The DETECT V Trial: Exploring Chemotherapy-Free Treatment for HER2+/HR+ Metastatic Breast Cancer

At the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain, Wolfgang Janni, MD, PhD, presented the second interim analysis data from the DETECT V trial (NCT02344472). This study investigated the option of a chemotherapy-free alternative for treating patients with HER2-positive (HER2+) and hormone receptor-positive (HR+) metastatic breast cancer (MBC) by utilizing a dual HER2-targeted therapy (trastuzumab and pertuzumab) combined with endocrine therapy (ET). With the standard of care traditionally involving chemotherapy plus HER2-targeted treatment, the potential of a less toxic, chemotherapy-free regimen may be a promising option for improving patient outcomes and quality of life, explained Janni.

With the standard of care traditionally involving chemotherapy plus HER2-targeted treatment, the potential of a less toxic, chemotherapy-free regimen may be a promising option for improving patient outcomes and quality of life. Image Credit: © Premreuthai - stock.adobe.com

In his presentation, Janni, professor and chair of the Department of Obstetrics and Gynecology at the University of Ulm, Germany, outlined the trial’s objectives, methods, and the implications of its results for practice. Although the study did not demonstrate a significant difference in progression-free survival (PFS) and overall survival (OS) between the 2 cohorts, Janni noted that they did observe a higher incidence of diarrhea in the chemotherapy-containing arm and prolonged neutropenia in the chemotherapy-free arm.

Overview of The DETECT V Trial

The DETECT V trial is a randomized phase 3 trial investigating 2 dual HER2-targeted therapies using trastuzumab and pertuzumab, either in combination with chemotherapy or ET, for the treatment of HER2+ and HR+ MBC. Given the significant toxicities associated with chemotherapy, particularly in long-term management of metastatic disease, the possibility of a chemotherapy-free regimen offers the potential for a less burdensome treatment option, explained Janni.

Following intiation, the study was later amended to include the addition of ribociclib (Kisqali; Novartis), a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, because of its proven efficacy in patients with HR+ MBC. This amendment was incorporated after the first 124 patients had been enrolled, allowing the researchers to further investigate the benefit of combining ribociclib with ET in both treatment arms.

Study Design

The DETECT V trial randomly assigned patients to 1 of 2 treatment arms:

1. Dual HER2-targeted therapy (trastuzumab and pertuzumab) combined with chemotherapy, and
2. dual HER2-targeted therapy (trastuzumab and pertuzumab) combined with ET.

The study aimed to assess several outcomes, with the primary end point being tolerability. Secondary end points included PFS and OS. The trial included 271 patients who completed therapy and an additional 54 patients in the follow-up phase.

PFS and OS

Surprisingly, the analysis revealed no significant difference between the chemotherapy and chemotherapy-free arms in terms of PFS or OS. This finding was consistent in both univariate and multivariate analyses, suggesting that for patients with HER2+ and HR+ breast cancer, a chemotherapy-free regimen may not compromise overall treatment efficacy. This lack of significant difference was observed despite expectations that chemotherapy might outperform ET in combination with dual HER2-targeted treatment.

However, the analysis did show a significant increase in PFS and OS when comparing patients treated with ribociclib to those who did not receive the CDK4/6 inhibitor. The hazard ratios for PFS and OS were 0.52 and 0.42, respectively, strongly favoring the addition of ribociclib to ET. This finding emphasizes the potential role of CDK4/6 inhibitors in improving survival outcomes in this patient population.

Tolerability and Adverse Events

The primary end point of the study focused on tolerability, comparing the incidence of serious adverse events (AEs) and AEs of grade III or higher between the 2 arms. Surprisingly, there was no significant difference in the overall incidence of serious AEs between the chemotherapy and chemotherapy-free arms, even with longer follow-up and the addition of ribociclib.

However, there were notable differences in the types of AEs experienced by patients in the 2 treatment arms. Patients in the chemotherapy-containing arm experienced higher rates of diarrhea, while those in the chemotherapy-free arm, especially those treated with ribociclib, had a higher incidence of prolonged neutropenia. The longer exposure to ribociclib may have contributed to this increased neutropenia, as CDK4/6 inhibitors are known to impact white blood cell counts.

Additionally, in the ribociclib cohort, liver enzyme abnormalities were more frequent, although no treatment-associated deaths were reported. This safety profile suggests that while ribociclib adds efficacy, it also introduces additional risks that need to be managed during treatment.

Impact of Ribociclib: A New Frontier in Chemotherapy-Free Treatment?

One of the most significant findings of this interim analysis was the impact of ribociclib on survival outcomes, according to Janni. The addition of this CDK4/6 inhibitor to ET in both arms appeared to substantially improve PFS and OS compared to patients who did not receive ribociclib. These results are consistent with the growing body of evidence supporting the use of CDK4/6 inhibitors in HR+ MBC, where they have shown to extend survival while maintaining a manageable AE profile.

In this study, the ribociclib cohort demonstrated a 48% reduction in the risk of disease progression and a 58% reduction in the risk of death compared to the non-ribociclib cohort. This impressive improvement in survival outcomes raises the question of whether ribociclib should be considered a standard component of treatment for patients with HER2+ and HR+ MBC, especially in those seeking a chemotherapy-free option.

Limitations and Future Directions

While the DETECT V trial provides important insights, Janni acknowledged several limitations of the study. First, it was powered for tolerability comparisons, not for PFS or OS comparisons between the 2 treatment arms. This means that while the trial offers valuable data, it may not be definitive in terms of survival outcomes, Janni explained. Additionally, the non-randomized nature of the comparison between patient cohorts before and after the addition of ribociclib may introduce potential bias. The follow-up period for the ribociclib cohort is also shorter, limiting the ability to draw long-term conclusions about its efficacy and safety.

Future studies should address these limitations by conducting randomized trials that are designed to evaluate survival outcomes in patients receiving ribociclib as part of a chemotherapy-free regimen. Moreover, longer follow-up will be necessary to fully understand the long-term impact of ribociclib on patient survival and quality of life.

Conclusion

The second interim analysis of the DETECT V trial presented by Janni at ESMO Congress 2024 offers compelling evidence that a chemotherapy-free regimen combining dual HER2-targeted therapy with ET, particularly with the addition of ribociclib, may be an effective treatment option for patients with HER2+ and HR+ MBC. While the study did not demonstrate a significant difference in PFS or OS between the chemotherapy and chemotherapy-free arms, the addition of ribociclib was associated with substantial improvements in survival outcomes. These findings represent an important step toward reducing the toxicity of treatment for patients with MBC while maintaining or even enhancing efficacy.

REFERENCE

Janni W. Mini oral session 2: Breast cancer, metastatic. ESMOCongress 2024; Barcelona, Spain; September 13-17, 2024.