Ribociclib/Everolimus Elicits Responses in Dedifferentiated Liposarcoma

The combination of ribociclib (Kisqali) and everolimus (Afinitor) elicits responses in patients with advanced dedifferentiated liposarcoma (DDLPS) and offers a tolerable safety profile, according to Margaret von Mehren, MD, who added that these responses have not previously been seen in this patient population with CDK4 inhibitors.

The phase 2 SAR-096 trial (NCT03114527) met its primary end point of more than 8 patients without progression at 16 weeks. Investigators observed 2 confirmed partial responses in the cohort with advanced DDLPS.

“In the DDLPS [cohort], we saw interesting activity in terms of disease stabilization,” von Mehren said. “We also saw 2 patients in the first 21 [who have been enrolled] who had a response, which is not something that has been seen in the other studies looking at CDK4 inhibitors.”

In an interview with OncLive®, von Mehren, chief of the Division of Sarcoma Medical Oncology; physician director of the Clinical Trials Office; associate director of Clinical Research; and professor of the Department of Hematology/Oncology at Fox Chase Cancer Center, discussed the value of ribociclib plus everolimus for patients with DDLPS, and how further research will be focused on biomarker analysis.

OncLive®: What was the rationale for combining ribociclib with everolimus in patients with advanced DDLPS?

Von Mehren: The presentation at ASCO this year focused on the DDLPS arm, and the rationale is different for the dedifferentiated [arm compared with] the leiomyosarcoma arm. In leiomyosarcoma, there oftentimes are abnormalities in the PTEN pathway. PTEN is important in the cell cycle and cell growth, and CDK4 inhibits that pathway. There was PTEN loss in the [patients with] leiomyosarcoma. We know that from other studies that CDK4 inhibitors might be useful in that setting. However, it has become apparent that sometimes when there is resistance, it seems to involve the mTOR pathway. Everolimus is an mTOR inhibitor, and thus the reason for putting them together.

In DDLPS, the rationale is [similar], but the underlying biology is different. Patients with DDLPS are known for having amplification on regions of chromosome 12. In that region is MDM2 amplification, which oftentimes is what pathologists look at to confirm [the patient has] dedifferentiated liposarcoma. In that region is also the CDK4 gene. [Therefore], upregulation of CDK4 using a CDK4 inhibitor may allow for loss of inhibition of cell cycle. Again, due to resistance mechanisms, the combination with everolimus might be better. In DDLPS, there have been some prior studies looking at CDK4 inhibitors, and for the most part [the trials have shown] disease stabilization. The question that we asked in this study is, if we were to combine these 2 pathway inhibitors, would we get a better outcome than what has been seen previously?

What were the key findings of this trial?

In the DDLPS [cohort], we saw interesting activity in terms of disease stabilization. We also saw 2 patients in the first 21 [who have been enrolled], had a response, which is not something that has been seen in the other studies looking at CDK4 inhibitors. [Whenever it’s] a small study at 2 institutions, you don't want to claim victory, but I think that it is an interesting finding and suggests that this is how we should move forward.

Another key finding is that combining these 2 agents was not excessively toxic, but there were certainly patients in whom neutropenia and lymphocytopenia limited their ability to take the medication on a consistent basis. The dosing schema [in this trial] is this something that's feasible in the long term for patients.

You said that at the meeting you're going to be primarily focusing on the one patient group, so if this question isn't applicable, that's absolutely fine. Did you find that the combination yielded different results between the 2 patient subgroups?

The leiomyosarcoma subgroup was presented last year at ASCO or the year before, but we did not see the same kind of activity. We did see some stable disease, but we didn't meet the predefined, pre-specified level of activity to consider it successful.

Was there any other kind of notable adverse effects that you noticed with this combination?

We saw some [adverse events] that we would have anticipated with these medications. There were 1 or 2 cases of pneumonitis, which [is anticipated] with everolimus. Some patients had some gastrointestinal toxicity, but nothing excessive.

Where do you think future research efforts need to be focused from here?

[From this trial], we've seen some activity, [which is] interesting, [but] it's not a home run. The question is, is there another agent that should be added or an alternative? Or is there a different schedule that might be more interesting? We are trying to look at some of correlative studies, and have some samples before therapy and on therapy, [which are] somewhat limited, unfortunately, begging the question [of whether] there is a predictive marker that might help select patients who might do better. Or is there something that we see in terms of lack of efficacy [that might be a] predictive marker? We're going to see what we can determine from that, but at this point, that hasn't been fleshed out.

For patients who have sarcoma, oral therapies are a great option, so working together with Sujana Movva, MD, of Memorial Sloan Kettering Cancer Center, and Suzanne George, MD, of Dana-Farber Cancer Institute who helped design the study, will be interesting. We'll look forward to seeing what next steps we can add or combine with this regimen to move it forward.

Is there anything else that you would like your colleagues to take away from this research?

I think that most people who are really dedicated to sarcoma understand this already, but I think this study is nice, because it showed that 1 regimen with lots of biologic rationale in 2 sarcoma subtypes showed very different results. [The results highlight] the importance of doing studies that allow you to define the patient population that a particular regimen works in. The days of doing broad, soft tissue sarcoma studies are over, which is true in many diseases. Now, everything's becoming subsetted. In sarcoma, we have 50 different histologies, if not more. Increasingly, we're appreciating that we really need to do specific studies within specific histologies.

Reference

Von Mehren M, Movva S, Handorf E, et al. Outcomes in the dedifferentiated liposarcoma cohort of SAR-096, a phase II trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS). J Clin Oncol. 2021;39(suppl 15):11515. doi:10.1200/JCO.2021.39.15_suppl.11515