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Highlights From the 2021 SABCS Symposium
  • CME

Joyce O'Shaughnessy, MD
Sara Tolaney, MD, MPH
Released: February 25, 2022

Ribociclib Plus Letrozole in HR+/HER2- Advanced Breast Cancer

MONALEESA-2: Ribociclib Plus Letrozole in HR+/HER2- Advanced Breast Cancer

Joyce O’Shaughnessy, MD:
MONALEESA‑2 looked at first‑line metastatic, postmenopausal, hormone receptor–positive, HER2‑negative patients who were randomized to letrozole plus placebo vs letrozole plus ribociclib.5 This double-blind, randomized phase III study enrolled 668 patients.

The primary analysis for this study reported the longest median OS result that we have seen in the metastatic setting.6 Adding ribociclib to letrozole showed an impressive improvement in OS over letrozole plus placebo in the first‑line setting (63.9 vs 51.4 months, HR: 0.76; 95% CI: 0.63-0.93; P = .004).

MONALEESA-2: OS by Type and Number of Metastases

Joyce O’Shaughnessy, MD:
I presented these current findings on prospectively identified, clinically relevant subsets from MONALEESA-2 at SABCS 2021. The previously observed OS advantage for ribociclib plus letrozole held across all subsets, including the number and location of metastases, and prior chemotherapy or ET, although the analysis was not powered to demonstrate significance. Patients with liver metastases are the most difficult patients we manage. Remarkably, in this study, the 6-year OS data showed that 31% of patients with liver metastases treated with letrozole plus ribociclib were still alive compared with 19% of those treated with letrozole plus placebo.

Similarly, after receiving the combined treatment, the bone-only patients, who might be treated with ET alone, saw a median OS of 72 months compared with 54 months for those receiving only letrozole. This is an impressive difference.

So, there is not a clinically relevant patient subset who did not benefit from the addition of ribociclib. In my practice I have increased utilization of ribociclib in the first‑line metastatic setting given the large OS benefit.

MONALEESA-2: Conclusions

Joyce O’Shaughnessy, MD:
I think this cements ribociclib as a very important agent improving survival in the first‑line setting. Have these data changed your practice in terms of using more ribociclib, Dr. Tolaney?

Sara Tolaney, MD, MPH:
I think these were important data, and they clearly show survival advantage in a first‑line postmenopausal population with the combination of a CDK4/6 inhibitor and an AI. Currently, ribociclib is the only agent that has OS benefit with an AI, as we have not yet seen the OS data from PALOMA‑2 with palbociclib (NCT01740427) or MONARCH 3 with abemaciclib (NCT02246621). But PFS benefits with the 3 agents have been remarkably similar.

It does bring up the question, if you are prescribing therapy with an AI and CDK4/6, should you only be using ribociclib, because it is the only agent with OS benefit right now? At my institution, we try to have a uniform approach to patients, and people had mixed feelings about it because we do not yet know if there is an OS benefit with abemaciclib or with palbociclib in combination with an AI. Most of our group felt that they wanted to have choice of CDK4/6 inhibitor, but some did feel that ribociclib would be their preferred choice at this time, because it does lead to survival benefit. I think it is hard. Again, these data are very impressive and definitely support the use of ribociclib upfront, which is great.

Joyce O’Shaughnessy, MD:
I have started to use more ribociclib, but I utilize the others as well, particularly abemaciclib. I think that the broader mechanism of action and the continuous dosing of abemaciclib leads to better outcomes for those least likely to benefit from ET.

MONALEESA-2, -3, and -7: Ribociclib Plus ET for HR+/HER2- Advanced Breast Cancer

Sara Tolaney, MD, MPH:
Continuing with the MONALEESA trials, Carey and colleagues looked at pooled data from MONALEESA- 2, -3, and -7 in a retrospective exploratory analysis of intrinsic subtypes and their relationship to OS. The 3 studies together provided data on 2066 postmenopausal patients with hormone receptor–positive, HER2-negative advanced breast cancer who received ribociclib plus ET compared with placebo plus ET.7

Among the 2066 intention-to-treat (ITT) patients, intrinsic subtyping identified 997 patients for the biomarker group using a customized panel of 36/50 PAM50 genes. The OS benefit associated with ribociclib plus ET was comparable in the biomarker group to the ITT group (HR: 0.76 and 0.75, respectively).

MONALEESA-2, -3, and -7 Correlative Analysis: Intrinsic Subtype Prognostic for OS

Sara Tolaney, MD, MPH:
A previous analysis found that PFS favored ribociclib in the luminal A, luminal B, and HER2-enriched intrinsic subtypes but not the basal-like subtype.8 Looking closer at the HER2‑enriched patients, in general, they do not fare well. If the basal-like subgroup is removed, the HER2-enriched has the worst outcomes but they have the largest incremental benefit from the addition of ribociclib compared with the other subtypes. This is interesting and not what I anticipated, suggesting there was some benefit for all the patients.

In the analysis presented at SABCS, the authors analyzed correlations between intrinsic subtypes and OS. These data suggest that there is survival advantage across all the intrinsic subtypes except for basal-like, and again there is a larger relative advantage for the HER2‑enriched subtype, a type that often does not respond well.

MONALEESA-2, -3, and -7: Conclusions

Sara Tolaney, MD, MPH:
This study concludes that intrinsic subtype is associated with OS and supports similar findings for PFS in this patient population. Although I think this approach is intriguing, it raises questions about clinical relevance. Should we identify patients who have basal‑like cancer up front and withhold a CDK4/6 inhibitor? Do these intriguing data mean that there is a certain advantage for ribociclib over other CDK4/6 inhibitors for HER2-enriched patients? We do not have the answers to these questions. I do not think these data will affect clinical practice at this time because we are not testing patients for intrinsic subtype, and the basal-like subgroup who do not benefit from this treatment is very small.

Planning is underway for prospective studies to randomize patients who have HER2‑enriched subtype to ET with ribociclib or ET with palbociclib, trying to tease out whether the advantage that has been seen in the HER2‑enriched group is driven specifically by ribociclib and would not be seen with palbociclib (HARMONIA, NCT05207709). There is another cohort that is a single‑arm study looking at giving basal‑like cancers chemotherapy in the upfront setting because they did not derive benefit from ribociclib upfront.

Joyce O’Shaughnessy, MD:
I think that this subtype study is intriguing and hypothesis generating, and I am glad there will be follow-up trials. But I agree, I do not think these data apply to the clinic yet. We would not go looking for these intrinsic subtypes at this time. However, if this approach pans out, and I think it is too soon to tell, it might have treatment implications for our germline BRCA patients, potentially in the metastatic/adjuvant setting. Fortunately, in the adjuvant setting, I think we soon will have an FDA approval for adjuvant olaparib for those patients at high risk of recurrence.

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