Key Points• Different therapeutic agents are currently available for the treatment of RRMM.• By performing an NMA, we identified a lenalidomidedexamethasone 1 mAb regimen as the most active therapeutic option in this setting.Despite major therapeutic advancements, multiple myeloma (MM) is still incurable and relapsed/refractory multiple myeloma (RRMM) remains a challenge; the rational choice of the most appropriate regimen in this setting is currently undefined. We performed a systematic review and 2 standard pairwise meta-analyses to evaluate the efficacy of regimens that have been directly compared with bortezomib or immunomodulatory imide drugs (IMiDs) in head-to-head clinical trials and a network meta-analysis (NMA) to determine the relevance of each regimen on the basis of all the available direct and indirect evidence. Sixteen trials were included in the pairwise meta-analyses, and 18 trials were included in the NMA. Pairwise meta-analyses showed that a 3-drug regimen (bortezomib-or IMiD-based) was superior to a 2-drug regimen in progression-free-survival (PFS) and overall response rate (ORR). NMAshowed that an IMiD backbone associated with anti-MM monoclonal antibodies (mAbs) (preferably) or proteasome inhibitors had the highest probability of being the most effective regimen with the lowest toxicity. The combination of daratumumab, lenalidomide, and dexamethasone ranked as the first regimen in terms of activity, efficacy, and tolerability according to the average value between surface under the cumulative ranking curve of PFS, overall survival, ORR, complete response rate, and safety. This is the first NMA comparing all currently available regimens evaluated in published randomized trials for the treatment of RRMM, but our results need to be interpreted taking into account differences in their patient populations. Our analysis suggests that IMiDs plus new anti-MM mAb-containing regimens are the most active therapeutic option in RRMM.

Taxane‐related peripheral neuropathy (TrPN) is a dose‐limiting toxicity with important interindividual variability. Genetic polymorphisms in absorption, distribution, metabolism, and excretion (ADME) genes may account for variability in drug efficacy and/or toxicity. By the use of Affymetrix drug‐metabolizing enzyme and transporter microarray platform, in a retrospective case‐control study, the correlation between ADME polymorphic variants and grades ≥ 2−3‐TrPN was investigated. In a breast cancer (BC) training set, five single‐nucleotide polymorphisms in NR1I3 and UDP‐glucuronosyltransferase (UGT)2B7 genes were correlated to grades ≥ 2−3‐TrPN protection. By receiver operating characteristic curves, the grades ≥ 2−3‐TrPN‐related candidate biomarkers in an independent series of 54 patients with BC (17 cases and 37 controls) were validated. NR1I3 was correlated to paclitaxel‐TrPN and UGT2B7 to docetaxel‐TrPN. Moreover, a genetic signature of prognostic relevance for BC outcome was found. Our findings might have potential relevance for personalized management of patients with BC for prevention of treatment failure in ultrametabolizer genetic variants.

We evaluated if standard hormonal therapy (HT) could be improved by the addition of mammalian target of rapamycin inhibitors (mTOR-I) in metastatic luminal breast cancer. A meta-analysis on 4 phase II-III randomized clinical trials was performed. Pooled hazard ratio (HR) for progression free survival (PFS)/ time to progression (TTP) was 0.62 in favor of mTOR-I+HT arm (95% confidence interval [CI] 0.55-0.70; p<0.0001). There was significant heterogeneity for PFS/TTP (Cochran's Q 32, p<0.0001, I2 index 90.6%). Pooled HR for overall survival (OS) was 0.84 in favor of the combination arm (95% CI 0.71-0.99; p=0.04). Heterogeneity was not significant (Cochran's Q 4.47, p=0.1, I2 index 55.3%). Pooled risk ratio (RR) for objective response rate (ORR) was 0.88 in favor of experimental arm (95% CI 0.85-0.91; p<0.0001). Heterogeneity was not significant (Cochran's Q 2.11, p=0.3, I2 index 5.2%). Adverse events (AEs), in particular those of grade 3-4, mostly occurred in mTOR-I+HT arm. Combination therapy of HT plus mTOR-I improves the outcome of metastatic luminal breast cancer patients. Our results provide evidence of a class-effect of these targeting molecules.

Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that 1 year (yr) of neratinib 240 mg/day after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in 2840 patients with early-stage HER2+ breast cancer at 2 yr (hazard ratio 0.67; 95% CI 0.50–0.91; p=0.009) [Chan 2016] and 5 yr (hazard ratio 0.73; 95% CI 0.57-0.92; p=0.008) [Martin 2017]. A prespecified subgroup analysis by hormone receptor (HR) status suggested enhanced efficacy with neratinib in patients with HR+ (2-yr hazard ratio 0.51; 95% CI 0.33–0.77) vs. HR– tumors (2-yr hazard ratio 0.93; 95% CI 0.60–1.43). The efficacy of neratinib was also greater in patients who initiated treatment within 1 yr of prior trastuzumab compared with those who started neratinib later. The European Medicines Agency's Committee for Medicinal Products for Human Use recently recommended neratinib for use in patients with HR+ tumors who initiate treatment within 1 yr of completing trastuzumab-based adjuvant therapy. Subgroup analyses from ExteNET examining iDFS benefits in this patient population are presented here. Methods: Patients with early-stage HER2+ breast cancer who completed trastuzumab-based (neo)adjuvant therapy were assigned to oral neratinib 240 mg/day or placebo for 1 yr. Randomization was stratified by HR status (determined locally before trial entry), nodal status, and trastuzumab regimen. Endocrine therapy was allowed in patients with HR+ disease. The primary endpoint, iDFS, was tested by 2-sided log-rank test and hazard ratios (95% CI) were estimated using Cox proportional hazards models. Kaplan-Meier methods were used to estimate iDFS rates. Secondary endpoints were DFS-DCIS, time to distant recurrence, distant DFS, and CNS recurrences. The primary analysis was conducted at 2 yr, and a sensitivity analysis conducted at 5 yr. Clinicaltrials.gov:NCT00878709. Results: Of the 2840 patients (neratinib, n=1420; placebo, n=1420), 1631 (57%) had HR+ disease (neratinib, n=816; placebo, n=815). Most (93%) HR+ patients were receiving endocrine therapy at baseline. 1334 of 1631 (82%) patients with HR+ tumors were randomized to start neratinib within 1 yr of last trastuzumab dose (neratinib, n=670; placebo, n=664). iDFS benefits from neratinib in this population are shown in the table. Secondary endpoints were also improved with neratinib vs. placebo in this population. Safety data in this subset will be presented at the meeting. Table. iDFS in patients with an interval between last trastuzumab dose and randomization of ≤1 yr  HR+ population (N=1334)ITT population (N=2297)  Hazard ratiob  Hazard ratiob  Δ, %a(95% CI)P-valueΔ, %a(95% CI)P-value2-yr analysisc+4.50.490.002+2.90.630.006  (0.30–0.78)  (0.45–0.88) 5-yr analysisd+5.10.580.002+3.20.700.006  (0.41–0.82)  (0.54–0.90) aDifference in iDFS rates between neratinib vs. placebo; bNeratinib vs. placebo; cData cut-off: July 2014; dData cut-off: March 2017 Conclusions: Neratinib may have enhanced and sustained efficacy in patients with HR+ disease who initiate treatment within 1 yr of trastuzumab-based adjuvant therapy. Citation Format: Gnant M, Martin M, Holmes F-A, Jackisch C, Chia SK, Iwata H, Moy B, Martinez N, Mansi J, Morales S, Ruiz-Borrego M, von Minckwitz G, Buyse M, Delaloge S, Bhandari M, Murias Rosales A, Galeano T, Fujita T, Luczak A, Barrios CH, Saura C, Rugo HS, Chien J, Johnston SR, Spencer M, Xu F, Barnett B, Chan A, Ejlertsen B. Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early-stage breast cancer: Subgroup analyses from the phase III ExteNET trial [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 P2-13-01.

Background: The international, randomized, placebo-controlled phase III ExteNET trial showed that a 1-year course of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in patients with early-stage HER2+ breast cancer (BC) (hazard ratio 0.67; 95% CI 0.50–0.91; p=0.009) [Chan et al. Lancet Oncol 2016]. The significant iDFS benefit with neratinib was maintained after a median 5 years' follow-up (hazard ratio 0.73; 95% CI 0.57-0.92; p=0.008) [Martin et al. ESMO 2017]. At both time-points, marked benefit with neratinib was evident in patients with hormone receptor (HR)+ tumors, whereas in patients with HR– disease, initial improvements with neratinib diminished after completing treatment. We report exploratory analyses from the ExteNET trial done to better characterize the effects of neratinib in the HR+ subgroup. Methods: Patients with early-stage HER2+ BC were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year after standard primary therapy and trastuzumab-based adjuvant therapy. Randomization was stratified by HR status (locally assessed), nodal status, and trastuzumab regimen. Adjuvant endocrine therapy was recommended for patients with HR+ disease. Data concerning disease recurrences were collected prospectively during year 1-2 post-randomization, and from medical records during year 3–5 post-randomization. Primary endpoint: iDFS. Secondary endpoints: DFS including ductal carcinoma in situ (DFS-DCIS); time to distant recurrence (TTDR); distant DFS (DDFS); cumulative incidence of central nervous system (CNS) recurrences; overall survival (OS). Hazard ratios (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Clinicaltrials.gov: NCT00878709. Results: 2840 patients were randomized (neratinib, n=1420; placebo, n=1420); 1631 (57%) patients had HR+ tumors (neratinib, n=816; placebo, n=815). 93% and 94% of HR+ patients in the neratinib and placebo groups, respectively, were receiving adjuvant endocrine therapy at baseline. Efficacy outcomes in the HR+ cohort after a median follow-up of 5.2 years are shown in the table. In subgroup analyses of the HR+ cohort, hazard ratios for iDFS were 0.49 in centrally confirmed HER2+ patients (n=951), and 0.58 in patients who had completed prior trastuzumab ≤12 months before randomization (n=1334). CNS recurrence and OS data are not yet mature.  Updated 2-year analysis5-year analysis  Hazard ratiobP-value Hazard ratiobP-value Δ, %a(95% CI)(2 sided)Δ, %a(95% CI)(2 sided)iDFS4.10.49 (0.31–0.75)0.0014.40.60 (0.43–0.83)0.002DFS-DCIS4.80.45 (0.29–0.69)&lt;0.0015.10.57 (0.42–0.79)&lt;0.001DDFS3.10.52 (0.32–0.84)0.0084.00.60 (0.42–0.85)0.004TTDR2.90.52 (0.31–0.85)0.013.80.61 (0.42–0.86)0.006a. Difference in event rates between neratinib vs placebo; b. Neratinib vs placebo Conclusions: Neratinib was associated with an absolute iDFS benefit of 4.4% in patients with HR+/HER2+ BC after 5 years' follow-up. HR/HER2 receptor cross-talk may underpin the notable effect of neratinib in patients with HR+ tumors when given in combination with endocrine therapy. Citation Format: Chia SKL, Martin M, Iwata H, Moy B, Lalani AS, Holmes FA, Mansi J, von Minckwitz G, Buyse M, Delaloge S, Ejlertsen B, Yao B, Murias Rosales A, Hellerstedt B, Cold S, Inoue K, Shen Z-Z, Galeano T, Barrios CH, Chan A. Effects of neratinib after trastuzumab-based adjuvant therapy in hormone receptor-positive HER2+ early-stage breast cancer: Exploratory analyses from the phase III ExteNET 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 P1-13-03.