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Purpose:As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings.Patients and Methods:In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination.Results:The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)].Conclusions:Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

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Purpose: As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings. Patients and Methods: In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination. Results: The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)]. Conclusions: Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

1015 Background: As monotherapies, both ERI (a chemotherapeutic microtubule inhibitor) and PEMBRO (a programmed death [PD]-1 blocking immunotherapy) have shown promising antitumor activity in mTNBC. Emerging data suggest that the addition of immunotherapy to traditional chemotherapy holds promise for mTNBC. This open-label, single-arm, phase 1b/2 study evaluated the safety and efficacy of ERI + PEMBRO in mTNBC. Methods: Patients (pts) with mTNBC and ≤2 prior systemic anticancer therapies for metastatic disease were enrolled and stratified by prior number of therapy (Stratum 1, 0; Stratum 2, 1–2). Pts received IV ERI 1.4 mg/m2 on day (d)1 and d8 and IV PEMBRO 200 mg on d1 of a 21-d cycle. The primary objectives were safety and objective response rate (ORR per RECIST 1.1 by independent imaging review). Assessments also included efficacy outcomes by PD ligand-1 (PD-L1) expression status; PD-L1+ was defined as a combined positive score ≥1 using the PD-L1 IHC 22C3 pharmDx. Results: As of data cutoff (July 31, 2019), 167 pts (Stratum 1, n=66; Stratum 2, n=101) were enrolled and treated. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were fatigue (66%), nausea (57%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). No deaths were considered treatment related. The overall ORR was 23.4% (95% CI: 17.2–30.5). Efficacy outcomes by PD-L1 status (PD-L1+, n=74; PD-L1-, n=75) and stratum are presented (table). Conclusions: ERI + PEMBRO has activity in pts with mTNBC. There was a trend toward more robust activity for the combination among patients with PD-L1+ tumors compared to PD-L1- tumors in the first-line setting (Stratum 1); whereas, in the later-line setting (Stratum 2) similar survival outcomes were observed among the PD-L1+ and PD-L1- pts. ERI + PEMBRO shows promise for mTNBC with efficacy that appears greater than historical reports of either agent alone. Clinical trial information: NCT02513472 . [Table: see text]

BACKGROUND The level of the DNA repair protein O6-methylguanine-DNA methyltransferase is an important determinant of the response of tumor cells in culture to alkylating nitrosoureas. In these cells, the abundance of messenger RNA (mRNA) is directly correlated with repair activity. PURPOSE Our purpose was to compare transferase mRNA levels with the repair activity in primary human tumors. METHODS Human transferase mRNA was measured in tissue samples from brain tumors, normal lung, lung tumors, ovarian tumors, and normal human liver by use of an RNA protection assay with an antisense probe prepared from the cloned gene. RESULTS Normal and tumor tissue samples from the same patient had similar transferase activity levels, but transferase expression varied widely among tissue samples from different patients. Brain and lung samples, on average, had transferase mRNA levels closer to those in liver samples than their transferase activity levels. In two cases, tissue samples which were transferase deficient by the activity assays were found to lack transferase mRNA. CONCLUSIONS Deficiencies in transferase activity are due to reduced or absent mRNA transcription or processing. In brain and lung, there may be post-transcriptional control of mRNA expression. The wide interindividual variation in transferase expression is also seen at the transcription level. IMPLICATIONS These are among the first measures of transferase mRNA expression in primary human tissue. More samples should be examined to extend these observations.

The resistance of human tumor strains in culture to cell killing by alkylating nitrosoureas is correlated with their levels of the DNA repair activity O6-methylguanine-DNA methyltransferase. Strains with the Mer- phenotype have no activity and are extremely sensitive. However, the relationship between the sensitivity of human tumors in vivo and transferase levels is not known, and even the existence of Mer- human tumors in vivo has been questioned. In this study 73 human tumor and normal tissue samples from brain, lung, and ovary were assayed for transferase levels and methylpurine glycosylase activity. For each organ, transferase levels varied over 100-fold, and Mer- tumors were detected in each group. There was no correlation between transferase and glycosylase levels, indicating that the absence of transferase in some tumor samples was not an artifact due to necrosis or inactivation of enzymes in the extract.