Rebecca Dent, MD, MSc, FRCP, is deputy chief executive officer (clinical) and a senior consultant at the National Cancer Centre Singapore

Dr Dent on the Potential Role of Dato-DXd for Immunotherapy-Ineligible TNBC

“Some would argue that [all patients] likely benefit from this antibody-drug conjugate. Ninety-one of the patients [had a] PD-L1 [CPS below 10], and 9% [of patients had] a PD-L1 [CPS above 10]. It looks like both of those groups benefited.”

Rebecca Dent, MD, MSc, FRCP, deputy chief executive officer (clinical) and a senior consultant at the National Cancer Centre Singapore, discussed the clinical implications of the phase 3 TROPION-Breast02 trial (NCT05374512) evaluating datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) vs investigator’s choice of chemotherapy in the frontline setting in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) who were ineligible for immunotherapy.

Dent suggested that the benefits of this TROP-2–directed antibody-drug conjugate likely extend to most patients with TNBC. She noted that TROPION-Breast02 comprehensively assessed the efficacy of Dato-DXd across patients with varying levels of PD-L1 expression. In the study, 91% of patients were classified as having PD-L1–low disease with a combined positive score (CPS) of less than 10, whereas 9% of patients had disease that was designated as PD-L1 high with a CPS of at least 10. Both subgroups derived therapeutic benefit from Dato-DXd.

Dent described the ongoing efforts to further augment the efficacy of Dato-DXd in patients with TNBC. Ongoing trials that are exploring the combination of Dato-DXd with immune checkpoint inhibition, she explained, and more robust data may result from these combination trials over time.

Dent also noted that given the known biological expression profile of TROP-2 in the oral mucosa and the epithelium of the cornea, certain local toxicities were expected, including mucositis, which was predominantly reported as grade 1 and 2. At data cutoff, 90% of mucositis cases had successfully resolved, and no patients were required to exit the study because of mucositis. However, Dent emphasized that mucositis prophylaxis is necessary.

Regarding ocular surface adverse effects, Dent detailed the management procedures used in the trial, including baseline eye examinations, which were subsequently followed every 3 treatment cycles. She reiterated the importance of prophylaxis, specifically the use of eye drops, and stated that dose reductions might provide further help in managing these toxicities, given the understanding that ocular toxicities are potentially linked to TROP-2 expression.

A reassuring element of the Dato-DXd safety profile, Dent noted, pertains to interstitial lung disease (ILD) and pneumonitis. She reported that the occurrence of ILD/pneumonitis was rare in both treatment arms examined.

Videos

Rebecca Dent, MD, MSc, FRCP, discussed the future implications of data with first-line Dato-DXd in locally recurrent inoperable or metastatic TNBC.

Dr Dent on the Efficacy of First-Line Dato-DXd in TNBC

“What's remarkable is how consistent the data are.”

Rebecca Dent, MD, MSc, FRCP, deputy chief executive officer (clinical) and a senior consultant at the National Cancer Centre Singapore, discussed key efficacy findings from the phase 3 TROPION-Breast02 trial (NCT05374512) investigating first-line datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) vs investigator’s choice of chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) who were ineligible for immunotherapy.

The study met its dual primary end points of progression-free survival (PFS) as assessed by blinded independent central review (BICR), and overall survival (OS), Dent began. Regarding the PFS findings, Dato-DXd demonstrated a statistically significant and clinically meaningful improvement compared with chemotherapy, with a median PFS for the Dato-DXd group (n = 323) of 10.8 months (95% CI, 8.6-13.0) compared with 5.6 months (95% CI, 5.0-7.0) for the chemotherapy group (n = 321), representing a 5.3-month difference and a 43% reduction in the risk of progression or death (HR, 0.57; 95% CI, 0.47-0.69; 

The median OS for patients receiving Dato-DXd reached 23.7 months (95% CI, 19.8-25.6) compared with 18.7 months (95% CI, 16.0-21.8) for those who received chemotherapy; Dato-DXd reduced the risk of death by 21% (HR 0.79; 95% CI, 0.64-0.98; 

 = .0291). This survival benefit observed in the first-line setting is significant because the study population predominantly had a PD-L1 combined positive score of less than 10, according to Dent. She stated that observing such results in this TNBC population and setting had not been seen before these findings.

A remarkable aspect of the data was its consistency across key efficacy measures, Dent emphasized. When evaluating clinical effectiveness, the initial focus often lies on whether a patient is achieving a response, she noted. Dato-DXd achieved more than a doubling of the confirmed objective response rate (ORR) compared with chemotherapy. The ORR for patients receiving Dato-DXd was 62.5% compared with 29.3% for those who received chemotherapy. Furthermore, the study demonstrated a higher complete response rate with Dato-DXd (9.0%) vs chemotherapy (2.5%).

With Dato-DXd, the median duration of response reached 12.3 months (95% CI, 9.1-15.9) compared with 7.1 months (95% CI, 5.6-8.9) for chemotherapy. Despite the median total treatment duration for Dato-DXd being more than double that of chemotherapy (8.5 months, range, 0.7-38.0 vs 4.1 months, range, 0.1-32.0), the rates of grade 3 and serious treatment-related adverse effects were similar between the arms, and discontinuation rates were lower with Dato-DXd.

Rebecca Dent, MD, MSc, FRCP, discusses data from the TROPION-Breast02 trial of frontline Dato-DXd vs chemotherapy in locally recurrent metastatic TNBC.

Rebecca Dent, MD, senior consultant and head of Medical Oncology Department, National Cancer Center, Singapore, discusses the findings from the phase 2 LOTUS trial that treated patients with inoperable locally advanced/metastatic triple-negative breast cancer (TNBC) with first-line ipatasertib plus paclitaxel.

At the 2020 ESMO Breast Cancer Virtual Meeting, the data for the final overall survival (OS) outcomes in the phase 2 LOTUS trial were presented, says Dent; there are about 60 patients in each arm. The overall primary endpoint was PFS and researchers saw a prolonged benefit in the biomarker-positive population, as well as the intent-to-treat population. In the intent-to-treat population, ipatasertib/paclitaxel improved the median OS by 9 months, leading to a median OS of 25.8 months.

A phase 3 trial will be needed to confirm results; however, investigators saw a hazard ratio (HR) of .8 and an improvement of about 15% in 1-year OS.

When looking at the overall biomarker subset, which included 

 mutations, as defined by next-generation sequencing, all of these showed numerical improvements in OS with the combination, but the numbers are too small at this point, Dent adds. Moreover, patients who were 50 years and older had an improvement in OS from 15 to 35 months, leading to a 60% reduction in the risk of death. This patient subgroup might be more susceptible to AKT inhibition but this is hypothesis generating, concludes Dent.

Rebecca Dent, MD, discusses the findings from the phase 2 LOTUS trial that treated patients with inoperable locally advanced/metastatic triple-negative breast cancer with first-line ipatasertib plus paclitaxel.

Dr. Dent on Final LOTUS Findings in TNBC

Rebecca Dent, MD, senior consultant, National Cancer Center, Singapore, discusses ipatasertib in the treatment of patients with triple-negative breast cancer (TNBC).

Ipatasertib is an oral AKT inhibitor that showed a promising trend toward improving overall survival (OS) in addition to paclitaxel in findings from the phase II LOTUS study of patients with locally advanced or metastatic TNBC. For patients who received ipatasertib plus paclitaxel, median OS was 23.1 months compared with 18.4 months for patients randomized to placebo plus paclitaxel.

Compared to some of the older AKT inhibitors, which are allosteric, ipatasertib has much better tolerability, Dent explains. Preclinical and early data have shown that blocking AKT is impactful in patients with 

mutations, those who have mutations upstream such as 

, says Dent. These are critical pathways in terms of survival for patients with breast cancer, as they are activated in about 40% of TNBC cases, she adds.

Rebecca Dent, MD, senior consultant, National Cancer Center, Singapore, discusses ipatasertib in the treatment of patients with triple-negative breast cancer.

Dr. Dent Discusses Ipatasertib in Triple-Negative Breast Cancer

Rebecca Dent, MD, senior consultant, National Cancer Center, Singapore, discusses the results of the LOTUS trial in patients with triple-negative breast cancer (TNBC).

The primary endpoint of the study was progression-free survival (PFS). There was modest improvement in the overall intent-to-treat population. However, researchers saw a big impact on PFS in the biomarker-positive group.

A panel was done by Foundation Medicine on either archived or fresh tissue that looked at 

. Patients with those alterations showed a 4- to 5-month improvement in PFS which Dent states is a fairly profound improvement in PFS in TNBC.

Researchers also looked at response, duration of response (DOR), and clinical benefit rate. The same trend was seen in terms of improved outcomes with ipatasertib, but the real benefit, says Dent, was seen in the DOR. The DOR almost doubled with the addition of ipatasertib in the biomarker-positive population. The phase III study is ongoing.

Rebecca Dent, MD, senior consultant, National Cancer Center, Singapore, discusses the results of the LOTUS trial in patients with triple-negative breast cancer.

Rebecca Dent, MD, MSc, FRCP

Articles

Dr Dent on the Potential Role of Dato-DXd for Immunotherapy-Ineligible TNBC

Dr Dent on the Efficacy of First-Line Dato-DXd in TNBC

Dr. Dent on Final LOTUS Findings in TNBC

Dr. Dent Discusses Ipatasertib in Triple-Negative Breast Cancer

Dr. Dent Discusses the LOTUS Trial in Triple-Negative Breast Cancer