Martín, Miguel

Abstract Background: A recent exploratory subgroup analysis pooling data from over 1000 patients (pts) in MONARCH 2 (final analysis) and MONARCH 3 (interim analysis) demonstrated that pts with clinical characteristics that predict for worse outcome (e.g. liver metastases, progesterone receptor [PgR]-negative status, high-grade tumors) received the largest benefit from the addition of abemaciclib to endocrine therapy (ET). There is also interest in determining the extent to which abemaciclib improves progression-free survival (PFS) in pts with favorable prognostic factors (e.g. bone-only disease, long treatment-free interval [TFI]). Here we present an update of the subgroup analyses of the MONARCH 3 study using data from the preplanned final PFS analysis. Methods: Enrollment criteria and study designs were previously described (Sledge et al. J Clin Oncol. 2017; Goetz et al. J Clin Oncol. 2017). An exploratory pooled analysis was conducted using data from MONARCH 2 (NCT02107703) and the MONARCH 3 (NCT02246621) preplanned final PFS analysis to identify significant prognostic factors regardless of therapy received. Using the updated MONARCH 3 data, PFS and objective response rate (ORR) (in pts with measurable disease) were examined within the prognostic subgroups that had been previously identified as being statistically significant. Additionally, subpopulation treatment effect pattern plot (STEPP) methodology was used to evaluate the association between TFI following adjuvant ET and outcomes of NSAI alone or with abemaciclib. Results: Assessment of clinical factors from MONARCH 2 and MONARCH 3 (final PFS data) confirmed that the following factors remained significantly prognostic regardless of treatment received: bone-only disease, liver metastases, tumor grade, PgR status, and ECOG performance status. In MONARCH 3, prognosis was poor in pts with liver metastases, PgR-negative tumors, and high-grade tumors. While all subpopulations benefited from the addition of abemaciclib to ET regardless of prognosis, pts with these three poor prognostic factors received substantial benefit from abemaciclib, with PFS hazard ratios (HR) ranging from 0.4 to 0.5 and with differential improvement in ORR typically >30%. Furthermore, STEPP analysis of TFI (on the MONARCH 3 pts who had received adjuvant ET) demonstrated that pts who had a shorter TFI had a worse prognosis and received relatively greater benefit from abemaciclib plus NSAI than did pts with a longer TFI. Patients with bone-only disease or a long TFI also received benefit from abemaciclib, but to a relatively lesser extent (HR ranging from approximately 0.6 to 0.8). Conclusions: This exploratory analysis of the preplanned final PFS data from MONARCH 3 confirms previous findings that pts with poor prognostic factors may receive relatively greater benefit from the addition of abemaciclib to ET. Citation Format: Joyce O'Shaughnessy, Matthew P. Goetz, George W. Sledge, Miguel Martin, Yong Lin, Tammy Forrester, Ian C. Smith, Angelo Di Leo, Stephen Johnston. The benefit of abemaciclib in prognostic subgroups: An update to the pooled analysis of MONARCH 2 and 3 [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 CT099.

Abstract Background: Abemaciclib is an orally administered, selective CDK4 & 6 inhibitor dosed on a continuous schedule. In patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), abemaciclib demonstrated clinical activity as monotherapy in MONARCH 1 and efficacy with a generally tolerable safety profile in combination with fulvestrant in MONARCH 2. At the MONARCH 3 (NCT02246621) interim analysis, abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) significantly improved progression-free survival (PFS) (hazard ratio [HR], 0.543; 95% confidence interval [CI], 0.409, 0.723; p=.000021) and objective response rate (ORR) (measurable disease: abemaciclib arm, 59.2%; placebo arm, 43.8%; p=.004) with a generally tolerable safety profile as initial treatment for HR+, HER2- ABC. Here we present the MONARCH 3 results from the preplanned final PFS analysis. Methods: MONARCH 3 is a double-blind, Phase 3 study of abemaciclib/placebo (150 mg, twice daily continuous schedule) + NSAI (1 mg anastrozole or 2.5 mg letrozole, daily) in postmenopausal women with HR+, HER2- ABC who have had no prior systemic therapy for advanced disease. Endocrine therapy (ET) naïve pts or pts with disease relapse >12 months after (neo)adjuvant ET were randomized 2:1 and stratified by metastatic site (visceral, bone-only, or other) and prior ET (aromatase inhibitor, no ET, or other). The primary objective was investigator-assessed PFS. Additional objectives included ORR, clinical benefit rate (CBR), duration of response (DoR), overall survival (OS), and safety and tolerability. The study was powered to 80% at 1-sided α=.025 assuming a HR of 0.67 in favor of abemaciclib + NSAI, with the final analysis at 240 PFS events. Results: 493 pts were randomized to abemaciclib + NSAI (n=328) or placebo + NSAI (n=165). At the final PFS analysis, 246 PFS events had occurred. Abemaciclib + NSAI significantly extended PFS (HR, 0.540; 95% CI, 0.418, 0.698; p=.000002; median: abemaciclib arm, 28.18 vs placebo arm, 14.76 months). PFS was improved across all subgroups. For pts with measurable disease, the ORR was 61.0% in the abemaciclib arm and 45.5% in the placebo arm (p=.003), and the CBR was 79.0% in the abemaciclib arm and 69.7% in the placebo arm (p=.037). The median DoR was 27.39 months in the abemaciclib arm compared to 17.46 months in the placebo arm. OS was immature at the time of analysis. Adverse events were consistent with previous reports. Conclusions: Abemaciclib + NSAI demonstrated a generally tolerable safety profile and was an effective initial treatment for pts with HR+, HER2- ABC, significantly improving PFS and ORR. Citation Format: Matthew P. Goetz, Miguel Martin, Angelo Di Leo, Seock-Ah Im, Ahmad Awada, Tammy Forrester, Martin Frenzel, Joanne Cox, Susana Barriga, Masakazu Toi, Hiroji Iwata, Stephen Johnston. MONARCH 3: Abemaciclib as initial therapy for patients with HR+, HER2- advanced breast cancer - Results from the preplanned final PFS analysis [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 CT040.

Abstract Background: Abemaciclib is an orally administered, selective inhibitor of cyclin-dependent kinases 4 & 6 that is dosed on a twice daily continuous schedule. Abemaciclib has demonstrated clinical efficacy with a generally tolerable safety profile in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer in combination with fulvestrant in MONARCH 2 (NCT02107703) and in combination with non-steroidal aromatase inhibitors (NSAI) in MONARCH 3 (NCT02246621). These analyses were conducted to evaluate if patient and disease characteristics may better inform in whom and when abemaciclib should be initiated to define optimal treatment strategies. Methods: MONARCH 2 and 3 enrolled patients with HR+, HER2- advanced breast cancer. In MONARCH 2, patients whose disease had progressed while receiving endocrine therapy were treated with abemaciclib/placebo plus fulvestrant. In MONARCH 3, patients were treated with abemaciclib/placebo plus NSAI as initial therapy for advanced disease. An exploratory pooled analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (progression-free survival [PFS] and objective response rate [ORR] in patients with measurable disease) were examined for patient subgroups corresponding to each of the identified significant prognostic factors. Subpopulation treatment effect pattern plot (STEPP) methodology was performed to examine the association between treatment-free interval (TFI) following adjuvant endocrine therapy and outcomes of endocrine therapy alone or in combination with abemaciclib in MONARCH 3. Results: Analyses of clinical factors in over 1000 patients confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor (PgR) status, and ECOG performance status. Prognosis was poor in patients with liver metastases, PgR-negative tumors, and high-grade tumors. While all subpopulations benefited from the addition of abemaciclib to endocrine therapy regardless of prognosis, substantial benefit of abemaciclib was observed in poor prognosis subgroups, characterized by large increases in PFS (hazard ratios = 0.4 to 0.5) and ORR (over 30%). In addition, STEPP analysis of TFI on a subset of the MONARCH 3 population showed that patients with the shortest TFI appeared to have a poorer prognosis and received more benefit from the addition of abemaciclib compared to patients with longer TFI. Conclusions: This exploratory analysis has provided data that could help optimize treatment strategies by identifying that patients with poor prognostic factors may receive greater benefit from the addition of abemaciclib to endocrine therapy. Citation Format: Goetz MP, O'Shaughnessy J, Sledge Jr. GW, Martin M, Lin Y, Forrester T, Mockbee C, Smith IC, Di Leo A, Johnston S. The benefit of abemaciclib in prognostic subgroups: An exploratory analysis of combined data from the MONARCH 2 and 3 studies [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 GS6-02.

Purpose Trastuzumab and pertuzumab are human epidermal growth factor receptor 2 (HER2) –targeted monoclonal antibodies, and trastuzumab emtansine (T-DM1) is an antibody–drug conjugate that combines the properties of trastuzumab with the cytotoxic activity of DM1. T-DM1 demonstrated encouraging efficacy and safety in a phase II study of patients with previously untreated HER2-positive metastatic breast cancer. Combination T-DM1 and pertuzumab showed synergistic activity in cell culture models and had an acceptable safety profile in a phase Ib and II study. Methods In the MARIANNE study, 1,095 patients with centrally assessed, HER2-positive, advanced breast cancer and no prior therapy for advanced disease were randomly assigned 1:1:1 to control (trastuzumab plus taxane), T-DM1 plus placebo, hereafter T-DM1, or T-DM1 plus pertuzumab at standard doses. Primary end point was progression-free survival (PFS), as assessed by independent review. Results T-DM1 and T-DM1 plus pertuzumab showed noninferior PFS compared with trastuzumab plus taxane (median PFS: 13.7 months with trastuzumab plus taxane, 14.1 months with T-DM1, and 15.2 months with T-DM1 plus pertuzumab). Neither experimental arm showed PFS superiority to trastuzumab plus taxane. Response rate was 67.9% in patients who were treated with trastuzumab plus taxane, 59.7% with T-DM1, and 64.2% with T-DM1 plus pertuzumab; median response duration was 12.5 months, 20.7 months, and 21.2 months, respectively. The incidence of grade ≥ 3 adverse events was numerically higher in the control arm (54.1%) versus the T-DM1 arm (45.4%) and T-DM1 plus pertuzumab arm (46.2%). Numerically fewer patients discontinued treatment because of adverse events in the T-DM1 arms, and health-related quality of life was maintained for longer in the T-DM1 arms. Conclusion T-DM1 showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.

Abstract Introduction: Small studies have indicated a possible correlation between a HER2 gene polymorphism at codon 655 and trastuzumab-associated cardiotoxicity. Association between a synonymous coding variant rs7853758 within the SLC28A3 gene and anthracycline induced cardiotoxicity has also been reported. This study aimed to validate these correlations and assess for any relationship with prognosis. Methods: Genomic DNA was isolated from 666 patients enrolled in a large trial of adjuvant chemotherapy in HER2 amplified early breast cancer (BCIRG 006). Genotyping was conducted using Sequenom MassARRAY System for HER2 G->A polymorphism at amino acid codon 655 (rs1136201) and variant rs7853758 (L461L) within the SLC28A3 gene. Results: Of the 666 patients analyzed, 216 patients were treated with anthracycline based therapy, 226 with trastuzumab based therapy, and 224 with regimens containing both an anthracycline and trastuzumab. Compared with the overall results of the BCIRG006 study (N=3,222), in the subset of patients genotyped in this analysis, a less robust improvement in disease free survival (DFS) was observed for the trastuzumab arms than control arm (HR, 0.821). When stratified for prognostic features, the hazard ratio in favor of trastuzumab was consistent with that of the overall study (HR, 0.674). Samples from 662 patients were successfully genotyped for rs1136201. Of these, 424 (64%) were AA, 30 (4.5%) were GG, 208 (31%) were AG genotype. Samples from 665 patients were successfully genotyped for rs7853758. Of these, 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. There was no correlation seen between mean left ventricular ejection fraction (LVEF) and HER2 genotype at codon 655 in patients treated with trastuzumab. Of patients tested for the HER2 polymorphism, cardiac dysfunction [defined as > 10% decline in LVEF or clinical congestive heart failure (CHF)] developed in 16% of patients with AA, 17% of patients with GG and 20% of patients with AG. There was also no correlation between mean LVEF and variant rs7853758 in patients treated with anthracyclines. The percentage of patients who developed cardiac dysfunction was 13%, 17% and 21% in AA, GG, and AG genotypes respectively. No correlation between disease free survival and any of the genotypes was seen. Conclusion: In the largest analysis to date to evaluate for relationship between cardiac toxicity and HER2 polymorphism, we did not find a correlation with rs1136201 HER2 polymorphism and trastuzumab induced cardiac toxicity. Our study also did not show a correlation between variant rs7853758 (L461L) and anthracycline induced cardiotoxicity. Neither polymorphism correlated with prognosis. Citation Format: Peddi PF, Hurvitz SA, Fasching PA, Wang L, Cunningham J, Weinshilboum RM, Liu D, Quinaux E, Fourmanoir H, Robert NJ, Valero V, Crown J, Falkson C, Brufsky A, Pienkowski T, Eiermann W, Martin M, Bee V, Slamon DJ. Genetic polymorphism and correlation with treatment induced cardiotoxicity and prognosis in HER2 amplified early breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-09.

Learning Objectives Analyze the clinical trial data for the treatment of breast cancer. Evaluate the risk of cardiotoxicity associated with the use of trastuzumab. Design and conduct a practical approach to managing patients with trastuzumab-associated cardiotoxicity. This article is available for continuing medical education credit at CME.TheOncologist.com.