Using a Biomarker-Driven Approach in TNBC

Tiffany A. Traina, MD

Patients diagnosed with early-stage triple-negative breast cancer (TNBC) in the first-line setting are likely to have been treated with polychemotherapy including anthracyclines, taxanes, and platinum-based regimens. Further adding to the complexity of treatment regimens are immune checkpoint inhibitors, PARP inhibitors, and antibody-drug conjugates (ADCs).

The challenge for the clinician is prioritizing the available treatment options based on the National Comprehensive Cancer Network guidelines for breast cancer, which focus on active agents, preferred single-agent chemotherapy approaches, and doublet options for certain patients at high risk.¹ During her presentation at the 39th Annual Chemotherapy Foundation Symposium (CFS®) Innovative Cancer Therapy for Tomorrow® conference, Tiffany A. Traina, MD, delineated a biomarker-driven approach to managing metastatic TNBC.²

She noted the importance of determining the patient’s PD-L1–positive or –negative status in the first line, the role of sacituzumab govitecan (Trodelvy) and pembrolizumab (Keytruda) in the second line, and the biomarkers for NTRK fusion and germline pathogenic BRCA 1/2 in the third-line setting. In particular, Traina said the biomarker of necessity to be aware of is the germline BRCA 1/2.

“One treatment alternative for patients who are PD-L1 negative and BRCA 1/2 positive is to lead with a PARP inhibitor,” said Traina, vice chair of oncology care, Department of Medicine, and section head, Triple Negative Breast Cancer Clinical Research Program at Memorial Sloan Kettering Cancer Center in New York, New York, during her presentation. By using a biomarker-driven approach, which identifies actionable targets, Traina can choose a more personalized option when treating these patients. “Is there a biomarker that is predictive for benefit over just a single-agent chemotherapy?” she asked.

In the second-line setting, Traina noted that the indication for pembrolizumab for solid tumors with tumor mutational burden (TMB) high, defined as greater than 10 mutations/megabase, or microsatellite instability (MSI) high is an important one to pay attention to when reviewing results from the next-generation sequencing reports. “Although your patient may have a PD-L1–negative tumor, you may have a target because of the high TMB,” she added.

For the third-line setting, results from basket trials have identified larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) as potential treatments in patients whose tumors harbor NTRK fusions.

Checkpoint inhibitors

In the KEYNOTE-355 trial (NCT02819518), 1372 patients were screened, with 847 randomly assigned to treatment: 566 patients received pembrolizumab/ chemotherapy and 281 patients received placebo/ chemotherapy.³ Patients were randomized 2:1 and were stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥ 1 or < 1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no).

Dual primary efficacy end points were progression-free survival (PFS) and overall survival (OS) assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat (ITT) populations. Investigators reported that for patients with a CPS greater than or equal to 10, adding pembrolizumab to chemotherapy significantly improved PFS by 35%. Traina emphasized that patients who experienced a quick relapse within 6 months of receiving adjuvant therapy, as defined by a greater than 12-month disease-free interval, experience a significant unmet need. “We need to do better even beyond the use of checkpoint inhibitors and chemotherapy [in this population],” Traina said.

Updated findings presented at the European Society for Medical Oncology Congress 20214 showed that OS for patients with a CPS score of 10 or greater improved by 7 months (pembrolizumab + chemotherapy, 23.0 months; placebo + chemotherapy, 16.1 months; HR, 0.73; 95% CI, 0.55-.95; P = .0093).

Traina said these data are consistent with the concept that inhibition of PD-1/PD-L1 is important for the subset of patients with PD-L1–positive TNBC. But, she added, the question about improving patient selection to predict who will benefit from immunooncology in the first-line setting remains.

PARP inhibition

For a patient at any age, the importance of knowing their germline BRCA status cannot be overlooked especially because PARP inhibitors are actionable and prevalent in TNBC, Traina explained.

Patients who have pathogenic germline BRCA mutations, in the randomized phase 3 OlympiAD (NCT02000622)5 and EMBRACA (NCT01945775)6 trials, have shown a profound improvement in PFS when PARP inhibitors vs treatment of physician’s choice of chemotherapy were used in this population.

In the OlympiAD study, olaparib monotherapy resulted in a median PFS that was 2.8 months longer than with standard chemotherapy. Further, risk of progression or death was 42% lower with olaparib monotherapy than with standard therapy. Response rates also favored the PARP inhibitor group, which was 59.5% vs 28.8% for the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group compared with 50.5% in the control group. Discontinuations because of toxicities was 4.9% in the experimental arm vs 7.7% in the control arm.

In the EMBRACA study, talazoparib (Talzenna) provided a PFS benefit (8.6 months) compared with standard chemotherapy (5.6 months). The PARP inhibitor group also had a higher response rate at 62.6% than the standard chemotherapy group at 27.2% (OR, 5.0; 95% CI, 2.9-8.8; P < .001). Hematologic grade 3/4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively

Efforts to expand the role of PARP inhibitors beyond patients with germline BRCA mutations are ongoing. The TBCRC 048 trial (NCT03344965) has enrolled patients who had somatic mutations other than BRCA 1/2 that could lead to homologous recombination pathway defects.7 Eligible patients had metastatic breast cancer with measurable disease and germline mutations in non-BRCA 1/2 genes (cohort 1) or somatic mutations in these genes or BRCA 1/2 (cohort 2). Patients with prior treatment with a PARP inhibitor, platinum-refractory disease, or progression on more than 2 chemotherapy regimens (metastatic setting) were ineligible for the trial.

A total of 54 patients were enrolled. Seventy-six percent had estrogen receptor–positive, HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA 1/2, ATM, or CHEK2. In cohort 1, the objective response rate (ORR) was 33% (90% CI, 19%- 51%) and in cohort 2, 31% (90% CI, 15%-49%). Confirmed responses were seen only with germline PALB2 (ORR, 82%) and somatic BRCA 1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12-not available [NA]) for germline PALB2, and 6.3 months (90% CI, 4.4-NA) for somatic BRCA 1/2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone.

ADCs

Turning to ADCs, Traina highlighted the results of the ASCENT trial (NCT02574455), which evaluated sacituzumab govitecan vs single-agent chemotherapy of the physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic TNBC (FIGURE8 ).⁸

The median PFS was 5.6 months (95% CI, 4.3-6.3) with sacituzumab govitecan and 1.7 months (95% CI, 1.5-2.6) with chemotherapy (HR, 0.41; 95% CI, 0.32-0.52; P < .001). The median OS was 12.1 months (95% CI, 10.7-14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8-7.7) with chemotherapy (HR, 0.48; 95% CI, 0.38-0.59; P < .001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy.

“Investigators reported a profound improvement in PFS of 60% associated with sacituzumab as compared with standard chemotherapy,” Traina said. “And even [more] impressive, not only was this durable and across all subgroups observed, there was a 52% improvement in overall survival,” she said (TABLE⁸ ).

Other studies evaluating ADCs in TNBC include DS8201-A-J101 (NCT02564900) with trastuzumab deruxtecan, which was shown to have a high drug to antibody ratio, a stable linker payload, and a tumor-selectable cleavable linker,⁹ and TROPION-PanTumor01 (NCT03401385),10 a first-in-human trial enrolling patients with TNBC as well as non–small cell lung cancer who have relapsed on standard therapies or for whom no standard treatment is available.

These approaches are promising and have shown benefit and activity in the TNBC setting over traditional chemotherapy, Traina concluded.

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