Novel Therapies Propelling Progress in Breast Cancer

Alexander A. Hindenburg, MD

The emergence of novel agents, such as CDK4/6 inhibitors and PI3K inhibitors, is shifting the standard of care for patients in metastatic, hormone receptor (HR)—positive, HER2-negative breast cancer, explained Alexander A. Hindenburg, MD.

"There have been new developments and we are improving outcomes to allow patients a better quality of life," Hindenburg said. "In metastatic, HR-positive disease, we are keeping them away from chemotherapy longer. These patients are generally unable to be cured, but they are now treatable."

For example, updated results from the phase III MONALEESA-7 trial showed that the combination of the CDK4/6 inhibitor ribociclib (Kisqali) and endocrine therapy elicited an estimated overall survival rate of 70.2% at 42 months versus 46.0% for placebo and endocrine therapy in pre- or perimenopausal women with HR-positive, HER2-negative advanced breast cancer.

While these developments have generated excitement in the space, there are challenges with sequencing that need to be addressed, he added.

"We have made tremendous strides improving outcomes with these drugs, but we do not know the order they should be used in," Hindenburg explained.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Hindenburg, a clinical assistant professor, Department of Medicine, NYU Langone’s Perlmutter Cancer Center, discussed these novel agents and ongoing clinical trials supporting their future application in this space.

OncLive^®: Could you highlight the emergence of CDK4/6 inhibitors and the data supporting their use?

Hindenburg: There are three agents available: palbociclib (Ibrance), ribociclib, and abemaciclib (Verzenio). There have been 7 trials now with these agents—4 in the first-line setting and 3 in the second-line setting. These trials [show] remarkable similarity in terms of outcome. Their efficacy, hazard ratios, prolongation of progression-free survival (PFS) and P values appear to be about the same; however, their toxicity profiles are different.

Most recently, the MONALEESA-7 trial showed a significant survival benefit with ribociclib. It was impressive, but it was a homologous cohort of premenopausal women who had higher-risk disease. It is still unknown whether or not ribociclib is better than the other agents, but this was the first survival benefit [reported with a CDK4/6 inhibitor]. If you look at a prior trial with palbociclib in the second-line setting, patients who had improved survival were the ones who were previously sensitive to hormonal therapy. The hazard ratio is about the same, so the jury is still out.

You said that these agents are similar in efficacy, but they differ in their toxicity profiles. What are some factors to keep in mind when selecting a CDK4/6 inhibitor for a patient?

Palbociclib and ribociclib are actually very similar in structure. Their main toxicity is neutropenia. In contrast, abemaciclib, which is a more potent CDK4 inhibitor, is less toxic in terms of myelosuppression and low white blood cell count, but [is more toxic] in terms of diarrhea. [It is rare, but] abemaciclib can lead to venous thrombotic events, liver function abnormalities and elevated creatinine. Ribociclib has the potential adverse event of prolonged QT intervals, so you have to monitor patients with electrocardiograms.

If somebody has a propensity for diarrhea, you would not choose abemaciclib. If a patient is otherwise well, you can choose from the drugs [while monitoring] for myelosuppression. [Overall], these drugs are safe, and it would be very rare that somebody would develop neutropenia.

How are you approaching sequencing in your own practice?

That is a very interesting question. I will use one of these drugs and then I will combine them, usually with an aromatase inhibitor in the first-line setting. Now, the real question is what to do afterward. The standard answer would be just to use fulvestrant (Faslodex), but a lot of people, myself sometimes included, are continuing patients on a CDK4/6 inhibitor and adding fulvestrant. [Alternatively], you could switch them over to an mTOR inhibitor. Now, the PI3K inhibitors would be one of the drugs of choice.

What ongoing trials exploring these inhibitors are you excited to learn more about?

The sequencing is a very important question and combining these drugs with an mTOR inhibitor makes sense.

Also, there are ongoing trials studying the use of these inhibitors as upfront therapy and in the adjuvant setting, especially for those with high-risk disease. Examples are the phase III PALLAS study with palbociclib and the phase II monarcHER study with abemaciclib.

Could you share insight on the PATINA trial?

All patients on the PATINA trial received chemotherapy for a few cycles, and were then randomized to receive HER2-directed therapy plus hormonal therapy [with or without palbociclib]. It a tantalizing trial because some data [show that] those mechanisms that create resistance to HER2-directed therapy are the upregulation of the CDK pathway.

Also, only 10% of patients have triple-positive disease and it is a distinctly different entity. Some of those patients behave more like a luminal-type [of breast cancer]; it [comes down to determining] the driving pathway in these patients. Some are more sensitive to anti-hormonal therapy while others are more HER2-neu driven. It is important for us to distinguish between the two.

You also covered updates with PI3K inhibitors in this space in your presentation. Could you elaborate on some of the work that is being done?

There were a number of PI3K inhibitors that have been studied; alpelisib (Piqray) is the one that really showed efficacy. The PFS was very impressive; however, the hazard ratio was not. I am not sure that it is 100% ready for primetime, simply because everolimus (Afinitor) is also [effective] and it works in PIK3CA mutations. Also, everolimus will work in those with PTEN mutations. In HR-positive breast cancer, 40% of patients will have the PIK3CA mutation, but 30% will have the PTEN mutation. Don't forget everolimus yet.

Where will future research focus in breast cancer?

The research will be focused on sequencing and on the mechanisms of resistance to these drugs. Why do people develop resistance? We already know that mutations in the mTOR pathway exist, but we aren't clear what makes cells resistant to CDK4/6 inhibitors. Studies such as PALOMA-3 study [are exploring that question].

Hurvitz SA, Im S-A, Lu Y-S, et al. Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: overall survival (OS) results. J Clin Oncol. 2019;37(suppl; abstr LBA1008).