Treatment Of Physician's Choice Research Articles

Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial

BackgroundThe phase III OlympiAD study (NCT02000622) showed a statistically significant progression-free survival benefit with olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with a germline BRCA mutation and human epidermal growth factor receptor 2-negative metastatic breast cancer. From this study, we report the effect of olaparib on health-related quality of life (HRQoL). MethodsPatients were randomised 2:1 to olaparib monotherapy (300 mg twice daily) or single-agent TPC. The primary HRQoL end-point was mean change from baseline in the two-item global health status/QoL score determined from patient-completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module (EORTC QLQ-C30) questionnaires and assessed using a mixed model for repeated measures. Symptoms and functioning domains, best overall response and time to deterioration of QoL were also evaluated. ResultsOverall questionnaire compliance rates were 93.2% for olaparib and 76.3% for TPC. Between-treatment global health status/QoL comparison showed a significant improvement in the olaparib arm versus the TPC arm, with mean change of 3.9 (standard deviation 1.2) versus −3.6 (2.2), a difference of 7.5 points (95% confidence interval [CI]: 2.48, 12.44; P = 0.0035). A higher proportion of patients in the olaparib arm showed a best overall response of ‘improvement’ in global health status/QoL (33.7% vs 13.4%). Median time to global health status/QoL deterioration was not reached in olaparib patients and was 15.3 months for TPC patients (hazard ratio: 0.44 [95% CI: 0.25, 0.77]; P = 0.004). For EORTC QLQ-C30 symptoms and functioning subscales, only nausea/vomiting symptom score was worse in the olaparib arm than in the TPC arm (across all visits compared with baseline). ConclusionHRQoL was consistently improved for patients treated with olaparib, compared with chemotherapy TPC.

Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial.

5506 Background: Data from a randomized Phase II trial (NCT00628251) of olaparib (capsules, 200 or 400 mg bid, n=32 per arm) vs pegylated liposomal doxorubicin (PLD, n=33) in gBRCAm OC pts with recurrence ≤12 months after prior platinum therapy indicated efficacy for olaparib (Kaye et al. JCO 2012). However, the efficacy of PLD was higher than previously reported in this setting. We led a confirmatory Phase III, open-label study of olaparib vs non-platinum chemotherapy in gBRCAm PSR OC pts (NCT02282020). Methods: Pts were randomized (2:1) to olaparib tablets (300 mg bid) or chemotherapy treatment of physician’s choice (TPC) (paclitaxel [P; 80 mg/m2 on day 1 (D1), D8, D15, D22 every 4 weeks (q4w)], topotecan [T; 4 mg/m2 D1, D8, D15 q4w], gemcitabine [G; 1000 mg/m2 D1, D8, D15 q4w] or PLD [50 mg/m2 D1 q4w]) until progression, stratified by: TPC, prior lines of chemotherapy (2–3 vs ≥4) and platinum-free interval (6–12 vs >12 months). Primary endpoint: ORR (blinded independent central review [BICR]). Secondary endpoints included PFS and safety. Results: 266 gBRCAm PSR OC pts were randomized (olaparib, n=178; TPC, n=88 [ PLD, n=47; P, n=20; G, n=13; T, n=8]); 12 in the TPC arm withdrew before receiving study treatment. 223 pts (84%) had baseline BICR measurable disease (olaparib, n=151; TPC, n=72). ORR was 72% with olaparib vs 51% with TPC (OR 2.53, 95% CI 1.40–4.58; P=0.002). HR for PFS by BICR was 0.62 (95% CI 0.43–0.91; P=0.013; median 13.4 vs 9.2 months [olaparib vs TPC]) and by investigator assessment was 0.49 (95% CI 0.35–0.70; P<0.001; median 13.2 vs 8.5 months, respectively). Most common adverse events (AEs) with olaparib were nausea (65% vs 34% [TPC]) and anemia (50% vs 25%) and with TPC were palmar-plantar erythrodysesthesia (PPE; 36% vs 1% [olaparib]) and nausea. Most common grade ≥3 AEs in either arm were anemia (21% [olaparib] vs 0 [TPC]), PPE (0 vs 12%) and neutropenia (6% vs 11%). For olaparib vs TPC, serious AEs were reported by 24% vs 18% and AEs led to treatment discontinuation in 7% vs 20%. Conclusions: Pts with gBRCAm PSR OC receiving olaparib monotherapy had a significant, clinically relevant improvement in ORR and PFS vs TPC, with no new safety signals. Clinical trial information: NCT02282020.

A phase 3 trial evaluating efficacy and safety of lenvatinib in combination with pembrolizumab in patients with advanced endometrial cancer.

TPS5607 Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor receptors 1–3, fibroblast growth factor receptors 1–4, platelet-derived growth factor receptor α, RET, and KIT. Pembrolizumab (PEMBRO) is a monoclonal antibody targeting programmed cell death receptor 1 (PD-1). Preliminary analyses of a phase 1b/2 study of LEN + PEMBRO showed promising antitumor activity and a manageable safety profile in advanced endometrial cancer (EC). Methods: A multicenter, randomized, open-label, phase 3 study (KEYNOTE-775/E7080-G000-309; clinicaltrials.gov NCT03517449) will evaluate efficacy and safety of LEN + PEMBRO vs treatment of physician’s choice (TPC) in patients with advanced EC. Patients must be aged ≥ 18 years, have advanced EC that progressed after 1 prior platinum-based therapy, have measurable disease per RECIST v1.1, and an Eastern Cooperative Oncology Group performance status ≤ 1. Patients must have mismatch repair (MMR) status confirmed by central laboratory via immunohistochemistry on archived or fresh tumor biopsy. ~780 patients (~120 MMR-deficient; ~660 MMR-proficient) will be randomized to receive LEN 20 mg orally once daily and PEMBRO 200 mg intravenously (IV) every 3 weeks (Q3W) or TPC. Patients will be randomized first according to MMR status; MMR-proficient patients will be further stratified by ECOG PS, geographic region, and prior history of pelvic radiation. TPC is either doxorubicin 60 mg/m2 by IV Q3W or paclitaxel 80 mg/m2 by 1-hour IV infusion weekly (3 weeks on/1 week off). The dual primary endpoints are progression-free survival (PFS; per RECIST v1.1 by blinded independent central review) and overall survival (OS). The PFS analysis will occur at the planned interim analysis (~363 OS events in MMR-proficient patients; ~524 PFS events), and the study will have 99% power to detect a hazard ratio (HR) of 0.55 with a 1-sided 0.0005 significance level. A final OS analysis will occur at 518 OS events, when the study will have 90% power to detect a HR of 0.75 with a 1-sided 0.0245 significance level. Secondary endpoints include objective response rate, health-related quality of life, safety and tolerability, and pharmacokinetics. Clinical trial information: NCT03517449.

OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer

BackgroundIn the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician’s choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation (BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population. Patients and methodsOlympiAD, a Phase III, randomized, controlled, open-label study (NCT02000622), enrolled patients with a germline BRCAm and HER2-negative mBC who had received ≤2 lines of chemotherapy for mBC. Patients were randomized to olaparib tablets (300mg bid) or predeclared TPC (capecitabine, vinorelbine, or eribulin). OS and safety were secondary end points. ResultsA total of 205 patients were randomized to olaparib and 97 to TPC. At 64% data maturity, median OS was 19.3months with olaparib versus 17.1months with TPC (HR 0.90, 95% CI 0.66–1.23; P = 0.513); median follow-up was 25.3 and 26.3months, respectively. HR for OS with olaparib versus TPC in prespecified subgroups were: prior chemotherapy for mBC [no (first-line setting): 0.51, 95% CI 0.29–0.90; yes (second/third-line): 1.13, 0.79–1.64]; receptor status (triple negative: 0.93, 0.62–1.43; hormone receptor positive: 0.86, 0.55–1.36); prior platinum (yes: 0.83, 0.49–1.45; no: 0.91, 0.64–1.33). Adverse events during olaparib treatment were generally low grade and manageable by supportive treatment or dose modification. There was a low rate of treatment discontinuation (4.9%), and the risk of developing anemia did not increase with extended olaparib exposure. ConclusionsWhile there was no statistically significant improvement in OS with olaparib compared to TPC, there was the possibility of meaningful OS benefit among patients who had not received chemotherapy for metastatic disease. Olaparib was generally well-tolerated, with no evidence of cumulative toxicity during extended exposure.

362TiP - ATTAIN: Phase III study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC)

362TiP - ATTAIN: Phase III study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC)

Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol.

Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP).Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, γH2AX, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses.Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47-63 CTCs/mL; range, 0-2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP-treated patients with low C2D1Top1+ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01).Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348-57. ©2018 AACR.

Abstract CT038: OlympiAD final overall survival: Olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm)

Abstract Background: A significant progression-free survival benefit was shown in OlympiAD (NCT02000622) for patients (pts) with HER2-negative mBC and a gBRCAm receiving olaparib vs TPC (hazard ratio [HR] 0.58; 95% confidence interval [CI], 0.43, 0.80; P<0.001). Interim overall survival (OS) data were reported at primary analysis (46% maturity); prespecified final OS data are now reported. Methods: OlympiAD was a randomized Phase III trial in pts with HER2-negative mBC and a gBRCAm who had received ≤2 lines of chemotherapy for mBC. Randomization (2:1) to olaparib tablet monotherapy (300 mg bid) or single-agent TPC (capecitabine, vinorelbine or eribulin) was stratified by prior chemotherapy (no/yes), prior platinum (no/yes) and receptor status (ER+ and/or PR+ vs TNBC). Data cut-off was 25 September 2017. Results: Of 302 randomized pts, 205 received olaparib and 91 received TPC (6 TPC pts declined treatment). At final OS analysis, 192/302 deaths had occurred (64% maturity). HR for OS in the olaparib vs TPC group was 0.90 (95% CI 0.66, 1.23; P=NS; median 19.3 months [mo] vs 17.1 mo). Median follow-up for OS was 18.9 mo for olaparib vs 15.5 mo in the TPC group. More pts in the TPC group received subsequent therapy with PARP inhibitors, cytotoxic chemotherapy, platinum and hormonal treatment than in the olaparib group. Predefined subgroup analyses are shown for the three stratification factors (Table). SubgroupMedian OS (months)HR95% CINominal P*OlaparibTPCPrior chemotherapy for mBCNo (1L)22.614.70.510.29, 0.900.02Yes (2L/3L)18.817.21.130.79, 1.640.52Prior platinum for BCNo20.319.60.910.64, 1.330.63Yes17.213.30.830.49, 1.450.49Receptor statusER+ and/or PR+21.821.30.860.55, 1.360.51TNBC17.414.90.930.62, 1.430.75*Nominal P-values were calculated using a likelihood ratio test; OS stratification factors were prespecified but not alpha-controlled. 1L, first line; 2L, second line; 3L, third line; BC, breast cancer; ER, estrogen receptor; PR, progesterone receptor; TNBC, triple negative breast cancer CTCAE grade ≥3 adverse events were reported in 38 and 50% of pts receiving olaparib or TPC, respectively, at extended safety analysis. 39 (19%) pts and 15 (7%) pts received olaparib for >18 mo and >24 mo, respectively. Conclusions: At final analysis, median OS was 2.2 mo longer for olaparib monotherapy vs TPC in the overall population (not statistically significant). OlympiAD was not powered to show an OS difference for olaparib vs TPC. Benefit appeared greatest in pts with no prior chemotherapy for mBC (7.9 mo longer median OS in olaparib pts vs TPC). Olaparib safety profile was consistent with primary analysis indicating no relevant cumulative toxicity with extended exposure. Citation Format: Mark E. Robson, Seock-Ah Im, Elżbieta Senkus, Binghe Xu, Susan Domchek, Norikazu Masuda, Suzette Delaloge, Wei Li, Nadine Tung, Anne Armstrong, Wenting Wu, Carsten Goessl, Sarah Runswick, Pierfranco Conte. OlympiAD final overall survival: Olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT038.

EORTC QLQ-C30 (QLQ-C30) symptoms in patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) receiving olaparib vs chemotherapy treatment of physician’s choice (TPC) in OlympiAD.

1045Background: In the Phase III OlympiAD study, pts with HER2-negative mBC and a gBRCAm who received olaparib vs TPC showed statistically significant and clinically meaningful benefit in progressi...

Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer (OlympiAD): Efficacy in patients with visceral metastases.

1052Background: The OlympiAD study showed a significant progression-free survival (PFS) benefit for olaparib over chemotherapy treatment of physician’s choice (TPC) in patients with HER2-negative m...

ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs. treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC).

ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs. treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC).

Abstract P5-21-12: Tolerability of olaparib monotherapy versus chemotherapy in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: OlympiAD

Abstract Background The OlympiAD study (NCT02000622) showed a significant progression-free survival benefit for olaparib monotherapy over chemotherapy treatment of physician's choice (TPC) in patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). We examined olaparib tolerability in these pts to further characterize the most common adverse events (AEs). Methods OlympiAD was a randomized, open-label, Phase III study in gBRCAm, HER2-negative mBC pts who had received ≤2 chemotherapy lines in the metastatic setting. Pts were randomized 2:1 to olaparib tablet (300 mg bid) or single-agent TPC (capecitabine, eribulin or vinorelbine). Treatment continued until disease progression or unacceptable toxicity. Results 302 pts were randomized to olaparib (n=205) or TPC (n=97). Six TPC pts declined study treatment due to treatment allocation and were excluded from safety analyses. There were fewer Grade ≥3 AEs with olaparib vs TPC (36.6% vs 50.5%, respectively) and a low rate of discontinuation due to toxicity (4.9% for olaparib vs 7.7% for TPC). Anemia, nausea, vomiting, fatigue and headache were more frequent with olaparib, and neutropenia, decreased white blood cells (WBC) and palmar-plantar erythrodysesthesia (PPE) were more common with TPC. Incidence and outcome for the most common AEs (>20% pts in either arm) are shown in the table. There were no Grade ≥3 nausea or vomiting with olaparib. The first onset of nausea in either arm was typically within the first month of treatment. Prevalence of nausea with olaparib treatment was highest in the first 3 months (˜30% of pts), decreasing to ˜15% for the remainder of the study period. Grade ≥3 anemia was more frequent in the olaparib versus TPC arms. More olaparib pts required blood transfusion (18.0%) than TPC pts (5.5%), and there was more concomitant use of erythropoietin stimulating agents with olaparib than TPC (5.9% vs 1.0%, respectively). Anemia onset was early, typically in the first 3 months of starting treatment. The prevalence of anemia was relatively stable over time. Grade ≥3 neutropenia was more frequent in pts receiving TPC instead of olaparib. There was a slightly higher incidence of concomitant granulocyte-colony stimulating factor treatment with TPC (8.2%) vs olaparib (5.4%). Olaparib N=205 (%)TPC N=91 (%) Any grade [≥G3]Dose reduction [interruption]DiscontinuationAny grade [≥G3]Dose reduction [interruption]DiscontinuationNausea58 [0]1 [2]035 [1]2 [0]0Vomiting30 [0]1 [2]015 [1]2 [0]1Diarrhea21 [1]0 [1]022 [0]3 [1]0Anemia40 [16]14 [15]226 [4]1 [2]2Neutropenia27 [9]7 [10]050 [26]14 [18]2Decreased WBC16 [3]1 [4]021 [10]4 [1]0Fatigue29 [3]2 [2]023 [1]1 [1]0Headache20 [1]0 [0]015 [2]1 [0]0PPE1 [0]0 [0]021 [2]8 [6]1AEs of any cause. MedDRA preferred terms are combined for 1) anemia and 2) neutropenia Conclusions Gastrointestinal toxicity in either arm was mostly mild to moderate, and typically reported early after treatment initiation. Anemia was more frequent in olaparib pts but rarely led to treatment cessation. Olaparib tablets were generally well tolerated in HER2-negative mBC pts with a gBRCAm, with a lower rate of Grade ≥3 AEs compared with chemotherapy. Citation Format: Domchek SM, Robson M, Im S-A, Senkus E, Xu B, Masuda N, Delaloge S, Li W, Armstrong A, Conte P, Bannister W, Goessl C, Runswick S, Goel S, Tung N. Tolerability of olaparib monotherapy versus chemotherapy in patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: OlympiAD [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 P5-21-12.

Abstract P5-21-13: Olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: Asian subgroup analysis from the phase III OlympiAD trial

Abstract Background In the Phase III OlympiAD trial (NCT02000622, D0819C00003), olaparib (Lynparza™) showed a significant progression-free survival (PFS) improvement compared with chemotherapy treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) (Robson et al. NEJM 2017). Here, we present data from a subgroup analysis of Asian pts. It is not yet known whether Asian pts, in comparison with the global patient population, may experience instances of differential toxicity with olaparib therapy. Methods OlympiAD, an open-label, multicenter, Phase III trial, randomized (2:1) pts with HER2-negative mBC and a gBRCAm to olaparib tablets (300 mg twice daily) or single-agent TPC (21-day cycles of capecitabine, eribulin or vinorelbine). Pts must have received ≤2 lines of chemotherapy for mBC and prior anthracycline and taxane in the adjuvant, neo-adjuvant or metastatic setting. Primary endpoint was PFS by blinded independent central review (BICR). Region (Asia, Europe, North America, South America) was a pre-defined subgroup for PFS. Results The Asian subgroup analysis included pts randomized at centers in China, Japan, Korea and Taiwan. Of 87 Asian pts randomized (median age 46 years), 86 received study treatment (n=59, olaparib; n=27, TPC). In the olaparib group, 29/59 (49%) had estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) tumors, and 30/59 (51%) had triple negative breast cancer (TNBC). In the TPC group, 13/28 (46%) had ER+/PR+ tumors and 15/28 (54%) had TNBC. The primary endpoint, PFS by BICR, favored olaparib with a hazard ratio (HR) of 0.53 (95% confidence interval [CI] 0.29–0.97; median 5.7 vs 4.2 months; 77% maturity), and was supported by investigator-assessed PFS (HR 0.29, 95% CI 0.16–0.55). In the overall OlympiAD study population (N=302), the PFS by BICR favored olaparib with a HR of 0.58 (95% CI 0.43–0.80; P=0.0009). Within the Asian subgroup, objective response rate (ORR) (RECIST) was 64% for olaparib versus 38% for the TPC group. Time to second progression, PFS2, was longer for pts receiving olaparib versus TPC (HR 0.43, 95% CI 0.22–0.84; 57% maturity). Grade ≥3 adverse events (AEs) occurred in 46% and 59% of pts receiving olaparib and TPC, respectively. The most common grade ≥3 AE was anemia (olaparib, 20%; TPC, 15%). In both treatment groups, 7% of pts discontinued study treatment due to AEs (n=4, olaparib; n=2, TPC). The tolerability profile of olaparib between the subgroup of Asian pts and the overall OlympiAD population will be examined in our data presentation. Conclusion Olaparib demonstrated an efficacy benefit compared with TPC in pts with HER2-negative mBC and a gBRCAm in this subgroup analysis of Asian pts from the Phase III OlympiAD trial. Discontinuation rates due to toxicity were low, highlighting that olaparib was generally well-tolerated. The efficacy of olaparib within the subgroup of Asian pts was consistent with that shown for the full OlympiAD dataset; consistent hazard ratios were shown in favor of olaparib using the primary endpoint of PFS by BICR, and for the key secondary endpoints of PFS by investigator assessment, PFS2, and ORR. Citation Format: Im S-A, Xu B, Li W, Robson M, Ouyang Q, Yeh D-C, Iwata H, Park Y-H, Sohn JH, Tseng L-M, Goessl C, Wu W, Runswick S, Masuda N. Olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation: Asian subgroup analysis from the phase III OlympiAD trial [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 P5-21-13.

Abstract OT2-07-05: A phase III, randomized trial of sacituzumab govitecan (IMMU-132) vs treatment of physician choice (TPC) for metastatic triple-negative breast cancer (mTNBC)

Abstract Background: Metastatic TNBC has an aggressive course with limited therapy options and poor survival. Sacituzumab govitecan (IMMU-132) is a novel antibody drug conjugate consisting of SN-38, the active metabolite of the topoisomerase I inhibitor, irinotecan, conjugated to a humanized mAb targeting Trop-2, which is highly expressed in most epithelial cancers, including TNBC. We previously reported that patients (pts) with mTNBC treated with IMMU-132 after a median of 5 prior therapies from initial diagnosis achieved a 30% objective response rate (ORR), 8.9 mo median duration of response (DOR), and an acceptable safety profile with nausea, neutropenia, and diarrhea the most common toxicities (Bardia et al., JCO, 2017). IMMU-132 was awarded Breakthrough Designation by the FDA based on this data. Accordingly, we are enrolling additional patients with relapsed/refractory mTNBC with intention of seeking regulatory approval as a ≥3rd-line therapeutic option. Trial design: An international, open-label, Phase III study in pts with refractory/relapsed mTNBC after ≥2 prior chemotherapies for advanced disease or >1 therapy for pts who progress within 12 months of adjuvant therapy (NCT02574455). Pts are randomized 1:1 to receive either IMMU-132 (10 mg/kg IV, days 1 and 8 every 21 days) or TPC from one of 4 prespecified single-agent regimens (capecitabine, eribulin, vinorelbine or gemcitabine). Pts continue treatment until progression requiring discontinuation or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) and additional endpoints include overall survival (OS), ORR, DOR, safety and quality of life. Independent, blinded reads of scans will be performed. Eligibility criteria: Adults >18 yrs old, with metastatic breast cancer, triple-negative by most recent biopsy, measurable disease by CT or MRI as per RECIST1.1, ECOG performance score 0 or 1, adequate safety laboratories. Refractory/relapsed after ≥2 prior standard chemotherapy regimens for advanced disease, or >1 therapy for pts who progress within 12 months of adjuvant therapy. Pts must have received taxane and be eligible by investigator to receive at least one of the TPC agents. Pts with treated, non-progressive brain metastases are eligible. Specific aims: To compare IMMU-132 to TPC as measured by PFS, OS, ORR, DOR,QOL, adverse events, safety laboratories, incidence of dose delays and reductions, and treatment discontinuations due to toxicity. Statistical methods: Assuming a median PFS of 3 mo. and OS of 10 mo. with TPC vs. 5 and 15 mo. with IMMU-132, respectively, a study size of 328 patients has >95% and >80% power to detect a statistically significant difference in PFS and OS, respectively, between the two treatment arms. Present accrual and target accrual: Trial enrollment will begin prior to SABCS 2017 with approximately 328 patients expected to be enrolled over 18 months at approximately 100 institutions in North America, Europe and potentially elsewhere. Contact: Immu132@Immunomedics.com Citation Format: Bardia A, Rugo HS, Horne H, Wegener WA, Goldenberg DM, O'Shaughnessy J. A phase III, randomized trial of sacituzumab govitecan (IMMU-132) vs treatment of physician choice (TPC) for metastatic triple-negative breast cancer (mTNBC) [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 OT2-07-05.

Abstract OT2-07-10: ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC)

Abstract Background: EP is a next generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival (OS) at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). A Phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of OS (HR 0.087 p=0.08); a subset of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86] p<0.01) (Perez Lancet Oncol 2015). The current Phase 3 trial (ATTAIN) was designed for this subpopulation of pts having high unmet medical need. Methods: Pts with MBC with locally treated stable BM will be randomized 1:1 to EP vs TPC in an open-label, randomized Phase 3 study. Eligibility includes ECOG PS 0 or 1; adequate organ function who received prior ATC (in neo/adjuvant or locally advanced/MBC setting) pts must have had ≥1 prior cytotoxic regimen for MBC (triple negative BC) ≥2 prior cytotoxic regimens and either 1 prior hormone therapy (HR+ BC) or 1 prior HER2 targeted therapy (HER2+ BC). Pts must have undergone definitive local therapy of BM (whole brain radiation [RT] stereotactic RT or surgical resection as single-agent or combination) signs/symptoms of BM must be stable with steroids unchanged or decreasing for ≥ 7 days prior to randomization. Primary endpoint is OS. Key secondary endpoints: ORR and PFS by RECIST v1.1 and RANO-BM, clinical benefit rate (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 IV cytotoxic agents. Pts are stratified by region, PS and receptor status. 350 pts will be randomized to obtain number of events required at 90% power to detect a statistically significant improvement in OS (hypothesizing HR=0.67) 1 interim analysis at 50% of deaths (130 events) will be performed. PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for potential predictive markers of efficacy. Enrollment began early 2017. For enrollment information contact Dr. Alison Hannah, Dr. Mary Tagliaferri, or Minnie Kuo at StudyInquiry@nektar.com. NCT02915744 Citation Format: Tripathy D, Sara T, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves CJ, Diéras V, Müller V, Hannah A, Tagliaferri M, Cortés J. ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC) [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 OT2-07-10.

290P - OlympiAD: Health-related quality of life (HRQoL) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) receiving olaparib monotherapy vs standard single-agent chemotherapy treatment of physician’s choice (TPC)

290P - OlympiAD: Health-related quality of life (HRQoL) in patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm) receiving olaparib monotherapy vs standard single-agent chemotherapy treatment of physician’s choice (TPC)

OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm).

LBA4 Background: Olaparib is an oral PARP inhibitor with anti-tumor activity in HER2-negative mBC with a g BRCAm (NCT00494234). OlympiAD (NCT02000622) was a randomized, open-label, phase III study that assessed efficacy and safety of olaparib vs standard single agent chemotherapy treatment of physician’s choice (TPC) in pts with HER2-negative mBC and a g BRCAm. Methods: Pts aged ≥18 y with HER2-negative mBC (hormone receptor positive or triple negative [TN]) and a g BRCAm, who had received ≤2 chemotherapy lines for mBC, were randomized (2:1) to olaparib tablets (300 mg po bid) or TPC (21-day cycles of either capecitabine [2500 mg/m2 po days 1–14], vinorelbine [30 mg/m2 IV days 1 and 8] or eribulin [1.4 mg/m2IV days 1 and 8]). Treatment was continued until objective disease progression (RECIST v1.1) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR). Results: 302 pts were randomized (median age 44 y; 50% TN; 71% prior chemotherapy for mBC; 28% prior platinum) of whom 205 received olaparib and 91 received TPC (6 TPC pts were not treated). At 77% data maturity, PFS by BICR was significantly longer in pts treated with olaparib vs TPC (HR 0.58; 95% CI 0.43, 0.80; P=0.0009; 7.0 vs 4.2 months, respectively). Time to second progression (investigator-assessed) was also longer in the olaparib arm (HR 0.57; 95% CI 0.40, 0.83). Objective response rate was 59.9 and 28.8% in olaparib and TPC arms, respectively. Grade ≥3 adverse events (AE) occurred in 36.6 and 50.5% of olaparib and TPC pts, with AEs leading to discontinuation in 4.9 and 7.7% of pts, respectively. Mean change from baseline in global health-related quality of life (HRQoL, EORTC-QLQ-C30) across all timepoints favored olaparib (difference vs TPC 7.5; 95% CI 2.48, 12.44; P=0.0035). Conclusions: Olaparib tablet monotherapy provided a statistically significant and clinically meaningful PFS benefit to HER2-negative mBC pts with a g BRCAm, compared to standard TPC. The safety profile of olaparib was consistent with prior studies. The efficacy benefit was seen beyond the first progression and HRQoL also improved. Clinical trial information: NCT02000622.

ATTAIN: Phase 3 study of etirinotecan pegol (EP) vs treatment of physician's choice (TPC) in patients (pts) with metastatic breast cancer (MBC) who have stable brain metastases (BM) previously treated with an anthracycline, a taxane, and capecitabine (ATC).

TPS1120 Background: EP is a next generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival (OS) at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). A Phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of OS (HR 0.087; p = 0.08); a subset of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86]; p < 0.01) (Perez Lancet Oncol 2015). The current Phase 3 trial (ATTAIN) was designed for this subpopulation of pts having high unmet medical need. Methods: Pts with MBC with locally treated stable BM will be randomized 1:1 to EP vs TPC in an open-label, randomized Phase 3 study. Eligibility includes ECOG PS 0 or 1; adequate organ function who received prior ATC (in neo/adjuvant or locally advanced/MBC setting); pts must have had ≥1 prior cytotoxic regimen for MBC (triple negative BC); ≥2 prior cytotoxic regimens and either 1 prior hormone therapy (HR+ BC) or 1 prior HER2 targeted therapy (HER2+ BC). Pts must have undergone definitive local therapy of BM (whole brain radiation [RT]; stereotactic RT or surgical resection as single-agent or combination); signs/symptoms of BM must be stable with steroids unchanged or decreasing for ≥7 days prior to randomization. Primary endpoint is OS. Key secondary endpoints: ORR and PFS by RECIST v1.1 and RANO-BM, clinical benefit rate (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 IV cytotoxic agents. Pts are stratified by region, PS and receptor status. 350 pts will be randomized to obtain number of events required at 90% power to detect a statistically significant improvement in OS (hypothesizing HR = 0.67); 1 interim analysis at 50% of deaths (130 events) will be performed. PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for potential predictive markers of efficacy. Enrollment will begin early 2017. Clinical trial information: NCT02915744.

Abstract P1-12-05: Etirinotecan pegol: Survival advantage over standard of care drugs in a model of brain metastases of breast cancer

Abstract BACKGROUND: Brain metastasis of breast cancer is a significant cause of death among women with disseminated breast cancer. Chemotherapy, radiation, and surgery for these metastases provide only minimal benefit with considerable toxicity. The long-acting topoisomerase I inhibitor etirinotecan pegol (EP) is a novel treatment for disseminated breast cancer. EP consists of irinotecan attached to a 20kDa branched polymer via a releasable linker. The large molecular weight of EP results in tumor accumulation, including brain metastases, providing increased and sustained exposure to cytotoxic SN38. In the Phase 3 BEACON study, EP showed a significant survival benefit (HR 0.51; 95% CI 0.30-0.86) in a prespecified subgroup of women with history of treated, stable brain metastases compared to treatment of physicians choice (TPC) consisting of one of seven approved chemotherapy drugs (median OS 10.0 vs 4.8 mo). Nektar has filed a conditional marketing authorization in Europe for EP in patients with advanced breast cancer and brain metastases. A Phase 3 trial in this patient population is being initiated to support a potential U.S. filing. To further support the biological rationale for EP in these patients, an experimental preclinical model of brain metastases of breast cancer was conducted to compare the efficacy of EP to TPC in BEACON and the planned subsequent study. METHODS: Female athymic nude mice were inoculated with 1.75x105 MDA-MB-231-BrLuc cells via intracardiac injection. Starting on day 21, gemcitabine (60 mg/kg) and eribulin (1.5 mg/kg) were dosed IP every 4 days; EP (50 mg/kg), irinotecan (50 mg/kg), paclitaxel (6 mg/kg), vinorelbine (10 mg/kg), docetaxel (10 mg/kg), and vehicle (saline or dextrose) were dosed weekly via tail vein. Efficacy was measured by tumor burden and survival. Tumor burden was determined based on twice weekly bioluminescence measurements. Animals were euthanized according to international animal care guidelines. RESULTS: Median survival for all control arm groups (docetaxel, vinorelbine, eribulin, gemcitabine, irinotecan, and paclitaxel) were 39, 43, 41, 48, 35, and 42 days, respectively, none of which were significantly different from vehicle control median survival of 40 days (p>0.05). No animals receiving these drugs survived until the end of the 90-day trial. Median survival for the EP treatment group was 86 days (p<0.05) with a 40% survival rate at 90 days, the trial endpoint. Tumor burden increased nearly 100-fold in all TPC and vehicle groups, whereas EP significantly inhibited tumor growth. Quantitative autoradiography showed that EP accumulated ~10-fold in brain metastases, while accumulation in non-tumor brain tissue was only ~2-fold compared to irinotecan. EP at 50 mg/kg achieved plasma trough concentrations comparable to those observed in patients receiving the recommended dose of 145 mg/m2 every 21 days. CONCLUSIONS: In this model of brain metastases, EP preferentially accumulates in brain metastases, significantly reduces tumor burden progression and significantly improves survival in brain metastases of breast cancer compared to the most active chemotherapeutic agents available for advanced breast cancer and those used in the BEACON trial and planned subsequent Phase 3 study. Citation Format: Shah N, Mohammad AS, Adkins CE, Dolan EL, Griffith J, Jagannathan R, Hoch U, Lockman PR. Etirinotecan pegol: Survival advantage over standard of care drugs in a model of brain metastases of breast cancer [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 P1-12-05.

Chemotherapy principles of managing stage IV breast cancer in the United States.

The therapeutic landscape for metastatic breast cancer (MBC) has expanded greatly over the last three decades with an increasing availability of targeted therapies for specific breast cancer subtypes. However, cytotoxic chemotherapy remains an essential component for the management of endocrine refractory or triple negative MBC. Multiple chemotherapy agents have demonstrated activity in MBC as single agents and in combination. While taxanes are frequently recommended as the initial treatment of metastatic disease, capecitabine is a convenient oral therapy with well received toxicity profile. Eribulin is the only agent that demonstrated overall survival (OS) benefit in a phase III clinical trial when compared to treatment of physician choice in heavily pre-treated patients. Ixabepilone, gemcitabine, vinorelbine and platinum agents have demonstrated activity and, therefore, constitute additional therapeutic options. In this review, we will discuss the data supporting the use of different cytotoxic agents and the general principles in guiding the use of chemotherapy.

Abstract S5-05: Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study

Abstract Introduction The phase 3, randomized, open-label, TH3RESA study (BO25734/TDM4997g; NCT01419197) compared trastuzumab emtansine (T-DM1) with treatment of physician's choice (TPC) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), previously treated with a taxane (any setting), and both trastuzumab and lapatinib (advanced setting). Progression-free survival (PFS) and overall survival (OS) were co-primary endpoints. Results of the primary PFS analysis and the first interim OS analysis showed significantly improved PFS with T-DM1 compared with TPC and a trend for improved OS, although the stopping boundary was not reached (Krop IE, et al. Lancet Oncol 2014). The incidence of grade ≥3 adverse events (AEs) was lower with T-DM1 vs TPC (32% vs 43%). Here we report the results from the second interim analysis of OS from TH3RESA, which will serve as the final OS results. Methods Eligible patients were randomized 2:1 to receive T-DM1 (3.6 mg/kg IV every 3 weeks) or TPC. The pre-specified OS efficacy stopping boundary was an observed hazard ratio (HR) <0.75 or p<0.012. Crossover from TPC to T-DM1 following progressive disease was allowed from Sept 2012 onward. Results From Sept 14, 2011 to Nov 19, 2012, 602 patients were randomized to T-DM1 (n=404) or TPC (n=198). TPC comprised HER2-directed regimens (83%) and single-agent chemotherapy (17%). At the data cutoff for this analysis (Feb 13, 2015), 93 patients (47%) had crossed over from TPC to T-DM1. At a median follow-up time of 30.5 months, OS was significantly longer with T-DM1 vs TPC (median OS 22.7 vs 15.8 months; HR=0.68 [95% CI, 0.54–0.85; p=0.0007]) and these results crossed the OS efficacy stopping boundary. A sensitivity analysis, in which patients were censored when they switched from TPC to T-DM1, also showed an OS benefit with T-DM1 vs TPC (median 22.7 vs 15.6 months; HR=0.58 [95% CI: 0.43–0.77; p=0.0002]). The OS benefit was consistently observed across subgroups defined by age, visceral involvement, hormone receptor status, number of prior regimens, and TPC type. The T-DM1 group had nearly twice the mean exposure to the planned study treatment as the TPC group (7.93 vs 4.08 months). In treated patients, the incidence of grade ≥3 AEs was 40.0% and 47.3% in the T-DM1 and TPC arms, respectively. Grade ≥3 AEs occurring in ≥3% of either treatment arm were neutropenia (T-DM1, 2.5%; TPC, 15.8%), febrile neutropenia (T-DM1, 0.2%; TPC, 3.8%), thrombocytopenia (T-DM1, 6.0%; TPC, 2.7%), anemia (T-DM1, 3.5%; TPC, 3.3%), dyspnea (T-DM1, 2.5%; TPC, 3.8%), diarrhea (T-DM1, 0.7%; TPC, 4.3%), and asthenia (T-DM1, 1.0%; TPC, 3.3%). Conclusions In this population of patients with advanced breast cancer who previously received a taxane, trastuzumab, and lapatinib, treatment with T-DM1 resulted in a statistically significant and clinically meaningful improvement in OS compared with TPC. A lower incidence of grade ≥3 AEs was observed with T-DM1 and its safety profile was consistent with previous studies. These data further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer. Citation Format: Wildiers H, Kim S-B, Gonzalez-Martin A, LoRusso PM, Ferrero J-M, Yu R, Smitt M, Krop I. Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA 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 S5-05.