MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.
The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Rationale for Combining Antibody-Drug Conjugates with Immunotherapy
Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.
TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.
Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.
“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
Study Design
The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.
“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.
During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.
“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.
Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
Promising Anti-tumor Activity
The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.
“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.
The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.
Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”
She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
Encouraging survival trends
Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.
During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”
These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
Relationship between biomarker expression and response
The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).
“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.
Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
Safety of combination treatment
The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.
All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).
The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.
“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.