lines, and measurable disease. Patients were evaluated for BRCAmut and HRD status (MyChoice HRD Test). Patients received niraparib 300 mg once daily until progression; dose could be lowered to 200 mg or 100 mg due to treatment-emergent adverse events (TEAEs). The primary endpoint was objective response rate (ORR) per RECIST v1.1 in patients treated in 4th or 5th line who were HRDpos, platinum sensitive, and PARPi naïve. RESULTS: 463 patients were treated. Of these, 161 were platinum refractory, 151 platinum resistant, and 120 platinum sensitive to their last line of platinum therapy. Of note, 83 patients were primary platinum resistant or refractory (42 and 41, respectively). Median number of prior lines of therapy was 4 (range 2-16), and 27% of patients were treated in 6th or later line. 100% of patients received prior platinum, 99.6% received prior taxane, 81% received prior doxorubicin, 63% received prior bevacizumab, and 59% received prior gemcitabine. In the primary efficacy population (N=45), ORR was 29% (95% CI: 16-44, P=0.0003), disease control rate (DCR) was 71% (95% CI: 56-84), and duration of response (DOR) was 9.2 months (95% CI: 5.9-NE); overall survival (OS) was not reached (95% CI: 18.5-NE). The efficacy outcomes in all 456 patients with measurable disease at baseline treated in 4th or later line demonstrated a DCR of 49% with 2 complete responses (CR), 36 partial responses (PR), and 187 patients with stable disease (SD). The responses were durable with a median DOR of 9.4 months, a clinical benefit rate (CR+PR+SD) at 16 weeks of 29%, and median OS of 17.2 months (95% CI: 14.9-19.8) among all patients treated in 4th or later line. 266 (57.5%) patients had grade ≥3 treatment-related TEAEs. Grade ≥3 thrombocytopenia event (thrombocytopenia or decreased platelet count) by dose at onset of the event was 27.5% at 300 mg, 4.7% at 200 mg, and 2.7% at 100 mg. The other most common grade ≥3 TEAEs were anemia (26.3%) and neutropenia (8.2%). Hematologic TEAEs were most frequent in the first month and decreased in frequency and severity after dose reduction during months 2-3. CONCLUSIONS: Niraparib demonstrated durable anticancer activity in this heavily treated (≥3 lines) ROC population, including platinum-resistant or BRCAwt patients. Toxicities were consistent with previous niraparib studies. DISCLOSURE Funded by TESARO, Inc. Citation Format: Kathleen Moore, Angeles Secord, Melissa Geller, David Miller, Noelle Cloven, Gini Fleming, Andrea E. Wahner Hendrickson, Masoud Azodi, Paul Disilvestro, Amit Oza, Mihaela Cristea, Jonathan S. Berek, John Chan, Yong Li, Kaiming Sun, Katarina Luptakova, Ursula A. Matulonis, Bradley J. Monk. QUADRA: A PHASE 2, OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE SINGLE-AGENT NIRAPARIB TREATMENT IN PATIENTS WITH RELAPSED OVARIAN CANCER (ROC) WHO HAVE RECEIVED ≥3 PRIOR CHEMOTHERAPY REGIMENS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-101.

Abstract Tamoxifen (T) is a pro-drug that undergoes CYP2D6-mediated metabolic activation to metabolites that more potently inhibit estrogen stimulated growth compared to the parent drug. While many studies have examined the role of CYP2D6 genotype in T-treated postmenopausal women, the role of CYP2D6 metabolism in premenopausal women (pre-MW) receiving T, with or without ovarian function suppression (OFS) or exemestane (E) and OFS is unknown. Methods: SOFT randomized 3066 (pre-MW) from 2003-2011 in 27 countries, stratified according to prior receipt or nonreceipt of chemotherapy and nodal status, to receive 5 years of T, T+OFS, or E+OFS. We designed a pharmacogenetics substudy (activated October 2010) to collect blood DNA from North American (NA) patients (pts) or to extract non-tumor DNA from available formalin fixed paraffin embedded (FFPE) tissue blocks. For pts with a blood sample, CYP2D6 was genotyped beginning with the Luminex Tag-It Mutation Detection Kit and when needed, with a copy number variation assay and/or sequencing assays. For pts with FFPE-derived DNA, CYP2D6 genotyping for *3, *4, *6, *9, *10, *17 and *41 was performed using a Taqman Allelic Discrimination Assay. CYP2D6 phenotypes were called by classifying pts on the basis of a combination of poor (PM: *3, *4, *5, *6, *7, *8), slow (SM: *10), intermediate (IM: *9, *17, *29, *41) and extensive metabolizer alleles (EM; all others). Activity scores (AS) from phenotypes assigned for each allele: 0 if PM, 0.25 if SM, 0.5 if IM and 1 if EM allele, and multiplied x2 or x3 if duplicate or triplicate. With concomitant use of potent CYP2D6 inhibitor, AS=0; use of weak inhibitor subtracted 0.5. Metabolizer status was defined by CYP2D6 genotype alone or in combination with CYP2D6 inhibitor use at randomization from the AS: extensive (AS 1.25 to 3), intermediate (AS &gt;0.5 to &lt;1.25), slow/poor (AS 0 to 0.5) metabolizer status. The laboratory was blinded to all clinical data. The substudy primary objective was to assess the association between disease-free survival (DFS) and CYP2D6 metabolizer status in the T arm, and secondarily in the T + OFS, and E + OFS arms. A Cox model estimated hazard ratios comparing status according to treatment assignment, with prespecified prognostic factors. Results: 1200/3047 (39%) randomized pts in the intention-to-treat (ITT) population had successful CYP2D6 genotyping and 50% received prior chemotherapy. Following randomization, 435/1023 (42%) NA pts provided a blood sample and CYP2D6 genotypes were derived in 435/435. Non-tumor tissue was macrodissected from 1277 available FFPE blocks, resulting in DNA concentrations of &gt; 0.3 ng/ml in 1053, and successfully derived CYP2D6 genotypes for 765/3047 pts (25%). 182 (15%) pts had DFS events after 8 yrs median follow-up. Metabolizer status from genotype was 57% extensive, 29% intermediate, 15% slow/poor. Metabolizer status was not associated with DFS in pts assigned T alone (P=0.60; Table), nor in pts assigned T+OFS (P=0.41) or E+OFS (P=0.30). 11% of pts used CYP2D6 inhibitors concomitantly at randomization; for 8% it changed the metabolizer status. The results using this definition were consistent. Conclusion: This retrospective-prospective SOFT pharmacogenetics substudy found no relation of CYP2D6 metabolizer status with DFS in premenopausal pts receiving T, T + OFS, or E + OFS. Given that 50% were pretreated with chemotherapy, further study is needed regarding the role of CYP2D6 metabolism in patients treated with T monotherapy. TableTreatment GroupN pts (N events)Comparison (N pts)Hazard Ratio95% CITamoxifen324 (56)Intermediate (114) vs Extensive (210)0.780.43-1.39Tamoxifen265 (52)Slow/Poor (55) vs Extensive (210)1.110.58-2.13Tamoxifen + OFS357 (46)Intermediate (122) vs Extensive (235)0.730.38-1.40Tamoxifen + OFS299 (45)Slow/Poor (64) vs Extensive (235)1.250.64-2.43Exemestane + OFS344 (46)Intermediate (107) vs Extensive (237)0.590.28-1.22Exemestane + OFS293 (47)Slow/Poor (56) vs Extensive (237)1.130.56-2.27 Citation Format: Matthew P. Goetz, Gini F. Fleming, Mary Kuffel, John R. Hawse, John L. Black, Richard Weinshilboum, James N. Ingle, Patrizia dell’Orto, Olivia Biasi, Roswitha Kammler, Sherene Loi, Marco Colleoni, Giuseppe Viale, Prudence A Francis, Meredith M Regan. The role of CYP2D6 mediated tamoxifen metabolism in the suppression of ovarian function trial (SOFT) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-09.

Background Lymphedema is an adverse effect of breast cancer treatment that causes swelling and pain in the arm and hand. We tested 2 lymphedema prevention interventions and their impact on health‐related quality of life (HRQOL) in a group‐randomized trial at 38 cooperative group sites within the United States. Methods Patients were recruited before breast surgery. Sites were randomly assigned to education‐only (EO) lymphedema prevention or education plus exercise and physical therapy (LEAP). Lymphedema was defined as a ≥10% difference in arm volume at any time from baseline to 18 months postsurgery. HRQOL was assessed using the Functional Assessment of Cancer Therapy–Breast plus 4 lymphedema items (FACT‐B+4). Longitudinal mixed model regression analysis, adjusting for key demographic and clinical variables, examined participants' HRQOL by intervention group and lymphedema status. Results A total of 547 patients (56% LEAP) were enrolled and completed HRQOL assessments. The results revealed no differences between the interventions in preventing lymphedema ( P = .37) or HRQOL (FACT‐B+4 total score; P = .8777). At 18 months, the presence of lymphedema was associated with HRQOL at borderline significance ( P = .0825). However, African American patients reported greater lymphedema symptoms ( P = .0002) and better emotional functioning ( P = .0335) than patients of other races or ethnicities. Lower HRQOL during the intervention was associated with younger age ( P ≤ .0001), Eastern Cooperative Oncology Group performance status >0 ( P = .0002), ≥1 positive lymph nodes ( P = .0009), having no education beyond high school ( P < .0001), having undergone chemotherapy ( P = .0242), and having had only axillary node dissection or sentinel node biopsy versus both ( P = .0007). Conclusion The tested interventions did not differ in preventing lymphedema or in HRQOL outcomes. African American women reported greater HRQOL impacts due to lymphedema symptoms than women of other races or ethnicities.

Background Lymphedema affects many women who are treated for breast cancer. We examined the effectiveness of an education‐only (EO) versus education plus sleeve compression/exercise intervention (lymphedema education and prevention [LEAP]) on lymphedema incidence and range of motion (ROM) in a group‐randomized trial across 38 cooperative group sites. Methods The treating institution was randomly assigned to either EO or LEAP by a study statistician. All patients at a treating institution participated in the same intervention (EO or LEAP) to minimize contamination bias. Participants completed surveys, arm volume measurements, and self‐reported ROM assessments before surgery and at 12 and 18 months after surgery. Lymphedema was defined as a ≥10% difference in limb volume at any time post‐surgery up to 18 months after surgery or diagnosis by a health provider. Cochran‐Mantel‐Haenszel tests were used to compare lymphedema‐free rates between groups, stratified by lymph node surgery type. Self‐reported ROM differences were compared between groups. Results A total of 554 participants (56% LEAP) were included in the analyses. At 18 months, lymphedema‐free rates were 58% (EO) versus 55% (LEAP) ( P = .37). ROM for both arms was greater in LEAP versus EO at 12 months; by 18 months, most women reported full ROM, regardless of group. In LEAP, only one‐third wore a sleeve ≥75% of the time; 50% performed lymphedema exercises at least weekly. Conclusion Lymphedema incidence did not differ by intervention group at 18 months. Poor adherence in the LEAP group may have contributed. However, physical therapy may speed recovery of ROM. Further research is needed to effectively reduce the incidence and severity of lymphedema in patients who have breast cancer.

6010 Background: The efficacy of treatment for recurrent endometrial cancer (EC) remains limited. Vascular endothelial growth factor and inflammatory chemokines are proangiogenic factors and immune modulators involved in immune suppression. Reprogramming the tumor microenvironment by combining antiangiogenic and immunotherapy (IO) could enhance antitumor responses. Methods: A 2:1 randomized phase 2 trial compared the combination of cabozantinib and nivolumab (Arm A) versus nivolumab (Arm B) in recurrent EC. Primary endpoint was progression free survival (PFS) assessed by RECIST 1.1 (NCT03367741). Women with recurrent measurable EC were eligible. There were no limits on prior therapy, but at least one prior platinum-based chemotherapy was required. Patients (pts) were stratified according to MSI status and assessed by CT every 8 weeks. Cabozantinib was given at 40 mg daily (Arm A) and nivolumab at 240 mg, on D1 and D15 of a 28-day cycle for 4 cycles, followed by 480 mg every 4 weeks (Arms A & B). Pts with carcinosarcoma or prior IO were enrolled in an exploratory cohort and received combination treatment (Arm C). A baseline biopsy was required for all pts. CyTOF analysis was performed on fresh biopsies. Results: 76 evaluable pts were enrolled (Arm A: 36, Arm B: 18, Arm C: 9 carcinosarcoma, and 20 post IO including 7 pts crossed over from Arm B). 55% of pts had received ≥3 prior lines of therapy. Two pts were MSI high in Arm A and none in Arm B. The Kaplan-Meier estimated median PFS was 5.3 (95% CI: 3.5-9.5) months in Arm A and 1.9 (95% CI: 1.6-3.8) months in Arm B, with a log-rank p = 0.07, which met the significance level of 0.1 used for sample size calculation. Objective response rate (ORR) was 25% for Arm A and 16.7% for Arm B; stable disease (SD) was seen in 44.4% vs 11.1%, respectively. Clinical benefit (ORR+SD) was significantly higher in arm A vs B (p < 0.001). In Arm C-carcinosarcoma, one patient had a partial response (11.9 months duration) and four SD. In Arm C-prior IO, six pts responded and eight had SD. The most common related AEs in Arm A were diarrhea (47.2%), elevated liver enzymes (44.4%), fatigue (38.9%), anorexia, hypertension, and nausea (30.6%), mainly grade 1/2. Preliminary CyTOF analysis across treatment arms identified multiple immune subsets for further interrogation including activated CD8+ and CD4+ T cells. Conclusions: Cabozantinib plus nivolumab demonstrates improved PFS compared to nivolumab in heavily pre-treated women with recurrent EC. In-depth CyTOF analysis of the tumor microenvironment to identify predictive immune biomarkers of response is ongoing. Clinical trial information: NCT03367741.

1016 Background: The ph III EMBRACE trial of E vs physician’s choice of tx led to FDA approval of E as ≥3rd-line tx for MBC pts with prior exposure to anthracyclines/taxanes. The ph III BOLD 301 trial of E vs capecitabine in advanced BC treated with anthracyclines/taxanes showed a nonsignificant trend to improved median OS for all pts; pre-planned analysis by HER2 status revealed a nominally significant benefit for HER2- pts. Methods: RU011201I is an investigator initiated ph III trial with 1:1 randomization to E (1.4 mg/m2 D1,8 q21days) vs P (90 mg/m2 D1,8,15 q28days) within strata defined by (neo)adjuvant taxanes (yes/no), HR status (+/-), and line of tx (1st/2nd). Pts had measurable or non-measurable disease by RECIST v1.1; new or progressive mets; peripheral neuropathy (PN) gr<2; ≤1 prior chemotx regimens for advanced or MBC. Asymptomatic brain mets with stable MRIs for >3 mos were allowed. (Neo)adjuvant taxanes were allowed if >12 mos between tx completion and disease recurrence. Radiographic studies occur q12wks. Survival data are collected q12wks after the Off-Tx Visit. Pts reported side effects weekly; post-baseline symptomatic AE rates worse than baseline were compared between arms using Fisher’s exact tests. We report clinical outcomes and the primary objective related to PRO-CTCAE use. Results: 201 pts enrolled 3/2014 - 5/2018 with 33.8 mos median f/u; 3 are on tx as of 2/20/20 (1E, 2P). Pt characteristics were the same between E vs P: median age 62 yrs (range 27-85); 42% prior taxane; 78% ER+; 70% starting 1st line tx. Baseline lesion distribution was similar except for lung mets (37E, 53P). No difference was seen between E vs P in PFS (5.7 vs 5.9 mos; P=0.72), OS (18.1 vs 16.4 mos; P=0.75), TTF (5.3 vs 4.9 mos; P=0.82), DOR (10.8 vs 12.3 mos; P=0.84), or number of metastatic events (55 vs 54). 37E and 36P pts required ≥1 dose reduction. Hematologic toxicities ≥ gr 3 were higher with E (40 vs 22%). PN events were similar: 56 vs 58 total, 4 vs 7 motor, 52 vs 51 sensory. Median duration of PN and median time to 1st PN event were 74 vs 140 and 56 vs 41 days. Worsened numbness/tingling severity and other pt-reported AE rates were similar, but worsened numbness/tingling interference (63% vs 78%, P=0.04) and vomiting frequency (35% vs 57%, P=0.005) were lower with E. Conclusions: Clinical outcomes were equivalent with E vs P as 1st/2nd line tx for HER2- advanced BC. The nature and severity of PN were similar between arms, but time of onset, duration, and interference with daily living favor E. E may be a suitable treatment option in this setting. Clinical trial information: NCT02037529 .

1024 Background: The combination of platinum agents and PARP inhibitors may benefit patients (pts) with BRCA-associated metastatic breast cancer (MBC). We report on the response and clinical benefit rates when combining the PARP inhibitor veliparib (V) and carboplatin (carb) in a phase I trial. Methods: BRCA carriers with MBC were eligible. Carb starting at an AUC of 6 was given IV in 21-day cycles (C) and V was given orally twice daily (BID) at dose levels (L) L1 through L5. Results: Twenty-eight pts (26 eligible) carrying BRCA1 (12) or BRCA2 (15), or both (1) mutations were accrued between June 2010 and June 2012. The median age (32-66) was 45 years. The number (#) of prior chemotherapy regimens given for MBC was 1 (0-5); 70% of BCs were ER+, and 7% were HER2+. The schema, dose limiting toxicities (DLT) during C 1, median # of Cs on trial, and maximum tolerated dose (MTD) are shown. There were 3 (12%) complete and 9 (35%) partial responses (PR). Unconfirmed PR or stable MBC (median duration: 8 months [6-10+]) were seen in 7 pts (27%); the clinical benefit rate was74%. The median progression-free survival (PFS) is 7.8 months (95% CI 7.3-9.5). The pt with Fallopian tube cancer had a CR. DLTs with C 1 were seen in 2/6 evaluable pts at L1 (1 pt w/grade 3 hyponatremia and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to de-escalation of carb. At L2, 1 pt had grade 4 PLT. At L5, 1 pt had grade 4 PLT, and 2 pts grade 3 PLT (1 pt also experienced grade 4 granulocytopenia [ANC]), defining the MTD at carb AUC 5 and V 150 mg BID (L4). Dose delays and/or dose adjustments due to grade ≥ 2 toxicities for ANC or PLT were seen during the first 3 Cs at L1 (100%), L2 (50 %), L3 (67%), L4 (83 %), and at L5 (67%). Conclusions: The combination of carb and V is active, and is associated with substantial clinical benefit rate and managable hematologic toxicities in BRCA carriers with MBC. Further definition of the role of V is warranted. [Table: see text]