David Cescon, MD, PhD, Clinician Scientist at the Princess Margaret Cancer Centre in Toronto, Canada, was the invited discussant of the two MONALEESA analyses.1,2
He noted that the most recent overall survival analysis, presented at the European Society for Medical Oncology (ESMO) Congress 2021, showed “remarkable median overall survival” of more than 5 years with the addition of ribociclib to endocrine therapy in advanced hormone receptor–positive, HER2-negative breast cancer.3 The subgroup analysis by O’Shaughnessy et al showed this benefit was consistent across “different ends of the clinical spectrum, from bone-alone disease to liver metastases at enrollment.” And ,“not surprisingly,” he added, “these clinical features retained their prognostic significance. Patients with bone-alone disease had markedly increased median overall survival vs those with liver metastases [72.6 months vs 38.1. months with the combination].” He further noted that patients with bone-alone disease derived a 16-month absolute improvement with the combination, vs endocrine therapy alone.
David Cescon, MD, PhD
“From this we can confirm with overall survival, as previously shown for progression-free survival, that the relative ribociclib benefit is consistent and that anatomic factors retain prognostic significance. This highlights the fact that the absolute overall survival benefit does vary by patient population. Indeed, as we consider who to treat or not with CDK4/6 inhibitors in the first line, it’s perhaps patients with the more indolent metastatic disease who gain the largest absolute benefit in overall survival,” he said.
Dr. Cescon continued: Carey et al presented a correlative sample analysis from pooled data from MONALEESA-2, -3, and -7, focusing on intrinsic molecular subtypes based on PAM50, which have shown to be prognostic in early and advanced breast cancers. The sample consisted mostly of luminal tumors but also included nonluminal ones, mostly represented by HER2-enriched tumors. “The overall survival benefit of ribociclib added to endocrine therapy was consistent across the three main subtypes, but not present in basal-like tumors. It was not surprising to see that a CDK4/6 inhibitor may not be effective therapy for that group,” he said.
Dr. Cescon cautioned that “our understanding of intrinsic subtypes in advanced breast cancer is evolving,” and there is variability in testing for subtypes at this time. “Switching subtypes can also occur between primary and metastatic disease…. In paired biopsies, some of the less aggressive subtypes in the primary tumor have been shown to evolve to more aggressive subtypes when metastatic.” Furthermore, an intrinsic subtype may correlate with other clinical, anatomic, and genomic features. In the PALOMA-2 and -3 studies of palbociclib, visceral disease tended to be composed of the more aggressive luminal B and HER2-enriched subtypes than bone-alone disease, he said.
“The question is, what is the clinical utility of this information?” he asked. As Dr. Carey mentioned, the HARMONIA trial will evaluate the clinical utility of intrinsic subtyping and test ribociclib vs palbociclib in the HER2-enriched subtype…. This study will be of great interest in the ongoing development of this hypothesis,” he said.
DISCLOSURE: Dr. Cescon has served in consulting or advisory roles for AstraZeneca, Exact Sciences, Eisai, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer, and Roche; has received institutional research funding from GlaxoSmithKline, Inivata, Merck, Pfizer, and Roche; is a member of a trial steering committee for AstraZeneca, Merck, and GlaxoSmithKline; and holds a patent (US62/675,228) for methods of treating cancers characterized by a high expression level of the SKA3 gene.
REFERENCES
1. O’Shaughnessy J, et al: Overall survival subgroup analysis by metastatic site from the phase 3 MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with HR+/HER2– advanced breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-01. Presented December 8, 2021.
2. Carey LA, et al: Correlative analysis of overall survival by intrinsic subtype across MONALEESA-2, 03, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2– advanced breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS2-00. Presented December 8, 2021.
3. Hortobagyi GN, et al: Overall survival results from the phase III MONALEESA-2 trial of postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative advanced breast cancer treated with endocrine therapy ± ribociclib. ESMO Congress 2021. Abstract LBA17_PR. Presented September 19, 2021.
