The September 2023 European Society for Medical Oncology (ESMO) Virtual Plenary presentation of the NATALEE health-related quality-of-life (QOL) findings was discussed by Michail Ignatiadis, MD, PhD, and Stephen R.D. Johnston, MD, PhD. Dr. Ignatiadis is Director of the Breast Medical Oncology Clinic & Program at the Institut Bordet, Brussels, and Chair of the Breast Cancer Group of the European Organisation for Research and Treatment of Cancer (EORTC). Dr. Johnston is Professor of Breast Cancer Medicine at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London.
Michail Ignatiadis, MD, PhD
Stephen R.D. Johnston, MD, PhD
“For adjuvant endocrine therapy, we’ve made progress over 20 years with tamoxifen, aromatase inhibitors, ovarian suppression, and duration of therapy. However, an unmet need is a means for preventing early relapse with what appears to be endocrine-resistant disease,” Dr. Johnston noted.
In the metastatic setting, inhibitors of cyclin-dependent kinases 4/6 (CDK4/6) have helped meet this need, “dramatically” reducing the risk of breast cancer recurrence, Dr. Johnston noted. In the pivotal trials of all three CDK4/6 inhibitors, hazard ratios for disease progression were consistent (0.54–0.58), as was the early separation of the Kaplan-Meier curves. “This suggests that in endocrine-sensitive first-line patients, CDK4/6 inhibitors are overcoming endocrine resistance and controlling disease, so it was logical to do the adjuvant studies,” he added.
In the adjuvant setting, ribociclib in NATALEE1 and abemaciclib in monarchE2 significantly improved invasive disease–free survival, with respective hazard ratios of 0.748 (P = .0014) after a median follow-up of 28 months and 0.644 (P < .0001) after a median follow-up of 42 months. Palbociclib in the PALLAS trial3 failed to do.
NATALEE’s Main Finding in QOL
In the current analysis of NATALEE, health-related QOL was largely maintained by patients receiving adjuvant ribociclib, as it was for patients receiving abemaciclib in monarchE.2 However, as the discussants pointed out, the patient-reported outcomes were assessed by different instruments in these studies.
“We have heard that [with ribociclib], we don’t have decreased quality of life, but we don’t have improved quality of life. We have a health-related QOL that is maintained,” Dr. Ignatiadis observed. “Of note, there was no difference between the two arms in terms of physical, social, emotional, and functional well-being at any time point.”
Adverse Events With Ribociclib vs Abemaciclib
Dr. Johnston emphasized that for patient selection, it is important to appreciate the toxicity profiles of the CDK4/6 inhibitors. With abemaciclib, the predominant toxicity is diarrhea, followed by neutropenia and then fatigue. “Fatigue is important in the adjuvant setting, particularly when many of these patients have just come off chemotherapy,” he commented.
Both discussants emphasized that the treatment discontinuation rate caused by adverse events was 19% in each study, “but they were for different reasons,” Dr. -Johnston noted. For NATALEE, treatment discontinuations were most frequently liver-related (8.9%) or caused by arthralgias (1.3%). In monarchE, they were mostly diarrhea (5.3%) and fatigue (2.0%). In both trials, treatment-related discontinuations typically occurred within the first few months. To help patients continue on therapy, clinicians must establish the right dose for individual patients, he said.
“These studies are showing us that globally, the adverse-event profile is not impacting quality of life, but it belies the fact that individual toxicities can have an impact,” Dr. Johnston said.
Decrease in Completing Patient Reported Outcomes Measures
The decrease in completing patient reported outcomes (PROs) measures in both arms over time was a factor Dr. Ignatiadis saw as important when interpreting the study’s health-related QOL findings from the NATALEE trial. Although initially PROs have been reported in over 2,000 patients in each arm, by 3 years, fewer than half that many patients completed PROs, he pointed out. Consequently, he offered a caveat to the researchers’ conclusion:
“No patient-reported outcomes measures have been reported for more than half the patients in both arms at cycle 37, and there was a decrease of at least 5 points in physical functioning/global health status at the end-of-treatment visit in both arms. Thus, the statement that physical functioning or global health status is maintained over time in both arms is not justified for all patients. I would say quality of life was maintained for those patients in both arms who continue to complete the PROs over time,” he explained.
Importance of Longer Follow-up
Both Dr. Johnston and Dr. Ignatiadis agreed on the importance of NATALEE showing benefit in patients with node-negative disease (hazard ratio = 0.630), but only 20% of patients have completed 3 years of treatment, and the median follow-up is 28 months. “It’s a positive trial, which is great news in a wider group of patients, including those with stage II N0,” declared Dr. Johnston. “Although at the moment, the analysis shows benefit in all prespecified subgroups, there isn’t statistical confidence on that until we have much more follow-up…. We are really keen to understand whether the 3% separation of the curves at 36 months will continue.”
Dr. Ignatiadis agreed: “Longer follow-up is needed to get more mature efficacy and also safety data in the adjuvant setting. This will help patients and physicians better estimate the benefit/risk ratio of ribociclib, especially for intermediate-risk patients.”
DISCLOSURE: Dr. Ignatiadis reported financial relationships with Novartis and Seattle Genetics. Dr. Johnston reported financial relationships with Eli Lilly, Puma Biotechnology, Pfizer, Novartis, Sanofi Genzyme, Novartis, AstraZeneca, and Roche/Genentech.
REFERENCES
1. Slamon DJ, Stroyakovskiy D, Yardley DA, et al: Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2– early breast cancer: Primary results from the phase III NATALEE trial. 2023 ASCO Annual Meeting. Abstract LBA500. Presented June 4, 2023.
2. Johnston SRD, Toi M, O’Shaughnessy J, et al: Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): Results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol 24:77-90, 2023.
3. Gnant M, Dueck CC, Frantal S, et al: Adjuvant palbociclib in HR+/HER2– early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-07. Presented December 7, 2021.
