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PDF file - 30K, Estimated maximal concentration (Cmax) and total area under the concentration-time curve (AUClast) of total and free oxaliplatin with and without vismodegib

PDF file - 25K, A comparison of steady-state 5-FU concentrations with and without vismodegib co-treatment

Supplemental Section for Resubmission - Clean Version

PDF file - 33K, Estimated maximal concentration (Cmax) and total area under the concentration-time curve (AUClast) of irinotecan (and metabolites SN-38 and SN-38G) with and without vismodegib

Figure S2 displays a graph of the plasma concentrations of total docetaxel for patients dosed with 60/mg/m2 of BIND-014 on the Q3W schedule.

PDF file - 25K, A comparison of serum concentrations of bevacizumab with and without vismodegib co-treatment

PDF file - 57K, A summary of primer/probes used for qRT-PCR profiling of Hh pathway genes

Purpose: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).Experimental design: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.Results: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89–1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43–60) and 46% (90% CI: 37–55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.Conclusions: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy. Clin Cancer Res; 19(1); 258–67. ©2012 AACR.

Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)–targeted nanoparticle, containing docetaxel.Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m2 and 15 to 45 mg/m2, respectively.Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non–small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors.Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m2 every three weeks or 40 mg/m2 weekly. Clin Cancer Res; 22(13); 3157–63. ©2016 AACR.

PDF file - 24K, A comparison of vismodegib steady-state plasma concentrations (Css) between patients receiving FOLFOX and FOLFIRI

PDF file - 61K

The maximum tolerated dose of the panobinostat and carfilzomib combination in patients with relapsed/refractory multiple myeloma (RRMM) was not reached in our previous dose-escalation study. We report additional dose levels in the phase I/II, single-arm, multicenter, standard 3+3 dose-escalation expansion-cohort study (NCT01496118). Patients with RRMM were treated with panobinostat 30 mg, carfilzomib 20/56 mg/m2 (N = 3), or panobinostat 20 mg, carfilzomib 20/56 mg/m2 (N = 33). Treatment cycles lasted 28 days; panobinostat: days 1, 3, 5, 15, 17, 19; carfilzomib: days 1, 2, 8, 9, 15, 16. For dose level 6 (DL 6), median age was 63 years (range, 49-91 years), 60.6% were male, 42.4% were high risk. Patients received a median of two prior therapies (range 1-7); proteasome inhibitors (PI; 100%), immunomodulatory imide drugs (IMiD; 78.8%), and stem cell transplant (36.4%); 48.5%, 51.1% , and 24.2% were refractory to prior PI or prior IMiD treatment or both, respectively. Patients completed a median of seven (range 1-40) treatment cycles. Overall response rate (primary endpoint) of evaluable patients in the expansion cohort (N = 32): 84.4%; clinical benefit rate: 90.6%. With a median follow-up of 26.1 months (range, 0-72.5 months), median (95% CI) progression-free survival, time-to-progression and overall survival of patients was 10.3 (6.1, 13.9), 11.7 (5.6, 14.5), and 44.6 (20.8, N/A) months, respectively. Common adverse events (AEs) included thrombocytopenia (78.8%), nausea (63.6%), fatigue (63.6%), diarrhea (51.5%), and vomiting (51.5%). Seven patients had serious treatment-related AEs. There was one treatment-related death. In conclusion, panobinostat plus carfilzomib is an effective steroid-sparing regimen for RRMM. This article is protected by copyright. All rights reserved.

Purpose: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer. Patients and Methods: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. Results: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Conclusions: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.

Aim Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using '3 + 3' dose escalation. Methods In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non-small-cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent. Results Fifty of 68 enrolled patients received imalumab. The most common treatment-related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose-limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients). Conclusions Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.

Background: The recent introductions of pertuzumab (P) and neratinib (N) have made counseling patients with HER2-positive breast cancer (BC) regarding the potential benefits of various adjuvant systemic regimens more complex and challenging. The HER RISK initiative was conceived as a novel means to support adjuvant therapy decision-making by providing input from BC clinical investigators (CIs). Methods: 30 CIs were recruited to provide numeric estimates of the potential benefit in 5-year disease-free survival (DFS) of various adjuvant therapeutic regimens and postadjuvant N for 24 HER2-positive BC scenarios along with their likely treatment recommendations. 50 community-based oncologists (CBOs) were then recruited and asked to provide the same estimates for 4 of the scenarios evaluated. They were then shown the responses from the CIs and asked to provide their perspectives on this information and its potential value as an educational resource. A modest honorarium was provided to CI and CBO participants. Results: There was a clear relationship between projected benefit of adding P or N and use of these agents in the 4 situations evaluated (Table). More than two thirds of CIs believe P improves DFS in cases with 2 positive nodes, and most generally recommend its inclusion in adjuvant therapy. However, for the 2 node-negative cases, CIs perceived the benefit of adding P to be minimal or absent and generally did not recommend this treatment. The numeric estimates and practice patterns of the CBOs were similar to those of the CIs, but P was perceived to be somewhat more beneficial by CBOs and was used more frequently in the node-negative scenarios. In terms of the decision to recommend postadjuvant N, CI responses strongly correlated with ER and nodal status. Almost all stated that N would provide benefit for a patient with ER-positive disease and 2 positive nodes and indicated that they would generally recommend N in that setting. CIs’ perceived benefit of N in the node-negative cases was minimal or absent, with few recommending it even for the ER-positive scenarios. N is commonly recommended by CBOs in the node-positive scenario — similar to the CIs — but more of these clinicians perceive a benefit to N in the node-negative cases and recommend its use. When asked whether they obtained clinical value from reviewing these types of estimates, 48 CBOs (96%) found the information useful and 34 (68%) stated that having access to it was likely to affect their practices. 45 CBOs (90%) would share the 5-year DFS estimates and treatment recommendations from the CIs with interested patients if available in an online format. Conclusions: The numeric estimates and practice patterns of CIs and CBOs were generally similar for the scenarios presented, but both P and N were perceived to be somewhat more beneficial and were used more frequently by CBOs than CIs in node-negative cases. Even in node-positive cases, CIs and CBOs estimated the benefit of P and N to be modest but in many cases sufficient to warrant their use. For both groups, there was a clear relationship between the estimated benefit of therapy and its use. CBOs found value in the graphical presentation of the CI estimates and practice patterns and would use them as part of patient counseling. The next phase of this ongoing project will evaluate whether integrating this information into shared decision-making is feasible and beneficial for CBOs. Case scenarioUse of pertuzumab (P)CI (N = 30)CBO (N = 50)Median 5-year DFS estimate w/chemo/TIncr Ben = 0Incr Ben > 0Median 5-year DFS estimate w/chemo/TIncr Ben = 0Incr Ben > 0(%)(No.)(No.)(%)(No.)(No.)ER-, 2+ nodes8212980248MED: 3%MED: 5%(1 uses P)(26 use P)(2 use P)(45 use P)ER+, 2+ nodes8562480446MED: 2%MED: 5%(3 use P)(21 use P)(3 use P)(40 use P)ER-, N-, 1.6-2.0-cm tumor941812901139MED: 1%MED: 3%(0 use P)(2 use P)(0 use P)(11 use P)ER+, N-, 1.6-2.0-cm tumor95246901238MED: 1%MED: 3%(0 use P)(2 use P)(0 use P)(13 use P)Use of neratinib (N) after chemo/TER-, 2+ nodes821515801931MED: 3%MED: 3%(0 use N)(4 use N)(2 use N)(14 use N)ER+, 2+ nodes8532780248MED: 3%MED: 3%(0 use N)(18 use N)(0 use N)(35 use N)ER-, N-, 1.6-2.0-cm tumor94264902030MED: 2%MED: 2%(0 use N)(1 uses N)(0 use N)(4 use N)ER+, N-, 1.6-2.0-cm tumor951713901139MED: 2%MED: 3%(0 use N)(1 uses N)(1 uses N)(16 use N)CI = clinical investigator; CBO = community-based oncologist; DFS = disease-free survival; chemo/T = chemotherapy/trastuzumab; Incr Ben = incremental benefit (pertuzumab added to chemo/T, neratinib after adjuvant chemo/T); MED = median estimated incremental benefit; N- = node-negative Citation Format: Neil Love, Sara A Hurvitz, Hope S Rugo, Lowell Hart, Gloria Kelly, Kirsten Miller, Trenton Cruse, Douglas Paley, Jonathan Moss, Kathryn Ziel. Evaluating the potential utility of presenting breast cancer clinical investigator estimates for numeric treatment benefit and recommendations for the use of two anti-HER2 adjuvant therapies: HER RISK [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 P1-18-23.

Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [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 P2-13-02.

Purpose: Standard-of-care treatment for metastatic hormone receptor–positive (HR+), HER2-negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i. Patients and Methods: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis. Results: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1–51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported. Conclusions: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.

Purpose Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. Methods Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. Results Overall, 103 women were enrolled [median age 60 years (range 34–83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0–3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. Conclusions Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination. ClinicalTrials.gov number NCT02091960

Chemotherapy-related amenorrhea (CRA) is a surrogate for ovarian toxicity and associated risk of infertility and premature menopause. Here, we compare CRA rate with paclitaxel (T)-trastuzumab (H) to that with ado-trastuzumab emtansine (T-DM1). Patients with T1N0 HER2 + early-stage breast cancer (eBC) enrolled on the ATEMPT trial and were randomized 3:1 to T-DM1 3.6 mg/kg IV every (q) 3 weeks (w) × 17 vs. T 80 mg/m2 with H IV qw × 12 (4 mg/kg load → 2 mg/kg), followed by H (6 mg/kg IV q3w × 13). Enrollees who self-reported as premenopausal were asked to complete menstrual surveys at baseline and every 6–12 months for 60 months. 18-month CRA (no periods reported during prior 6 months on 18-month survey) was the primary endpoint of this analysis. Of 512 ATEMPT enrollees, 123 who began protocol therapy and answered baseline and at least one follow-up menstrual survey were premenopausal at enrollment. 76 had menstrual data available at 18 months without having received a gonadotropin-releasing hormone agonist or undergone hysterectomy and/or oophorectomy. Median age was 45 (range 23–53) among 18 who had received TH and 46 (range 34–54) among 58 who had received T-DM1. The 18-month rate of CRA was 50% after TH and 24% after T-DM1 (p = 0.045). Amenorrhea at 18 months was less likely in recipients of adjuvant T-DM1 than TH. Future studies are needed to understand how T-DM1 impacts risk of infertility and permanent menopause, and to assess amenorrhea rates when T-DM1 is administered after standard HER2-directed chemotherapy regimens.

Introduction Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). Methods In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1–5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy. Results Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P

Background This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients. Methods In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction. Results Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72-96% (60th percentile) and 97-100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis. Conclusions This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs. Trial registration MONALEESA-2 (NCT01958021) first posted October 8, 2013; MONALEESA-3 (NCT02422615) first posted April 21, 2015; MONALEESA-7 (NCT02278120) first posted October 29, 2014.

Purpose Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). Methods A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection. Results Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m2 dose would induce a 40–50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m2 administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m2 but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m2 doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m2 was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03. Conclusion Integrated PK/PD, safety, and efficacy data support 240 mg/m2 as the RP2D for trilaciclib. ClinicalTrials.gov Identifiers NCT02243150; NCT02499770; NCT02514447.

Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy‐induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double‐blind, placebo‐controlled Phase II study in patients with newly diagnosed extensive‐stage small cell lung cancer (ES‐SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count

Background: Ribociclib (ribo) + letrozole (LET) demonstrated efficacy and safety in first-line treatment of patients (pts) with hormone receptor–positive (HR+), HER2− advanced breast cancer (ABC). Most endocrine therapy (ET)–naive pts with de novo ABC respond to ET, but first-line monotherapy with ET or fulvestrant elicited only moderate efficacy in the FALCON study of pts with visceral metastases (mets). Visceral mets are associated with poor prognosis and may warrant novel treatment options in addition to ET. Here, we present clinical outcomes of treatment with ribo in pts with de novo ABC and visceral mets. Methods: In the MONALEESA-2 study, postmenopausal women with HR+, HER2− ABC (N=668) were randomized (1:1) to receive either ribo 600 mg/d or placebo (3 wk on/1 wk off) + LET 2.5 mg/d (continuous). The primary endpoint was median progression-free survival (mPFS). Results: All pts in this analysis (n=227) had de novo ABC; 108 pts had visceral mets (ribo, n=53; placebo, n=55). Baseline characteristics were similar between the ribo and placebo groups. The median follow-up time was 26.4 months. In pts with visceral mets, mPFS was significantly higher in the ribo group (30.3 months) than in the placebo group (14.1 months; hazard ratio, 0.52; 95% CI, 0.295–0.905; P=0.019). Rates of PFS in these pts in the ribo vs placebo group, respectively, were 76% vs 60% at 12 months and 60% vs 36% at 24 months. Among the pts with visceral mets, clinical benefit rate (CBR) was 79% vs 71% in the ribo vs placebo group, and overall response rate (ORR) in pts with measurable disease at baseline was 55% vs 46%, respectively. In pts without visceral mets (ribo, n=61; placebo, n=58), PFS rates in the ribo vs placebo group, respectively, were 87% vs 72% at 12 months and 66% vs 51% at 24 months. Safety results were consistent with the overall population, and responses were durable with ribo + LET irrespective of whether the pts had visceral or nonvisceral mets. Conclusions: Clinical outcomes from this analysis of the MONALEESA-2 study are consistent with those of the overall population, and ribo + LET prolonged the mPFS and improved ORR and CBR in pts with de novo ABC with visceral mets vs placebo + LET. Citation Format: O'Shaughnessy JA, Arteaga CL, Hart LL, Lindquist DL, Beck JT, Purkayastha DD, Caria N, Hortobagyi GN. Treatment benefit of ribociclib + letrozole in patients with de novo disease and visceral metastases from the MONALEESA-2 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-01.

Background: In the MONALEESA (ML) trials, addition of ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) to endocrine therapy (ET) prolonged progression-free survival (PFS) in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). RIB was generally well tolerated, with adverse events (AEs) managed effectively by dose modifications. Here we present efficacy data for RIB-based regimens of interest for the proposed indication (i.e. with a non-steroidal aromatase inhibitor [NSAI] or fulvestrant [FUL]) from ML-2, -3, and -7 in pts who received no prior ET for ABC and who had ≥1 RIB dose reduction, to explore the efficacy of RIB in pts who need to dose reduce. Methods: Pts included in this analysis were: postmenopausal women with HR+, HER2– ABC and no prior ET for ABC who received RIB (600 mg; 3-weeks-on/1-week-off) with letrozole (2.5 mg/day; ML-2 [NCT01958021]), or FUL (500 mg per label; ML-3 [NCT02422615]); and premenopausal women with no prior ET and ≤1 line of chemotherapy for ABC who received RIB with an NSAI (anastrozole: 1 mg/day; letrozole: 2.5 mg/day; ML-7 [NCT02278120]) plus goserelin (3.6 mg every 28 days). Dose reductions for RIB (600 to 400 to 200 mg) were permitted. Primary endpoint was PFS. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), and safety. Results: In ML-2, -3, and -7, ≥1 RIB dose reduction occurred (n/N) in 169/334 (51%), 92/238 (39%), and 91/246 (37%) pts assigned to RIB, respectively. AEs were the main reason for dose reduction, with all-grade neutropenia the most common AE leading to dose reduction (ML-2 69%, ML-3 80%, ML-7 82%). Median PFS (months) was prolonged with RIB vs placebo in pts without a RIB dose reduction (ML-2: 27.7 vs 16.0; ML-3: not reached [NR] vs 18.3; ML-7: 23.8 vs 13.8); median PFS in pts with ≥1 RIB dose reduction was: ML-2 25.3, ML-3 NR, and ML-7 27.5 months. In pts with measurable disease and without a RIB dose reduction, ORR was 46% (ML-2), 43% (ML-3), and 48% (ML-7); CBR was 70%, 68%, and 79%, respectively. In pts with measurable disease and ≥1 RIB dose reduction, ORR was 62% (ML-2), 57% (ML-3), and 55% (ML-7); CBR was 88%, 85%, and 88%, respectively. The most common Grade 3/4 AEs in the RIB vs placebo groups (≥5% of pts in either ML trial, irrespective of causality or dose reduction) were neutropenia (ML-2: 62% vs 1%; ML-3: 55% vs 0; ML-7: 65% vs 4%), leukopenia (ML-2: 21% vs 1%; ML-3: 12% vs 0; ML-7: 16% vs 1%), hypertension (ML-2: 13% vs 13%; ML-3: 5% vs 5%; ML-7: 2% vs 3%), increased alanine aminotransferase (ML-2: 10% vs 1%; ML-3: 10% vs 0; ML-7: 5% vs 1%), and increased aspartate aminotransferase (ML-2: 6% vs 1%; ML-3: 6% vs 0; ML-7: 4% vs 1%). Conclusions: Results from the ML-2, -3, and -7 trials suggest that pts who start on 600 mg of RIB and require dose reduction for the management of their AEs, or for other reasons, continue to derive clinical benefit. Citation Format: Beck JT, Neven P, Sohn J, Chan A, Sonke GS, Bachelot T, Campos-Gomez S, Martin M, Bardia A, Alam J, Miller M, Diaz-Padilla I, Kong O, Hart L. Ribociclib treatment benefit in patients with advanced breast cancer with ≥1 dose reduction: Data from the MONALEESA-2, -3, and -7 trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-06.

1017 Background: The phase 3 ML-2, -3, and -7 trials all demonstrated consistent and statistically significant OS benefit with RIB (starting dose: 600 mg/d 3 wk on/1 wk off) vs PBO in pts with HR+/HER2− ABC. RIB dose mod (reductions and/or interruptions) when needed did not impact OS benefit with RIB + endocrine therapy (ET) in previous analyses of ML-3/-7. Here we present data on the effect of RIB dose mod on OS in postmenopausal pts with HR+/HER2− ABC in ML-2. Methods: ML-2 (NCT01958021) enrolled postmenopausal pts randomized 1:1 to first-line RIB + letrozole (LET) or PBO + LET. Landmark (LM) analyses of OS were performed to evaluate the association between dose reductions (yes vs no) and OS. Multiple LM times were considered to determine the sensitivity of the findings. As an alternative to LM analysis, a Cox proportional hazards model with a time-varying covariate was performed. Two time-dependent variables, dose reduction (with/without mod from 600 mg starting dose) and relative dose intensity 2 (RDI2), were included in the respective model as covariates to explore the association with OS. To account for differences in time to first dose mod, RDI2 reflects the post–dose mod period. Median (m) OS was obtained using a modified Kaplan-Meier method. Results: At data cutoff (June 10, 2021; m follow-up, 49.35 [range, 0-86.7] mo), 209 of 334 pts (62.6%) had ≥ 1 RIB dose reduction and 125 of 334 (37.4%) had 0 RIB dose reduction. LM analyses by dose reduction are presented (Table). mOS was 66.0 (95% CI, 57.6-75.7) mo in pts with ≥ 1 RIB dose reduction vs 60.6 (95% CI, 42.5-79.2) mo in pts with no RIB dose reductions (HR, 0.87 [95% CI, 0.65-1.18]). RDI2 was classified according to tertile: low (< 64.27%), medium (64.27%-95.86%), and high (> 95.86%). In pts with low, medium, and high RDI2, mOS was 62.6 (95% CI, 50.0-80.7) mo, 63.9 (95% CI, 48.8-not reached [NR]) mo, and 65.3 (95% CI, 50.5-NR) mo, respectively (HR low vs high, 0.99 [95% CI, 0.69-1.42]; HR medium vs high, 0.97 [95% CI, 0.62-1.38]). Conclusions: In this exploratory analysis of ML-2, OS benefit was maintained in pts with HR+/HER2− ABC who required mod from the recommended starting dose of RIB (600 mg/d 3 wk on/1 wk off). No relationship was observed between OS and RIB dose reduction or RDI2; OS benefit with RIB was observed in all groups. Clinical trial information: NCT01958021. [Table: see text]

8568 Background: Trilaciclib is a short-acting CDK4/6 inhibitor administered prior to chemotherapy for multilineage myeloprotection. Reduced occurrence of chemotherapy-induced myelosuppression (CIM) events across neutrophil, red blood cell, and platelet lineages was reported in 3 Phase 2 clinical trials of trilaciclib versus placebo in patients with extensive-stage small cell lung cancer (ES-SCLC). In this post-hoc trial analysis, we further assessed the impact of trilaciclib on the occurrence of single and concurrent multilineage CIM events. Methods: Analyses were conducted separately by line of chemotherapy. In the first-line (1L) setting, pooled data from the G1T28-05 and G1T28-02 trials, in which trilaciclib or placebo was administered prior to etoposide, carboplatin, and atezolizumab [E/P/A] and E/P, respectively, were used. In the 2/3L setting, analyses were based on data from the G1T28-03 trial where patients received trilaciclib or placebo prior to topotecan. The proportion of patients with single and concurrent multilineage CIM events and incidence rate were estimated per cycle and during the first 4 cycles of chemotherapy. Severe (grade ≥ 3 per CTCAE definition) CIM events of neutropenia (SN), anemia (SA), and thrombocytopenia (ST) were assessed. Concurrent CIM events were defined as having 2 or 3 lineage-specific CIM events overlap for ≥ 1 day. As sensitivity analyses, the occurrence of CIM events in patients with ES-SCLC receiving 1L treatment in the G1T28-05 and G1T28-02 studies was analyzed separately. Results: Compared with placebo, fewer patients receiving trilaciclib had single-lineage CIM events and concurrent events in 2 or 3 lineages during cycles 1–4 of 1L chemotherapy using pooled data from G1T28-05 and G1T28-02 (Table). A similar trend was observed in the 2/3L setting. Generally, SN occurred more frequently in earlier cycles, whereas SA and ST tended to occur later. The sensitivity analysis in each individual 1L trial yielded consistent results with the pooled analysis. Conclusions: Patients with ES-SCLC receiving trilaciclib prior to chemotherapy had fewer single and concurrent multilineage CIM events than patients receiving placebo. Clinical trial information: NCT03041311, NCT02499770, NCT02514447. [Table: see text]

Background The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single‐arm, open‐label phase 2 study. Methods Eligible patients with platinum‐treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28‐day cycles in a 3‐stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate. Results Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent‐to‐treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose‐normalized maximum serum concentration [Cmax] after TIW dosing of 0.2 ng/mL/mg). Conclusions To the authors’ knowledge, the current study represents the first clinical trial using genomic‐based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting., After the genomic‐based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, single‐agent mocetinostat appears to be associated with significant toxicities that limit drug exposure. This may have contributed to the limited activity noted in the current phase 2 study (response rate of 11%) among heavily pretreated patients with platinum‐refractory disease.

Background Lapatinib is an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor that crosses the blood–brain barrier and is active against central nervous system (CNS) metastases. Cabazitaxel is a taxoid that is effective against taxane-resistant metastatic breast cancer (MBC) and has distinguished itself by its ability to cross the blood–brain barrier. The present phase II study ( ClinicalTrials.gov identifier, NCT01934894 ) evaluated the combination of these agents to treat HER2+ MBC patients with CNS metastases. Materials and Methods Patients with HER2+ MBC and ≥ 1 untreated or progressive, measurable CNS metastasis were eligible. Using a 3+3 dose escalation design, patients were treated with escalating doses of intravenous cabazitaxel every 21 days and oral lapatinib daily in 21-day treatment cycles. Intracranial disease restaging was performed every 2 cycles for the first 8 cycles and then every 3 cycles until progression or unacceptable toxicity. Results Eleven patients were treated at 2 dose levels. Six patients were treated at dose level 1 (intravenous cabazitaxel 20 mg/m2 plus oral lapatinib 1000 mg daily), and five were treated at dose level 2 (intravenous cabazitaxel 25 mg/m2 plus oral lapatinib 1000 mg daily). The most common treatment-related adverse events were myelosuppression, diarrhea, fatigue, and skin toxicity. A total of 5 dose-limiting toxicity events occurred. No intra- or extracranial objective responses were observed. Conclusion The combination of cabazitaxel plus lapatinib was not feasible because of toxicity and because no objective CNS activity was seen in the 5 evaluable patients. The role of cabazitaxel to treat breast cancer patients with CNS metastases remains undefined.

Background: Endocrine-based therapy is the standard of care for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), in whom delaying disease progression is the primary goal. In the randomized Phase 3 MONALEESA-2 study (ClinicalTrials.gov identifier, NCT01958021), first-line ribociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) + letrozole significantly prolonged progression-free survival (PFS) compared with placebo + letrozole in postmenopausal women with HR+, HER2− ABC (hazard ratio, 0.556; 95% confidence interval [CI], 0.429–0.720) at the interim analysis cutoff date. Here, we present safety and efficacy data from US patients who were enrolled in the MONALEESA-2 study. Methods: Postmenopausal women (N=668) with HR+, HER2− ABC who did not receive prior systemic treatment for ABC and had an Eastern Cooperative Oncology Group performance status score of ≤1, adequate bone marrow and organ function, and no history of active cardiac dysfunction were randomized 1:1 to receive either ribociclib (600 mg/d, 3 weeks on/1 week off) + letrozole (2.5 mg/d, continuous) or placebo + letrozole. The primary end point was locally assessed PFS. The data cutoff for this analysis was January 29, 2016. Results: Baseline demographics, patient disposition, and prior therapy were well balanced across treatment groups in the US subset (N=213; ribociclib group, n=100; placebo group, n=113). Median treatment duration was 16.3 months. In US patients, median PFS was significantly prolonged in the ribociclib group (median PFS, not reached [NR]; 95% CI, 17.1 months to NR) versus the placebo group (median PFS, 14.4 months [95% CI, 11.1–18.4 months]; hazard ratio, 0.451 [95% CI, 0.281–0.724]; P=0.000363), with a median follow-up of 11.0 months. In a subsequent preplanned analysis of overall survival, median PFS was 27.6 months in the ribociclib group versus 15.0 months in the placebo group (hazard ratio, 0.527; 95% CI, 0.351–0.793). The overall response rate (ORR) was significantly greater in the ribociclib group (ORR, 38.0%; 95% CI, 28.5–47.5%) versus the placebo group (ORR, 26.5%; 95% CI, 18.4–34.7%; P=0.040). A trend toward benefit was observed with ribociclib in all subgroups (including age, disease burden, prior therapy, and biomarker status), which was consistent with the overall population. No on-treatment deaths occurred. The most common all-grade adverse events, irrespective of causality, were neutropenia (ribociclib, 69.0%; placebo, 3.7%), nausea (ribociclib, 65.0%; placebo, 39.4%), fatigue (ribociclib, 56.0%; placebo, 46.8%), and diarrhea (ribociclib, 41.0%; placebo, 32.1%). The most common grade 3 (≥25% in either group) and grade 4 (≥10% in either group) AE was neutropenia (grade 3: ribociclib, 39.0%; placebo, 0%; grade 4: ribociclib, 14.0%; placebo, 0%). Two patients (2.0%) in the ribociclib group and none in the placebo group experienced febrile neutropenia. Conclusions: The US patients in the MONALEESA-2 study derived significant PFS benefit from ribociclib + letrozole compared with placebo + letrozole, with a 55% reduction in the relative risk of disease progression. The safety profile was consistent with and comparable to the global study population. Citation Format: Yardley DA, Hart L, Favret A, Blau S, Diab S, Richards D, Sparano J, Beck JT, Richards P, Ward P, Ramaswamy B, Tsai M, Pluard T, Tolaney S, Esteva F, Small T, Purkayastha D, Miller M, Hortobagyi G. Efficacy and safety of ribociclib plus letrozole in US patients enrolled in the MONALEESA-2 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 P5-21-27.

This abstract was not presented at the symposium.

Background: The androgen receptor (AR) is expressed in >75% of hormone receptor (HR)+ tumors. AR signaling has been associated with resistance to endocrine therapy (ET). Aromatase inhibitors (AIs) divert estrogen precursors to androgens; in preclinical models enzalutamide (ENZA) blocked both estrogen- and androgen-mediated growth of HR+ cells. In a phase 1 study of ET+ENZA in breast cancer, doubling the dose of exemestane (EXE) to 50 mg was necessary to restore exposure observed with 25 mg.1 Methods: This placebo (PBO)–controlled phase 2 trial randomized patients (pts) with HR+/HER2-normal advanced/metastatic breast cancer (MBC) to either 25 mg EXE+PBO or 50 mg EXE+160 mg ENZA daily (NCT02007512). Two parallel cohorts enrolled pts who had no prior ET (C1) or who had received 1 prior ET for MBC (C2). Randomization was stratified on resistance to prior ET and prior exposure to AI. Tissue samples for biomarker development were mandatory. Brain metastases or a history of seizure was exclusionary. One prior chemotherapy regimen for MBC was permitted. Response was assessed every 8 weeks for 48 weeks, then every 12 weeks. Crossover to ENZA+EXE was allowed at disease progression. A gene signature–based biomarker (Bmkr) indicating AR signaling predictive of response to ENZA was developed using a training set of RNAseq data from 2/3 of randomized pts and validated using a test set of data from the remaining 1/3 of pts. Progression-free survival (PFS) according to RECIST v1.1 was the primary endpoint in the intent-to-treat (ITT) population and in the Bmkr+ subgroup of each cohort. Secondary endpoints included clinical benefit rate at 24 weeks (CBR24), best overall response, and safety. Results: A total of 247 pts were randomized (C1, n=127; C2, n=120). In C1, 50 pts (39.4%) were Bmkr+; in C2, 35 pts (29.2%) were Bmkr+. Statistically significant improvements in median PFS and CBR24 were observed only in the Bmkr+ population with no prior ET (Table). The most common adverse events (AEs) reported in the ENZA+EXE arms were nausea (39%) in C1 and fatigue (37%) in C2. In C1, 9 pts (15%) and 10 pts (16%) discontinued the study due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. In C2, 11 pts (18%) and 5 pts (8%) discontinued due to AEs in the ENZA+EXE and PBO+EXE arms, respectively. Conclusions: In the first reported randomized trial of ENZA in HR+ MBC, ENZA+EXE was well tolerated with no new safety signals. The study met its primary endpoint in pts with Bmkr+ MBC with no prior ET. 1. Schwartzberg et al. Clin Cancer Res. 2017 Mar 9 [Epub ahead of print]. C1: No Prior ETC2: 1 Prior ET ITTBmkr+ITTBmkr+EXE+ENZA | PBOENZA | PBOENZA | PBOENZA | PBO n=63 | n=64n=24 | n=26n=60 | n=60n=15 | n=20Primary endpointPFS, median, months11.8 | 5.816.5 | 4.33.6 | 3.96.0 | 5.3(95% CI)(7.3, 15.9) | (3.5, 10.9)(11.0, NR) | (1.9, 10.9)(1.9, 5.5) | (2.6, 5.4)(2.3, 26.7) | (1.8, 6.7)Hazard ratio0.820.441.020.55(95% CI)(0.54, 1.26)(0.21, 0.96)(0.66, 1.59)(0.23, 1.36)P value0.36310.03350.92120.1936Secondary endpointCBR24, n (%)39 (62) | 29 (45)20 (83) | 10 (38)12 (20) | 19 (32)6 (40) | 6 (30)(95% CI)(49, 74) | (33, 58)(63, 95) | (20, 59)(11, 32) | (20, 45)(16, 68) | (12, 54)P value0.06090.00120.14430.5374 Citation Format: Krop I, Abramson V, Colleoni M, Traina T, Holmes F, Estevez L, Hart L, Awada A, Zamagni C, Morris P, Schwartzberg L, Chan S, Wheatley D, Gucalp A, Biganzoli L, Steinberg J, Gianni L, Trudeau M, Tudor IC, Markova D, Barry E, Tarazi J, Stewart R, Winer E, Yardley DA. Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive 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 GS4-07.

Purpose Determine the efficacy and safety of first-line ribociclib plus letrozole in patients with de novo advanced breast cancer. Methods Postmenopausal women with HR+ , HER2− advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021). Patients were randomized to ribociclib (600 mg/day; 3 weeks-on/1 week-off) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was investigator-assessed progression-free survival; predefined subgroup analysis evaluated progression-free survival in patients with de novo advanced breast cancer. Secondary endpoints included safety and overall response rate. Results Six hundred and sixty-eight patients were enrolled, of whom 227 patients (34%; ribociclib plus letrozole vs placebo plus letrozole arm: n = 114 vs. n = 113) presented with de novo advanced breast cancer. Median progression-free survival was not reached in the ribociclib plus letrozole arm versus 16.4 months in the placebo plus letrozole arm in patients with de novo advanced breast cancer (hazard ratio 0.45, 95% confidence interval 0.27–0.75). The most common Grade 3/4 adverse events were neutropenia and leukopenia; incidence rates were similar to those observed in the full MONALEESA-2 population. Ribociclib dose interruptions and reductions in patients with de novo disease occurred at similar frequencies to the overall study population. Conclusions Ribociclib plus letrozole improved progression-free survival vs placebo plus letrozole and was well tolerated in postmenopausal women with HR+, HER2− de novo advanced breast cancer.

Purpose Determine the efficacy and safety of first-line ribociclib plus letrozole in elderly patients with HR+, HER2− advanced breast cancer. Methods 668 postmenopausal women with HR+, HER2− advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021); 295 patients were aged ≥ 65 years. Patients were randomized to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was PFS, which was evaluated in elderly (≥ 65 years) and younger ( 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm in both subgroups; most events were grade 1/2. In elderly patients, grade 1/2 anemia and fatigue were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm and discontinuation rates were similar in both arms. Conclusions Addition of ribociclib to letrozole is a valid therapeutic option for elderly patients with HR+, HER2− advanced breast cancer in the first-line setting.

This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. Sixty-seven patients received TAK-228 6–40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1. TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months. TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors. NCT01351350.

Purpose The Letrozole (Femara) Versus Anastrozole Clinical Evaluation (FACE) study compared the efficacy and safety of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor (HR) –positive and node-positive early breast cancer (eBC). Methods Postmenopausal women with HR-positive and node-positive eBC were randomly assigned to receive adjuvant therapy with either letrozole (2.5 mg) or anastrozole (1 mg) once per day for 5 years or until recurrence of disease. Patients were stratified on the basis of the number of lymph nodes and human epidermal growth factor receptor 2 status. The primary end point was 5-year disease-free survival (DFS), and the key secondary end points were overall survival and safety. Results A total of 4,136 patients were randomly assigned to receive either letrozole (n = 2,061) or anastrozole (n = 2,075). The final analysis was done at 709 DFS events (letrozole, 341 [16.5%]; anastrozole, 368 [17.7%]). The 5-year estimated DFS rate was 84.9% for letrozole versus 82.9% for anastrozole arm (hazard ratio, 0.93; 95% CI, 0.80 to 1.07; P = .3150). Exploratory analysis showed similar DFS with letrozole and anastrozole in all evaluated subgroups. The 5-year estimated overall survival rate was 89.9% for letrozole versus 89.2% for anastrozole arm (hazard ratio, 0.98; 95% CI, 0.82 to 1.17; P = .7916). Most common grade 3 to 4 adverse events (> 5% of patients) reported for letrozole versus anastrozole were arthralgia (3.9% v 3.3%, and 48.2% v 47.9% for all adverse events), hypertension (1.2% v 1.0%), hot flushes (0.8% v 0.4%), myalgia (0.8% v 0.7%), dyspnea (0.8% v 0.5%), and depression (0.8% v 0.6%). Conclusion Letrozole did not demonstrate significantly superior efficacy or safety compared with anastrozole in postmenopausal patients with HR-positive, node-positive eBC.

Background: In MONALEESA-2, -3, and -7, ribociclib plus endocrine therapy (ET) prolonged progression-free survival (PFS) versus placebo plus ET in women with hormone receptor-positive, HER2– advanced breast cancer (ABC). This pooled analysis of the MONALEESA studies further evaluated the safety of ribociclib plus ET and provides insight into the efficacy of ribociclib based on dose intensity (DI). Methods: Data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET), and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy (PFS, overall response rate [ORR], and clinical benefit rate [CBR]) was analyzed according to ribociclib relative dose intensity. Safety was analyzed in all patients and those with and without ≥1 ribociclib dose reduction. Findings: The adverse event (AE) profile in the 1066 and 823 women in this analysis who received ribociclib plus ET and placebo plus ET, respectively, was consistent with previous reports. All-grade neutropenia (74% vs 5%) and nausea (45% vs 27%) were the most common AEs with ribociclib vs placebo, and neutropenia was the most frequent grade 3/4 AE (60% vs 2%). Across MONALEESA-2, -3 and -7, 41.8% of patients (range, 32.8% to 54.5%) required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median ribociclib relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3, and 98.0% and 66.3% in MONALEESA-7. Median PFS was 24.8, 24.9, and 29.6 months for patients who received 30th, 60th, and 90th percentile ribociclib relative DI, respectively, with a numerically higher ORR observed in the lowest relative DI group. Interpretation: This analysis confirms the safety profile of ribociclib plus ET in women with HR+/HER2– advanced breast cancer and demonstrates that the clinical benefit of ribociclib is preserved when dose modifications are undertaken to manage AEs. Trial Registration: MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), MONALEESA-7 (NCT02278120) Funding Statement: MONALEESA-2, -3, and -7 were supported by Novartis Pharmaceuticals Corporation. Declaration of Interests: Dr. Burris reports consulting or advisory for AstraZeneca, Bristol-Myers Squibb, FORMA Therapeutics, Janssen, MedImmune, Mersana, Novartis, Roche/Genentech, TG Therapeutics; grants from AbbVie, Agios, AstraZeneva, Bayer, BioMed Valley Discoveries, Boehringer Ingleheim, Bristol-Myers Squibb, Celgene, Celdex, CytomX Therapeutics, eFFECTOR Therapeutics, Gilead Sciences, GlaxoSmithKline, Immunocore, Incyte, Janssen, Jounce Therapeutics, Lilly, Loxo, Macrogenics, MedImmune, Merck, Mersana, Milennium, Moderna Therapeutics, Novartis, Pfizer, PTC Therapeutics, Roche/Genentech, Seattle Genetics, Takeda, Tarveda Therapeutics, Tesaro, TG Therapeutics, Valent Technologies, Vasastern, Vertex; Dr. Chan has nothing to disclose; Dr. Bardia reports consulting or advisory for Immunomedics, Pfizer, Novartis, Genentech/Roche, Merck, Radius Health, Spectrum Pharma, Taiho Pharma, Biothernostics Inc., Sanofi, Daichi Pharma, Puma; personal fees from Biothernostics Inc., Pfizer, Novartis, Genentech/Roche, Merck, Radius Health, Immunomedics, Spectrum Pharma, Taiho Pharma, Sanofi, Daiichi Pharma, Puma; grants from Genentech/Roche, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Mersana, Innocrin, Biothernostics Inc.; Dr. Beck has nothing to disclose; Dr. Sohn has nothing to disclose; Dr. Neven has nothing to disclose; Dr. Tripathy reports consulting or advisory for Novartis, Pfizer, Genomic Health, GlaxoSmithKline; personal fees from Novartis, Pfizer, Genomic Health, GlaxoSmithKline; research grant from Novartis; Dr. Im reports consulting or advisory for AstraZeneca, Novartis, Hanmi, Pfizer, Eisai, Amgen, MediPacto, Genentech/Roche, Lilly; personal fees from AstraZeneca, Novartis, Hanmi, Pfizer, Eisai, Amgen; MediPacto, Genentech/Roche, Lilly; grants from AstraZeneca, Pfizer, Genentech/Roche; Dr. Chia reports consulting or advisory for Novartis, Pfizer, Hoffman LaRoche, Eli Lilly; personal fees from Novartis, Pfizer, Hoffman LaRoche, Eli Lilly; Dr. Esteva reports consulting or advisory for Novartis, Pfizer, Genentech/Roche, Celltrion Healthcare, Seattle Genetics; personal fees from Novartis, Pfizer, Genentech/Roche, Celltrion Healthcare, Seattle Genetics; grants from Novartis, Pfizer, GlaxoSmithKline, Genentech/Roche; Dr. Hart reports consulting or advisory for Novartis; personal fees from Novartis; grants from Novartis; Dr. Zarate reports employment and stock ownership from Novartis; Dr. Antonia Ridolfi reports employment and stock ownership from Novartis; Dr. Rodriguez-Lorenc reports employment and stock ownership from Novartis; Dr. Yardley reports consulting or advisory for Biothernostics Inc., Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Eisai, Genentech/Roche, NanoString Technologies, Novartis; personal fees from Biothernostics Inc., Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Lilly, Eisai, Genentech/Roche, NanoString Technologies, Novartis; grants from Daiichi Sankyo, Lilly, Eisai, Novartis, Abbvie, AstraZeneca, Clovis Oncology, Immunomedics, InventisBio, Lilly, MedImmune, Medivation, Merck, Oncothyreon, Pfizer, Syndax, Tesaro. Ethics Approval Statement: All studies were conducted in accordance with Good Clinical Practice guidelines and the provisions of the Declaration of Helsinki. The institutional review board at each participating center reviewed the protocol and any amendments, and all patients provided written informed consent.

Background Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. Patients and methods This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. Results A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). Conclusion Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. Clinical Trail number NCT02499770.

e15080 Background: Olaparib, rucaparib, and niraparib are 3 poly-ADP-ribose polymerase inhibitors (PARPi) approved by the FDA for ovarian, breast, pancreatic, prostate, fallopian tube and peritoneal cancers with BRCA mutations. Several ongoing clinical trials aim to determine the efficacy of PARPi in various other cancer types, including specific cancer subtypes, such as clear cell renal cell carcinoma and cholangiocarcinoma either as monotherapy or combination therapy; however, eligibility for PARPi therapy requires the identification of the primary tumor type and confirmation of BRCA mutation. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor types and subtypes for metastatic patients with unknown or uncertain diagnoses. Multimodal biomarker testing, including next-generation sequencing (NGS), enables identification of actionable biomarkers to guide targeted therapy selection. In the current study, a database of metastatic cases that integrates tumor type with biomarker analysis was characterized to identify those eligible for PARPi treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of cases submitted for CancerTYPE ID testing with tissue-guided multimodal biomarker testing by NGS, including tumor mutational burden (TMB) fluorescent in situ hybridization (FISH), and microsatellite instability (MSI), and immunohistochemistry (IHC) (NeoTYPE profiles, Neogenomics). For the current study, metastatic cancers classified as ovarian, breast, pancreatic, or prostate were identified in the database, followed by NGS analysis to detect mutations in BRCA1 or BRCA2. Results: The current analysis included 2151 CancerTYPE ID cases, from which 71 ovarian, 47 breast, 12 pancreatic and 15 prostate cancer cases were identified. Out of 46 cases of ovarian cancer with molecular biomarker results, NGS identified 7 (15.3%) cases with BRCA1 mutation and 4 (8.7%) cases with BRCA2 mutation. Additionally, 4 (10.5%) cases with BRCA1 mutation and 1 (2.6%) case with BRCA2 mutation out of 38 cases of breast cancer with BRCA results were detected. No cases of prostate cancer or pancreatic cancer with mutations in BRCA1 or BRCA2 were detected. Conclusions: These findings in metastatic patients demonstrate the clinical utility of tumor type identification combined with molecular biomarker profiling, leading to additional options for patients with advanced disease. Specifically, analysis of the MOSAIC database identified a subset of patients with metastatic cancers eligible for PARPi therapy based on tumor type and BRCA mutation status. As new and approved PARPi are evaluated for efficacy in additional tumor types, patients can be identified that may be eligible for these targeted cancer drugs.

4110 Background: PEN-221 is a small molecule drug conjugate composed of a SSTR2 binding somatostatin analog linked to the toxin DM1. PEN-221-001 was a study which assessed the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-221 in well differentiated neuroendocrine tumors (NETs) and small cell lung cancer. Here we present the efficacy outcomes for patients enrolled in the GI mid-gut cohort and the safety data for the entire study. Methods: Pts with advanced, SSTR2+ (by imaging) GI mid-gut NETs were enrolled in this cohort of the study. The primary objective was to determine the safety and efficacy of PEN-221 given intravenously, every (q) 3 weeks in patients with documented radiographic progression within the 6 months prior to enrollment. Patients previously treatment with cytotoxic chemotherapy were excluded. Preliminary efficacy was assessed using RECIST 1.1. A clinically meaningful efficacy result was defined as a Clinical Benefit Rate (CBR) > 75% and a median progression-free survival (mPFS) > 8 months. Results: 32 patients (17M/15F) were enrolled between January 2018 to June 2020 and the data cut-off for this report is July 31, 2020. The first nine patients were treated at the phase 1 determined Maximum Tolerated Dose of 18 mg. After review of the safety, tolerability, and PK data from these pts, the regimen was amended to 8.8 mg/m2 for all subsequent pts to achieve more uniform exposures (AUC) across all pts and reduce toxicity in pts with lower body-surface areas (BSA). The mean number of cycles received by pts in this cohort was 7 (range 1-18), with 5 pts still on treatment at time of data lock. PEN-221 was well tolerated in all pts at the dose of 8.8 mg/m2. The most frequent (≥20% pts) PEN-221 related adverse events of any grade were fatigue (39%), nausea (38%), diarrhea (35%), decreased appetite (30%), infusion reaction (24%), AST/ALT/Alk Phos increase (24%), and peripheral neuropathy (21%). Only 14 (10%) of these events were grade 3 or greater. Grade 3 PEN-221 related adverse events which were reported in 2 or more pts included fatigue (7.6%), ALT/AST/Alk Phos increase (7.6%), and peripheral neuropathy (3%). PEN-221 plasma median t1/2 was ̃4.5 h, with exposures uniform using BSA based dosing. Of the 26 pts who were evaluable for response, 23 (88.5%) had stable disease (SD) reported as their best response with a CBR of 88.5%. Target lesion shrinkage was observed in 10 (38%) patients. The median PFS for this cohort was 9 months (CI 5 – 16.5 months). Tumor marker data (Neuron Specific Enolase, Chromogranin A, 5-Hydroxyindoleacetic Acid, and Circulating Tumor Cells) will also be presented. Conclusions: PEN-221 appears well tolerated at 8.8 mg/m2 q 3 weeks and has demonstrated efficacy exceeding its clinical efficacy goals with a CBR of 88.5% and a mPFS of 9 months. A randomized trial of PEN-221 in GI mid-gut NET patients is now in development. Clinical trial information: NCT02936323.

1011 Background: Approximately 20% of pts diagnosed with TNBC are aged ≥65 y. Often, older pts are less fit for chemotherapy due to a greater rate of comorbidities, increased use of medications, and pre-existing frailty or functional loss. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. The landmark phase 3 ASCENT study (NCT02574455) showed improved outcomes with SG vs single-agent chemotherapy of physician’s choice (TPC) in pts with relapsed/refractory mTNBC (median progression-free survival [PFS], 5.6 vs 1.7 mo; median overall survival [OS], 12.1 vs 6.7 mo). Here we assess the impact of age on the efficacy and safety of SG in ASCENT. Methods: Pts with mTNBC refractory/relapsing after ≥2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Safety outcomes were assessed in all treated pts. This prespecified subgroup analysis assessed the impact of age (pts ≥65 y) on PFS, OS, and safety. Results: Of 529 pts enrolled, 468 were BMNeg (median age, 54 y); of these, 44/235 pts (19%) who received SG and 46/233 pts (20%) who received TPC were aged ≥65 y. SG treatment improved median PFS vs TPC in pts ≥65 y (7.1 vs 2.4 mo; HR, 0.22; 95% CI, 0.12-0.40). SG vs TPC treatment also improved median OS in pts ≥65 y (15.3 vs 8.2 mo; HR, 0.37; 95% CI, 0.22-0.64). Treatment with SG vs TPC resulted in higher ORR (50% vs 0%) and clinical benefit rate (CBR, 61% vs 9%) in pts ≥65 y. Of the 7 pts ≥75 y who received SG, 2 had partial response, 4 had stable disease [SD], and 1 had SD > 6 mo as best response. In pts < 65 y, median PFS for SG vs TPC was 4.6 vs 1.7 mo (HR, 0.46; 95% CI, 0.35-0.59), and median OS was 11.2 vs 6.6 mo (HR, 0.50; 95% CI, 0.40-0.64), respectively; the ORR and CBR were 31% vs 6% and 41% vs 9%, respectively. Pts ≥65 y treated with SG vs TPC had similar rates of all grade and grade ≥3 treatment-emergent adverse events (TEAEs). TEAEs leading to dose reduction were similar in pts ≥65 y in the SG vs TPC arms (35% vs 33%) and were lower in pts < 65 y (19% vs 24%). Key treatment-related TEAEs leading to dose reduction in pts ≥65 y in the SG vs TPC arms were neutropenia (including febrile neutropenia; 14% vs 25%), fatigue (10% vs 4%), diarrhea (6% vs 0%), and nausea (4% vs 0%). TEAEs leading to treatment discontinuation with SG vs TPC were low in pts ≥65 y (2% vs 2%) and < 65 y (5% vs 6%). There were no treatment-related AEs leading to death in any SG-treated age group. Conclusions: Irrespective of age, pts who received SG had a significant survival benefit vs TPC, with a tolerable safety profile. Proactive AE monitoring and management will allow optimal therapeutic exposure to SG in older pts. Clinical trial information: NCT02574455 .

Background Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222). Materials and methods Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) and MET immunohistochemistry (IHC) expression-positive populations. Results Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC-positive populations. An improvement in PFS was noted in the MET IHC-negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo. Conclusion Onartuzumab combined with mFOLFOX-6 and bevacizumab did not significantly improve efficacy outcomes in either the ITT or MET IHC-positive populations. MET expression by IHC was not a predictive biomarker in this setting. The Oncologist 2017;22:264-271 IMPLICATIONS FOR PRACTICE: The addition of onartuzumab to mFOLFOX-6 plus bevacizumab did not improve outcomes in patients with previously untreated metastatic colorectal cancer in this randomized, phase II study. Although initial results with onartuzumab were promising, a number of phase II/III clinical trials have reported a lack of improvement in efficacy with onartuzumab combined with standard-of-care therapies in several tumor types. Furthermore, negative study data have been published for rilotumumab and ficlatuzumab, both of which block hepatocyte growth factor binding to the mesenchymal-epithelial transition (MET) receptor. MET immunohistochemistry was not a predictive biomarker. It remains to be seen if other biomarkers or small molecule inhibitors may be more appropriate for inhibiting this oncogenic pathway.

Background: Around 15,000 US patients per year are diagnosed with de novo ABC. Due to the absence of prior systemic treatment for breast cancer, tumors of patients with de novo ABC may exhibit a different disease biology, which could result in different tumor responses compared with patients who have relapsed breast cancer. Ribociclib is an orally bioavailable cyclin-dependent kinase (CDK) 4/6 inhibitor. Results from MONALEESA-2, a double-blind, placebo-controlled, randomized Phase 3 trial (NCT01958021), demonstrated that first-line therapy with ribociclib + letrozole significantly improved progression-free survival (PFS) vs placebo + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC. Many patients with de novo ABC receive endocrine therapy in the first line and in subsequent lines; here we present results from the MONALEESA-2 study in a subpopulation of patients with de novo ABC. Methods: Postmenopausal women (N=668) with HR+, HER2– ABC who had no prior systemic therapy for ABC were randomized 1:1 (stratified by liver and/or lung metastases) to receive ribociclib (600 mg/day; 3-weeks-on/1-week-off) + letrozole (2.5 mg/day; continuous) or placebo + letrozole. Patients with de novo ABC were eligible. Additional eligibility criteria included measurable disease or ≥1 predominantly lytic bone lesion, Eastern Cooperative Oncology Group performance status ≤1, and adequate bone marrow/organ function. Prior CDK4/6 inhibitors or systemic therapy for ABC were prohibited. Patients may have received ≤14 days of letrozole or anastrozole for ABC. The primary endpoint was locally assessed PFS; a predefined subgroup analysis evaluated PFS in patients with de novo ABC. Results: In total, 227 patients with de novo ABC were enrolled. Patients with de novo ABC were equally distributed with 114 (34%) and 113 (34%) in the ribociclib + letrozole and placebo + letrozole arms, respectively. Median duration of exposure to study treatment in the ribociclib + letrozole vs placebo + letrozole arms was 14.1 vs 12.8 months. Treatment was discontinued in 84 (37%) patients with de novo ABC (ribociclib + letrozole vs placebo + letrozole, n [%]; 34 [30%] vs 50 [44%]). Reasons for treatment discontinuation (ribociclib + letrozole vs placebo + letrozole, n [%]) included disease progression (21 [18%] vs 41 [36%]), patient/physician decision (5 [4%] vs 6 [5%]), and adverse events (6 [5%] vs 3 [3%]). PFS was increased in patients with de novo ABC who received ribociclib + letrozole vs placebo + letrozole (hazard ratio=0.448 [95% confidence interval: 0.267–0.750]). The 12-month PFS event-free probability in patients with de novo ABC was 82% in the ribociclib + letrozole arm vs 66% in the placebo + letrozole arm. Conclusions: The combination of ribociclib + letrozole significantly improved PFS compared with placebo + letrozole in postmenopausal women with HR+, HER2– de novo ABC at diagnosis and therefore may become an important treatment option in the de novo ABC setting. Keywords: Advanced breast cancer; CDK4/6 inhibitor; Letrozole; Ribociclib Citation Format: O'Shaughnessy J, Petrakova K, Sonke GS, André F, Conte P, Arteaga CL, Cameron DA, Hart LL, Villanueva C, Jakobsen EH, Lindquist D, Souami F, Li X, Germa C, Hirawat S, Hortobagyi GN. First-line ribociclib plus letrozole in patients with de novo HR+, HER2– advanced breast cancer (ABC): A subgroup analysis of the MONALEESA-2 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 P4-22-05.

Background: The addition of first-line ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) to letrozole (LET) significantly improved progression-free survival (PFS) compared with placebo (PBO) + LET in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the Phase III MONALEESA-2 study. Identifying biomarkers that predict response to treatment remains a key challenge in pts with HR+ ABC. Here we analyze results from MONALEESA-2 by molecular alterations detected in circulating tumor DNA (ctDNA) at baseline, including PIK3CA mutations and other alterations considered to be important in HR+ ABC. Methods: Postmenopausal women (N=668) with HR+, HER2– ABC who had not received any prior therapy for ABC were randomized 1:1 to RIB (600 mg/day; 3-weeks-on/1-week-off) + LET (2.5 mg/day; continuous) or PBO + LET. The primary endpoint was PFS. Biomarker analysis of the ctDNA mutation profile was an exploratory endpoint. Plasma samples for ctDNA analysis were collected at baseline and end of treatment. ctDNA was analyzed using next-generation sequencing with a targeted panel of ˜550 genes. Results: Baseline ctDNA was successfully sequenced in 494 pts (RIB + LET: n=212; PBO + LET: n=215); 67 (14%) of 494 pts were removed from the analysis due to limited tumor DNA in circulation. 427 (86%) pts had ≥1 alteration, including 1,573 mutations, 513 short insertions/deletions, 166 amplifications, and 8 translocations. Alterations (frequency) were commonly observed in the following genes: PIK3CA (33%), TP53 (12%), ZNF703/FGFR1 (5%), and ESR1 (4%), and in genes involved in receptor tyrosine kinase (RTK) signaling (12%). RIB + LET treatment benefit was consistent in pts with wild-type (WT) and altered PIK3CA, and in pts with WT and altered TP53 (Table). RIB + LET improved PFS regardless of RTK or ZNF703/FGFR1 alterations. However, there was a weak trend for increased benefit in pts with WT vs altered RTK genes and in pts with WT vs altered ZNF703/FGFR1 genes. These results should be interpreted with caution due to the small number of pts with these alterations. There were too few ESR1 alterations for firm conclusions to be drawn. Events, n/NMedian PFS, months Gene(s)RIB + LETPBO + LETRIB + LETPBO + LETHazard ratio (95% confidence interval)PIK3CAWT54/14393/14229.614.70.44 (0.31–0.62)Altered40/6955/7319.212.70.53 (0.35–0.81)TP53WT72/180129/19427.614.70.44 (0.33–0.59)Altered22/3219/2110.25.50.43 (0.23–0.83)ZNF703/FGFR1WT88/202139/20524.814.60.47 (0.36–0.62)Altered6/109/1010.611.40.73 (0.23–2.29)RTKWT81/189128/18724.814.40.46 (0.35–0.61)Altered13/2320/2821.311.40.72 (0.34–1.53) Conclusions: Consistent RIB + LET treatment benefit was observed compared with PBO + LET, irrespective of the status of baseline ctDNA biomarkers. Citation Format: Hortobagyi GN, Stemmer S, Campone M, Sonke GS, Arteaga CL, Paluch-Shimon S, Petrakova K, Villanueva C, Nusch A, Grischke E-M, Chan A, Jakobsen E, Marschner N, Hart LL, Alba E, Ohnstand HO, Blau S, Yardley DA, Solovieff N, Su F, Germa C, Yap Y-S. First-line ribociclib + letrozole in hormone receptor-positive, HER2-negative advanced breast cancer: Efficacy by baseline circulating tumor DNA alterations in MONALEESA-2 [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 PD4-06.

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.

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 .