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PURPOSE This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer, including those with estrogen receptor gene alpha ( ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor–positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

Background: Targeting the estrogen receptor (ER) has proven to be one of the most successful strategies in treating HR+ (ER+ and PR+) and HER2- breast cancer. Selective estrogen receptor degraders (SERD) can be used as single agents or in combination with CDK4/6 inhibitors such as palbociclib. Fulvestrant is currently the only approved agent in its class and is limited by poor oral bioavailability necessitating monthly intramuscular injections. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft models and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development. Methods: A first-in-human phase 1 study was conducted to evaluate D-0502 in women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objectives are to evaluate the PK properties and the preliminary anti-tumor activities. Patients received D-0502 orally once daily in 28-day cycles. The study has completed dose escalation (phase 1a), and dose expansion and combination studies (phase 1b) are ongoing. In phase Ia, patients were enrolled and evaluated using conventional 3+3 dose-escalation to identify the MTD of D-0502 as a single agent. The phase 1b was divided into 2 stages. In Stage 1, D-0502 was evaluated with palbociclib at a dose below the MTD first before escalating to the MTD. Stage 1 also included patients in China treated at a dose below and at the MTD as single agent as well as in combination with palbociclib. Stage 2 will further evaluate the MTD for both single agent and combination of D-0502 with palbociclib. Results: At the time of this abstract submission, phase 1a dose escalation is completed, R2PD has been identified, and no DLTs were observed. PK analysis of D-0502 indicates a dose proportional increase in exposure as the dose increases, and the exposure has exceeded the potential therapeutic exposure level based on preclinical studies. The Phase Ib Stage 1 portion has also completed enrollment and the study is currently enrolling patients into phase Ib Stage 2. D-0502 as a single agent or in combination has been well tolerated with radiological tumor response and clinical benefit response (CBR) observed. Safety, PK and preliminary efficacy data will be reported at the meeting presentation. Conclusion: A first-in-human phase 1 study of D-0502 has been initiated in women with advanced or metastatic HR-positive and HER2-negative breast cancer. D-0502 has been well tolerated and achieved significant exposure and preliminary clinical activity in patients. Further results will be presented at the meeting. Citation Format: Cynthia Osborne, Donald A Richards, Sharon T Wilks, Sami Diab, Dejan Juric, Kate Lathrop, Andrea Silber, William Edenfield, Amardeep Aulakh, Ben Cho, Binghe Xu, Tao Sun, Quchang Ouyang, Yanxia Shi, Kathryn Stazzone, Zhe Shi, Ling Zhang, Yaolin Wang, Erika P Hamilton. A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer [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 PS11-26.

Background Trilaciclib is an intravenous (IV) cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Preliminary data showed that adding trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly increased overall survival (OS) compared with GCb alone among patients with metastatic triple-negative breast cancer (mTNBC) (Tan et al., Lancet Oncol. 2019;20:1587-1601). Here, final antitumor efficacy results (objective response rate [ORR], progression-free survival [PFS], and OS) are reported for the whole study population, and in cohorts according to CDK4/6 dependence and level of programmed death ligand-1 (PD-L1) expression. Methods This was a randomized, open-label, phase 2 study of patients with mTNBC who had received ≤2 previous lines of chemotherapy in the recurrent/metastatic setting (NCT02978716). Patients were randomized (1:1:1) to receive GCb on days 1 and 8 (group 1, n=34), trilaciclib prior to GCb on days 1 and 8 (group 2, n=33), or trilaciclib alone on days 1 and 8 and prior to GCb on days 2 and 9 (group 3, n=35), in 21-day cycles. PFS and OS (prespecified secondary endpoints) were assessed in the intention-to-treat (ITT) population, and ORR in response-evaluable patients. Patient tumors were characterized as CDK4/6 independent (basal-like) or indeterminate (HER2-enriched, normal-like, luminal A/B) according to the established PAM50 signature, or CDK4/6 dependent (luminal androgen receptor) or indeterminate (basal-like 1/2, mesenchymal) according to the established Lehmann signature. PD-L1 expression was scored as negative or positive if Results Median follow-up was 8.4 months (range: 0.1-25.7) for group 1, 14.0 months (1.3-33.6) for group 2, and 15.3 months (3.5-33.7) for group 3. The ORR among response-evaluable patients was 7/24 (29.2%) in group 1, 15/30 (50.0%) in group 2, and 12/31 (38.7%) in group 3. Median PFS (95% confidence interval [CI]) in the ITT population was 5.7 (3.3, 9.9) months in group 1, 9.4 (6.1, 11.9) months in group 2, and 7.3 (6.2, 13.9) months in group 3, with hazard ratios (HRs) of 0.62 (P = 0.2099) and 0.63 (P = 0.1816), for groups 2 and 3 versus group 1, respectively. Overall, 73.5%, 39.4%, and 57.1% of patients in groups 1, 2, and 3 had died. Median OS (95% CI) was 12.6 (6.3, 15.6) months in group 1, not reached (NR) (10.2, NR) in group 2 (HR = 0.31, P = 0.0016), and 17.8 (12.9, 32.7) months in group 3 (HR = 0.40, P = 0.0004). For groups 2 and 3 combined, median OS was 19.8 (14.0, NR) months (HR = 0.37, P Conclusions Mature data from this study confirm that administering trilaciclib prior to GCb enhances antitumor efficacy compared with GCb alone, with statistically significant improvements in OS. Subgroup analyses suggest that adding trilaciclib prior to GCb benefits patients regardless of CDK4/6 dependence status and PD-L1 expression. Additional immune subtyping analyses are ongoing and will be presented. Group 1Group 2Group 3PD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePatients, n171016101616ORR, n (%)4 (23.5)3 (30.0)8 (50.0)4 (40.0)7 (43.8)4 (25.0)Median PFS, months (95% CI)3.5 (2.2, NR)9.5 (5.2, NR)7.9 (4.3, NR)11.9 (8.8, NR)9.0 (6.2, NR)6.9 (6.4, NR)P value (Wald Test)––0.3470.6040.0690.766HR (95% CI)––0.70 (0.3, 1.5)0.76 (0.3, 2.2)0.46 (0.2, 1.1)1.16 (0.4, 3.1)Median OS, months (95% CI)10.5 (6.3, 18.8)13.9 (12.6, NR)20.1 (10.2, NR)NR (9.4, NR)32.7 (15.3, NR)17.8 (12.9, NR)P value (Wald Test)––0.0280.0830.020.239HR (95% CI)––0.35 (0.1, 0.9)0.34 (0.1, 1.2)0.33 (0.1, 0.8)0.57 (0.2, 1.5)HR and P values are for comparisons between group 2 versus group 1, and group 3 versus group 1.+ve, positive; –ve, negative; CI, confidence interval; HR, hazard ratio; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival. Citation Format: Joyce O'Shaughnessy, Gail S Wright, Anu R Thummala, Michael A Danso, Lazar Popovic, Timothy J Pluard, Hyo S Han, Željko Vojnović, Nikola Vasev, Ling Ma, Donald A Richards, Sharon T Wilks, Dušan Milenković, Jie Xiao, Jessica A Sorrentino, Janet Horton, Antoinette R Tan. Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: Final analysis of a randomized phase 2 trial [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 PD1-06.

Elevated expression of AURKA adversely affects prognosis in ER+ breast cancer and is associated with resistance to taxanes, endocrine therapy, and PI3K inhibitors. A recent randomized phase II trial of combined paclitaxel plus alisertib (P+A) in recurrent ovarian cancer patients (pts) showed improved progression-free survival (PFS) compared to paclitaxel (P) alone (Falchook G. JAMA Oncol 2019). We conducted a randomized phase II trial of P alone versus P+A in pts with ER+ HER2- metastatic breast cancer (MBC). Methods: The primary objective of the trial was PFS in the intent-to-treat (ITT) population with secondary endpoints of overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR; CR+PR+SD>6 mos), safety and analysis of archival breast cancer for molecular predictors of benefit from alisertib. ER+ HER2- MBC pts who had had prior endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, > 12 mos treatment-free interval from neo/adjuvant taxane therapy, and who had measurable or evaluable lytic bone disease were randomized to receive P 90 mg/m2 IV D1, 8, 15 on a 28-day cycle or P 60mg/m2 D1, 8, 15 plus A 40 mg PO BID D1-3, 8-10, 15-17 on a 28-day cycle until disease progression or unacceptable toxicity. Pts were stratified by prior neo/adjuvant taxane (yes/no) and by whether they were receiving first (1L)- or second (2L)-therapy for MBC. Proportions of ORR and CBR were compared using Chi-square test between the two study arms. Kaplan-Meier estimator was applied to estimate OS and PFS and univariate Cox regression was used to assess the hazard ratio of study treatment. Results: 139 pts were randomized (69 to P+A; 70 to P) in the US Oncology Network between 2/2015 and 2/2018 and 136 pts received treatment on trial. At data cut-off, 76% of pts had had a documented PFS event and the median followup was 19.7 mos. The median age was 62 and 69% of pts received trial therapy as 1L treatment; 41% had had prior neo/adjuvant taxane therapy. Median PFS in the ITT population was 10.2 mos with P+A vs 7.1 mos with P alone, HR 0.56, 95% CI 0.37-0.84, p=0.005. Median OS was 29.8 mos with P+A vs 24.4 mos with P alone, HR 0.85, p=0.486. ORR and CBR in the response evaluable population were 31% and 67%, respectively, in the P+A arm vs 34% and 57%, respectively, in the P alone arm (p>0.05). Grade 3/4 adverse events (AEs) occurred in 83% of P+A pts vs 47% with P alone. The main grade 3/4 AEs with P+A vs P were neutropenia 59% vs 15%, anemia 10% vs 1%, febrile neutropenia 1.5% vs 0, diarrhea 11% vs 0, stomatitis 15% vs 0, peripheral neuropathy 1.5% vs 9%. 1 pt died of sepsis with P+A. Conclusions: Addition of oral A to weekly P significantly improved PFS, the primary endpoint, compared with P alone, and toxicity with P+A was manageable with A dose reduction. These data support further evaluation of alisertib in ER+ HER2- MBC pts. Citation Format: Joyce O'Shaughnessy, Kristi McIntyre, Sharon Wilks, Ling Ma, William Fintel, Margaret Block, David Andorsky, Michael Danso, Nicholas Koutrelakos, Tracy Locke, Amy Scales, Lauren Steckel, Yunfei Wang. Randomized, multicenter phase II trial of weekly paclitaxel with or without the oral selective aurora kinase A (AURKA) inhibitor, Alisertib, in patients with ER+ HER2- metastatic breast cancer [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 PD7-10.

Background Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus. Materials and Methods This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1–2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks. Results A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity. Conclusion Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse. Implications for Practice This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.

Purpose: As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings. Patients and Methods: In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination. Results: The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)]. Conclusions: Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

Background LIV-1, a transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells. It is associated with lymph node involvement and metastatic progression. SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which disrupts microtubulin and induces apoptosis. Methods This ongoing, phase 1 study evaluates safety, tolerability, pharmacokinetics, and antitumor activity of SGN-LIV1A (q3wks IV) in women with LIV-1-positive, unresectable, locally advanced or metastatic breast cancer (LA/MBC) (NCT01969643). Patients (pts) with measurable disease and ≥2 prior cytotoxic regimens for LA/MBC are eligible. Pts with ≥ Grade 2 neuropathy are excluded. Response is assessed per RECIST v1.1; pts with stable disease (SD) or better can continue treatment until disease progression or intolerable toxicity. At completion of dose escalation in hormone receptor-positive/HER2-negative (HR+/HER2–) and triple-negative (TN) pts, expansion cohorts were opened to further evaluate safety and antitumor activity of monotherapy in TN pts. Tumor biopsies are evaluated for LIV-1 expression. Results To date, 69 pts (18 HR+/HER2–, 51 TN) have received a median of 3 cycles (range, 1–12) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 56 yrs. Pts had a median of 3 prior cytotoxic regimens for LA/MBC; 58 had visceral disease and 37 had bone metastases. No dose-limiting toxicities (DLTs) occurred in 19 DLT-evaluable pts; maximum tolerated dose was not exceeded at 2.8 mg/kg. Expansion cohorts of TN pts were opened at 2.0 and 2.5 mg/kg. Treatment-emergent adverse events (AEs) reported in ≥25% of pts were fatigue (59%), nausea (51%), peripheral neuropathy (44%), alopecia (36%), decreased appetite (33%), constipation (30%), abdominal pain, diarrhea, and neutropenia (25% each). Most AEs were Grade 1/2; AEs ≥ Grade 3 included neutropenia (25%) and anemia (15%). Febrile neutropenia occurred in 2 pts whose total dose exceeded 200 mg per cycle, including 1 treatment-related death due to sepsis. No other treatment-related deaths occurred on-study. Seven pts discontinued treatment due to AEs. In dose escalation, activity was observed in 17 efficacy evaluable (EE) HR+/HER2- pts, with a disease control rate (DCR= CR+PR+SD) of 59% (10 SD), including 1 pt with SD ≥24 wks. Among the 44 EE TN pts (dose escalation plus expansion cohorts), the objective response rate (ORR) was 32% (14 PR) with a confirmed PR rate of 21%, DCR was 64% (14 PR, 14 SD), and clinical benefit rate (CBR=CR+PR+SD ≥24 wks) was 36% (16 pts). For TN pts, median PFS was 11.3 wks (95% CI: 6.1, 17.1); 10 pts remain on treatment. Of 631 MBC tumor samples of all clinical subtypes evaluated for LIV-1, 91% were positive; 75% had moderate-to-high expression (H-score ≥100). Conclusions LIV-1 is expressed in almost all MBC tumors. SGN-LIV1A monotherapy was generally well tolerated and showed encouraging antitumor activity in heavily pretreated TN MBC, with a PR rate of 32%, confirmed PR rate of 21%, and CBR (≥24 wks) of 36%. Response duration data continue to evolve. Enrollment continues in the TN monotherapy expansion cohort. Citation Format: Modi S, Pusztai L, Forero A, Mita M, Miller KD, Weise A, Krop I, Burris III H, Kalinsky K, Tsai M, Liu MC, Hurvitz SA, Wilks S, Ademuyiwa F, Diab S, Han HS, Kato G, Nanda R, O'Shaughnessy J, Kostic A, Li M, Specht J. Phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with heavily pretreated triple-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 PD3-14.

This abstract was not presented at the symposium.

Background Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2 − metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial. Patients and Methods In the present prospective analysis of hormone receptor-positive (HR + )/HER2 − and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m 2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity. Results We enrolled 54 HR + and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR + and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR + and TN patients, respectively). The median OS was 17.9 months for HR + patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment. Conclusion Ixabepilone plus carboplatin is active even in later-line HR + and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.

Background: GR is variably expressed in TNBC and high expression is associated with poor prognosis in estrogen receptor-negative (ER-) early stage breast cancer. Treatment with mifepristone (MIFE) potentiates the effectiveness of chemotherapy in GR+ TNBC xenografts. Enrollment is complete in this study of patients with GR+ TNBC treated at the recommended Phase 2 dose (RP2D) of MIFE in combination with eribulin. Objectives: To determine the safety, tolerability, pharmacokinetics (PK) and clinical activity of the MIFE plus eribulin combination in pts with GR+ TNBC at the RP2D. Methods: Eligibility: In Part 1 (dose finding), pts with solid tumors; in Part 2 (expansion phase), pts with TNBC (GR result required at time of screening in Part 1, but could be pending at time of screening in Part 2). Up to 5 prior chemotherapy regimens for advanced disease; ECOG PS 0-1; adequate end-organ function. Design: 3 + 3 dose escalation scheme. After a 7-day lead-in of oral daily MIFE alone, MIFE was continued daily and eribulin was given on days 1 and 8 of a 21-day cycle. GR+ was defined as >10% of tumor cells with any intensity of GR staining. Results: 16 pts with metastatic breast cancer were treated in Part 1, and 21 pts with TNBC were treated in Part 2. Median age was 54 (range 30-81). MTD/RP2D was MIFE 300 mg/day + eribulin 1.1 mg/m2. Safety: DLT in Part 1 was neutropenia. Neutropenia occurred in 23/36 total patients (2 Grade [G] 1, 10 G3, 11 G4); 2 instances included neutropenic fever. Recovery of WBC was brisk with growth factor support. Neuropathy was observed in 8 pts (5 G1, 1 G2, 2 G3). Other most common AEs (fatigue, hypokalemia, nausea, alopecia) were mainly G1 or G2; among these, G3/G4 events were limited to fatigue (4 G3), hypokalemia (3 G3 and 1 G4) and nausea (1 G3). There were 2 instances of G1 vaginal bleeding. There was no impact of MIFE on eribulin PK. Efficacy: There were 23 evaluable pts with TNBC across Parts 1 and 2 treated at the RP2D: 21 GR+, 2 GR status unknown; median of 3 prior chemotherapy regimens; 1 patient had received prior eribulin. Responses were: 3 PR, 8 SD, 11 PD and one too early to assess. Median PFS was 9 weeks. Conclusions: MIFE plus eribulin was well tolerated and appears to be an active treatment regimen. Five TNBC patients had a PFS longer than the upper 95% CI for PFS (i.e., >15 wks) reported by Aogi et al. for TNBC treated with eribulin (Annals of Oncology 2012?23:144148). Clinical trial information: NCT02014337. Citation Format: Han HS, Wilks S, Paplomata E, Modiano MR, Becerra C, Braiteh FS, Spira AI, Pluard TJ, Richards DA, Conzen SD, Baker G, Fishman RS, Marcantonio A, O'Shaughnessy J, Nanda R. Efficacy results of a phase 1/2 study of glucocorticoid receptor (GR) antagonist mifepristone (MIFE) in combination with eribulin in GR-positive triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-15.

Background: nab-Paclitaxel (nab-P)–containing regimens have demonstrated efficacy and safety in triple-negative breast cancer (TNBC). In the absence of a standard of care for metastatic (m) TNBC, tnAcity evaluated the efficacy and safety of 3 common chemotherapy combination regimens: nab-P + carboplatin (nab-P/C) or gemcitabine (nab-P/G) vs G/C as first-line treatment (Tx) for patients (pts) with mTNBC based on a ranking algorithm of efficacy and safety. Results of the phase 2 portion are reported here. Methods: Pts with pathologically confirmed mTNBC, no prior cytotoxic chemotherapy for metastatic disease, and no brain metastases were enrolled. Pts received (1:1:1) nab-P 125 mg/m2 + C AUC 2, nab-P 125 mg/m2 + G 1000 mg/m2, or G 1000 mg/m2 + C AUC 2, all given on d 1 and 8 every 3 weeks. The phase 2 primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), percentage of pts initiating cycle 6 receiving doublet therapy, and safety. Results: 191 pts were included in the phase 2 portion. Median age was 55, 53, and 59 years in the nab-P/C, nab-P/G, and G/C groups, respectively. Overall, 98% of pts had an ECOG PS of 0 - 1, 83% were white, and 48% were treated in North America. Most pts (81%) had relapsed disease. Median Tx duration was 25, 18, and 20 weeks, and 47%, 33%, and 52% of pts had ≥ 1 dose reduction for both agents in the nab-P/C, nab-P/G, and G/C groups, respectively. Key efficacy and safety results are summarized in the table. PFS was significantly longer with nab-P/C vs either nab-P/G or G/C (median, 7.4 vs 5.4 mo, P = 0.03 and 7.4 vs 6.0 mo, P = 0.02). Overall, 179 pts discontinued Tx; of these, 55% discontinued due to progression and 16% due to adverse events (AEs). Grade ≥ 3 AEs in ≥ 10% of pts were mainly hematologic. The rank sum of the algorithm for 5 key weighted efficacy and safety endpoints favored nab-P/C. Table 1 nab-P/Cnab-P/GG/CEfficacyn = 64n = 61n = 66PFS, median, mo7.4a5.4b6.0ORR, %71.937.743.9OS, median, mo16.411.913.7Pts initiating cycle 6 with a doublet, %64.155.750.0Safetyn = 64n = 60n= 64Myelosuppression-related events, %c53.141.767.2Pts discontinuing all Tx due to AE, %18.820.021.9Serious TEAEs, %29.736.737.5Grade ≥ 3 AEs, %Neutropenia40.633.348.4Anemia7.88.315.6Thrombocytopenia4.73.314.1Peripheral neuropathy4.75.01.6Deaths due to TEAE, n (%)1 (2)2 (3)2 (3)a P = 0.03 vs nab-P/G; P = 0.02 vs G/C; b P = 0.85 vs G/C; c Including grade ≥ 3 neutropenia, thrombocytopenia, anemia, bleeding, febrile neutropenia, or red blood cell/platelet transfusion. Conclusions: In this phase 2 study, nab-P/C demonstrated a statistically significant longer PFS and a better risk/benefit profile vs nab-P/G or G/C as first-line Tx in pts with mTNBC. These data demonstrate nab-P/C efficacy in mTNBC and address a relevant question around a nab-P/C chemotherapy backbone for this difficult-to-treat tumor type. Further studies are warranted in the context of immunotherapies and targeted agents. NCT01881230. Citation Format: Yardley D, Coleman R, Conte P, Cortes J, Brufsky A, Shtivelband M, Young R, Bengala C, Ali H, Eakel J, Schneeweiss A, de la Cruz Merino L, Wilks S, O'Shaugnessy J, Glück S, Li H, Beck R, Barton D, Harbeck N. nab-paclitaxel + carboplatin or gemcitabine vs gemcitabine/carboplatin as first-line treatment for patients with triple-negative metastatic breast cancer: Results from the randomized phase 2 portion of the tnAcity trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-03.

Background: P is a novel cyclin-dependent kinase 4/6 inhibitor approved in the United States and Canada in combination with endocrine therapy for HR+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (ABC). Despite promising trial results, not all patients respond to P. Moreover, despite a median age at diagnosis of 62 years, elderly patients are underrepresented in targeted therapy trials, including the PALOMA studies assessing P. It is important to understand P use in real-world practice settings, including tolerability and outcomes in the vulnerable older population. In addition, understanding the mechanisms of P response or resistance is critical to identify clinical factors and biomarkers that can predict which patients will benefit from P. This multicenter observational and biomarker study will seek to address these and other data gaps. Trial Design: This is a prospective, noninterventional study of 1500 patients treated with P from 100 US and 10 Canadian sites. Study duration will span 2 years of recruitment and 3 years of follow-up after P treatment, until patient withdrawal from the study or death. Study participation is not intended to alter routine treatment; all treatment decisions, including type and timing of disease monitoring, are at the discretion of the treating physician and patient. Eligibility: Eligible patients are aged ≥18 years with a diagnosis of adenocarcinoma of the breast with (1) evidence of advanced or metastatic disease not amenable to treatment with curative intent, (2) documented HR+/HER2- status, and (3) planned treatment with P. Patients with a life expectancy Aims: In a large real-world cohort of HR+/HER2- ABC patients treated with P in routine clinical practice, this study aims to assess the following: prescribing and treatment patterns for ABC before, during, and after P therapy; overall clinical response to P; biomarker assessment investigating potential mechanisms of response and resistance to P based on genomic analyses of blood samples; patient quality of life, as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30; geriatric assessments in patients aged ≥70 years at enrollment based on the G8 Geriatric Screening Tool and the Activities of Daily Living questionnaire; and sequencing of treatment for metastatic disease. Other outcomes to be assessed include survival and toxicity. Methods: Data will be collected from routine clinical assessments. Patients will have the option to provide blood samples drawn at standard-of-care intervals at baseline, during P treatment, and at the end of treatment for potential biomarker identification. Analyses will be primarily descriptive, with point estimates and confidence intervals as well as Kaplan-Meier methods used to assess time-to-event outcomes. Accrual: Presently, 46 patients from 20 sites are enrolled. Funding: Pfizer Inc. Citation Format: Tripathy D, Bardia A, Blum JL, Rocque G, Wilks S, Lakhanpal S, Migas J, Cappelleri J, Perkins J, Comstock G, Wang Y. POLARIS: Palbociclib (P) in hormone receptor-positive (HR+) advanced breast cancer: A prospective multicenter noninterventional study [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 OT3-05-03.

Background POLARIS is an ongoing, prospective, real-world (RW) study of palbociclib (PAL) in patients (pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). A biomarker goal of this study was to evaluate serial changes in circulating tumor DNA (ctDNA) dynamics among pts with long-term clinical response to PAL plus endocrine therapy (ie, received ≥18 cycles). Methods The data set included pts who received PAL combination therapy, gave consent for blood collection to obtain ctDNA, and had long-term clinical response. The Guardant360 Next-Generation Sequencing platform, which analyzed approximately 73 genes, was used to sequence ctDNA for somatic single-nucleotide variants, including copy number variants. Longitudinal ctDNA changes (at baseline and various time points) and the RW clinical response to PAL are described. Results As of December 17, 2020, 35 pts of 1280 enrolled received ≥18 cycles of PAL combination therapy, with blood samples collected over a minimum of a 24-month period. Pts received PAL plus an aromatase inhibitor (n=16) or fulvestrant (n=19). Median age was 64 years. Thirty pts (85.7%) were white, 29 (82.9%) were postmenopausal, 31 (88.6%) had an Eastern Cooperative Oncology Group score of 0 or 1, 12 (34.3%) had visceral disease, 9 (25.7%) had de novo disease, and 24 (68.6%) had recurrent disease. Six pts (17.1%) had a RW best overall response (BOR) of complete response (CR), 9 (25.7%) had partial response (PR), and 20 (57.1%) had stable disease (SD). Two pts had disease progression resulting in change of therapy at cycles 25 and 38, respectively. Biomarker samples were collected from a median (range) total number of 9 (3-12) visits. The median (range) number of somatic variants detected was 4 (0-11) and included the most prevalent somatic mutations (eg, PIK3CA, TP53, BRCA1/2, FGFR2, GATA3). No ctDNA mutations were detected in 6 pts (17%) post baseline up to 24 months. Among 15 pts who achieved CR/PR, 12 (80%) either had no detectable or sustained very low ctDNA burden or had corresponding ctDNA decrease. Among 16 pts who remained with SD, 12 (75%) either had no detectable or sustained very low ctDNA burden or had ctDNA decrease. Among 8 pts whose disease progressed, 5 (63%) had an increasing trend in ctDNA mutation frequency. Conclusions This study is among the first to provide serial blood-based tumor genotyping data from routine clinical practice. Interim data indicate that even pts with ongoing detectable ctDNA have a BOR of CR, PR, or SD with PAL for HR+/HER2- ABC, suggesting certain mutations might not be drivers of PAL resistance. Dynamic changes of ctDNA mutations may be predictive for treatment response, and may have clinical utility in disease surveillance monitoring. Additional longitudinal data will be presented. Pfizer; NCT03280303 Citation Format: Joanne L. Blum, Aditya Bardia, Sharon Wilks, Steven L. McCune, Carrie L. Dul, John J. Migas, Derrick W. Spell, Zhe Zhang, Yuan Liu, Yao Wang, Debu Tripathy. Longitudinal ctDNA changes in patients with long-term response to palbociclib combination therapy for advanced breast cancer: A preliminary analysis from the real-world POLARIS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB033.

Importance Elevated expression of AURKA adversely affects prognosis in estrogen receptor (ER)-positive and ERBB2 (formerly HER2)-negative and triple-negative breast cancer and is associated with resistance to taxanes. Objective To compare paclitaxel alone vs paclitaxel plus alisertib in patients with ER-positive and ERBB2-negative or triple-negative metastatic breast cancer (MBC). Design, setting, and participants In this randomized clinical trial conducted with the US Oncology Network, participants were randomized to intravenous (IV) paclitaxel 90 mg/m2 on days 1, 8, and 15 on a 28-day cycle or IV paclitaxel 60 mg/m2 on days 1, 8, and 15 plus oral alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. Stratification was by prior neo or adjuvant taxane and by line of metastatic therapy. Eligible patients were those who had undergone endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, more than 12 months treatment-free interval from neo or adjuvant taxane therapy, and with measurable or evaluable lytic bone-disease. Data were analyzed from March 2019 through May 2019. Main outcomes and measures The main outcome was progression-free survival (PFS) with secondary end points of overall survival (OS), overall response rate, clinical benefit rate, safety, and analysis of archival breast cancer tissues for molecular markers associated with benefit from alisertib. Results A total of 174 patients were randomized, including with 86 randomized to paclitaxel and 88 patients randomized to paclitaxel plus alisertib, and 169 patients received study treatment. The final cohort included 139 patients with a median (interquartile range [IQR]) age of 62 (27-84) years with ER-positive and ERBB2-negative MBC, with 70 randomized to paclitaxel and 69 randomized to paclitaxel plus alisertib. The TNBC cohort closed with only 35 patients enrolled due to slow accrual and were not included in efficacy analyses. The median (IQR) follow-up was 22 (10.6-25.1) months, and median (IQR) PFS was 10.2 (3.8-15.7) months with paclitaxel plus alisertib vs 7.1 (3.8-10.6) months with paclitaxel alone (HR, 0.56; 95% CI, 0.37-0.84; P = .005). Median (IQR) OS was 26.3 (12.4-37.2) months for patients who received paclitaxel plus alisertib vs 25.1 (11.0-31.4) months for paclitaxel alone (HR, 0.89; 95% CI, 0.58-1.38; P = .61). Grade 3 or 4 adverse events occurred in 56 patients (84.8%) receiving paclitaxel plus alisertib vs 34 patients (48.6%) receiving paclitaxel alone. The main grade 3 or 4 adverse events with paclitaxel plus alisertib vs paclitaxel alone were neutropenia (50 patients [59.5%] vs 14 patients [16.4%]), anemia (8 patients [9.5%] vs 1 patient [1.2%]), diarrhea (9 patients [10.7%] vs 0 patients), and stomatitis or oral mucositis (13 patients [15.5%] vs 0 patients). One patient receiving paclitaxel plus alisertib died of sepsis. Conclusions and relevance This randomized clinical trial found that the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved PFS compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction. These data support further evaluation of alisertib in patients with ER-positive, ERBB2-negative MBC. Trial registration ClinicalTrials.gov Identifier: NCT02187991.

Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Citation Format: Heather C Beckwith, Diana C Medgyesy, Jame Abraham, Rita Nanda, Katherine HR Tkaczuk, Ian E Krop, Lajos Pusztai, Shanu Modi, Monica M Mita, Jennifer M Specht, Sara A Hurvitz, Hyo S Han, Kevin Kalinsky, Sharon Wilks, Joyce O’Shaughnessy, Lowell L Hart, Hope S Rugo, Zahi I Mitri, Phillip M Garfin, Howard A Burris III. SGNLVA-001: A phase 1 open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer [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 OT-03-03.

Therapeutic antibodies to immune checkpoints show promising results. Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD-L1 receptor (programmed death 1). We investigated PD-L1 protein expression and messenger RNA (mRNA) levels in SCLC.PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28-8 PD-L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor-infiltrating immune cells (TIICs) obtained from a limited-disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive-disease SCLC was assessed for PD-L1 protein expression in tumor cells with Dako 28-8 antibody only.The overall prevalence of PD-L1 protein expression in tumor cells was 16.5%. In the limited-disease cohort, the prevalences of PD-L1 protein expression in tumor cells with SP142 and Dako 28-8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD-L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD-L1 protein/mRNA expression was associated with the presence of more TIICs (p0.05). The extensive-disease cohort demonstrated a 14.9% positivity of PD-L1 protein expression in tumor cells with Dako 28-8 antibody.A subset of SCLCs is characterized by positive PD-L1 and/or mRNA expression in tumor cells. Higher PD-L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD-L1 in SCLC is lower than that published for NSCLC. The predictive role of PD-L1 expression in SCLC treatment remains to be established.

Aim: APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen. Methods: HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication). Results: A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions. Conclusion: APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Background: High tumor GR expression is associated with poor prognosis in estrogen receptor (ER) negative early-stage breast cancer. Co-treatment with M, a GR antagonist, potentiates effects of chemotherapy in ER- breast cancer xenograft studies. Herein we describe results of a phase 1 dose-escalation study of M plus E, with an ongoing dose expansion cohort in pts with GR+ TNBC. Objectives: Determine 1) safety and tolerability, 2) recommended phase 2 dose (RP2D) of M + E, and 3) characterize pharmacokinetics (PK) and clinical activity of M in pts with GR+ TNBC. Methods: Eligibility: 1) relapsed/refractory breast, ovarian, prostate, urothelial, sarcoma, or non-small cell lung cancer; 2) 2-5 prior chemotherapy regimens for advanced disease; 3) ECOG PS 0-1; and 4) adequate end-organ function. Study used a 3 + 3 dose escalation scheme. After a 7 day lead-in of M alone, M was administered by mouth daily in combination with E given IV on days 1 and 8 of a 21 day cycle. Results: 13 pts in Part 1 Dose escalation with metastatic breast cancer (MBC) were treated with M+E: 5 TNBC, 8 GR+ tumors, 2 GR- tumors, and 3 of unknown GR status. Pts were treated at 3 dose levels (DL)[M mg/d, E mg/m2]: 3 at DL1 [600, 1.1] 4 at DL-1a [300, 1.4], and 6 at DL-1 [300, 1.1]. Median duration of treatment was 90+ days. Neutropenia leading to delay of E was dose limiting in 4 pts. CTAE Grade 3/4 neutropenia was observed in 10 pts over all DL, but easily managed (9 pts with growth factor support). Other grade 3+ toxicities were neuropathy (2 pts) and onycholysis (1 pt). No other significant toxicity was noted. RP2D was determined as 300mg/d M and 1.1mg/m2 E. At this DL there were no DLTs. PK of M and E were as predicted from published literature with no evidence of drug-drug interaction (DDI). A total of 6 pts received this dose (3 TNBC; 3 MBC). All 3 TNBC were GR+. 1 had partial response, 1 had stable disease, and 1 had progressive disease. A phase I/II study of M+E is now in progress. To date, 3 GR+ TNBC pts have been treated for a median of 28+ days. Conclusion: M + E is a novel combination designed to improve antitumor activity. It is well tolerated with evidence of clinical activity and no evidence of DDI. RP2D is 300mg M + E 1.1mg/m2. Study is ongoing in expansion phase where recruitment is limited to pts with GR+ TNBC. Additional PK and clinical data will be presented. Citation Format: Wilks S, Modiano M, Spira A, Becerra C, Walling J, Nguyen D, Baker G, Conzen SD, Nanda R. Phase 1 study of GR antagonist mifepristone (M) in combination with eribulin (E) in advanced solid tumors, with dose expansion in patients (pts) with GR-positive triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-21.

Background:Managing delayed chemotherapy-induced nausea and vomiting (CINV) associated with HEC is an unmet need. AC-based HEC is often administered to breast cancer patients (pts), a mostly female, high-CINV-risk population. APF530, an extended-release formulation of granisetron, demonstrated superior complete response (CR; no emesis [vomiting, retching] + no rescue medication use) in delayed-phase (>24-120 h) CINV with HEC (ASCO criteria) vs ondansetron (Ond) (65% vs 57%, P=0.014), each combined with a neurokinin-1 antagonist and dexamethasone (Dex) (NCT02106494). This post hoc analysis evaluated efficacy and safety of APF530 in pts receiving AC-based therapy. Methods: In this randomized, double-blind, multicenter trial, pts scheduled to receive single-day HEC were stratified by cisplatin ≥50 mg/m2 yes/no and randomized 1:1 to APF530 500 mg SC (granisetron 10 mg) or Ond 0.15 mg/kg IV. Pts received concomitant Dex 12 mg IV and fosaprepitant 150 mg IV on day 1 and oral Dex on days 2-4. The primary end point was CR in the delayed phase. Secondary and other end points included CR in acute (0-24 h) and overall (0-120 h) phases, and complete control (CC; CR and no more than mild nausea) and total response (TR; CR and no nausea) in acute, delayed, and overall phases. Rates were compared using 95% confidence intervals (CIs) for treatment differences; post hoc analysis was not powered to detect treatment differences in the AC subgroup. Safety assessments included adverse events (AEs), injection-site reactions (ISRs), laboratory parameters, and vital signs. Results: A total of 589/902 pts (65%) in the modified intent-to-treat population received AC-based HEC (APF530 291, Ond 298). Baseline demographics were balanced between treatment arms. The majority of pts in the AC subgroup were female (APF530 99%, Ond 98%). Delayed-phase CR was higher with APF530 vs Ond, approaching statistical significance (APF530 64%, Ond 56%; P=0.062) in the AC subgroup, similar to the benefit seen in the larger study. No appreciable benefit of APF530 vs Ond was observed in the acute phase, and trends favorable to APF530 were observed in the overall phase (Table). APF530 was well tolerated. Most AEs were ISRs, generally mild or moderate, and resolved by end of study. Phase, n (%)APF530OndansetronTreatment DifferenceN=291N=298(95% CI), %Complete responseDelayed185 (64)167 (56)8 (-0.4, 15.4)Overall163 (56)153 (51)5 (-3.4, 12.7)Acute205 (70)204 (69)1 (-5.4, 9.4)Complete controlDelayed171 (59)156 (52)7 (-1.6, 14.4)Overall149 (51)143 (48)3 (-4.9, 11.3 )Acute193 (66)191 (64)2 (-5.5, 9.9)Total responseDelayed119 (41)107 (36)5 (-2.9, 12.8)Overall100 (34)94 (32)2 (-4.8, 10.4)Acute164 (56)173 (58)-2 (-9.7, 6.3) Conclusions: APF530 demonstrated an apparent clinical benefit in delayed-phase CR in pts receiving AC-based HEC, concordant with the statistically significant benefit seen in the overall study population. Prevention of CINV in this patient population continues to be a treatment challenge and further investigation is needed. Citation Format: Schnadig I, Agajanian R, Dakhil S, Taylor C, Wilks S, Cooper W, Mosier M, Payne Y, Klepper M, Vacirca J. Phase 3 comparison of APF530 versus ondansetron, each in a guideline-recommended 3-drug regimen for prevention of chemotherapy-induced nausea and vomiting due to anthracycline + cyclophosphamide (AC)–based highly emetogenic chemotherapy (HEC) regimens: A post hoc subgroup analysis of the MAGIC trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-07.

Background: Oral stomatitis is a frequent adverse event (AE) associated with mTOR-inhibitor therapy, and can impact treatment adherence. In the BOLERO-2 trial in patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC) treated with exemestane (EXE) plus everolimus (EVE), the incidence of all-grade stomatitis or related AEs was 67%, with 24% and 8% of pts developing Grade (G) 2 and G3 stomatitis or related AEs, respectively (Perez et al ASCO 2013 Abst 7029). In BOLERO-2, 24% of pts required EVE dose reduction for stomatitis (Rugo et al Ann Oncol 2014;25:808). The current study evaluated 2 different steroid-based mouth rinses for the prevention or amelioration of oral stomatitis in pts with MBC treated with EVE. Methods: This prospective randomized phase II study enrolled postmenopausal pts (planned accrual=100) with HR+ MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor plus EVE (10 mg/day). Eligible pts were randomized, blinded, 1:1 to prophylactic treatment with 1 of 2 oral rinses (ARM 1: MMW 480 ml recipe: 320 mL oral Benadryl, 2 g Tetracycline, 80 mg Hydrocortisone, 40 mL Nystatin suspension, water; or ARM 2: Prednisolone 15mg/5mL oral solution). Pts were instructed to swish/expectorate 10 ml of the assigned rinse 4 x daily starting with Day 1 of EVE treatment, for a total of 12 wks. The primary objective was to determine the incidence of G≥2 stomatitis during the first 12 wks of treatment. Secondary objectives included assessment of AEs (all grades), determination of the percentage of pts requiring dose interruption and/or dose reduction of EVE or discontinuation of therapy due to toxicity, and evaluation of the impact of the oral rinses on the duration and severity of stomatitis. Results: As of April 16, 2015, a total of 48 pts have been randomized and 47 pts have received treatment, with a mean time on mouth rinse of 68 days (range 2-84 days). Median age was 65 yrs (range 31-82 yrs). Twelve patients developed an oral AE and the incidence of all-grade stomatitis was 25% (n=12/48). The incidence of G1 stomatitis was 17% (8/48), G2 stomatitis was 8% (4/48) and there were no G3 events. The 4 G2 stomatitis AEs occurred within the first 30 days of treatment. One pt (1/48; 2%) required EVE dose delay. One pt developed oral candidiasis while on the steroid mouth rinse and no pts have stopped the steroid mouth rinse therapy due to mouth rinse-related toxicity. Conclusion: These preliminary data are the first from a prospective trial to provide evidence of a reduced incidence of mTOR-associated stomatitis with prophylactic use of a steroid mouth rinse. The 25% incidence of all-grade and 8%/0% incidence of G2/3 stomatitis compare favorably with the 67% and 24%/8% incidence of all-grade and G2/3 stomatitis, respectively, in BOLERO-2. These preliminary data also demonstrated the safety and tolerability of these 2 steroid mouth rinses. The incidence of stomatitis on each study arm will be available when accrual is completed. The prophylactic use of steroid mouth rinses substantially decreases the incidence of G2/3 stomatitis and the need for EVE dose interruption/reduction. Citation Format: Jones VL, Jensen LL, McIntyre KJ, Oommen SP, Patt DA, Cortas TE, Harris RP, Wilks ST, Fox P, O'Shaughnessy JA. Evaluation of miracle mouthwash (MMW) plus hydrocortisone versus prednisolone mouth rinses as prophylaxis for everolimus-associated stomatitis: Preliminary results of a randomized phase II study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-15-06.

e15587 Background: Interval breast cancers (BC) are detected between routine screening mammograms and are associated with worse prognosis, requiring more aggressive treatment compared to screen-detected BC identified during scheduled mammograms. Identifying molecular differences between interval BC and screen detected BC may lay the foundation for developing novel therapies. In this study, we compared gene expression profiles of interval BC to screen-detected BC. Methods: This analysis included a subset of 2260 patients enrolled in the FLEX Registry (NCT03053193), an ongoing, prospective study evaluating primary tumor samples from stage I-III BC patients who receive 70-gene risk of recurrence testing (70GS), 80-gene molecular subtyping (80GS), and consent to collection of clinically annotated full genome data. Interval BC were diagnosed < 12 months following a normal screening mammogram. Breast tumors were classified by 70GS as having a Low Risk (LR) or High Risk (HR) of distant metastases. Tumors were classified as Luminal, HER2, or Basal type by 80GS. Differential gene expression analysis was performed with limma and subsequent pathway analysis with DAVID and GSEA. Differences in the proportion of 70GS or 80GS results, 70GS index, and Ki67 were assessed by Chi-squared test or t-test. Results: In this study, 81% (1834/2260) of patients had screen-detected BC and 19% (426) had interval BC. A higher proportion of interval BC (51%) were HR compared to screen-detected BC (44%; p = 0.01). Most LR tumors were invasive ductal carcinoma (78% interval and 73% screen-detected) and over 99% were Luminal type. Between the two LR groups, 70GS indices were similar and there was no significant difference in transcriptional profiles. Basal and HER2 subtypes were more frequent among HR interval BC compared to screen-detected BC (p = 0.03). HR interval BC had 70GS indices of higher risk compared to HR screen-detected BC (p = 0.02). Differentially expressed genes in HR interval BC compared to HR screen-detected BC were associated with MYC signaling and mitosis, which was concordant with higher Ki67 by IHC (p = 0.007). Conclusions: This real-world data analysis shows interval BC are not all biologically High Risk and can be further stratified by the 70GS, aiding in treatment decisions. Preliminary results suggest that following 70GS LR classification, there is no biological difference between interval BC and screen-detected BC. In contrast, there are distinct biological processes associated with HR interval BC, which may have implications in the management of these cancers. Clinical trial information: NCT03053193.

1015 Background: As monotherapies, both ERI (a chemotherapeutic microtubule inhibitor) and PEMBRO (a programmed death [PD]-1 blocking immunotherapy) have shown promising antitumor activity in mTNBC. Emerging data suggest that the addition of immunotherapy to traditional chemotherapy holds promise for mTNBC. This open-label, single-arm, phase 1b/2 study evaluated the safety and efficacy of ERI + PEMBRO in mTNBC. Methods: Patients (pts) with mTNBC and ≤2 prior systemic anticancer therapies for metastatic disease were enrolled and stratified by prior number of therapy (Stratum 1, 0; Stratum 2, 1–2). Pts received IV ERI 1.4 mg/m2 on day (d)1 and d8 and IV PEMBRO 200 mg on d1 of a 21-d cycle. The primary objectives were safety and objective response rate (ORR per RECIST 1.1 by independent imaging review). Assessments also included efficacy outcomes by PD ligand-1 (PD-L1) expression status; PD-L1+ was defined as a combined positive score ≥1 using the PD-L1 IHC 22C3 pharmDx. Results: As of data cutoff (July 31, 2019), 167 pts (Stratum 1, n=66; Stratum 2, n=101) were enrolled and treated. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were fatigue (66%), nausea (57%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). No deaths were considered treatment related. The overall ORR was 23.4% (95% CI: 17.2–30.5). Efficacy outcomes by PD-L1 status (PD-L1+, n=74; PD-L1-, n=75) and stratum are presented (table). Conclusions: ERI + PEMBRO has activity in pts with mTNBC. There was a trend toward more robust activity for the combination among patients with PD-L1+ tumors compared to PD-L1- tumors in the first-line setting (Stratum 1); whereas, in the later-line setting (Stratum 2) similar survival outcomes were observed among the PD-L1+ and PD-L1- pts. ERI + PEMBRO shows promise for mTNBC with efficacy that appears greater than historical reports of either agent alone. Clinical trial information: NCT02513472 . [Table: see text]

TPS1104 Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Clinical trial information: NCT01969643 .

Background: The majority of patients (pts) with advanced ER+ breast cancer (BC) will experience progression of disease after endocrine therapy (ET) due to acquired resistance, including development of ESR1 mutations (mut). Response to conventional ET agents, including aromatase inhibitors and fulvestrant, in late lines of therapy is poor with overall response rates (ORR) less than 10% and median progression free survival (mPFS) of 2-3 months. Elacestrant is a novel, nonsteroidal, oral SERD with marked antitumor activity documented in multiple in vivo pt derived xenograft models of BC, including those derived from heavily pretreated pts and those with ESR1 mut. Methods: RAD1901-005 is a multi-part phase 1 study of elacestrant with the primary objective to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Secondary objectives are safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Part A was dose escalation with 3+3 design (capsule; doses 200, 400 and 600 mg QD); Part B was safety expansion (capsule); Part C was expansion (tablet); Part D expansion (tablet) was added by amendment to study later line pts including prior CDK4/6 inhibitor (i) use (NCT02338349). Key eligibility criteria: advanced or metastatic (m) ER+, HER2- BC; postmenopausal status. For Parts A-C: ≤2 prior chemotherapy regimens (CT) for mBC and >6 mo ET with progression (PD). For Part D: ≤1 prior CT for mBC, ≥2 prior lines of ET including PD on fulvestrant, and CDK4/6i. We present updated and final results from the trial (all parts). Results: From April 2015 to March 2018, 57 pts were enrolled: Part A: 13, B: 20, C: 14, D: 10 (of 36 planned; enrollment was terminated due to change in regulatory strategy). MTD/RP2D was 400 mg QD. For all pts treated at 400 mg (n=50): stage IV 100%; visceral disease 70%; median prior lines of tx 3 (Part D: 4), including median of 1 prior line of CT and 3 prior lines of ET; prior CDK4/6i 52% (Part D: 100%); prior fulvestrant 50% (Part D: 100%); prior mTORi 26%. At baseline, 51% of pts had detectable ESR1 mut, including D538G, Y537S/N/C, L536H/P/R, S436P and E380Q. Among pts treated with 400 mg tablet (n=24), treatment-emergent adverse events in ≥20% were nausea, hypertriglyceridemia, hypophosphatemia, vomiting, dyspepsia, constipation, hypokalemia, fatigue, back pain, myalgia, headache, and urinary tract infection; the majority were grade 1 and 2. There were no treatment-related deaths. 13% of pts discontinued due to AEs. Antitumor activity is summarized in Table 1. There were 6 confirmed partial responses; median duration of response was 24.9 wk; median time to response was 8.2 wk. One pt with ESR1 mut with best response of SD remains on treatment at 3 yr. Conclusion: Elacestrant at the RP2D of 400 mg QD has an acceptable safety profile and demonstrated significant single-agent anti-tumor activity in heavily pretreated (mostly 4th line or greater) ER+, HER2- mBC pts. Activity was seen following prior fulvestrant, prior CDK4/6i, and in pts with ESR1 mut. The ORR of 19.4% and mPFS of 4.5 mo compare favorably with those reported for fulvestrant and AIs given in earlier treatment settings. Elacestrant monotherapy vs. standard of care ET monotherapy is currently being studied in ER+, HER2- mBC with 1 or 2 lines of prior tx including prior CDK4/6i, in the phase 3 “EMERALD” study (NCT03778931). Table 1. Efficacy OutcomesParts A-CPart DOverallORR, % (RECIST-evaluable pts) (n/N)27.3% (6/22)0% (0/9)19.4% (6/31)Clinical Benefit Rate, % (PR+SD ≥24 wk) (n/N)47.4% (18/38)22.2% (2/9)42.6% (20/47)mPFS (95% CI), mo, N=50 (ITT population)5.4 (3.7, 11.2)1.9 (1.8, 8.6)4.5 (1.9, 7.4) Citation Format: Virginia Kaklamani, Aditya Bardia, Sharon Wilks, Amy Weise, Donald Richards, Wael Harb, Cynthia Osborne, Robert Wesolowski, Meghan Karuturi, Paul Conkling, Rebecca Bagley, JungAh Jung, Teeru Bihani, Maureen Conlan, Peter Kabos. Final analysis of phase 1 study of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer [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 PD7-07.

Background: ER+ metastatic breast cancer (mBC) remains a clinical challenge as most patients (pts) eventually have disease progression on treatment (tx). Multiple molecular mechanisms of resistance to standard-of-care drugs have been reported including mutations in ESR1 (mESR1) or PIK3CA (mPIK3CA); understanding how these affect response to subsequent tx is important. Elacestrant (RAD1901), an investigational oral selective estrogen receptor degrader (SERD), has demonstrated preclinical efficacy in pt-derived xenograft models of ER+ BC, including models harboring mESR1 and mPIK3CA. Elacestrant was evaluated in 2 phase 1 clinical trials (NCT02650817, NCT02338349) in postmenopausal women with ER+/HER2- mBC, including pts that had received multiple prior endocrine tx (median=3) and targeted tx, including CDK4/6 inhibitors (38%). Circulating tumor DNA (ctDNA) collected in these 2 trials was used to characterize the molecular features of this heavily pretreated population and correlate them with elacestrant response. Methods: ctDNA samples were collected at baseline (BL), on-tx (OT) and end-of-tx (EOT). BL samples were analyzed using the Guardant360® assay (Guardant Health) to detect genomic alterations in 73 relevant genes. Changes in BL mESR1 allele frequency of 12 single nucleotide variants (SNVs) in the ligand binding domain of ESR1 were assessed in paired OT and EOT ctDNA samples using the OncoBEAM™ platform (Sysmex Inostics). Response was assessed using RECIST v1.1. Results: Among 73 pts enrolled in these 2 trials, 57 had BL samples. At least 1 alteration was detected in 93% (n=53) of pt samples, with alterations detected in 52 of the 73 genes in the Guardant360® panel. The most frequently detected BL alterations were in ESR1 (47%) and PIK3CA (44%), with alterations in both genes observed in 21% of pts. At BL, 25% (14/57) of pt samples had >1 mESR1; the most commonly detected mESR1 were Y537S (56%), D538G (56%), and Y537N (26%). Following elacestrant tx, there was a decrease in mESR1 allele frequency in 100% of samples (11/11 mESR1 SNVs decreased OT in 9/9 pts). In paired EOT samples from pts lacking mESR1 at BL analyzed to date (N=23), 1 new mESR1 was detected in 1 pt. Among response-evaluable (RE) pts with mESR1 at BL (n=16), there were 4 partial responses (PR; 25%); clinical benefit rate (CBR) at 24 weeks (ie, stable disease + PR) in clinical benefit evaluable (CBE) pts was 52% (11/21); and median progression-free survival (mPFS) in intention-to-treat (ITT) pts was 8.6 mo. Among RE pts with mPIK3CA at BL (n=16), there were 2 PRs (13%); CBR at 24 weeks in CBE pts was 24% (5/21); and mPFS (ITT pts) was 1.9 mo. Conclusions: Relevant genomic alterations, especially in ESR1 and PI3KCA, were detected at BL in a significant proportion of heavily pretreated postmenopausal women with ER+/HER2- mBC enrolled in elacestrant phase 1 trials. Clinical benefit, including PR, was observed in pts with genomic alterations, including mESR1 and PIK3CA. Elacestrant monotherapy vs. standard of care endocrine tx is currently being studied in the phase 3 “EMERALD” study in ER+/HER2- mBC pts, including pts with mESR1, who have received 1 or 2 prior lines of endocrine tx and prior CDK4/6i (NCT03778931). Citation Format: Teeru Bihani, JungAh Jung, Hitisha K Patel, Aditya Bardia, Peter Kabos, Virginia Kaklamani, Agnes Jager, Philippe Aftimos, Sharon Wilks, Elisabeth de Vries, Wael Harb, Donald Richards, Amy Weise, Robert Wesolowski, Catharina CW Menke-van der Houven van Oordt, Paul Conkling, Patrick Neven, Maureen G Conlan. Genomic alterations detected by circulating tumor DNA and correlation with response to treatment with elacestrant, an oral selective estrogen receptor degrader, in phase 1 trials in postmenopausal women with ER+/HER2- advanced/metastatic breast cancer [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 P5-01-05.

283 Background: Cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon and rectum will account for 17% of incident cancer diagnoses and 26% of cancer-related deaths in the US in 2019. We developed a methylation-based cfDNA early multi-cancer detection test that also can predict the tissue of origin (TOO) of these and other cancers types; performance of this test for gastrointestinal (GI) tract cancers is reported here. Methods: The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, multi-center, observational, case-control study with longitudinal follow-up, enrolling individuals with cancer ( > 20 cancers, all stages, newly diagnosed) and without cancer. Plasma cfDNA was subjected to a cross-validated targeted methylation (TM) sequencing assay. Methylation fragments were combined across targeted genomic regions and assigned a probability of cancer and a predicted TOO. GI cancer classes were upper GI (esophagus/stomach, n = 67), pancreas/gallbladder/extrahepatic bile duct (n = 95), liver/intrahepatic bile duct (n = 29), and colon/rectum (n = 121). Results: Detection across all GI cancers was 82% (95% CI 77-86) at a > 99% pre-set specificity. Overall predicted TOO accuracy was 92% (88-95) among the samples for which TOO was predicted (6/255 had indeterminate predicted TOO). The table shows performance by GI cancer type. Conclusions: Simultaneous detection at high specificity ( > 99%) of multiple cancer types, including GI cancers across stages at high sensitivity (82%), was shown using TM analysis of cfDNA. Accurate (92%) localization of cancers to specific regions of the GI tract was also achieved. Detection of multiple GI cancers from a single noninvasive blood test could be a practical method for detecting GI and other cancers, and may facilitate diagnostic work-ups. Clinical trial information: NCT02889978. [Table: see text]

Background Trilaciclib (T) is an IV cyclin dependent kinase (CDK) 4/6 inhibitor and first-in-class myelopreservation agent. Previous results from this phase II trial demonstrated that adding T to GC in mTNBC resulted in: 1) a longer duration and higher administered total dose of chemotherapy, 2) higher response rates and longer PFS, and 3) reduction in the frequency of some myelosuppression events. We now report preliminary OS and updated PFS.TableLBA22TableGroup 1 GC D1, 8 n=34Group 2 Trilaciclib + GC D1, 8 n=33Group 3 Trilaciclib D1, 2, 8, 9 + GC D2, 9 n=35Group 2 + Group 3 n=68Progression-free survival (PFS)Patients with events [n (%)]18 (52.9%)19 (57.6%)18 (51.4%)37 (54.4%)Median PFS (95% CI) [months]5.7 (3.4, 9.2)9.4 (6.1, 13.0)7.3 (6.2, 12.9)8.8 (6.4, 10.9)HR0.600.590.59p-value0.12560.11670.0628Overall survival (OS)Patients with death [n (%)]19 (55.9%)11 (33.3%)14 (40.0%)25 (36.8%)Median OS (95% CI) [months]12.6 (6.3, 15.6)20.1 (10.2, NE)17.8 (12.9, NE)20.1 (15.3, NE)HR0.370.390.40p-value0.04110.00440.0032 Methods This randomized, phase II, open-label study enrolled mTNBC patients with 0-2 prior chemotherapy regimens for recurrent/metastatic disease. Patients were randomized to GC alone on day 1, 8 (Group 1) or T + GC (Group 2) or T + GC (Group 3) using an alternative schedule (T D1, 2, 8, 9 + GC D2, 9) every 21 days until disease progression or unacceptable toxicity. The primary endpoint was reduction in GC-related neutropenia. PFS and OS were secondary endpoints. Results Among 102 enrolled patients, 98 were treated. 52% had ECOG PS 0 and 37.3% received prior chemotherapy for mTNBC. Median follow-up is 10.5 months; 3 patients remain on treatment. There have been no SAEs related to T. Drug exposure in Group 2/3 patients receiving T (median 168 days, 8 cycles) is longer than with GC alone (median 101 days, 4 cycles). PFS and OS in the intent to treat (ITT) population are summarized in the table below. Groups 2+3 (receiving T) had longer PFS compared with GC alone, HR of 0.59, p=0.0628, and OS was statistically improved with HR of 0.37 and 0.39 in Groups 2 and 3, p=0.0411 and p=0.0044, respectively. ORR were 36.7%, 50.0%, and 33.3% in Groups 3, 2, and 1, respectively. Conclusions The addition of T to GC resulted in a significant increase in OS in both T groups. Previously observed PFS benefit with T was also confirmed. Clinical trial identification NCT02978716. Legal entity responsible for the study G1 Therapeutics, Inc. Funding G1 Therapeutics, Inc. Disclosure J. O'Shaughnessy: Honoraria (self): AbbVie Inc; Honoraria (self): Agendia; Honoraria (self): Amgen Biotechnology; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene Croporation; Honoraria (self): Eisai; Honoraria (self): Genentech; Honoraria (self): Genomic Health; Honoraria (self): GRAIL; Honoraria (self): Immunomedics; Honoraria (self): Heron Therapeutics; Honoraria (self): Ipsen Biopharmaceuticals; Honoraria (self): Jounce Therapeutics; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Myriad; Honoraria (self): Novartis; Honoraria (self): Ondonate Therapeutics; Honoraria (self): Pfizer. G.S. Wright: Honoraria (self): Total Health Conferencing; Shareholder / Stockholder / Stock options: Roche Holdings Ltd; Shareholder / Stockholder / Stock options: Odonate Therapeutics; Shareholder / Stockholder / Stock options: Puma Biotech; Research grant / Funding (institution), Shareholder / Stockholder / Stock options, PI does not receive direct research funding; institution received payment for conduct of trials: Macrogenics ; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: AbbVie; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Incyte; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Genentech; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Novartis; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Lilly; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Janssen; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Astellas; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Celgene; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: AstraZeneca; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Bristol-Myers Squibb; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Boehringer Ingelheim; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Medivation; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Merrimack; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Pfizer. A. Thummala: Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Comprehensive Cancer Centers of Nevada. H.S. Han: Advisory / Consultancy: Lilly; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Novartis; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Pfizer; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: TapImmune; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Seattle Genetics; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: BMS Prescient; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Horizon; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Karyopharm. S. Wilks: Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: US Oncology. J.A. Sorrentino: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics. Z. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics. J.K. Horton: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics; Honoraria (self), Research grant / Funding (self): Varian Medical Systems; Honoraria (self): Qfix; Leadership role: International Journal of Radiation Oncology, Biology, Physics; Leadership role: American Board of Radiology; Leadership role: ASTRO. A.R. Tan: Advisory / Consultancy: Celgene; Advisory / Consultancy: Immunomedics; Advisory / Consultancy, Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Merck; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: G1 Therapeutics; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Roche; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Leadership role, Breast Cancer Leader: Caris Precision Oncology Alliance. All other authors have declared no conflicts of interest.

Introduction: Eribulin mesylate is a nontaxane microtubule dynamics inhibitor that has showed an overall survival benefit relative to other commonly used agents in patients with ≥2 prior MBC therapies. Primary data from a phase 2 trial for first-line eribulin + trastuzumab [TRAS] in HER2+ patients with MBC showed an objective response rate of 71%, clinical benefit rate of 84.6%, disease control rate of 96.2%, PFS of 11.6 months, and tolerability similar to known profiles for these agents. Here, we present prespecified QoL, efficacy, and safety/tolerability results. Methods: Patients received eribulin mesylate 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle and initial TRAS (8 mg/kg IV/day 1), followed by 6 mg/kg on day 1 of each subsequent cycle. Response, PFS, QoL as measured by EORTC QoL assessment tool (QLQ-C30) and QLQ-BR23, and tolerability were assessed. Percentage of patients with at least ±10-point change from baseline was calculated at each visit. Time to deterioration was defined as time from first dose to worsening in QoL score that reached minimally clinically important difference (MID) (ie, 10 points in global health status [GHS] in QLQ-C30) without further improvement of at least MID; this was estimated overall and by response status. Results: At cycle 6 (n=44; completion rate=84.6% of 52 patients enrolled), more patients fell in the stable category (within +/-10 points change from baseline), except for pain (47.7% with improvement), cognitive functioning (45.5% worsening), fatigue and systemic therapy side effects (50% worsening for each), and arm symptoms (47.7% improvement) (Table). Median times to deterioration for GHS/QoL were 7.6 months overall (n=51), and 7.6 and 7.0 months for responders (n=36) and nonresponders (n=15), respectively (HR 0.73; 95% CI 0.32, 1.68; P=0.446). Mean symptom scores in EORTC QLQ-C30 were significantly correlated with corresponding AE rates for fatigue (r=0.31), nausea/vomiting (r=0.50), pain (r=0.41), dyspnea (r=0.49), insomnia (r=0.35), constipation (r=0.30), and diarrhea (0.40; P≤0.03 for all comparisons). The most common treatment-related AEs (all grade incidence ≥25%) were alopecia (88.5%), fatigue (69.2%), peripheral neuropathy (69.2%), neutropenia (59.6%), nausea (46.2%), diarrhea (32.7%), anemia (25%), constipation (25%), and decreased appetite (25%). Table. Qol EORTC QLQ-C30 Scores: Change from Baseline to Cycle 6 (n=44)Functional orCategory, n (%)Symptom ScaleImprovedStableWorsenedGHS/Qol13 (29.5)23 (52.3)8 (18.2)Physical10 (22.7)26 (59.1)8 (18.2)Role13 (29.5)20 (45.5)11 (25.0)Emotional17 (38.6)18 (40.9)9 (20.5)Cognitive6 (13.6)18 (40.9020 (45.5)Social12 (27.3)18 (40.9)14 (31.8)Fatigue14 (31.8)8 (18.2)22 (50.0)Nausea/vomiting9 (20.5)24 (54.5)11 (25.0)Pain21 (47.7)14 (31.8)9 (20.5)Dyspnea12 (27.3)19 (43.2)13 (29.5) Conclusions: Given the improvements in pain and in arm and breast symptoms, long median time to deterioration in functioning/symptom scales in this analysis, and the tumor response rates and safety profile in the primary analysis, combination eribulin/TRAS may be an acceptable treatment option for locally recurrent or HER2+ MBC and merits further study in larger clinical trials. Citation Format: Lee Schwartzberg, Sharon Wilks, Shannon Puhalla, Joyce O'Shaughnessy, Erhan Berrak, James Song, David Cox, Linda Vahdat. Quality of life results from a phase 2, multicenter, single-arm study of eribulin mesylate plus trastuzumab as first-line therapy for locally recurrent or metastatic HER2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-17-03.

Background: Currently, no therapies are approved specifically for EGFR-overexpressing tumors. AVID100 is a novel anti-EGFR antibody drug conjugate (ADC, DM1 payload) that was rationally designed for anti-tumor efficacy without accompanying on-target, off-tumor toxicity by employing an EGFR function-blocking antibody moiety. Although EGFR is overexpressed in a multitude of malignancies including squamous non-small cell lung cancer (sqNSCLC), head and neck carcinoma (HNSCC) and triple-negative breast cancer (TNBC), historically limited activity has been reported for EGFR monoclonal antibodies or EGFR TKIs in unselected patients. This emphasizes the need to develop novel and more efficacious agents targeting EGFR, and for biomarker- directed approaches to enrich for patients likely to respond. In pre-clinical models, AVID100 showed potent anti-tumour efficacy and a Phase 1 dose-escalation study in patients with advanced solid malignancies concluded that AVID100 was well tolerated at doses expected to be therapeutically active. An RP2D of 220 mg/m2 (~6 mg/kg) was established. Methods: This open-label, multicenter, multicohort, prospective Phase 2a study (NCT03094169) is designed to further evaluate the safety, tolerability, and preliminary efficacy of AVID100 when administered at 6 mg/kg Q3W per iv infusion in patients with locally advanced/unresectable or metastatic solid tumor malignancies of epithelial origin, and with documented EGFR over-expression. Additional endpoints include PK profiling and exploratory biomarkers. sqNSCLC and HNSCC patients with EGFR IHC of 3+ as well as mTNBC patients whose EGFR IHC shows 3+ intensity in ≥ 50% of tumor cells, or ≥ 2+ intensity in ≥ 75% of tumor cells, are eligible to enroll. Patients must have measurable disease according to RECIST v1.1 at enrolment and disease status is assessed radiographically every 6 weeks. EGFR over-expression positivity is established by a validated IHC assay (DAKO EGFRpharmDX) conducted by a central laboratory. Initial validation of the EGFR IHC was carried out retrospectively on archival tissue microarrays (US Biomax, Derwood, MD) from advanced sqNSCLC, HNSCC and TNBC patients. Results Initial validation of the EGFR IHC assay conducted with archival tissue samples yielded EGFR 3+ positivity in ≥ 50% of tumor cells for 30% (32 out of 105 samples tested) of sqNSCLC and 22% (31 out of 140) of HNSCC samples. Among TNBC samples tested, 6% were EGFR 3+ in ≥ 50% of tumor cells and 25% EGFR 2 or 3+ in ≥ 50% of tumor cells (16 and 62 out of 249, respectively). The prospective Phase 2a trial assessing AVID100 in patients selected for EGFR overexpression was is actively accruing and one sqNSCLC, four SCCHN and three TNBC patients had been enrolled at time of writing. Conclusions A significant proportion of retrospectively assessed sqNSCLC, HNSCC and TNBC patient samples were found to overexpress the EGFR. The prospective Phase 2a trial assessing AVID100, a novel growth factor receptor function-blocking anti-EGFR ADC, remains ongoing and updated results will be presented at the meeting. Citation Format: Jason Melear, Nehal Lakhani, Joyce A O'Shaughnessy, Sharon T Wilks, Saad Khan, Sree R Chandana, Anthony W Tolcher, Kyri P Papadopoulos, Yvette Cole, Karla Rivas, Ria Ghosh, Sandra Sinclair, Robert Lutz, Paul I Nadler, Debra L Wood, Barbara Burtness. Novel anti-EGFR antibody-drug conjugate AVID100: A phase 2a trial in patients with EGFR-overexpressing advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A088. doi:10.1158/1535-7163.TARG-19-A088

200 Background: Real-world practice patterns often differ from treatment in clinical trials. We assessed real-world standard-of-care treatment with palbociclib (PAL) in the context of previously reported PALOMA trial results. Methods: POLARIS is a prospective, observational study of PAL in patients (pts) with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. Baseline demographics, clinical characteristics, initial treatment dose, dose modifications, dose delays, and adverse events (AEs) during the first 6 months (mo) of treatment were analyzed. Results: 412 pts enrolled at 92 US sites had at least 6 mo of PAL treatment; 73% received PAL in the first-line setting and 27% in second or later line. While a majority of pts received the recommended dose of 125 mg/d; 6% and 1% started at 100 mg and 75 mg, respectively. Physician-reported reasons for choosing a lower dose were: comorbidities (31%), pt age (21%), past treatment (10%), patient preference (3%), and other (34%). Selected pt and clinical characteristics, dosing, and treatment outcomes in POLARIS and in PALOMA-2 are shown in Table. Conclusions: In a real-world data set of 6 mo of PAL treatment, most pts started at the recommended dose, with tolerability and safety outcomes consistent with those reported in clinical trials. Differing populations, treatment patterns, and outcome reporting in real world vs trial settings underscore the need to study real-world practices and outcomes. Clinical trial information: NCT03280303 [Table: see text]

Background: Activation of the PI3K/mTOR pathway is thought to be involved in resistance to TRAS. BOLERO-3 is a randomized phase 3, double-blind, placebo-controlled, international, clinical trial evaluating the addition of the mTOR inhibitor EVE (5 mg/day) to TRAS plus vinorelbine (25 mg/m2) in patients with HER2+ advanced breast cancer resistant to TRAS and who were previously treated with a taxane. A total of 569 adult women were randomized 1:1 to receive EVE (n = 284) or PBO (n = 285). Study treatment represented the 2nd, 3rd, or 4th line of chemotherapy-containing regimen for 83% of patients in the metastatic setting. The primary endpoint, progression-free survival based on local radiologic assessment, was significantly longer in the EVE arm versus PBO (HR = 0.78; P = .0067) at a median follow-up of 20 months. Methods: Study drugs were continued until disease progression or unacceptable toxicity. Incidences of adverse events (AEs) were monitored continuously. Dose modifications and discontinuations were recorded. Results: The median duration of exposure to study treatment was similar across treatment groups: 24.8 weeks for EVE, 25.1 weeks for TRAS, and 24.0 weeks for vinorelbine (EVE arm); and 22.9 weeks for PBO, 24.0 weeks for TRAS, and 23.1 weeks for vinorelbine (PBO arm). The AEs were consistent with known drug-safety profiles. Class-effect AEs with mTOR inhibitors (including stomatitis, rash, noninfectious pneumonitis, and hyperglycemia) were higher in the EVE arm and were mainly grade 1/2. Grade 3 class-effect AEs each occurred in Conclusions: The safety of the combination of EVE, TRAS, and vinorelbine was considered manageable in this heavily pretreated patient population. Overall, the results from BOLERO-3 demonstrate that EVE can be combined with TRAS and chemotherapy to improve efficacy in TRAS-resistant HER2+ advanced breast cancer previously treated with a taxane. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-15-03.

Background: Eribulin mesylate, a non-taxane microtubule dynamics inhibitor, has been approved for patients with metastatic breast cancer (MBC) who have previously received ≥2 chemotherapeutic regimens for MBC. We present final data from a phase 2 study that evaluated efficacy and safety of eribulin + trastuzumab as first-line therapy for locally recurrent or metastatic human epidermal growth factor receptor 2 positive (HER2+) BC. Methods: Patients received eribulin mesylate at 1.4 mg/m2 IV on days 1 and 8 of each 21-day cycle and an initial trastuzumab dose of 8 mg/kg IV on day 1, followed by 6 mg/kg on day 1 of each subsequent cycle. Endpoints include objective response rate (ORR), safety, progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 6-12 weeks thereafter per RECIST 1.1. Results: Fifty-two patients with a median age of 60 years (range 31- 81) were treated; 96% had stage IV disease, 73% had visceral disease, and 48% had liver metastases. Thirty one patients had prior neo/adjuvant chemotherapy (11 had prior anthracycline, and 22 had prior taxane). Patients received a median of 10(0, 33) cycles of eribulin and 11(1, 31) cycles of trastuzumab. ORR was 67% with median TTR of 1.3 months and PFS of 11.5 months (Table). The most common (>5%) Grade 3/4 treatment related treatment emergent (TRTE) AEs were neutropenia (n = 20; 38.5%), peripheral neuropathy (n = 14; 26.9%) and febrile neutropenia (n = 4; 7.7%). Serious TRTE AEs occurred in 14 patients and included neutropenia (n = 9; 17.3%), febrile neutropenia (n = 4; 7.7%), and peripheral neuropathy (n = 3; 5.8%). Reasons for discontinuation were AEs (n = 7) and PD (n = 22). Table. Summary of Efficacy EndpointsEfficacy EndpointsEribulin/Trastuzumab N = 52Objective Response Rate, n (%)35 (67)- Complete Response (CR)2 (4)- Partial Response (PR)33 (64)Stable Disease (SD)15 (29)Progressive Disease (PD)1 (2)Not Evaluable1 (2)Overall Clinical Benefit Rate, n (%)42 (81)Time to First Objective Response, median months (95% CI)1.3 (1.2, 1.4)Duration of Objective Response, median months (95% CI)a11.1 (6.5, 17.8)Progression-Free Survival, median months (95% CI)11.5 (7.3, 13.5)Duration of Stable Disease, median months (95% CI)7.1 (5.2, 13.5)Clinical Benefit Rate = ORR+ ≥6 mo SD; an = 35 Conclusions: This study suggests that the combination of eribulin + trastuzumab first-line therapy for locally recurrent or metastatic HER2+ BC has an acceptable safety profile and results in considerable tumor response with a long DOR. Additional larger studies with this combination are warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-12.

Background: Activation of the PI3K/mTOR pathway is implicated in resistance to trastuzumab. Accordingly, the BOLERO-3 study evaluated the efficacy of adding everolimus (EVE), an mTOR inhibitor, to vinorelbine and trastuzumab. At the final progression-free survival (PFS) analysis, EVE significantly improved PFS vs PBO (hazard ratio [HR] = 0.78; log-rank P = .0067) but EVE-treated patients had higher rate of grade 3/4 toxicity. To further qualify the benefit:risk of adding EVE to trastuzumab-based therapy, per-protocol, patient-reported, health-related quality-of-life (HRQoL) data were analyzed. Methods: BOLERO-3 is a randomized phase 3, double-blind, placebo-controlled, international multicenter trial. Taxane-pretreated patients (N = 569) with trastuzumab-resistant, HER2+, advanced breast cancer were randomized (1:1) to treatment with EVE or placebo (PBO) plus vinorelbine and trastuzumab. The European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire C30 (QLQ-C30) (including the breast cancer-specific BR23 module) was administered at baseline and every 6 weeks thereafter until progression. The QLQ-C30 consists of 30 items combined into 15 subscales, including Global Health Status and functional subscales, where higher scores (range, 0 to 100) indicate better HRQoL. Time to definitive deterioration (TTD) based on a 10% decrease from baseline for GHS and for the physical, emotional, and social function subscales was determined using the Kaplan-Meier method. Treatment arms were compared using a 2-sided log-rank test stratified by prior use of lapatinib. Results: Overall, there was no significant difference in median TDD of HRQoL between treatment arms. The median TTD in global health status score was 8.3 months for EVE (95% confidence interval [CI], 6.9-11.5) vs 7.3 months for PBO (95% CI, 5.6-10.4; P = .8386). The median TTD in the physical, emotional, and social function subscale scores showed no significant difference between arms. For example, median TTD in the physical function subscale score was 12.0 months (95% CI, 8.3-14.1) for EVE vs 12.5 months (95% CI, 8.3-20.9) for PBO (P = .4251), and median TTD in the emotional function subscale score was 15.2 months (95% CI, 9.2-17.3) for EVE vs 12.5 months (95% CI, 9.7-16.4) for PBO (P = .8140). Conclusions: These analyses demonstrate that, despite increased frequency of adverse events observed with the addition of EVE to the standard treatment of vinorelbine and trastuzumab, overall and functional HRQoL scores were not negatively impacted in patients with trastuzumab-resistant, HER2+, advanced breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-18.

Purpose Two recent phase III trials, BOLERO-1 and BOLERO-3 (Breast Cancer Trials of Oral Everolimus), evaluated the addition of everolimus to trastuzumab and chemotherapy in human epidermal growth factor receptor 2–overexpressing advanced breast cancer. The current analysis aimed to identify biomarkers to predict the clinical efficacy of everolimus treatment. Methods Archival tumor samples from patients in BOLERO-1 and BOLERO-3 were analyzed using next-generation sequencing, immunohistochemistry, and Sanger sequencing. Results Biomarker data were available for 549 patients. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 samples and in 32% and 12% of BOLERO-3 samples, respectively. PI3K pathway was hyperactive (PIK3CA mutations and/or PTEN loss and/or AKT1 mutation) in 47% of BOLERO-1 and 41% of BOLERO-3 samples. In both studies, differential progression-free survival (PFS) benefits of everolimus were consistently observed in patient subgroups defined by their PI3K pathway status. When analyzing combined data sets of both studies, everolimus was associated with a decreased hazard of progression in patients with PIK3CA mutations (hazard ratio [HR], 0.67; 95% CI, 0.45 to 1.00), PTEN loss (HR, 0.54; 95% CI, 0.31 to 0.96), or hyperactive PI3K pathway (HR, 0.67; 95% CI, 0.48 to 0.93). Patients with wild-type PIK3CA (HR, 1.10; 95% CI, 0.83 to 1.46), normal PTEN (HR, 1.00; 95% CI, 0.80 to 1.26), or normal PI3K pathway activity (HR, 1.19; 95% CI, 0.87 to 1.62) did not derive PFS benefit from everolimus. Conclusion This analysis, although exploratory, suggests that patients with human epidermal growth factor receptor 2–positive advanced breast cancer having tumors with PIK3CA mutations, PTEN loss, or hyperactive PI3K pathway could derive PFS benefit from everolimus.

Background: Eribulin mesylate, a novel non-taxane microtubule dynamics inhibitor, has been approved for patients with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for MBC. This study evaluates efficacy and safety of eribulin + trastuzumab (TRAZ) as first-line therapy for human epidermal growth factor receptor 2 positive (HER2+) locally recurrent or MBC. Methods: Patients received eribulin mesylate at 1.4 mg/m2 IV on days 1, 8 and TRAZ initial dose of 8 mg/kg IV on day 1 every 21 days, followed by 6 mg/kg on day 1 of each subsequent cycle. For study inclusion, patients could have been previously treated with TRAZ, but at least 12 months should have passed since any prior neoadjuvant or adjuvant chemotherapy was used. Endpoints include objective response rate (ORR) (primary), safety, progression free survival (PFS), time to response (TTR), and duration of response (DOR). Tumor assessments are evaluated every 6 weeks for the first 6 cycles and every 6–12 weeks thereafter per RECIST 1.1. Results: Updated results presented here as of June 1, 2012; 37 of 52 planned patients have been treated. Patient characteristics are as follows: median age: 58 years (range, 31–81), 70% have luminal subtype, 95% are stage IV disease, and 73% have visceral disease, 46% had prior neo/adjuvant, 22% had prior anthracycline and 32% had prior taxane, 35% had original diagnosis of MBC. Patients received median of 7 (1,20) cycles for eribulin and 9 (1,23) cycles for TRAZ. The most common treatment related AEs are reported in Table 1. Treatment-related serious AEs were reported for 4 (11%) patients; neutropenia 3 (8%) and febrile neutropenia 2 (6%) patients each. Eight patients have discontinued treatment due to disease progression (PD). Best patient responses are found in Table 2. Conclusions: Based on the updated preliminary results of this Phase II study, the combination of eribulin + trastuzumab as first-line therapy for HER2+ locally recurrent or MBC appears to demonstrate an acceptable safety profile with considerable tumor responses, including in patients with ER/PR+ disease. Accrual is ongoing and study completion is anticipated prior to SABCS 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-04.

Background In our original doxorubicin-cyclophosphamide/docetaxel-cyclophosphamide (AC/TC) adjuvant study (JCO 27: 1177–1183, 2009), we reported an incidence of febrile neutropenia (FN) of 5% (8% in women ≥65 years) with the TC regimen without prophylactic WBC growth factors but with a recommendation for prophylactic antibiotics. There is a paucity of data on the incidence of FN with the TC regimen aside from this clinical trial. Because we have been conducting a randomized adjuvant study of TC compared to other regimens, we used this opportunity to analyze the incidence of FN during the first course of chemotherapy with TC in the first cohort of randomized patients (US Oncology Network study 06090). The prophylactic use of WBC growth factors was at the investigator's discretion. Patients and Methods The study included 1298 patients entered between May 2007 and May 2009. Of these, 649 were included in the TC arm. Median age was 54 years (range 27–71), 75.5% were Caucasian, 561 (86.4%) were in PS 0 at baseline, and about half were node negative. Eight patients did not receive study treatment for various reasons. Among the 641 patients who received TC; 213 (33.3%) received pegfilgrastim, 48 (7.5%) received filgrastim and were not included in this analysis, and 380 (59.2%) patients did not receive either during the first cycle. Thus, this analysis focused on 593 women who did or did not receive prophylactic pegfilgrastim in cycle 1. Results: All patients with a reported adverse event of FN or with a reported AE of fever with some degree of neutropenia (in order to capture all possible cases of FN) during the first cycle of TC were identified [Table 1]. FN and fever + neutropenia occurred in a total of 6 (2.8%) patients who received pegfilgrastim and 36 (9.5%) patients who did not. A comparison of age, race, performance status and stage of disease between these 2 groups revealed that they were similar. The 213 patients who received pegfilgrastim were slightly older (median 56 years, range 27–71) compared to those who did not (median 53 years, range 30–71). During all 6 cycles, 41 patients reported FN, and 30 (73%) of these patients experienced FN during cycle 1. Conclusion: Among 593 women who received TC as adjuvant chemotherapy, the incidence of FN during the first cycle was under 10% whether or not the patients received prophylactic pegfilgrastim. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-09.

Introduction: Ixabepilone adds to the antitumor effectiveness of capecitabine in both ER+ and triple negative (TN) breast cancer. Ixabepilone has antitumor activity in taxane-refractory patients, and novel combinations are needed in this poor prognosis population. Carboplatin combined with gemcitabine or paclitaxel has activity in metastatic breast cancer; there is also demonstrated activity of the gemcitabine/carboplatin combination in the ER+ versus TN subsets. A Phase I study of ixabepilone + carboplatin in solid tumor patients demonstrated the safety of this combination.1 We conducted a Phase II trial of ixabepilone + carboplatin at the doses and schedule used in the Phase I trial to determine its effectiveness in hormone receptor positive (HR+) and TN patients. Methods: This was a Phase II, open label, nonrandomized parallel, noncomparative study of 2 groups. Patients could have received up to 2 lines of treatment for metastatic disease. All patients received ixabepilone 20 mg/m2 on Days 1 and 8 and carboplatin AUC=2.5 on Days 1 and 8 of each 21-day cycle. Patients were stratified as either (HR+) (n=50) or (TN) ER-/PR-/HER2− (n=53). Patients received drug until PD or intolerable toxicity. Patients continued treatment for as long as they responded (CR, PR, or SD). The primary objective was to evaluate objective response rate (ORR). Secondary objectives included evaluation of clinical benefit rate (CBR) defined as ORR (CR+PR)+SD≥6 months, progression-free survival (PFS), overall survival (OS), duration of responses, and toxicity. Results: Based on preliminary data, 96 patients (55 [57.3%] HR+ and 40 [41.7%] TN) received study treatment, with 1 patient found ineligible. Median age was 55.2 years; all were females; baseline PS of 0/1/2 was 50/44/2; stage at diagnosis I/II/III/IV/unknown was 12/38/23/21/2, respectively. PR was 26.3% overall. There were no CRs. CBR overall was 41.1% (39), 52.7% (29) for HR+ patients, and 25.6% (10) for TN patients. Median PFS was 7.6 months, and median OS was 12.7 months. The median time to response and duration of response in patients achieving a PR was 1.7 and 6.5 months, respectively. Grade 3/4 hematological toxicities included 49% neutropenia, 10.4% anemia, and 4.2% thrombocytopenia. The most common grade 3/4 non-hematologic toxicities included fatigue (8.3%), nausea (6.3%), neuropathy (6.3%), vomiting (5.2%), and dehydration (5.2%). Of 32 deaths during the study, one was due to neutropenic sepsis, and 25 were due to PD. Conclusion: The combination of ixabepilone plus carboplatin was a tolerable and active regimen for both HR+ and TN breast cancer. In general, it had expected hematologic and manageable non-hematological toxicities. Further follow-up of the remaining 12 patients still on treatment is ongoing. 1. Plummer R, et al. Clin Cancer Res. 2008 Dec 15;14(24):8288–8294. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-09.

Tamoxifen significantly reduces the risk of developing breast cancer in women at increased-risk. The usefulness of tamoxifen has been limited by its side effect profile, especially its propensity to worsen vasomotor symptoms. Hormone therapy (HT) has long been utilized to reduce vasomotor symptoms in peri- and post-menopausal women. The aim of this study was to compare the incidence of hot flashes, weight gain and other side effects associated with taking tamoxifen alone versus tamoxifen in combination with HT in high-risk women. One hundred eighty high-risk women were enrolled into one of two parallel study cohorts to receive tamoxifen alone (93 women) or tamoxifen with HT (87 women). Women were monitored at baseline, 3 months and then yearly for assessments of menopausal symptoms and toxicities associated with tamoxifen alone versus tamoxifen plus HT. We also assessed for differences in menopausal symptoms and toxicities by type of HT (estrogen vs. estrogen and progestin combination). Hot flash scores increased at 3 months and at 1 year compared with baseline in women on tamoxifen alone as well as for women on HT. Women on tamoxifen with estrogen only replacement had the greatest increase in hot flash scores, although this was not significantly different than the increase seen with tamoxifen alone. About 47% of participants on tamoxifen gained weight and there was a strong trend towards less weight gain in women on the combination of tamoxifen and HT, most pronounced for those on tamoxifen with estrogen alone replacement therapy. The addition of HT to tamoxifen therapy does not ameliorate tamoxifen-induced vasomotor symptoms. Tamoxifen associated weight gain, however, may be lessened by the addition of HT.

Summary Background Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab. Methods In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m 2 ) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov, number NCT01007942. Findings Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20·2 months (IQR 15·0–27·1). Median PFS was 7·00 months (95% CI 6·74–8·18) with everolimus and 5·78 months (5·49–6·90) with placebo (hazard ratio 0·78 [95% CI 0·65–0·95]; p=0·0067). The most common grade 3–4 adverse events were neutropenia (204 [73%] of 280 patients in the everolimus group vs 175 [62%] of 282 patients in the placebo group), leucopenia (106 [38%] vs 82 [29%]), anaemia (53 [19%] vs 17 [6%]), febrile neutropenia (44 [16%] vs ten [4%]), stomatitis (37 [13%] vs four [1%]), and fatigue (34 [12%] vs 11 [4%]). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group. Interpretation The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population. Funding Novartis Pharmaceuticals Corporation.

In this multicenter, phase II, single-arm study, 52 patients with recurrent or metastatic HER2-positive (D) breast cancer received first-line eribulin with trastuzumab. The objective response rate (ORR) was 71.2% (n [ 37) with a median time to first response (TTR) of 1.3 months; duration of response (DOR) and progressionfree survival (PFS) were 11.1 and 11.6 months, respectively. Eribulin/trastuzumab combination resulted in a substantial tumor response with an acceptable safety profile. Background: The aim of this study was to assess efficacy and safety of eribulin with trastuzumab as first-line therapy for locally recurrent or metastatic HER2þ breast cancer. Patients and Methods: In this multicenter, phase II, singlearm study, patients with recurrent or metastatic HER2þ breast cancer received eribulin mesylate at 1.4 mg/m 2 intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary end point was ORR, and secondary end points included PFS, TTR, DOR, and safety. Results: Fifty-two patients were enrolled. Fifty-one patients (98.1%) had metastatic disease, 25 (48.1%) with liver metastases, 24 (46.2%) with lung metastases, and 19 (36.5%) with bone metastases. Patients received a median of 10.0 cycles of eribulin and 11.0 cycles of trastuzumab. The ORR was 71.2% (n ¼ 37) with median TTR of 1.3 months, DOR of 11.1 months, and PFS of 11.6 months. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 20 (38.5%) patients, peripheral neuropathy in 14 (26.9%; all Grade 3) patients, fatigue in 4 (7.7%) patients, and febrile neutropenia in 4 (7.7%) patients. Conclusions: Because of the high ORR, prolonged median PFS, and acceptable safety profile, combination eribulin/trastuzumab is an acceptable treatment option for locally recurrent or metastatic HER2þ breast cancer.

Background: The current study explores T-cell (TC) clonality and molecular factors associated with this metric. Tumors employ multiple mechanisms to evade antitumor immune responses. One process involves TC inhibition via upregulation of immune checkpoint (IC) ligands in the tumor microenvironment (TME). Gradual upregulation of inhibitory receptor at their cellular surface results in a decreased capacity to proliferate and activate cytotoxic pathways against tumor cells presenting antigenic peptides.1 In melanoma, this subset of exhausted TCs has been described as highly clonal, where the majority of PD-1-expressing TC population shares the same TCR sequence specific against the same antigenic fragment.2 Previous studies have demonstrated that a clonal TCR repertoire appears to be associated in part with therapeutic responses during IC blockade.3 Methods: We performed TCR sequencing on 82 blood and 73 archival tumor tissue samples collected from ED SCLC patients (pts) in an ongoing longitudinal cohort study in US community oncology practices. Of these, 82 blood and 48 tissue samples had sufficient material available to quantify a clonality metric. To quantify TC abundance as a fraction of total nucleated cells, 82 blood and 58 tissue samples had sufficient material available. Results: Within the subset of 48 tumor samples, a more clonal (ie, less diverse) TCR repertoire was associated with less necrosis (P≤0.012) and lower levels of inflammatory cell infiltration in the local TME (P≤0.021). When pts were divided into 2 equal groups according to the median clonality level, pts with a less clonal TCR repertoire (n = 24/48) who were treated with non-immune-targeted therapy trended toward a longer overall survival (OS; 446 vs 301 days; P≤0.039). In contrast, the percentage of TCs in the TME did not correlate with improved survival (P≤0.412), necrosis (P≤0.131), and inflammation (P≤0.615). This observation differs from results in melanoma describing the impact of IC blockade where pts responding to therapy were associated with a more clonal TME TC population and increased CD8 TCs in the tumor compartment and at the invasive margin.3 In blood, while a less clonal TCR repertoire was associated with a similar but non-significant trend toward longer survival (P≤0.148), pts with increased TC abundance had longer OS (P≤0.025). No association was observed between clonality in TME and clonality (P≤0.571) or TC abundance (P≤0.965) in blood. Conclusion: We hypothesize that a diverse TCR repertoire in the TME and increased peripheral TC abundance are 2 predictors of longer OS in ED SCLC. To further explore factors that may influence TC responses in ED SCLC, the current TCR sequencing results will be integrated with transcriptome and whole genome sequencing analyses. References 1. Wherry EJ. Nat Immunol. 2011;12:492-99. 2. Gros A, et al. J Clin Invest. 2014;124:2246-59. 3. Tumeh PC, et al. Nature. 2014;515:568-71. Citation Format: Maen Hussein, Sharon Wilks, Marc Monte, Donald A. Richards, Jerome H. Goldschmidt, David Waterhouse, Lisu Wang, Saumya Pant, Erik Yusko, Ryan O. Emerson, Darin M. Taverna, Kaushal Desai, Spyro Mousses, Zhenhao Qi, Jason D. Hipp, Harlan Robins, Kimary Kulig, Cory Batenchuk. Characterization of the T-cell receptor (TCR) repertoire in extensive disease small cell lung cancer (ED SCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4159.

6018Background: BB503 (BBI-503) is an oral first-in-class cancer stemness kinase inhibitor. By targeting multiple serine-threonine stemness kinases, BB503 inhibits Nanog and other cancer stemness p...

e12550Background: GR is highly expressed in TNBC and is associated with a poor prognosis in estrogen receptor-negative (ER-) early stage breast cancer. Treatment with MIFE potentiates the effects of chemotherapy (ctx) in TNBC xenografts. Here we describe the results of an ongoing trial including outcomes to date in all patients with GR+ TNBC treated at the recommended Phase 2 dose (RP2D). Objectives: To determine the safety, tolerability, pharmacokinetics (PK) and clinical activity of the MIFE+E combination in pts with GR+ TNBC at the RP2D. Methods: Eligibility: Phase 1, pts with solid tumors; Phase 2, pts with GR+ TNBC; up to 5 prior ctx regimens for advanced disease; ECOG PS 0-1; adequate end-organ function. Design: 3 + 3 dose escalation scheme. After a 7-day lead-in of oral daily MIFE alone, MIFE was continued daily and E was given on days 1 and 8 of a 21-day cycle. Results: 16 pts with metastatic breast cancer were enrolled in Phase 1 (3 with GR+ TNBC). MTD/RP2D was MIFE 300 mg/day + E 1.1 mg/m2. To d...

68 Background: Managing chemotherapy-induced nausea and vomiting (CINV) associated with delayed ( > 24-120 h) highly emetogenic chemotherapy (HEC) is an unmet need. APF530, extended-release granisetron, provides sustained release over ≥ 5 days to prevent acute (0-24 h) and delayed CINV. This trial compared the efficacy and safety of APF530 in preventing CINV after HEC in a 3-drug regimen vs a standard 3-drug regimen with ondansetron (Ond). Methods: In this double-blind, multicenter study (NCT02106494), patients (pts) receiving single-day HEC (2011 ASCO guidelines) were randomized 1:1 to APF530 500 mg SC (10 mg granisetron) or Ond 0.15 mg/kg IV and stratified by cisplatin ( ≥ 50 mg/m2, yes/no). Pts were scheduled to receive concomitant dexamethasone (Dex) 12 mg IV + fosaprepitant (Fos) 150 mg IV on day 1 + PO Dex on days 2-4. The primary end point was delayed-phase complete response (CR) (no emesis, no rescue medication). Secondary end points included CR in acute and overall phases and complete control (CC; CR and no more than mild nausea) in acute, delayed, and overall phases. Treatment (tx) comparisons used chi-square test controlling for cisplatin. Adverse events (AEs) and injection-site reactions (ISRs) were assessed. Results: Modified intent-to-treat analysis included 902 pts (APF530, n = 450; Ond, n = 452) with baseline demographics balanced between tx groups. A significantly higher % of APF530 (65%) vs Ond (57%) pts had delayed-phase CR (P= .014). A significantly higher % of APF530 (61%) vs Ond (53%) pts had delayed-phase CC (P= .022, Table). CR and CC rates in acute and overall phases were numerically higher with APF530 vs Ond, but not statistically significant. APF530 was well tolerated. Most common AEs were ISRs, mostly mild or moderate. Conclusions: APF530 with Fos+Dex led to statistically higher CR and CC rates in delayed-phase CINV with HEC vs a standard 3-drug regimen of Ond with Fos+Dex. Clinical trial information: NCT02106494. [Table: see text]

TPS1106 Background: Treatment of mTNBC is an unmet clinical need. First-line nab-P with gem or carbo/bevacizumab has demonstrated efficacy and safety in female patients (pts) with mTNBC. nab-P sign...