ENHANCE 1 is a phase Ib/II clinical trial (NCT02513472) evaluating the use of eribulin mesylate in combination with the checkpoint inhibitor pembrolizumab in patients with metastatic triple-negative breast cancer (TNBC). At the 2017 San Antonio Breast Cancer Symposium, Sara Tolaney, MD, MPH, Associate Director of the Susan F. Smith Center for Women's Cancers, and Associate Director of the Clinical Research, Breast Oncology, Dana-Farber Cancer Institute, Boston, presented safety, efficacy, and survival data from this clinical trial (Spotlight Session PD6-13).
Regarding the results, Tolaney noted, “The combination of eribulin mesylate and pembrolizumab showed very encouraging efficacy in TNBC patients, irrespective of their PD-L1 status.”
TNBC Characteristics & Treatment
In TNBC, the patients' cancerous cells show negative pathology for estrogen (ER-), progesterone (PR-), and HER2 (HER2-) receptors. Approximately 10-15 percent of breast cancer patients have disease with this type of pathology. Generally speaking, this disease tends to be more aggressive than other forms of breast cancer, with increased chances for metastasis and recurrence. The increased chance for disease relapse is primarily in the first 3-5 years after treatment, but after that time, the recurrence rate drops rather abruptly to levels below those for hormone-driven breast cancers.
Treatment of patients with TNBC is complicated by the fact that the standard treatment option for this subtype of disease is just cytotoxic chemotherapy. For hormone-driven breast cancer, therapies like selective estrogen receptor modulators (SERMs) are used, such as tamoxifen or aromatase inhibitors (e.g., letrozole, anastrozole, exemestane). For HER2-positive breast cancer patients, targeted therapies such as trastuzumab may be appropriate.
Further complicating the treatment of TNBC is the fact that there are several different subtypes of the disease. Among the different subtypes are the following: two basal-like (BL-1, BL-2), immunomodulatory, luminal androgen receptor, mesenchymal, and mesenchymal stem-like (J Clin Invest 2011;121(7):2750-2767).
Spotlight Session PD6-13
In November 2010, the FDA granted approval for the use of the antineoplastic agent eribulin mesylate for the treatment of metastatic breast cancer patients who received prior anthracycline and taxane treatment in the adjuvant or metastatic setting, as well as two chemotherapy regimens for metastatic disease. This approval was largely based on the results obtained in the phase III EMBRACE trial (NCT00388726).
Eribulin mesylate is a structurally simplified analog of halichondrin B, a complex natural product that was first isolated in 1986 from the marine sponge Halichondria okadai. Mechanistically, eribulin is thought to exert its primary antimitotic effect via its binding to tubulin at or near the vinca domain. However, this may not be the only mode of action for eribulin.
“In addition to its antimitotic activity, in preclinical studies, eribulin was shown to alter tumor vasculature, reducing the hypoxia that can be associated with those cancerous lesions,” Tolaney explained. “There is also some preclinical evidence for this compound altering the phenotype of the cancer cells from the more-invasive mesenchymal to the less-metastatic epithelial type.”
When asked about the rationale for combining eribulin mesylate with the checkpoint inhibitor pembrolizumab, Tolaney said, “There was some evidence gained in preclinical studies which showed that eribulin mesylate could work synergistically with pembrolizumab for enhanced cancer immunotherapy.”
This preclinical work, which was performed in a murine Lewis lung carcinoma model, showed that treatment with eribulin mesylate inhibited the proliferation of the immunosuppressive tumor-associated M2 macrophages (Cancer Res 2013;73(1 Suppl):Abstract nr B90). Also, increased CD25 expression was noted on CD4+ Foxp3- T cells but not on the immunosuppressive CD4+ Foxp3+ T regulatory cells (Tregs).
ENHANCE 1 Details
The ENHANCE 1 phase Ib/II trial is an open-label, single arm, multicenter study that evaluated the use of eribulin mesylate and the anti-PD-1 checkpoint inhibitor pembrolizumab in metastatic TNBC patients who had no more than two prior systemic anticancer therapy regimens in the metastatic setting. Additionally, patients were required to have measurable disease using RECISTv1.1 criteria, and an ECOG PS of 0-1.
In the phase Ib portion of this multi-stage study, the primary endpoint was safety and tolerability. In addition, the dosage of eribulin mesylate was determined for the subsequent (phase II) part of the study.
The primary endpoint for the phase II portion of the study was the objective response rate (ORR). Secondary endpoints for this trial included the following: progression-free survival (PFS); overall survival (OS); duration of response (DOR); and efficacy in the PD-L1 positive patient subset.
For the phase Ib portion of the trial, patients (n=7) were dosed with eribulin mesylate at 1.4 mg/m2 IV on days 1 and 8 and 200 mg pembrolizumab on day 1 of each 21-day dosing cycle. However, during this initial phase, no DLTs were observed in the participants (six evaluable patients); consequently, the initial dosing scheme was utilized for the remaining patients (n=100) in the phase II portion of the study.
The median age of patients (n=107) in this study was 55 years, with a range of 32-88 years. Patients were stratified by the number of prior systemic anticancer regimens in the metastatic setting: Stratum 1—no prior treatment-61.7 percent of patients; Stratum 2—1-2 prior lines of treatment-38.3 percent of patients. Patients were also stratified using their PD-L1 status. Patients were deemed to be PD-L1 positive if there was staining in their stroma or ≥ 1 percent of tumor cells. The stratification for PD-L1 status was as follows: positive—45.8 percent; negative—45.8 percent; unavailable—8.4 percent.
The most common treatment-emergent adverse events (TEAEs) across all grades were fatigue (73.8%), peripheral neuropathy (62.6%), and nausea (61.7%). Grade 3 or 4 TEAEs were noted in 47.7 percent and 18.7 percent of patients, respectively. The most commonly noted of these grade 3 or 4 TEAEs were neutropenia (30.8%) and peripheral neuropathy (9.3%). A total of 24 patients (two from the Ib and 22 from the phase II portions of the trial, respectively) had TEAEs that led to withdrawal from treatment with the experimental medication.
For the evaluable patient population (n=106), the ORR was 26.4 percent (95% CI 18.3-35.9%). For the Stratum 1 (n=65) and Stratum 2 (n=41) patients, the ORRs were 29.2 percent (95% CI: 18.6-41.8%) and 22.0 percent (95% CI: 10.6-37.6%), respectively. For the 28 patients included in the ORR data (i.e., complete or partial responders), the median DOR was 8.3 months (95% CI: 6.5-12.9 months). Of these responders, 53.6 percent and 14.3 percent had DOR values greater than 6 or 12 months, respectively.
The median PFS value for the entire patient population (n=107) was 4.2 months (95% CI: 4.1-5.6 months). However, for the Stratum 1 (n=66) and Stratum 2 (n=41) participants, the median PFS values were 4.9 months (95% CI: 4.1-6.1 months) and 4.1 months (95% CI: 2.1-6.2 months), respectively.
In the entire patient population, the median OS was 17.7 months (95% CI: 13.7 months-not estimable). For the Stratum 1 and Stratum 2 patients, the median OS figures were 17.7 months (95% CI: 13.3 months-not estimable) and 16.3 months (95% CI: 12.4-19.2 months), respectively.
Ongoing Study Needed
When discussing the results from this trial, Tolaney noted, “The combination of eribulin mesylate with pembrolizumab demonstrated activity in TNBC patients regardless of their PD-L1 status. In the 106 patients who were evaluable for our studies, the ORR was 26.4 percent; of the three patients displaying a CR, two had PD-L1-positive tumors.
“The median OS for the evaluable patients in this trial was 17.7 months, which compares favorably for the typical 12-14 months observed for similar patients with eribulin mesylate monotherapy in previous studies,” she continued.
With regards to the safety data Tolaney explained, “The TEAEs which we observed were similar historically to those observed for either treatment as a monotherapy; we were pleased that there did not appear to be any synergistic toxicities for this combination.
“Given the multiple potential mechanisms of action for eribulin mesylate, such as tubulin-based antimitotic activity, vascular remodeling and alteration of cancer cells to the less-invasive epithelial-like phenotype, as well as the potential synergistic activity with immunotherapy-based checkpoint inhibitors, further study of this combination in the difficult-to-treat TNBC setting is clearly warranted.”
Richard Simoneaux is a contributing writer.
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