...investigators have evaluated less aggressive approaches, including a short course of adjuvant paclitaxel plus trastuzumab (APT). Pathological response to neoadjuvant therapy has been shown to be ...prognostic7 and also predicts benefit from adjuvant trastuzumab emtansine.8 However, the question of whether all patients with HER2-positive breast cancer should be treated with a full course of multidrug therapy to evaluate the need for more therapy has continued the search for a tool, akin to the 21-gene recurrence score for HER2-negative disease, to guide therapy selection for HER2-positive breast cancer. ...as the authors acknowledge, retrospective and prospective validation are clearly warranted before clinical use of the score.
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic ...topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.
Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval CI, 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).
Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).
The selection of optimal systemic therapy for early HER2-positive breast cancer has become exceedingly complex. Since the advent of adjuvant trastuzumab, several new drugs have shown substantial ...incremental benefits.1–4 Clearly, not all patients should receive these additional therapies. ...it is incumbent upon clinicians to carefully select patients who are the most likely to benefit from an escalation strategy. ...a meta-analysis of all studies with long-term follow-up evaluating duration of trastuzumab will be informative.
The remaining 18 625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. ...the majority of patients with HER2-positive breast cancer did not receive targeted ...therapy. Sam Ogden/Science Photo Library Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. ...gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. ...the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.10–13 With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important.
Poly-ADP-ribose polymerase 1 (PARP-1) and PARP-2 are DNA damage sensors that are most active during S-phase of the cell cycle and that have wider-reaching roles in DNA repair than originally ...described. BRCA1 and BRCA2 (Breast Cancer) proteins are involved in homologous recombination repair (HRR), which requires a homologous chromosome or sister chromatid as a template to faithfully repair DNA double-strand breaks. The small-molecule NAD+ mimetics, olaparib, niraparib, rucaparib, veliparib, and talazoparib, inhibit the catalytic activity of PARP-1 and PARP-2 and are currently being studied in later-stage clinical trials. PARP inhibitor clinical trials have predominantly focused on patients with breast and ovarian cancer with deleterious germline
and
mutations (g
) but are now expanding to include cancers with known, suspected, or more-likely-than-not defects in homologous recombination repair. In ovarian cancer, this group also includes women whose cancers are responsive to platinum therapy. Olaparib was FDA-approved in January 2018 for the treatment of g
metastatic breast cancers. g
+ predisposes women to develop triple-negative breast cancers, while women with g
+ tend to develop hormone-receptor-positive, human epidermal growth factor receptor 2 negative breast cancers. Although PARP inhibitor monotherapy strategies seem most effective in cancers with homologous recombination repair defects, combination strategies may allow expansion into a wider range of cancers. By interfering with DNA repair, PARP inhibitors essentially sensitize cells to DNA-damaging chemotherapies and radiation therapy. Certainly, one could also consider expanding the utility of PARP inhibitors beyond g
cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. Unfortunately, in numerous phase I clinical trials utilizing a combination of cytotoxic chemotherapy at standard doses with dose-escalation of PARP inhibitors, there has generally been failure to reach monotherapy dosages of PARP inhibitors due to myelosuppressive toxicities. Strategies utilizing angiogenesis inhibitors and immune checkpoint inhibitors are generally not hindered by additive toxicities, though the utility of combining PARP inhibitors with treatments that have not been particularly effective in breast cancers somewhat tempers enthusiasm. Finally, there are combination strategies that may serve to mitigate resistance to PARP inhibitors, namely, upregulation of the intracellular PhosphoInositide-3-kinase, AK thymoma (protein kinase B), mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway, or perhaps are more simply meant to interfere with a cell growth pathway heavily implicated in breast cancers while administering relatively well-tolerated PARP inhibitor therapy.
The poly(adenosine diphosphate-ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 ( BRCA1/2).
We conducted a ...randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review.
Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval CI, 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P=0.11 57% of projected events). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). 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. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status-quality-of-life and breast symptoms scales were observed.
Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation Pfizer; EMBRACA ClinicalTrials.gov number, NCT01945775 .).
NALA (ClinicalTrials.gov identifier: NCT01808573) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine ...(N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens.
Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m
twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m
twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL).
A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio HR, 0.76; 95% CI, 0.63 to 0.93; stratified log-rank
0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07;
2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8%
29.2%;
043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4;
1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74;
.0004). The most common all-grade adverse events were diarrhea (N+C 83%
L+C 66%) and nausea (53%
42%). Discontinuation rates and HRQoL were similar between groups.
N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.
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