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ESMO Studies Present New Treatment Options for Advanced Triple-Negative Breast Cancer

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NEW YORK – At the European Society for Medical Oncology's Virtual Congress on Saturday, researchers presented three studies aiming to refine the use of immunotherapy and antibody-drug conjugates in the treatment of advanced triple-negative breast cancer, an aggressive form of the disease that spreads quickly and has limited treatment options.

Although some cancer patients can have enduring benefit from immunotherapy, most do not. PD-L1 expression status can be informative in terms of identifying best responders to immunotherapy. In recent years, studies have shown that about 20 percent of TNBC patients express PD-L1, making them eligible for treatment with immunotherapeutic agents.

While the addition of immunotherapy to chemotherapy for PD-L1-positive patients can be beneficial, two divergent studies presented at ESMO showed that the chemotherapy backbone in such a regimen can impact patients' survival outcomes. Meanwhile, a third study presented at the meeting may provide some hope by adding a new antibody-drug conjugate to the list of treatment options for advanced TNBC patients.

In one presentation, Leisha Emens from the University of Pittsburgh Medical Center's Hillman Cancer Center showed the final overall survival analysis from IMpassion130, the pivotal Phase III study comparing atezolizumab (Roche's Tecentriq) plus nanoparticle albumin-bound paclitaxel (Celgene's Abraxane), or nab-paclitaxel for short, versus placebo plus nab-paclitaxel in previously untreated, locally advanced or metastatic TNBC.

The final progression-free survival analysis from this study was reported in 2018, and based on the findings, international guidelines now recommend atezolizumab plus nab-paclitaxel for patients with locally advanced or metastatic TNBC whose tumors express PD-L1 on tumor-infiltrating immune cells.

Additionally, the US Food and Drug Administration in March 2019 approved atezolizumab for this indication based on IMpassion130 data. Because the agency granted accelerated approval for the indication, continued approval is reliant on evidence confirming the regimen is truly benefiting patients.

The updated IMpassion130 analysis presented at ESMO demonstrated that the atezolizumab plus nab-paclitaxel regimen may help advanced TNBC patients live longer, especially if they express PD-L1. As of April 14, 666 of the 902 patients in the study had died. At a median follow-up of 18.8 months, median overall survival for the total cohort was 21 months for the 451 patients in the combination therapy arm compared to 18.7 months for the 451 patients in the monotherapy arm, and the three-year overall survival rate was 28 percent compared to 25 percent, respectively.

Importantly, in patients who were PD-L1-positive, the median overall survival was 25.4 months for the 185 patients in the combination therapy cohort compared to 17.9 months for the 184 patients in the monotherapy cohort, and the three-year overall survival rate was 36 percent compared to 22 percent.

The results, Emens said, "support a positive risk-benefit profile" for the combination of atezolizumab and nab-paclitaxel as a first-line treatment for patients with PD-L1-positive, previously untreated, locally advanced, or metastatic TNBC.

In another presentation, David Miles, of the Mount Vernon Cancer Centre in the UK, showed primary results from the IMpassion131 study — a double-blind placebo-controlled randomized Phase III trial of first-line paclitaxel, with or without atezolizumab for unresectable, locally advanced or mTNBC.

Because the IMpassion130 trial showed significantly improved progression-free survival and clinically meaningful overall survival benefits in patients with PD-L1-positive advanced TNBC on atezolizumab and nab-paclitaxel, the researchers decided to explore in IMpassion131 whether atezolizumab plus paclitaxtel would yield the same outcomes in first-line metastatic TNBC. Despite the similarity in their names, nab-paclitaxel and paclitaxel have shown to be very different chemotherapies.

Of the 651 patients in IMpassion131, 45 percent had PD-L1-positive metastatic TNBC. Unlike in IMpassion130, however, this combination therapy did not improve progression-free survival or overall survival in PD-L1-positive patients, or in the wider intent-to-treat cohort. Median progression-free survival was 5.7 months and 6 months in PD-L1-positive patients receiving placebo plus paclitaxel or atezolizumab plus paclitaxel, respectively. In the intent-to-treat cohort, progression-free survival was 5.6 months and 5.7 months, respectively.

Median overall survival was 28.3 months for the PD-L1-positive patients receiving the monotherapy and 22.1 months for the patients in the combination therapy arm. In the intent-to-treat cohort, median overall survival was 22.8 months and 19.2 months, respectively. The two-year overall survival rate also did not significantly improve with the combination regimen — PD-L1-positive patients in the monotherapy arm saw a two-year overall survival rate of 51 percent compared to 49 percent for the combination therapy. Patients in the intent-to-treat cohort had two-year overall survival rates of 45 percent and 42 percent, respectively.

"Clearly, this result throws open questions as to why we see a contrast with paclitaxel versus … nab-paclitaxel, and I'm sure that's going to be the subject of more exploration and discussion in the future," Miles said.

Genentech revealed in August that the IMpassion131 trial had failed to meet its primary endpoint of progression-free survival in PD-L1 positive, metastatic TNBC patients. Earlier this month, the FDA issued a safety alert, clarifying to patients and doctors that it has not approved the atezolizumab-paclitaxel combination for metastatic TNBC, but that it had granted accelerated approval to atezolizumab and nab-paclitaxel in this setting. "Healthcare professionals should not replace paclitaxel protein-bound (Abraxane) with paclitaxel in clinical practice," the agency cautioned. 

Separately, Massachusetts General Hospital Cancer Center's Aditya Bardia presented results from the ASCENT trial, a randomized Phase III study of sacituzumab govitecan (Immunomedics' Trodelvy) versus treatment of physician's choice (TPC), such as standard of care chemotherapy, in patients with previously treated mTNBC.

Sacituzumab govitecan is a first-in-class antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the active metabolite of irinotecan, SN-38, that allows for its release both intracellularly and in the tumor microenvironment. A Phase I/II study of the drug led to its accelerated approval by the FDA in April, after it showed a 33 percent objective response rate and a median progression-free survival of 5.5 months in patients with metastatic TNBC. The ASCENT study was initiated to confirm those results. 

Patients who had relapsed or refractory disease after two or more prior chemotherapies in the advanced or metastatic setting were randomized one-to-one to receive sacituzumab govitecan or single-agent treatment — capecitabine, eribulin, vinorelbine, or gemcitabine. The 235 patients receiving sacituzumab govitecan had median progression-free survival of 5.6 months, compared to 1.7 months for the 233 patients receiving treatments of physicians' choice. Similarly, median overall survival was 12.1 months versus 6.7 months in the sacituzumab govitecan group versus the physicians' choice group, respectively.

"The clinical benefit here confirms the use of sacituzumab govitecan as a standard therapy for patients with pretreated metastatic triple-negative breast cancer," Bardia said, adding that ongoing studies are analyzing the drug's potential in earlier lines of therapy, including the adjuvant and neoadjuvant settings, in combination with other targeted treatments, and in patients with HR-positive metastatic breast cancer.