TOPACIO was a phase I/II study evaluating the PARP inhibitor (PARPi) niraparib in combination with the anti-PD-1 antibody pembrolizumab in patients with locally advanced or metastatic triple-negative breast cancer (TNBC, n=55), irrespective of BRCA mutation status. In the efficacy-evaluable population (n=47) the objective response rate (ORR) was 21% and disease control rate (DCR) 49%. Although activity was greater in BRCA-MUT patients (7/15, ORR=47% and 12/15, DCR=80%), durable clinical benefit was seen in patients with BRCA-WT tumors (3/27, ORR=11% and 9/27, DCR=33%). Patients with PD-L1+ tumors (28/47, 60%) achieved higher ORR (9/28, 32%) than those with PD-L1neg tumors (1/13, 8%). It remains unstudied whether tumor gene expression or immune composition in baseline biospecimens is predictive of treatment response. Therefore, we conducted exploratory biomarker analyses to uncover gene expression patterns and immune states associated with treatment response.
Methods
Transcriptional profiling of baseline samples was performed using the BC360 (n=41) and PanCancer IO360 (n=42) panels (Nanostring) and multigene signatures were used to measure tumor and immune activities. Transcriptional analysis was paired with high-dimensional, single-cell cyclic immunofluorescence (CyCIF) of samples with adequate tissue for analysis (n=22) to characterize the immune microenvironment at single-cell resolution.
Results
BRCA-MUT tumors showed increased downstream interferon signaling and immune infiltration relative to BRCA-WT tumors (p < 0.05). Downstream interferon and immunoproteasome scores were elevated in objective responders (p < 0.05). Genes involved in WNT signaling (TANKS1, TANKS2, PARP4, and NETO2) associated with long-term response, defined by those still on therapy and responding at data cut off. Low NETO2 gene expression strongly associated with better ORR (p = 0.01). CyCIF analysis performed on whole tissue sections accounting for 2.97x106 single cells revealed that in BRCA-WT patients, baseline infiltration of immune cells – cells expressing CD45, CD3 (T cells), CD20 (B cells) or CD68/CD163 (macrophages) positively correlated with PFS (R=0.81, p=0.0004, Spearman's correlation). Further, elevated fractions of CD8+ and PD-1+ CD4+ T cells strongly associated with favorable PFS (R > 0.71, p < 0.0041). In BRCA-MUT patients, baseline immune composition did not correlate with clinical outcome by any metric studied.
Conclusions
NETO2 expression, WNT pathway, and interferon signaling associate with response to niraparib plus pembrolizumab. While BRCA-MUT tumors showed higher baseline immune cell abundance compared to BRCA-WT, immune and T cell infiltration was predictive of PFS duration only in BRCA-WT patients, suggesting divergent mechanisms of response to PARPi and ICB dependent on BRCA status.
Trial Registration
ClinicalTrials.gov identifier: NCT02657889.
Ethics Approval
The study was performed according to the ethical principles of the Declaration of Helsinki. The study protocol and/or other relevant documents received central approval by the Dana-Farber institutional review board and/or relevant competent authorities at each site. All patients supplied written informed consent for their participation in the study.
<div>AbstractPurpose:<p>We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC).</p>Patients and Methods:<p>Patients with mTNBC treated with 0–1 prior lines of chemotherapy received cisplatin 75 mg/m<sup>2</sup> i.v. followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for five doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORR) with a one-sided type I error of 0.1: an ORR >30% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease ≥6 months or complete or partial response.</p>Results:<p>A total of 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had <i>BRCA2</i> mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% [95% confidence interval (CI), 13–44], and median progression-free survival was 4.9 months (95% CI, 2.3–5.7). Treatment-related grade 3–5 adverse events occurred in 53% of patients, most commonly diarrhea in 21%. One death occurred because of sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T-cell infiltration.</p>Conclusions:<p>Among patients with mTNBC treated with 0–1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of >30%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation.</p></div>
