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A phase 2 study, ATRACTIB (NCT04408118), investigated a novel triple combination therapy for advanced triple-negative breast cancer (TNBC), demonstrating encouraging antitumor activity and a manageable safety profile in patients, predominantly those with PD-L1–negative disease. This research offers a potential new avenue for a patient population with significant unmet needs.1
TNBC, characterized by the absence of estrogen and progesterone receptors and HER2 overexpression, remains a highly aggressive subtype with a poorer prognosis compared to other breast cancer types. Current first-line treatment strategies for advanced TNBC are often guided by programmed cell death-ligand 1 (PD-L1) expression, as checkpoint inhibitors have shown benefit in PD-L1–positive disease. However, PD-L1–negative TNBC continues to pose a significant therapeutic challenge, with limited advancements beyond conventional chemotherapy.
The ATRACTIB trial, a multicenter, single-arm, phase 2 study, aimed to evaluate the efficacy and safety of a combination of atezolizumab (Tecentriq), paclitaxel, and bevacizumab (Avastin) as a first-line treatment for advanced TNBC, irrespective of PD-L1 status. The study enrolled 100 female patients, with a notable 97.6% of evaluable tumors being PD-L1–negative.
Key Efficacy Outcomes
The primary end point of investigator-assessed progression-free survival (PFS) was met, with a median PFS of 11.0 months (95% CI, 9.0–13.4; P <.001). This finding is particularly significant given that the study population was highly enriched for PD-L1–negative tumors, a group that has historically shown limited benefit from immunotherapy in prior pivotal trials. For patients with confirmed PD-L1–negative tumors (n = 83), the median PFS was 9.3 months (95% CI, 7.8–13.2).
The objective response rate was 63.0% (95% CI, 52.8%–72.4%), with 14% of patients achieving complete responses and 49% experiencing partial responses. The median overall survival (OS) was 27.4 months (95% CI, 23.4–37.4). While OS was a secondary end point and influenced by a high censoring rate (48% of patients censored due to study completion), the 12-month OS rate of 81.3% compares favorably with historical data from other advanced TNBC studies. The median duration of response was 10.1 months (95% CI, 7.3–13.9).
These results are noteworthy when compared to historical data from key trials in advanced TNBC. For instance, the IMpassion130 trial (NCT02425891), which evaluated atezolizumab plus nab-paclitaxel, reported a median PFS of 5.6 months and a median OS of 19.7 months in the PD-L1–negative cohort.2 Similarly, the KEYNOTE-355 trial (NCT02819518) demonstrated no significant PFS or OS benefit in PD-L1–negative patients treated with pembrolizumab alongside chemotherapy.3 The ATRACTIB findings suggest that the inclusion of bevacizumab may contribute to overcoming the lack of immunotherapy benefit observed in PD-L1–negative advanced TNBC in previous studies.
Safety Profile and Tolerability
The safety profile of the triplet combination was deemed manageable. All patients experienced at least 1 treatment-emergent adverse event (TEAE), with 61% presenting with grade 3 or 4 TEAEs. Discontinuation of any study treatment due to treatment-related TEAEs occurred in 48% of patients, with paclitaxel discontinuations being the most frequent (41%).1
Common nonhematological TEAEs of any grade included fatigue (63%), neurotoxicity (46%), diarrhea (44%), and alopecia (41%). The most frequent hematologic TEAEs were neutropenia (27%, 12% grade 3 or 4) and anemia (24%). Hypertension, related to bevacizumab, was reported in 26% of patients (6% grade 3, 1 grade 4 hypertensive crisis). Importantly, no treatment-related deaths or new safety signals were observed in this study, aligning with the known safety profiles of the individual agents.
The Role of Bevacizumab and Future Directions
The rationale for including bevacizumab, an anti-VEGF antibody, in this triplet regimen stems from its demonstrated synergistic effect with chemotherapy in HER2-negative advanced breast cancer and its potential immunomodulatory properties. Preclinical studies have shown that anti-VEGF therapies can enhance the antitumor activity of immune checkpoint inhibitors by normalizing tumor vasculature and promoting immune cell infiltration. The ATRACTIB findings lend clinical support to this hypothesis, suggesting that antiangiogenic agents may play a crucial role in extending the benefits of immunotherapy to a broader population, particularly those with PD-L1–negative disease.
The ATRACTIB study’s strengths include its substantial sample size for a phase 2 trial and its focus on the difficult-to-treat PD-L1–negative TNBC subgroup. However, its single-arm design limits the ability to formally assess the individual contribution of each agent or the precise synergy between bevacizumab and the atezolizumab-paclitaxel combination.
The evolving treatment landscape for TNBC, including the emergence of antibody-drug conjugates as first-line options, further underscores the need for effective combination strategies. For example, the BEGONIA trial (NCT03742102), evaluating datopotamab deruxtecan (Datroway; Dato-DXd) plus durvalumab (Imfinzi), demonstrated promising activity in a predominantly PD-L1–low population.4