Genentech’s Withdrawal of the Indication for Atezolizumab in Triple Negative Breast Cancer

Christine Barrett, PharmD
Clinical Pharmacy Specialist in Hematology/Oncology
Allegheny General Hospital
Pittsburgh, PA

Breast cancer is the most common cancer diagnosed in women in the United States.¹ Triple-negative breast cancer (TNBC) is an aggressive subtype that accounts for nearly one-fifth of all cases. It is defined by a lack of expression of both estrogen (ER) and progesterone (PR) receptors, as well as human epidermal growth factor receptor-2 (HER2). TNBC is associated with an earlier age of onset, higher rates of recurrence, and poorer prognosis in comparison to hormone-sensitive subtypes.2 Because it is not sensitive to endocrine therapy or HER2-targeted therapies, there are limited therapeutic options, and chemotherapy has been the standard for systemic treatment of TNBC.^2-3

As seen in many other types of cancer, immunotherapy has become an emerging treatment option in breast cancer. In comparison to other subtypes, TNBC is associated with higher levels of programmed cell death ligand 1 (PD-L1) expression. PD-1 and its ligand PD-L1 are immune checkpoint receptors expressed on activated T-cells and other immune cells; higher levels of expression of these receptors are associated with tumor immune resistance.¹ In addition, TNBC is also associated with increased genomic instability, and higher enrichment by tumor-infiltrating lymphocytes (TILs). These are all indications that TNBCs may be more immunogenic and therefore more responsive to immunotherapy.³

Atezolizumab is a humanized IgG1 antibody targeting PD-L1, which prevents its interaction with receptors PD-1 and B7-1, resulting in a reversal of T-cell suppression and therefore restoring antitumor T-cell activity.4 In March 2019, atezolizumab received accelerated approval from the US Food and Drug Administration (FDA) for use in combination with nab-paclitaxel in patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1. Atezolizumab was the first immune checkpoint inhibitor to receive approval in metastatic TNBC.³ The accelerated approval was based on preliminary results of progression-free survival in the IMpassion130 trial, and was contingent on the confirmatory results of the subsequent IMpassion131 study.³

The IMpassion130 trial enrolled 902 patients with previously untreated metastatic TNBC. Patients were randomized to receive atezolizumab 840 mg or placebo on days 1 and 15 in combination with nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 28 days for six cycles or more. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in both the intent-to-treat and PD-L1-positive subgroup, which comprised 40.9% of patients. PD-L1 positivity was defined as ≥ 1% expression on tumor-infiltrating immune cells. A statistically significant improvement in median progression-free survival was seen in both the intent-to-treat group (7.2 months versus 5.5 months; hazard ratio [HR] for progression or death 0.8, 95% confidence interval [CI] 0.69 to 0.92, p=0.002) and in the PD-L1-positive subgroup (7.5 months versus 5 months; HR 0.62, CI 0.49 to 0.78, p<0.001). There was a numerical improvement in median overall survival in the intent-to-treat group (21.3 months versus 17.6 months; HR 0.84, CI 0.69 to 1.02, p=0.08), however it was not statistically significant. Overall survival was also numerically improved in the PD-L1-positive subgroup (25 months versus 15.5 months); due to the hierarchical testing procedure of the study, statistical significance was not determined.

Results of the final overall survival analysis of IMpassion130 were recently published; the difference in median overall survival was still unable to reach statistical significance (21 months versus 18.7 months; HR 0.87, CI 0.75 to 1.02, p=0.077). In an exploratory analysis in the PD-L1-positive subgroup, the median overall survival was 25.4 months in the atezolizumab group in comparison to 17.9 months in the control group.⁶

The subsequent IMpassion131 was conducted in 651 patients with previously untreated metastatic TNBC. In this study, patients were randomized to receive atezolizumab 840 mg or placebo on days 1 and 15 in combination with paclitaxel 90 mg/m2 on days 1, 8, and 15 every 28 days for six cycles or more. The primary endpoint was investigator-assessed progression-free survival, which also followed hierarchical testing, but was tested first in the PD-L1-positive subgroup, which made up 45% of the study population. The IMpassion131 found that progression-free survival was not significantly improved with atezolizumab in either the PD-L1-positive subgroup (6 months versus 5.7 months; HR 0.82, CI 0.60 to 1.12, p=0.20) or the intent-to-treat population (5.7 months versus 5.6 months). The combination also did not improve overall survival in the PD-L1-positive subgroup (22.1 months versus 28.3 months) or the intent-to-treat population (19.2 months versus 22.8 months).⁷

Due to the unfavorable results of the IMpassion131, continued approval of atezolizumab in metastatic TNBC was discussed by the FDA Oncology Drugs Advisory Committee (ODAC) in April 2021. Although the committee voted to maintain the accelerated approval, after further evaluation by the FDA and the manufacturer Genentech, the manufacturer voluntarily withdrew the accelerated approval for atezolizumab in combination with nab-paclitaxel in metastatic TNBC on August 27, 2021.⁸

There have been several proposed reasons for the discrepancies between the results of IMpassion130 and IMpassion131, such as differences in baseline characteristics, the use of different taxanes, and the role of steroids. Differences in study populations with respect to tumor cell biology and other molecular markers were not collected in either study, which could affect patients’ overall prognosis and response to therapy. Other theories include a possible difference in immunogenic effects between nab-paclitaxel and paclitaxel and also a dampening of immunotherapy effects in combination with steroid pre-medications, although there is now data from the KEYNOTE-522 and KEYNOTE-355 studies which support the use of both nab-paclitaxel and paclitaxel in combination with immunotherapy.^9-12

The results of the IMpassion131 and the withdrawal of atezolizumab’s indication in combination with nab-paclitaxel highlight the ongoing challenges with immunotherapy in metastatic TNBC. Currently, there is an approval for immunotherapy in metastatic TNBC; this approval is with pembrolizumab in combination with chemotherapy in patients whose tumors express PD-L1 with a combined positive score (CPS) ≥ 10, based on the results of the KEYNOTE-355 study.¹² Future research in immunotherapy for metastatic TNBC should focus on developing more reliable predictive biomarkers and identifying patient populations more likely to benefit from immunotherapy.

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