CDK4/6 Inhibitors Expanding Treatment Options for ER+ Metastatic Breast Cancer

Maura N. Dickler, MD

More options are now available for combining and sequencing therapy for patients with estrogen (ER)—positive metastatic breast cancer (mBC), including the deployment of CDK4/6 inhibitors, as clinicians endeavor to individualize the sequencing of therapies to improve patient outcomes, according to Maura N. Dickler, MD.

Dickler, who is section head of the Endocrine Therapy Clinical Research Program at Memorial Sloan Kettering Cancer Center, reviewed how she is using research findings to inform treatment choices in her own practice, during her presentation at the 2016 International Congress on the Future of Breast Cancer.

One of the first challenges for clinicians, she explained, is whether to begin with endocrine therapy or chemotherapy, and Dickler said a number of factors impact that decision. These include not only the patient’s menopausal status, disease burden, and symptoms, but also her tumor biology and prior history of endocrine therapy.

“We know that patients are not just going to be treated with 5 years of endocrine therapy anymore. If they’re tolerating it, they’ll get at least 10 years of tamoxifen, potentially 10 years of an aromatase inhibitor (AI), or sequencing from tamoxifen to an AI, and that definitely complicates things when patients relapse,” Dickler noted.

For premenopausal women, ovarian suppression does add benefit, Dickler said. “My standard of care when I’m treating a woman with metastatic breast cancer is to ablate her ovaries, whether that’s medically, with an LHRH agonist, or surgically,” though she prefers oophorectomy when that approach aligns with the patient’s wishes. After ovarian ablation, treatment will follow protocols for postmenopausal women throughout the continuum of their endocrine therapy.

Several trials have shown that starting with an AI (such as letrozole, anastrozole, or exemestane) is better than tamoxifen in the first-line setting, Dicker noted, adding that typically her first-line approach is to give a nonsteroidal AI.

Targeting the CDK4/6 Pathway

Growth of ER+ breast cancer is dependent on cyclin D1, and thus there is a role for CDK4/6 inhibition. The CDK4/6 inhibitor palbociclib received accelerated FDA approval in February 2015, based on preliminary data from the phase II PALOMA-1 trial showing a 10-month improvement in median progression-free survival (PFS) in women receiving palbociclib with letrozole versus letrozole alone.

The phase III PALOMA-2 trial results reported at the 2016 ASCO Annual Meeting corroborated the benefit, with a median PFS of 24.8 months in the palbociclib/letrozole arm, versus 14.5 months with letrozole alone.¹“This is really an impressive increase,” Dickler said, with the addition of palbociclib reducing the risk of disease progression by 42%.

She added that it’s also important to note that patients in the letrozole-only arm did well in the first-line setting, experiencing PFS of more than 1 year; thus, it may be that not all patients will need the additional targeted agent, which adds cost and toxicity risk, notably myelosuppression.

The CDK4/6 inhibitor produced grade 3 neutropenia in more than half of the patients in PALOMA-2, for example, but generally this form of neutropenia was asymptomatic, and Dickler said that overall, the agent is well-tolerated.

Another first-line option in the ER+ metastatic setting would be to add fulvestrant to anastrozole. Although survival data with this option are mixed, Dickler said that patients who had not previously received tamoxifen derived the most benefit from the doublet.

“We now have options in the first-line setting,” said Dickler. For example, physicians could give an AI as a single agent in patients who have asymptomatic disease and mostly soft tissue or bone metastases. They could consider letrozole plus palbociclib in symptomatic patients with greater disease burden, and for patients who are endocrine therapy—naïve, giving anastrozole with fulvestrant could be considered.

Second- and Third-Line Therapy Options in ER+ mBC

Several randomized trials have examined which therapies are appropriate in the second-line setting, including the EFECT and SoFEA trials, which evaluated the combination of fulvestrant with exemestane. Results were disappointing however, Dickler noted, with median time to progression only about 3 months in both studies.

“We really need to do something for these patients, because it’s in the second-line setting where endocrine therapy alone is really not very effective.”

The PALOMA-3 study compared the addition of palbociclib to fulvestrant in the second-line setting where fulvestrant is typically used, although a survival analysis from the phase II FIRST study²suggested that fulvestrant could be used successfully in the first line, said Dickler.

In PALOMA-3, patients were randomized 2:1 to fulvestrant either with palbociclib (n = 347) or without (n = 147), and the addition of the CDK4/6 inhibitor significantly increased median PFS (3.8 months in the control arm vs 9.2 months in the palbociclib arm).³

“I think you can use CDK4/6 inhibitors—palbociclib is the only one approved right now—in either the first- or second-line setting,” said Dickler, adding that several randomized trials are currently recruiting patients to evaluate the use of other agents in this class in the hormone receptor (HR)—positive mBC setting, including abemaciclib and ribociclib, as well as palbociclib.

Dickler is an investigator on the phase II MONARCH-1 trial evaluating abemaciclib as a single agent in patients with advanced HR+/HER2-negative breast cancer, and she presented findings at the 2016 ASCO Annual Meeting.⁴

She explained that this trial involved heavily treated ER+/HER2- patients who had received at least 1, but no more than 2, chemotherapies {including a taxane) in the metastatic setting.

Typically the response rates to chemotherapy in this setting are around 10% to 20%, with a PFS of about 3 to 4 months, Dickler noted. In this trial, abemaciclib had an objective response rate of 19.7%, with stable disease of ≥6 months occurring in 22.7% of patients, translating to a clinical benefit rate of 42.4%.

She added that abemaciclib can be given continually. “It doesn’t need that 7 days off, because myelosuppression is less of a side effect,” although diarrhea is often reported with abemaciclib.

In the third-line setting, Dickler said that she often prescribes an mTOR inhibitor (such as everolimus) with exemestane, and if they have already had exemestane, she frequently gives everolimus in combination with tamoxifen, even if the patient has already had it in the adjuvant setting.

Dickler expressed optimism about expanded treatment options for ER+ mBC. “We are learning more about genomic alterations that may be targetable with investigational agents…there is a lot of exciting work going on in this arena.”

References:

1. Finn RS, Martin M, Rugo HS, et al. PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+/HER2— advanced breast cancer (ABC).J Clin Oncol.2016;34 (suppl; abstr 507).
2. Ellis MJ, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: overall survival analysis from the phase II FIRST study.J Clin Oncol.2015;33(32):3781-3787.
3. Turner NC, Ro J, Andre F, et al. PALOMA-3: A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy.J Clin Oncol.2015;33 (suppl; abstr LBA502).
4. Dickler MN, Tolaney S, Rugo HS, et al. MONARCH-1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease.J Clin Oncol.2016;34 (suppl; abstr 510).