No Significant PFS Association Is Seen Between Chemotherapy Backbone and HRD Status in First-Line TNBC

Marleen Kok, MD, PhD

The interaction between homologous recombination deficiency (HRD) status and chemotherapy backbone was not statistically significant in the first-line treatment of patients with metastatic triple-negative breast cancer (TNBC), according to findings from the phase 2 TRIPLE-B study (NCT01898117) presented at the 2024 ESMO Congress. However, a progression-free survival (PFS) improvement was statistically significant when atezolizumab (Tecentriq) was added to paclitaxel, and the difference was statistically significant when added to carboplatin plus cyclophosphamide.

Findings showed that in patients with non-HRD status, those treated with paclitaxel with or without atezolizumab or bevacizumab (Avastin; n = 49) achieved a median PFS of 5.9 months compared with 3.9 months for those given carboplatin plus cyclophosphamide with or without add-on therapy (n = 52; HR, 0.79; 95% CI, 0.53-1.18; log-rank P = .241).

In the HRD-positive cohort, the median PFS was 6 months for carboplatin plus cyclophosphamide with or without atezolizumab or bevacizumab (n = 61) vs 5.3 months for the paclitaxel with or without add-on therapy (n = 67; HR, 0.79; 95% CI, 0.55-1.12; log-rank P = .182). The P value for HRD status and chemotherapy was .1553.

Additionally, patients treated with carboplatin plus cyclophosphamide alone (n = 61) experienced a median PFS of 5.3 months, whereas the addition of atezolizumab to carboplatin plus cyclophosphamide (n = 63) resulted in a median PFS of 5.4 months (HR, 0.95; 95% CI, 0.66-1.38; log-rank P = .809). In the paclitaxel group (n = 62), the median PFS was 4.4 months compared with 6.5 months for paclitaxel plus atezolizumab (n = 61; HR, 0.53; 95% CI, 0.36-0.78; log-rank P = .001). The difference in PFS between paclitaxel plus atezolizumab and carboplatin/cyclophosphamide was statistically significant (HR, 0.64; 95% CI, 0.44-0.93; log-rank P = .018).

“According to the study team, future research should focus on assessing whether HRD measured on a pretreatment biopsy better predicts benefit of carboplatin plus cyclophosphamide with or without PD-1 or PD-L1 blockade,” lead study author Marleen Kok, MD, PhD, of the Netherlands Cancer Institute, said in a presentation of the data.

Study Design

TRIPLE-B was a randomized, unblinded, multicenter study that enrolled patients with metastatic TNBC who had not received prior cytotoxic therapy for metastatic disease and had measurable or evaluable disease per RECIST 1.1 criteria. Eligible patients needed to have a disease-free interval (DFI) of at least 12 months following prior neoadjuvant or adjuvant paclitaxel or platinum-based chemotherapy, or a DFI of at least 6 months after neoadjuvant or adjuvant docetaxel.

Patients were randomly assigned to 1 of 4 treatment arms. Notably, patients enrolled between 2013 and 2018 who were randomly assigned to an add-on arm received bevacizumab before atezolizumab was incorporated following a 2018 amendment. Patients received carboplatin plus cyclophosphamide alone (n = 74); paclitaxel alone (n = 77); carboplatin plus cyclophosphamide and atezolizumab (n = 63) or bevacizumab (n = 15); or paclitaxel plus atezolizumab (n = 61) or bevacizumab (n = 15). Following disease progression, patients were allowed to cross over to receive atezolizumab in combination with paclitaxel or carboplatin plus cyclophosphamide.

Stratification factors included prior neoadjuvant or adjuvant systemic therapy (yes vs no) and prior neoadjuvant or adjuvant treatment with a taxane (yes vs no).

The primary end point of the TRIPLE-B study was PFS for carboplatin plus cyclophosphamide with or without add-on therapy vs paclitaxel with or without add-on therapy, based on HRD status. Secondary end points included overall survival (OS) and the benefit of adding atezolizumab to carboplatin plus cyclophosphamide or paclitaxel in the intention-to-treat (ITT) population and patients with a PD-L1 combined positive score (CPS) of at least 10.

Patient Characteristics

As of the April 1, 2024, data cutoff, 345 patients were screened, and 305 patients were randomly assigned during the bevacizumab portion of the study (n = 58) and the atezolizumab portion (n = 247). The median study follow-up was 39.4 months.

The median age of the study population was 55 years (range, 27-80), and 65% had received prior neoadjuvant or adjuvant chemotherapy, including 56% who received a neoadjuvant or adjuvant taxane. Of the patients enrolled, 56% were HRD positive (n = 128) and 44% were HRD negative (n = 101); HRD status was unknown for 76 patients. Of the 156 patients who underwent germline testing, 9% harbored BRCA1/2 mutations. Thirty-four percent of evaluable patients (n = 112) had a PD-L1 CPS of at least 10. Sites of metastatic lesions included bone (47%), lung (45%), liver (32%), and brain (2%). Additionally, 26% of patients presented with de novo metastatic disease.

PFS in the PD-L1–Positive and Taxane-Pretreated Subgroups

In patients with PD-L1 CPS of at least 10, the combination of paclitaxel and atezolizumab (n = 18) showed a median PFS of 7.6 months vs 5.5 months for paclitaxel alone (n = 18; HR, 0.37; 95% CI, 0.17-0.77; log-rank P = .006). Similarly, paclitaxel plus atezolizumab demonstrated a superior benefit compared with carboplatin plus cyclophosphamide and atezolizumab, where patients (n = 10) had a median PFS of 4.6 months (HR, 0.36; 95% CI, 0.15-0.86; log-rank P = .017).

In contrast, the combination of carboplatin plus cyclophosphamide and atezolizumab showed no significant improvement in PFS compared with carboplatin plus cyclophosphamide alone (n = 11), where the median PFS was 5.6 months (HR, 1.18; 95% CI, 0.47-2.96; log-rank P = .707).

In taxane-pretreated patients (n = 148), the combination of paclitaxel and atezolizumab (n = 36) showed a median PFS of 7.6 months vs 4.2 months paclitaxel alone (n = 38; HR, 0.41 (95% CI, 0.25-0.68; log-rank P < .001). The median PFS was 5.2 months for carboplatin plus cyclophosphamide and atezolizumab (n = 36; HR vs paclitaxel vs atezolizumab, 0.56; 95% CI, 0.34-0.92; log-rank P = .018).

In this population, carboplatin plus cyclophosphamide and atezolizumab did not show a statistically significant improvement in PFS compared with carboplatin plus cyclophosphamide alone, where patients (n = 38) had a median PFS of 3.7 months (HR, 0.75; 95% CI, 0.47-1.2; log-rank P = .336).

OS Findings

Seventy-six percent of patients without prior first-line atezolizumab crossed over to receive the therapy in second-line treatment. Among those treated with carboplatin plus cyclophosphamide alone followed by paclitaxel plus atezolizumab (n = 61), the median OS was 14.3 months compared with 12.1 months for those given carboplatin plus cyclophosphamide plus atezolizumab in the first line. In patients given paclitaxel alone followed by carboplatin plus cyclophosphamide and atezolizumab (n = 62), the median OS reached 17.1 months; patients given paclitaxel plus atezolizumab in the first line (n = 61) had a median OS of 16.2 months.

Statistically significant differences in OS were not observed for first-line vs second-line carboplatin plus cyclophosphamide and atezolizumab (HR, 1.18; 95% CI, 0.79-1.76; log-rank P = .416), first-line vs second-line paclitaxel plus atezolizumab (HR, 1.00; 95% CI, 0.66-1.51; log-rank P = .997), or paclitaxel plus atezolizumab vs carboplatin plus cyclophosphamide and atezolizumab (HR, 0.70; 95% CI, 0.47-1.06; log-rank P = 0.092).

Reference

Kok M, Voorthuis R, de Boo L, et al. Carboplatin-cyclophosphamide versus paclitaxel with or without atezolizumab as first-line treatment for metastatic TNBC: Results from the TRIPLE-B study (BOOG 2013-01). Presented at: 2024 ESMO Congress; September 27-October 1, 2024; Barcelona, Spain. Abstract LBA20.