CDK4/6 Inhibitors Show Unmatched OS Benefit in Metastatic HR+ Breast Cancer

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Komal Jhaveri, MD, FACP, discusses updates in research for metastatic HR-positive, HER2-negative breast cancer.

Komal Jhaveri, MD

Komal Jhaveri, MD

Komal Jhaveri, MD

The recent readout of overall survival (OS) data with CDK4/6 inhibitors in patients with metastatic hormone receptor (HR)—positive, HER2-negative breast cancer has been unprecedented, according to Komal Jhaveri, MD, FACP.

“With all of the newer targeted therapies that are currently approved, there has been a lot of exciting data presented in 2019 and 2018 for breast cancer that has been unprecedented for our patients,” said Jhaveri, a section head within the Breast Medicine Service at Memorial Sloan Kettering Cancer Center.

For example, the phase III MONALEESA-3 trial showed that the combination of ribociclib (Kisqali) and fulvestrant (Faslodex) led to an approximate 28% reduction in the risk of death compared with placebo and fulvestrant in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer.1,2 The median OS was not reached with ribociclib and was 40.0 months with placebo (HR, 0.724; 95% CI, 0.568-0.924; P = .00455).

Similarly, the MONALEESA-7 trial looked at the addition of ribociclib to endocrine therapy in peri-/premenopausal women with advanced HR-positive, HER2-negative breast cancer. In updated findings presented at the 2019 ESMO Congress, overall survival (OS) was not reached for the patients on ribociclib versus 40.7 months for those on placebo (HR, 0.699; 95% CI, 0.501-0.976).3

In the phase III MONARCH 2 trial, adding the CDK4/6 inhibitor abemaciclib (Verzenio) to fulvestrant led to a median OS of 46.7 months compared with 37.3 months for placebo/fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who progressed on prior endocrine therapy (HR, 0.757; 95% CI, 0.606-0.945; P = .0137).4,5

In an interview during the 2019 OncLive® State of the Science Summit™ on Breast Cancer, Jhaveri discussed updates in research for metastatic HR-positive, HER2-negative breast cancer.

OncLive®: Could you give an overview of the MONALEESA clinical trial program?

Jhaveri: The MONALEESA trials were evaluating the role of ribociclib, 1 of the 3 CDK4/6 inhibitors approved for patients with HR-positive metastatic disease. The MONALEESA-7 trial examined premenopausal women who are treated in the first-line setting with ribociclib, ovarian suppression, and endocrine therapy. The partner could have been tamoxifen or an aromatase inhibitor (AI), depending on what the patient received for their disease previously, versus endocrine therapy alone without a CDK4/6 inhibitor. We already saw that the trial reported out an improvement in PFS for that triplet with ovarian suppression, endocrine therapy, and ribociclib.

At the 2019 ASCO Annual Meeting, we learned about the OS benefit that was seen in this trial, as well. This was the very first trial where we saw a positive signal, even though OS was not reached in the ribociclib arm of the study. That has been very exciting to see for our patients, and it is something that we've been looking forward to in metastatic disease.

At the 2019 ESMO Congress, we heard updates from the MONARCH 2 and MONALEESA-3 trials. MONARCH 2 evaluated abemaciclib with fulvestrant, and MONALEESA-3 evaluated fulvestrant with ribociclib. In the MONALEESA-3 trial, there was also a cohort of patients who were treated up front with this combination, something which is slightly unique from the other trials. Both of these studies have shown an OS benefit, telling us that we should be utilizing these agents for our patients. We were doing that already based on the PFS and their respective approvals, but it is very nice to see the OS benefit.

How does the PALOMA-3 study compare with the MONALEESA and MONARCH 2 trial?

The PALOMA-3 trial is evaluating the combination of fulvestrant with palbociclib (Ibrance). Similar to MONARCH 2 and MONALEESA-3, there were patients who were treated after they had progressed on a nonsteroidal AI.

However, unlike the MONARCH 2 and MONALEESA-3 trials, PALOMA-3 enrolled patients who had received chemotherapy for their metastatic disease, which was about 30% of patients on the study. This is slightly different than what we've seen in the MONARCH 2 population, where no chemotherapy was allowed. In PALOMA-3, we also saw a PFS benefit. That was the very first study we heard the results for, and we were already utilizing those data in our practice. The trial showed an improvement in OS benefit, but it was not statistically significant. However, that was not the primary endpoint.

How has the utility of PI3K inhibitors evolved in breast cancer?

We have come a very long way in our understanding of the biology of this pathway, which is implicated in breast cancer progression, specifically the role of endocrine resistance based on this pathway activation. We made a lot of attempts to figure out how we can target this pathway to further improve the outcomes for our patient population.

We started off with everolimus (Afinitor), which was approved based on the BOLERO-2 study. We showed that there was a PFS benefit in the second-line setting when patients had progressed on a nonsteroidal AI or up to 1 line of chemotherapy. There was an improvement in PFS and led to an approval of this agent.

Since then, our understanding of this pathway has evolved. We have tried multiple agents, including pan-PI3K inhibitors. Can we get an agent that not only will have improved efficacy, but perhaps a better toxicity profile? Having this narrow therapeutic window has been a challenge for our patients in the clinic. That has led to an introduction of the alpha-specific PI3K inhibitors. It's exciting to see that the very first alpha-specific PI3K inhibitor now has approval—which is alpelisib (Piqray)—which was approved in combination with fulvestrant, specifically for a PIK3CA-mutated population in which the benefit was most pronounced.

With all of these therapy options, how is sequencing in breast cancer?

When it comes to HER2-negative disease, we have a lot of evidence and unprecedented improvements in PFS and OS with the utilization of CDK4/6 inhibitors that are here to stay in the first- and second-line settings. However, we also have data for our biomarker-selected patient population, such as, those with PIK3CA mutations.

If you have this biomarker, you could offer them a PI3K inhibitor. We are now seeing [more mutations] by doing next-generation sequencing in the tumor, as well as using liquid biopsies with cell-free DNA. We know that patients with ESR1 mutations are likely not going to benefit from exemestane with everolimus, because those patients would not derive benefit from an AI.

Our knowledge is getting more refined. With more data, we are able to apply the sequential approaches, either initially based on not having a biomarker for CDK4/6 or with certain biomarker and risk populations with newer agents that are getting approved.

References

  1. Slamon DJ, Neven P, Chia S, et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) treated with fulvestrant (FUL) + ribociclib (rib). Ann Oncol. 2019;30(suppl_5): mdz394.007. doi: 10.1093/annonc/mdz394.007.
  2. Slamon DJ, Neven P, Chia SKL, et al. Ribociclib (RIB) + fulvestrant (FUL) in postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2—) advanced breast cancer (ABC): results from MONALEESA-3. J Clin Oncol. 2019;37(suppl; abstr 1000). doi: 10.1200/JCO.2018.36.15_suppl.1000.
  3. Lu Y, Bardia A, Vázquez RV, et al. Updated overall survival (OS) and quality of life (QoL) in premenopausal patients (pts) with advanced breast cancer (ABC) who received ribociclib (RIB) or placebo (PBO) plus goserelin and a nonsteroidal aromatase inhibitor (NSAI) in the MONALEESA-7 (ML-7) trial. Ann Oncol. 2019;30(suppl_5):v104-v142. doi: 10.1093/annonc/mdz242.
  4. Sledge Jr GW, Toi M, Neven P, et al. MONARCH 2: overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2 advanced breast cancer. Ann Oncol. 2019;30 (suppl_5): mdz394.006. doi: 10.1093/annonc/mdz394.006.
  5. Sledge Jr GW, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor—positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial [published online ahead of print September 29, 2019]. JAMA Oncol. doi:10.1001/jamaoncol.2019.4782.
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