Lin, Yong

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 Purpose: Growing mechanistic and epidemiologic evidence suggests that both metformin and statins have anti-cancer effects and are associated with reduced pancreatic cancer mortality. However, the joint effect of combination statin/metformin on pancreatic cancer mortality is unknown. By applying a robust analytic approach, we aim to examine the association between metformin and/or statin use and overall survival in a large cohort of patients with primary pancreatic adenocarcinoma (PDAC). Patients and Methods: 12,572 elderly patients with primary PDAC diagnosed between 2008 and 2012 were identified by using the Surveillance, Epidemiology, and End Results (SEER), and the detailed information on metformin and statin use was extracted from Medicare Part D. A Cox proportional hazard model with time-varying covariate adjusted for the propensity score was applied to assess the association of metformin and /or statin use with overall survival while controlling for potential confounders. Results: Of total 12,572 PDAC patients (median age = 76 years), 11,526 (91.77%) patients died before the study ended with a median follow-up of 3.8 months (interquartile range: 1.4-10.1). By the time-varying covariate analysis, statin use was significantly associated with an improved overall survival [Hazard ratio (HR), 0.938; 95% confidence interval (CI), 0.898 to 0.979], and more pronounced in post-diagnosis statin users (HR, 0.693; 95% CI, 0.555 to 0.864). However, metformin use was not significantly associated with overall survival (HR, 1.011; 95% CI, 0.939 to 1.091), neither in pre-diagnosis users (HR, 1.015; 95% CI, 0.970 to 1.061) nor in post-diagnosis users (HR, 0.990; 95% CI, 0.866 to 1.131). Additionally, no superior beneficial effect was observed for dual users (HR, 0.998; 95% CI, 0.947 to 1.053). Conclusions: Exposures to statin, not metformin, was significantly associated with reduced overall mortality of PDAC, indicating potential benefits of statin use on improving survival among PDAC patients. Further prospective validation is required to confirm these findings. Citation Format: Jian-Yu E, Shou-En Lu, Yong Lin, Judith M. Graber, David Rotter, Lanjing Zhang, Gloria M. Petersen, Kitaw Demissie, Grace Lu-Yao, Xiang-Lin Tan. Effects of concomitant metformin and statins on overall survival of pancreatic cancer patients: results from SEER-Medicare data analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3288. doi:10.1158/1538-7445.AM2017-3288

Abstract Background: Published evidence indicates that individual use of metformin and statin is associated with reduced cancer mortality. However, their differential and joint effects on pancreatic cancer survival are inconclusive. Methods: We identified a large population-based cohort of 12,572 patients ages 65 years or older with primary pancreatic ductal adenocarcinoma (PDAC) diagnosed between 2008 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. Cox proportional hazards models with time-varying covariates adjusted for propensity scores were used to assess the association while controlling for potential confounders. Results: Of 12,572 PDAC patients, 950 (7.56%) had used metformin alone, 4,506 (35.84%) had used statin alone, and 2,445 (19.45%) were dual users. Statin use was significantly associated with improved overall survival [HR, 0.94; 95% confidence interval (CI), 0.90–0.98], and survival was more pronounced in postdiagnosis statin users (HR, 0.69; 95% CI, 0.56–0.86). Metformin use was not significantly associated with overall survival (HR, 1.01; 95% CI, 0.94–1.09). No beneficial effect was observed for dual users (HR, 1.00; 95% CI, 0.95–1.05). Conclusions: Our findings suggest potential benefits of statins on improving survival among elderly PDAC patients; further prospective studies are warranted to corroborate the putative benefit of statin therapy in pancreatic cancer. Impact: Although more studies are needed to confirm our findings, our data add to the body of evidence on potential anticancer effects of statins. Cancer Epidemiol Biomarkers Prev; 26(8); 1225–32. ©2017 AACR.