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New Insights in Breast Cancer: Independent Conference Coverage of SABCS 2020

Sara Hurvitz, MD, FACP
Joyce O'Shaughnessy, MD
Released: February 19, 2021

CDK4/6 Inhibition in High-Risk Hormone Receptor–Positive/HER2-Negative EBC

monarchE: Adjuvant Abemaciclib Plus ET in High-Risk, Node-Positive, Hormone Receptor+/HER2- EBC

Sara Hurvitz, MD, FACP:
The international, randomized, open-label phase III monarchE trial aimed to evaluate 2 years of adjuvant abemaciclib with standard ET vs ET alone in patients with hormone receptor–positive/HER2-negative EBC who are at particularly high risk for recurrence.[1,2] Patients in cohort 1 had to have at least 4 positive lymph nodes or 1‑3 positive lymph nodes plus a grade 3 tumor and/or a tumor ≥ 5 cm whereas patients in cohort 2 had to have 1‑3 positive lymph nodes and tumor Ki-67 levels ≥ 20% by central testing without a grade 3 tumor and tumor size < 5 cm. The primary endpoint was iDFS and the primary analysis was planned after approximately 390 events.

monarchE: iDFS (Primary Endpoint)

Sara Hurvitz, MD, FACP:
In the initial report of this trial, with a median follow-up of 15.5 months, the iDFS was statistically significantly in favor of the abemaciclib arm, although the vast majority of patients were still receiving study treatment.[1] Median follow-up of 19.1 months results were presented at SABCS 2020 where the 2‑year iDFS was superior in the abemaciclib arm vs ET alone (92.2% vs 88.7%, respectively). This absolute difference was statistically significant with an HR of 0.75. Even the subset of patients with high Ki-67 tumors also appeared to benefit from abemaciclib plus ET with a very similar HR (0.70).

monarchE: iDFS by Subgroup

Sara Hurvitz, MD, FACP:
Most patient subgroups appeared to benefit from the addition of abemaciclib to ET.

monarchE: Distant Relapse-Free Survival

Sara Hurvitz, MD, FACP:
Of importance, the distant relapse free survival was also better in patients treated with abemaciclib plus ET compared with ET alone.

monarchE: Treatment-Emergent Adverse Events

Sara Hurvitz, MD, FACP:
The toxicity profile of abemaciclib is similar to what has been reported previously: diarrhea, with grade 3 diarrhea observed in close to 8% of patients on abemaciclib. Grade 3/4 neutropenia was seen in approximately 19% of patients, which is lower than we see with the other CDK4/6 inhibitors.

monarchE: Treatment-Emergent Adverse Events of Special Interest

Sara Hurvitz, MD, FACP:
In terms of adverse events of special interest, there was a slight increased risk of grade 3/4 transaminase elevation with abemaciclib therapy, and 2.3% of patients treated with abemaciclib had a venous thromboembolic event, which is consistent with previous studies. All grade interstitial lung disease was reported in 2.7% of patients in the abemaciclib arm, most of which were grade 1/2, but there was one pneumonitis related death associated with abemaciclib in this study.

PENELOPE-B: Palbociclib Plus ET in Hormone Receptor+/HER2- Breast Cancer at High Risk of Relapse After Neoadjuvant Chemotherapy

Sara Hurvitz, MD, FACP:
In contrast to monarchE, the PENELOPE‑B study evaluated only 1 year of adjuvant CDK4/6 inhibitor—palbociclib—added to standard ET vs ET alone in 1250 patients with hormone receptor–positive/HER2-negative nonmetastatic breast cancer.[3] In this randomized, double-blind, placebo-controlled phase III trial, patients were particularly high risk, as they had to have had residual disease after standard neoadjuvant chemotherapy and had to have other high‑risk clinical and pathologic features as defined by nodal status and the clinical-pathologic stage-estrogen/grade (CPS-EG) score.

PENELOPE-B: iDFS (Primary Endpoint)

Sara Hurvitz, MD, FACP:
With a median follow-up of 42.8 months, the longest follow-up of the reported adjuvant CDK4/6 inhibitor trials so far, there was no significant benefit associated with the addition of palbociclib to ET (HR: 0.93; P = .525). However, looking at the Kaplan-Meier curve, it is interesting to note this early separation of curves such that, at the 2 year and 3 year time points, palbociclib does seem to add some benefit that, in my opinion, looks strikingly similar to what we saw in the monarchE trial with abemaciclib plus ET. However, with longer follow-up, this apparent early separation of the curves disappears.

PENELOPE-B: OS Interim Analysis

Sara Hurvitz, MD, FACP:
There was no OS benefit observed with adjuvant palbociclib plus ET compared with ET alone (HR: 0.87; P = .420)

PENELOPE-B: Patient Disposition and Exposure

Sara Hurvitz, MD, FACP:
Fewer than 20% of patients discontinued palbociclib early. This is in contrast to the PALLAS adjuvant clinical trial of palbociclib in slightly less high‑risk patients, where approximately 40% of patients discontinued palbociclib early.[4]

Adjuvant CDK4/6 inhibition in High Risk Hormone Receptor+/HER2 EBC: Clinical Implications

Sara Hurvitz, MD, FACP:
To summarize this section on CDK4/6 inhibition in high‑risk hormone receptor–positive/HER2‑negative EBC, we have 2 drugs with similar mechanisms of action and similar PFS benefits in the metastatic disease setting that are showing seemingly discordant results in the adjuvant setting. This begs the question as to why these results are so different. Both studies enrolled high‑risk patients and had similar rates of dropout, so that would not explain the difference. It is possible that only 1 year of CDK4/6 inhibitor therapy in PENELOPE‑B was not long enough; recall that abemaciclib was given for up to 2 years in monarchE. It is also possible that abemaciclib is simply the better drug. After all, it has single‑agent efficacy, it is a more potent inhibitor, and it has demonstrated OS benefits in the metastatic setting. It is also possible, however, that the follow-up is not long enough in monarchE. It will be very important for us to follow out these data and make sure the curves do not come together over time after the CDK4/6 inhibitor has stopped.

At this time, there is no CDK4/6 inhibitor indication as adjuvant therapy outside of a clinical trial setting. However, if abemaciclib is approved by the FDA for this indication, I think it would be reasonable to present these data, in totality, to patients and offer the drug to those who fit the enrollment criteria for monarchE, with careful monitoring of longer‑term follow-up data to ensure that we are benefiting patients in the long run. It is also very important to keep in mind the adverse event profile associated with abemaciclib, namely grade 3/4 transaminase elevation, increased risk of diarrhea, increased risk of neutropenia, and venous thromboembolic events.

Joyce O’Shaughnessy, MD:
I agree that we need further follow-up from monarchE because breast cancer plays out during a long period of time. Particularly in light of the PENELOPE‑B trial results, it will be crucial to see if patients continue to have benefit after they stop the abemaciclib. In the data presented at SABCS, approximately 50% of patients were still receiving abemaciclib.

In PENELOPE‑B, there was not a durable benefit from palbociclib, unfortunately. Together with results from the PALLAS trial, which found no benefit of adding 2 years of adjuvant palbociclib to standard ET in patients with hormone receptor–positive/HER2-negative EBC, these data suggest that our patients will not benefit from adjuvant palbociclib. We will need to wait for longer follow-up from monarchE to know if abemaciclib, which has a broader spectrum of activity and is given continuously without a break, will lead to longer lasting benefit in this setting. We will also look forward to results from the ongoing phase III NATALEE trial of ribociclib plus ET as adjuvant therapy in this patient population.[5]

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