Cristofanilli Reviews CDK 4/6 Inhibitors in the Case of a Patient With ER-Positive Breast Cancer

During a current Targeted Oncology case-based peer perspectives live dinner occasion, Massimo Cristofanilli, MD, discussed with a set of physicians the considerations he makes when selecting treatment alternatives for patients with most breast cancers. Cristofanilli, a medicine professor within the Hematology and Oncology Division at the Robert H. Lurie Comprehensive Cancer Center, Northwestern Feinberg School of Medicine, explained the options for treatment based on the case scenario of a woman with estrogen receptor (ER)–positive breast cancer.

Case

A sixty three-year-vintage female with right-sided ductal carcinoma in situ (DCIS) refused endocrine remedy from her physician. She was provided with a left-sided mass thirteen months later. Her liver function tests (LFTs) were mildly increased, and a CT experiment showed 2 liver nodules, with the largest at 2 cm. A biopsy found grade 2 invasive ductal carcinoma, ER-tremendous, progesterone receptor (PR)-effective, HER2-poor, which changed into stage T3N1M1. She had an ECOG overall performance fame of 0.

TARGETED ONCOLOGY:

What are your initial impressions of this patient and case?

Cristofanilli: This is ER-wonderful cancer; that is a patient with liver metastasis. This is a postmenopausal woman diagnosed with proper-sided DCIS that was handled with surgical treatment and radiation. Then she refused endocrine therapy for prevention, which may be very important. Then thirteen months later, she gives with a left-sided mass, now a palpable mass. She had a few exams to see what changed into the breast: mammogram, ultrasound, biopsy, and a blood test. The LFT showed mildly increased tiers. Because of that, we order a CT test and try to identify if there are other problems, and she does have 2 liver lesions. The largest is two cm.
The biopsy demonstrates that she has ER-fine sickness. This is an ER-high-quality, metastatic analysis with de novo metastasis, bi-lateral breast cancer, and optimum overall performance status. The LFT may or may not be associated with her disease because the lesions are quite small, and importantly, she has not been uncovered to endocrine remedy. This opens up several possibilities. We reflect consideration on remedy right away. We want to hurry to do something for this female. Clearly, [there has been] relatively speedy progression; it’s far an aggressive ailment.

TARGETED ONCOLOGY: What are the therapeutic options for this affected person?

Cristofanilli: There is a spread of extensive treatment alternatives: endocrine therapy, CDK4/6 inhibitors, aromatase inhibitors [AIs], chemotherapy. We start to consider a CDK4/6 inhibitor with an AI as a primary-line option for de novo degree IV disorder. Chemotherapy won’t be an awesome recommendation [for this patient]. About endocrine remedy and CDK4/6 inhibition, we speak approximately some of the scientific factors first: medical presentation, age, menopausal method, and many others. If this had been a premenopausal woman, perhaps you’ll have considered chemotherapy. If the tumor becomes larger, it might no longer have made a difference [because] she is at stage IV. [Looking at] ER and PR fame, she has ER positivity. The pace of progression: She isn’t progressing; she has a de novo ailment—the extent of disease: predominant liver involvement. And, of the route, the signs: She is symptomatic. She merits a CDK4/6 inhibitor.

If she had received, let us say, Arimidex [anastrozole] for prevention, then [the use of an AI] might be a bit extraordinary, now not due to resistance however the opportunity of resistance. For this affected person, we’d use an AI and a CDK4/6 as the first-line remedy. The National Comprehensive Cancer Network guidelines are very open regarding the alternatives left to the medical doctor,1 which means that you may select and pick out from this menu. When you study the CDK4/6 inhibitors, you notice that there are three: abemaciclib [Verzenio], palbociclib [Ibrance], and palbociclib [Kisqali] with [an] AI, [and] with fulvestrant [Faslodex] for sufferers who progress on an AI. We keep constructing this listing. In the beyond, we had everolimus [Afinitor] with exemestane, and there’s a listing of other marketers that can be used later.

TARGETED ONCOLOGY: How do you decide which CDK4/6 inhibitor to apply?

Cristofanilli: We have 3 medical trials which have shown that after you use an AI—in a few cases, it does now not remember which AI—in combination with a CDK4/6, you absolutely have an improvement in final results. The [primary endpoint in all 3 trials] became median development-loose survival [PFS]. That turned into the primary endpoint that delivered the approval of these marketers. The one-of-a-kind ratios [between the 3] are quite comparable. It may be very tough to compare the specific studies steadily, and we need never do that. But one thing that you need to recall is if you examine the median PFS, the manipulate group is pretty regular typical. Patients in PALOMA-2 had been naïve sufficient to prior metastatic remedy for endocrine therapy—this allowed a few endocrine therapies—but common, there’s a considerable impact on PFS, [a] clinical benefit to the agent in the overall reaction.2

TARGETED ONCOLOGY:

Describe the 3 CDK4/6 inhibitors that are authorized for use in this setting and what clinicians should know approximately every. Cristofanilli: Up the front, the three marketers appear to be similar in a few respects; however, when you begin to pass into the info of those marketers, you notice there are differences within the time table, administration, dose, the adverse events [AEs], and the chemistry and targets. This relates to the reality that they’re concentrated on CDK with extraordinary potency. Palbociclib became the primary-in-elegance. The starting dose became 125 mg day by day at 3 weeks on, 1 week off; AEs encompass neutropenia [and thrombocytopenia], and there’s a scale of adjustment to dose whilst it’s miles important. Usually, the whole thing happens inside the starting for this agent.

Palbociclib is a 200-mg pill, [with a starting dose of] 600 mg each day, additionally at three weeks on, 1 off; [AEs saw with the agent include] neutropenia however additionally QTc [QT interval correct for heart rate] prolongation.
Abemaciclib usually starts offevolved at two hundred mg continuously, also can be used at 150 mg daily. [AEs include] fatigue, but broadly speaking, diarrhea and neutropenia. We know a way to manipulate these AEs.

TARGETED ONCOLOGY:

How do the consequences of these trials affect the way you deal with patients with a visceral ailment? Cristofanilli: Going returned to the evaluation of the exclusive studies, the populations are exceedingly comparable, the benefit is consistent across the special subtypes, and the PFS advantage is comparable respective of age, and this is a population this is postmenopausal basically. When you study [patients with] visceral metastases or no visceral metastases in the MONALISA-2 trial, describing the lung and liver metastases, there is a pretty constant [benefit with ribociclib].3 These sufferers, despite being within the first line [and] no matter being 30% or so de novo, four had visceral bone metastases, and the advantage is there. The patients with visceral sickness, in standard, had much less benefit than nonvisceral and bone-only disease…Overall, the liver is a little tougher to treat regardless of anything agent you use, which includes chemotherapy or direction. Some sufferers had received the previous remedy, like AIs, only if they had [a disease-free interval] >twelve months. Pretty a lot, all the first-line sufferers were now not symptomatic and ER-advantageous universal.