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

Shannon Connelly
Published Online:8:16 PM, Fri June 28, 2019
Massimo Cristofanilli, MD
Massimo Cristofanilli, MD
During a recent Targeted Oncology case-based peer perspectives live dinner event, Massimo Cristofanilli, MD, discussed with a group of physicians the considerations he makes when deciding on treatment options for patients with breast cancer. Cristofanilli, a professor of medicine in 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 63-year-old woman with right-sided ductal carcinoma in situ (DCIS) refused endocrine therapy from her physician. She presented with a left-sided mass 13 months later.

Her liver function tests (LFTs) were mildly elevated and a CT scan showed 2 liver nodules, with the largest at 2 cm. A biopsy revealed grade 2 invasive ductal carcinoma, ER-positive, progesterone receptor (PR)-positive, HER2-negative, which was stage T3N1M1. She had an ECOG performance status of 0.


TARGETED ONCOLOGY: What are your initial impressions of this patient and case?

Cristofanilli: This is an ER-positive cancer; this is a patient with liver metastasis. This is a postmenopausal woman who had a diagnosis of right-sided DCIS that was treated with surgery and radiation and then she refused endocrine therapy for prevention, which is very important. Then 13 months later, she presents with a left-sided mass, now a palpable mass. She had some tests to see what was going on in the breast: mammogram, ultrasound, biopsy, and a blood test. The LFT showed mildly elevated levels. Because of that, we order a CT scan and try to identify if there are any other problems, and she does have 2 liver lesions. The largest is 2 cm.

The biopsy demonstrates that she has ER-positive disease. This is an ER-positive, metastatic diagnosis with de novo metastasis, bi-lateral breast cancer with an optimal performance status. The LFT may or may not be associated with her disease because the lesions are relatively small, and importantly, she has not been exposed to endocrine therapy. This opens up a number of possibilities.

We think about therapy right away. We want to rush to do something for this woman. Clearly, [there has been] relatively fast progression; it is an aggressive disease.

TARGETED ONCOLOGY: What are the therapeutic options for this patient?

Cristofanilli: There are a variety of intensive treatment options: endocrine therapy, CDK4/6 inhibitors, aromatase inhibitors [AIs], chemotherapy.

We start to think about a CDK4/6 inhibitor with an AI as a first-line option for de novo stage IV disease. Chemotherapy might not be a good recommendation [for this patient].

With regard to endocrine therapy and CDK4/6 inhibition, we talk about a number of clinical factors first: clinical presentation, age, menopausal strategy, etc. If this were a premenopausal woman, maybe you would have considered chemotherapy. If the tumor was larger it would not have made a difference, [because] she is at stage IV. [Looking at] ER and PR status, she has ER positivity. Pace of progression: She is not progressing, she has de novo disease. Extent of disease: major liver involvement. And, of course, the symptoms: She is symptomatic. She deserves a CDK4/6 inhibitor.

If she had received, let us say, Arimidex [anastrozole] for prevention, then [the use of an AI] would be a little bit different, not because of resistance but the possibility of resistance.

For this patient, we would use an AI and a CDK4/6 as first-line treatment. The National Comprehensive Cancer Network guidelines are very open in terms of the choices left to the physician,1 meaning that you can pick and choose from this menu. When you look at the CDK4/6 inhibitors, you see that there are 3: abemaciclib [Verzenio], palbociclib [Ibrance], and ribociclib [Kisqali] with [an] AI, [and] with fulvestrant [Faslodex] for patients who progress on an AI. We keep building this list. In the past, we had everolimus [Afinitor] with exemestane, and there is a list of other agents that can be used later. 

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

Cristofanilli: We have 3 clinical trials that have shown that when you use an AI—in some cases it does not matter which AI—in combination with a CDK4/6, you definitely have an improvement in outcome. The [primary endpoint in all 3 trials] was median progression-free survival [PFS]. That was the first endpoint that brought the approval of these agents. The different ratios [between the 3] are pretty similar.

It is very difficult to compare the different studies in a way that is consistent, and we should never do that. But one thing that you need to remember is if you look at the median PFS, the control group is pretty consistent overall. Patients in PALOMA-2 were naïve enough to prior metastatic treatment for endocrine therapy—this allowed some endocrine therapy—but overall, there is a significant impact on PFS, [a] clinical benefit to the agent in overall response.2

TARGETED ONCOLOGY: Describe the 3 CDK4/6 inhibitors that are approved for use in this setting and what clinicians should know about each.

Cristofanilli: Up front, the 3 agents appear to be similar in some respects, but when you start to go into the details of these agents, you see there are differences in the schedule, administration, dose, the adverse events [AEs], and the chemistry and targets. This relates to the fact that they are targeting CDK with different potency.

Palbociclib was the first-in-class. The starting dose was 125 mg daily at 3 weeks on, 1 week off; AEs include neutropenia [and thrombocytopenia], and there is a scale of adjustment to dose when it is necessary. Usually, everything happens in the beginning for this agent.

Ribociclib is a 200-mg tablet, [with a starting dose of] 600 mg daily, also at 3 weeks on, 1 off; [AEs seen with the agent include] neutropenia but also QTc [QT interval correct for heart rate] prolongation.

Abemaciclib usually starts at 200 mg continuously, can also be used at 150 mg daily. [AEs include] fatigue, but primarily diarrhea and neutropenia. We know how to manage these AEs.

TARGETED ONCOLOGY: How do the results of these trials affect how you treat patients with visceral disease?

Cristofanilli: Going back to the comparison of the different studies, the populations are relatively similar, the benefit is consistent across the different subtypes, and the PFS benefit is similar respective of age, and this is a population that is postmenopausal primarily.

When you look at [patients with] visceral metastases or no visceral metastases in the MONALEESA-2 trial, describing the lung and liver metastases, there is a pretty consistent [benefit with ribociclib].3 These patients, in spite of being in the first line [and] in spite of being 30% or so de novo,4 had visceral bone metastases, and the benefit is there. The patients with visceral disease, in general, had less benefit than nonvisceral and bone-only disease…Overall, the liver is a little more difficult to treat irrespective of whatever agent you use, including chemotherapy, of course. Some patients had received prior therapy, like AIs, only if they had [a disease-free interval] >12 months. Pretty much all the patients in the first line were not symptomatic and ER-positive overall.

Let us start looking at palbociclib in relation to the MONALEESA-2 trial in regard to the visceral sites. This starts to make sense at some point. In general, the benefit is the same in terms of visceral and nonvisceral disease. And if you look at the liver versus lung involvement [compared with] the control group, you start to realize that liver metastases have the most typical [resistance to therapy]: 8.4-month median PFS for single-agent letrozole compared to 13.6 months with lung involvement. The most consistent kind of resistant disease is the one in the liver. Also, you see the difference with the combination [13.7 months vs 22.2 months, respectively]. These patients do much worse as a group.

I was involved with the PALOMA-3 trial—the design and the presentation of the data. We presented [these] data because this study was more mature. PALOMA-3 was essential in the initial indication for palbociclib. We had enough follow-up to start looking at overall survival [OS]. Everybody is criticized one way or another for PFS [as an endpoint], because [they ask] “What does it mean at the end of the day?”

Having the survival data was very important because we started to see that there was a 6-month difference in OS, [but] there was no statistical significance [HR, 0.81; P = .09]. But when you look at the 2 different groups of patients with endocrine-therapy sensitivity and resistance, you can see that you can have up to a 10-month advantage in survival when you have an endocrine-sensitive clinically defined group. So clearly there is a group of patients for which…a CDK 4/6 inhibitor is not only associated with improved PFS but can also extend survival, and this is important.

MONARCH 3 is the trial that allows choices in terms of AIs. There is consistent benefit even in patients who had prior AI or prior endocrine therapy. The one important part when we got to the MONARCH 2 and the MONARCH 3 trials is that when we look at the difference within the placebo group, abemaciclib got a response in the different subsets of patients. For example, in the liver metastases group, there is a difference of 33% in the overall response rate [compared with placebo in MONARCH 2] and 37% in MONARCH 3.

This is very important, because now you start to use clinical trial data. Just seeing these manual different options, I know that they are similar, but they are not exactly the same. And how do I choose 1 of the 3 for a specific patient?

TARGETED ONCOLOGY: Do the AEs associated with abemaciclib worry you?

Cristofanilli: Everybody knows abemaciclib causes diarrhea. [Clinicians should make sure to use] diet counseling and patient education, because the last thing you want to do is dose modification. Obviously, if there is a great need to, then absolutely do it.

It is pretty much all individual; everybody has a different reaction. Some patients have difficulty, but we have also seen neutropenia with palbociclib, and that is difficult to manage, as well.

This patient was started on abemaciclib and letrozole. We wanted to start with a combination, and we thought that this was appropriate for this patient who was not symptomatic and had a little bit of liver abnormality, but nothing to be described as a crisis. There was no chemotherapy, just the CDK 4/6 inhibitor.

TARGETED ONCOLOGY: What would you use after failure on a CDK4/6 inhibitor?

Cristofanilli: I think the question as to what to do after [a] first line CDK4/6 inhibitor is, right now, a research question. The only thing that we can say is that the only data that were presented were in regard to the SOLAR-1 trial, suggesting that a PI3K inhibitor [alpelisib] could potentially be one of the choices.6 It is not available right now, but approval may be coming. It still remains a research question, but it is not a reason to delay the use of a CDK4/6 inhibitor.

TARGETED ONCOLOGY: What if progressions occurred after the completion of endocrine therapy?

Cristofanilli: Let us say that disease progression occurred while she was on preventative therapy. While on adjuvant therapy, she had primary disease, so she was on some course of endocrine therapy. That would have been changing a little bit because that would have become resistant. Of course, we look at MONARCH 3, and there was a group of patients [who] had sensitive disease. They progressed within 36 months or so. You definitely use the time to progression or progression from endocrine therapy, adjuvant therapy, as a way to decide what to do.

TARGETED ONCOLOGY: Which single-agent AI would you use for this patient?

Cristofanilli: We know that there was a big use push to minimize the use of CDK4/6 inhibitors in the first line and to promote more first-line single agents. [The FALCON] study was presented a couple of times and published in The Lancet; it suggests that fulvestrant is better than anastrazole.7 I do not think we disagree on that. This study was very interesting because a majority of these patients were never exposed to endocrine therapy in the adjuvant setting and the majority were newly diagnosed, so it was a unique population.

In patients [who] have bone-only disease, they will have more benefit from fulvestrant and less from [anastrozole]. But with visceral metastases, there is no question that there is no difference. When you look at the numbers, it is difficult to compare; it is much less in terms of PFS when compared to the combination.

TARGETED ONCOLOGY: What are the major take-away points from these data?

Cristofanilli: Bottom line, clearly any patient with de novo disease with visceral metastases or bone disease in the first line deserves a CDK4/6 inhibitor. If they are endocrine-therapy sensitive, the benefit may translate eventually into a long-term OS benefit. If they are endocrine-therapy resistant, we do not know, and time will tell. But we need to start thinking about what to do after [CDK4/6 inhibitors], and of course, PI3K inhibitors may be an option. The 3 agents are similar according to the published data in the first- and second-line settings, but they are different drugs. For some indications, one may be better than others. For example, with liver metastases, abemaciclib could be a better choice. The drug is well tolerated overall. We know how to manage some of the AEs without any problems.

We are having a lot of success with these patients. I think a lot of people can tell that the ER-positive group has a lot of options. I have a patient [who] has been on a CDK4/6 inhibitor for 4 years, and they have no AEs. These are really changing and improving the patient’s quality of life.

TARGETED ONCOLOGY: Is the continuous dosing of abemaciclib an advantage over similar agents?

Cristofanilli: It could be. It is hard to tell, because there is no direct comparison. Nobody is going to do a direct comparison. I know that ribociclib is going to eventually be [administered as a] continuous dose, because reducing the dose may also take care of the QTc elongation. When you use this agent, in particular when you know the AE profile, the idea is to treat as long as possible continuously. The only reason why the ribociclib and the palbociclib initially require the one-week-off schedule is because of the neutropenia. You know that recovery is very important. The is no direct correlation between the dose and the efficacy. Certainly, with abemaciclib, the advantage is that it is the only one with a single-agent activity.
 
 
References
  1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Breast Cancer. Version 1.2019. NCCN website. nccn.org/professionals/physician_gls/pdf/breast.pdf. Published March 14, 2019. Accessed March 25, 2019.
  2. Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.
  3. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748. doi: 10.1056/NEJMoa1609709.
  4. O’Shaughnessy J, Petrakova K, Sonke GS, et al. Ribociclib plus letrozole alone in patients with de novo HR+, HER2- advanced breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat. 2018;168(1):127-134. doi: 10.1007/s10549-017-4518-8.
  5. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926-1936. doi: 10.1056/NEJMoa1810527.
  6. André F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase III SOLAR-1 trial. Ann Oncol. 2018;29(suppl 8;abstr LBA3_PR). doi: 10.1093/annonc/mdy424.010.
  7. Robertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg anastrazole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388(10063):2997-3005. doi: 10.1016/S0140-6736(16)32389-3.


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