Citations

TPS17 Background: Emerging studies suggest that breast cancer, particularly triple negative breast cancer (TNBC), may be sensitive to immunotherapy. However, the response rate of single agent immune checkpoint blockade agent in TNBC is rather low. Previous genomic study in residual tumor after neoadjuvant chemotherapy showed inverse correlations between MEK activation signature and the amount of tumor infiltrating lymphocytes (TILs) in residual disease samples as well as poor outcome. Preclinical study also showed that the combination of MEK inhibitor and anti-PD-L1 antibody in mouse model can eradicate TNBC tumors. Methods: This is a single arm, Phase I/II trial of Pembrolizumab (P) in combination with Binimetinib (B) in patients with unresectable locally advanced or metastatic TNBC. This trial is currently opened for accrual at Mayo Clinic in Florida and Minnesota. Patients with TNBC defined as ER ≤ 10% and PR ≤ 10% who received ≤ 3 prior lines with measurable disease will be enrolled. The primary objective of the Phase I part is to determine the maximum tolerated dose of B in combination with P and for the Phase II part is objective response rate (ORR) by RECIST criteria. The secondary endpoints include ORR by irRECIST, progression free survival, and overall survival. The total sample size is 15-38 patients with 6-12 patients in Phase I with 2 dose levels and 9-26 patients in Phase II. Simon’s Two-Stage Optimal Design is used to test the null hypothesis that this two-drug combination has an ORR of at most 15% vs. the alternative hypothesis that it has an ORR of at least 35%. Patients will receive single agent B for 2 weeks prior to starting P. A mandatory biopsy will be performed before starting B and an optional biopsy will be performed after 2 weeks of B. Tumor tissue will be evaluated for the amount and phenotypes of TILs, PD-L1 expression, and gene expression analysis using PanCancer Immune Profiling Panel, and PDJ amplification. Peripheral blood will be evaluated for circulating immunoregulatory cells, cytokine profiling, circulating tumor cells (CTCs), as well as p-ERK and PD-L1 expression on CTCs. Clinical trial information: NCT03106415.

Abstract Lessons Learned Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments. The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development. Background Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC. Methods We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and the toxicity of the combination. Results The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2–54). The median follow-up was 36.4 months (range 23.5–96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9–10.6) and the median OS was 15.0 months (95% CI, 11.3–28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%). Conclusion The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second - or later-line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.

In this issue of The Oncologist, Agarwal et al. report negative results from a phase I trial of LFA102. Although “negative” in terms of antitumor activity, the study provides useful pharmacokinetic and pharmacodynamic information. Future trials evaluating PRLR blockers alone and in combination with other agents may still be warranted in patients with breast and prostate cancer.

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

Purpose We compared efficacy of trastuzumab versus no trastuzumab in patients with small (≤ 2 cm) human epidermal growth factor receptor 2 (HER2) –positive breast cancer treated in randomized trials. Methods A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) –positive and HR-negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status. Results Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR-negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively. Conclusion Women with HER2-positive tumors ≤ 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and ≤ one positive lymph node may be candidates for trials assessing less aggressive treatment approaches.