Atezolizumab Plus Carboplatin Boosts Survival in Metastatic TNBC

Adding atezolizumab (Tecentriq) to carboplatin improved progression-free survival (PFS) and overall survival (OS) in patients with metastatic triple-negative breast cancer (TNBC), according to results of a randomized phase II trial.

Among 106 patients, the median PFS was 4.1 months with the combination compared with 2.2 months with carboplatin alone (HR 0.66, 95% CI 0.44-1.01, P=0.05), reported Jennifer Pietenpol, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues.

The median OS was 12.6 months with the added immune checkpoint inhibitor (ICI) versus 8.6 months with carboplatin (HR 0.60, 95% CI 0.37-0.96, P=0.03), they noted in JAMA Oncology. These survival improvements were demonstrated regardless of PD-L1 status.

The overall response rate (ORR) was also higher with the combination (30.4% vs 8% with carboplatin), as was the clinical benefit rate at 6 months (37.5% vs 18%).

Previous results from the phase III IMpassion 130 trial led to the accelerated approval of atezolizumab in combination with paclitaxel for PD-L1-positive metastatic TNBC. However, the subsequent phase III IMpassion131 trial evaluating atezolizumab in combination with paclitaxel failed to improve PFS or OS versus paclitaxel alone in this patient population, leading Genentech — atezolizumab’s developer — to voluntarily withdraw the accelerated approval in 2021.

The reasons for the negative findings in IMpassion131 “are unclear and suggest that anti-PD-L1 therapy efficacy may differ when combined with different chemotherapy,” wrote Pietenpol and colleagues.

In explaining the rationale behind this trial, the study authors said that, unlike taxanes, platinum agents are DNA intercalating agents and generate neoantigens that may stimulate an immune response. Therefore, this study was designed to prospectively evaluate the efficacy of adding atezolizumab to carboplatin.

In an editorial accompanying the study, Dionisia Quiroga, DO, PhD, and Margaret E. Gatti-Mays, MD, MPH, both of the Ohio State University in Columbus, noted that this trial (TBCRC 043) began in 2017 and that the management of TNBC has evolved since then, suggesting that the choice of single-agent carboplatin was “suboptimal, as evident by the median PFS of 2.2 months in the control arm.”

“In light of recent therapeutic advances in metastatic TNBC … in which median PFS has been 10 to 18 months, it is hard to justify using the combination of carboplatin plus atezolizumab in metastatic TNBC, even in a patient with a PD-L1-negative tumor,” they wrote.

While subgroup analyses showed that PD-L1 status did not affect survival with the immunotherapy, Quiroga and Gatti-Mays said that several clinical trials have found inconsistent clinical benefit in the metastatic breast cancer setting when using PD-L1 status as a biomarker of effect.

“Simply put, TBCRC 043 adds to the growing literature that PD-L1 is an imperfect biomarker for breast cancer,” they wrote.

Furthermore, the editorialists pointed out that patients with TNBC now receive carboplatin and/or pembrolizumab (Keytruda) in the neoadjuvant setting as standard of care, both of which were exclusion criteria for this study.

Finally, they noted that despite the higher ORR and OS seen with the combination, patients who received carboplatin plus atezolizumab had more high-grade severe adverse events. “This suggests that ICI-chemotherapy combinations are not without added toxic effects and highlights the need to better identify patients who will gain substantial benefit from treatment with ICIs,” they wrote.

The study was conducted from August 2017 to June 2021 and enrolled 130 patients with metastatic TNBC, 106 of whom were randomized to receive carboplatin alone or with atezolizumab 1,200 mg every 3 weeks until disease progression or unacceptable toxic effects, with a 3-year duration of follow-up. Mean age of participants was 55 years, 69% were white, and 19% were Black.

Pietenpol and team conducted a variety of correlative studies to evaluate associations between possible immune biomarkers and treatment response, and reported that patients with high tumor-infiltrating lymphocytes, high mutational burden, and prior chemotherapy had greater benefits with atezolizumab and carboplatin.

They also observed a trend toward greater benefit with the combination for patients with obesity (HR 0.52, P=0.10) and for patients with uncontrolled blood glucose levels at prediabetic (HR 0.62, P=0.13) and diabetic (HR 0.35, P=0.09) levels.

“Obesity has been associated with increased efficacy of PD-1/PD-L1 blockade and attributed to T-cell dysfunction, and retrospective studies have shown that patients with obesity with breast cancer achieved the highest benefit,” they wrote. “This benefit could be attributed to higher adipose tissue composition in the breast and augmented by metabolic syndrome conditions such as type 2 diabetes.”

“Future studies are needed to validate these findings and delineate the effects of blood glucose and obesity,” they added.

Regarding safety, the median duration of treatment for patients receiving atezolizumab plus carboplatin was 17.4 weeks, and 15.4 weeks for single-agent carboplatin. Compared with carboplatin alone, atezolizumab plus carboplatin was associated with a higher incidence of grade 3/4 serious adverse events (41% vs 8%). However, the authors noted that withdrawal of study drugs was similar between arms, with 6% of the carboplatin group and 4% of the combination group coming off study for toxic effects.

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