How CDK4/6 Inhibitors Are Shaking Up the Breast Cancer Paradigm

Joyce A. O’Shaughnessy, MD

CDK4/6 inhibitors have been game-changers in the care of patients with advanced and metastatic hormone receptor—positive, HER2-negative breast cancer. When added to endocrine therapy, these agents have led to the largest improvement in progression-free survival (PFS) seen to date in this breast cancer subtype, making this class of drugs preferable to chemotherapy for many patients.¹ Now, with 3 agents approved in various clinical settings and multiple ongoing studies, there have been questions about how best to optimize their use in clinical practice.

During a recent OncLive Peer Exchange^®, a panel of breast cancer experts discussed how they are using CDK4/6 inhibitors in their practices. They shared their insights on the tolerability and toxicity profiles of the FDA-approved CDK4/6 inhibitors, how they choose which agents to use for each patient, and how they select the next line of therapy after the patient progresses.

Available CDK4/6 Inhibitors: Indications, Outcomes, Use

In the past 4 years, FDA-approved uses for CDK4/6 inhibitors have expanded into firstline settings (Table 1).^2-11 During the Peer Exchange, the panelists agreed that they favor using CDK4/6 inhibitors over other options, including endocrine-based monotherapy or combination chemotherapy, for their patients in this population.

“As far as patients I’d just give endocrine therapy to, I think they are few and far between, but this may be an option for an older patient with de novo disease or a very long disease-free interval, who perhaps has some comorbidities where maybe you want to avoid the CDK inhibitor in the first-line setting,” Ruth O’Regan, MD, said. “As far as when I would use chemotherapy, [that would be for] people who have visceral crisis. But I tend to think about that as somebody who, if the cancer doubles one more time, they’re going to get in trouble,” she said. She noted that chemotherapy is still thought to work more quickly than other agents, leading it to be preferred in situations where more immediate results are needed, but that this assumption has not been definitively proved.

All 3 agents are taken orally, which further adds to their appeal, noted Hope S. Rugo, MD, FASCO. She added that these agents enable chemotherapy to be delayed for many patients, even those with more advanced disease. “I think the fact that we’ve seen similar efficacy in patients who have visceral disease at presentation, albeit with a hormone-type phenotype—you know, not a liver full of tumor, but the liver, lung disease, soft tissue, bone that we see with hormone receptor—positive disease—has been very encouraging to me,” she said.

Nevertheless, there is lingering concern over using CDK4/6 inhibitors in patients with liver metastasis or grade 3 disease, prompting some oncologists to favor chemotherapy in this setting.

However, Kevin Kalinsky, MD, MS, noted that CDK4/6 inhibitors can lead to significant responses in many of these patients. “For a patient who presents with de novo disease and bone-only disease, I think one of the notable things with these drugs is that we see significant response rates—they can be up to 50% or so, and the median time to response can be around 2 months,” he said.

Kalinsky noted that he might use chemotherapy if a patient’s liver has a high tumor burden that necessitates a rapid response but that he otherwise favors CDK4/6 inhibitors, even in the setting of liver metastasis.

Rugo concurred and said that she has also seen good responses with CDK4/6 inhibitors in such patients. “I’ve treated a number of young women who presented with de novo metastatic disease to the liver who’ve had CRs [complete responses] in the liver, and these patients are now on for 2 and 3 years with no disease—like 1 little non-FDG [fluorodeoxyglucose] avid remaining lesion,” she said. “It’s been very encouraging.”

Managing Toxicities Associated With CDK4/6 Inhibitors

The panelists noted that CDK4/6 are generally well tolerated. Although the adverse effect profile is similar between agents, palbociclib (Ibrance) and ribociclib (Kisqali) are more likely to cause neutropenia, whereas abemaciclib (Verzenio) is more likely to cause diarrhea (Table 2).^2,5,8

Neutropenia

Table. 1. Indications and Outcomes in Key Phase III Trials of FDA-Approved CDK4/6 Inhibitors^2-11

In the setting of grade 3 neutropenia (absolute neutrophil count [ANC], 500 to <1000/ mm³), dose modification is recommended, but the panelists noted it may not always be necessary if a patient is doing well on treatment. “If someone comes in at 800 or 900/ mm³, or if they’re doing well and they’re asymptomatic, I tend to let it go. Certainly, if they had infections, that’s a different story. But I am not so strict about that specific cutoff,” Kalinsky said. Joyce A. O’Shaughnessy, MD, said that she has a patient on palbociclib whose ANC count is hovering around 600/mm³ despite a dose reduction but that she is likely going to maintain the patient’s regimen because the patient is doing well on it and is asymptomatic. “At the grade 3 level for neutropenia, I’ve become more tolerant of it,” she said.

The panelists discussed the possibility that some laboratory studies, such as checking ANC levels on day 15 of treatment, might be excessive. “Even if you look at abemaciclib, the median time to development of neutropenia is about 4 weeks, and we’re checking every 2 weeks. It doesn’t make sense,” Kalinsky said, noting that he nevertheless continues to follow the label recommendations. In contrast, Rugo said that she does not check ANC at day 15 because it won’t affect her decision making.

Diarrhea

Table 2. Most Commonly Observed Adverse Effects With the FDA-Approved CDK4/6 Inhibitors^2,5,8

Rugo noted that diarrhea is more common with abemaciclib given at a higher dose as monotherapy compared with a lower dose in combination with hormone therapy. “[Those getting the lower dose] get some loose stools but generally manage it pretty well with Imodium. I think one of the hardest things for some people is just figuring out which dietary things may set them off, and we see that with other medications as well, even pertuzumab [Perjeta],” she said. Kalinsky said he makes sure that patients are educated about the risk of diarrhea and that they obtain an Imodium kit when they order their medication. Depending on the severity of their diarrhea, patients may also change their medication regimen. “If patients develop grade 2 diarrhea, they hold the medication. And if it goes down to grade 1, they can resume at that same dose. But if it’s a recurrent issue, then they dose reduce,” he said.

O’Shaughnessy said that diet modification also helps reduce diarrhea in her patients and that most of her patients end up making dietary changes. “Some patients will just stay away from the heavy, spicy foods or just eat smaller amounts,” she said. “One woman told me that if she eats a big salad, [which has a lot of fiber], she’ll have a loose stool…[so] they can pinpoint what [causes their diarrhea].”

Other Toxicities

Other toxicities the panelists reported to be particularly distressing to patients included fatigue and alopecia. Rugo said that she observes fatigue most frequently in older patients with metastatic disease. “We have dose reduced for fatigue,” she said, adding that she sometimes uses methylphenidate as well.

Although alopecia is rare with CDK4/6 inhibitors and not the same as what is commonly observed with chemotherapy, Kalinsky said he preemptively discusses it with his patients. “I had 1 patient who experienced it, [and she] was upset by the fact that she was having some hair thinning,” he said. Rugo concurred and said she also had a patient develop alopecia but that her patient had an underlying kidney condition that may have contributed.

Deciding Between CDK4/6 Inhibitors

Palbociclib, ribociclib, and abemaciclib have the same indications in the first- and second-line settings, with abemaciclib also approved as a monotherapy in subsequent lines (Table 1).^2,5,8 “All of the trials, both in the first and second line, if you look at the populations, the results are just absolutely superimposable,” O’Shaughnessy said, adding that all of the studies undertook subset analyses and those results showed benefit across all disease characteristics. This uniformity in benefit can make selecting between the 3 CDK4/6 inhibitors somewhat challenging.

O’Shaughnessy said one of the factors she considers is the potency of CDK4 and CDK6 inhibition. Among the 3 available first- and second-line options, abemaciclib is the most potent, with reported enzymatic half maximal inhibitor concentration (IC50) for CDK4 and CDK6 of approximately 2 nM and 10 nM, respectively.¹ “If I have a true luminal B—you know, a real virulent, ful-throttle luminal B&mdash;I will utilize abemaciclib,” she said. “When it comes to more indolent luminal A disease, I want to go for the least toxicity that I can get, and there I’m utilizing palbociclib and ribociclib pretty much exclusively,” she added.

O’Regan said she tends to favor palbociclib for her patients but that she considers abemaciclib in patients with brain metastases and central nervous system (CNS) involvement because the data are stronger in those settings. Abemaciclib has been shown to cross the blood—brain barrier more efficiently than palbociclib.¹ She would also consider abemaciclib in patients with leptomeningeal disease, although it is unclear how well it would work, O’Regan added.

Rugo was not convinced that there are enough differences in potency between the agents to favor use of one over another. “When we look at these forest plots, basically the agents work across multiple different prognostic subgroups, and I think that just like when we used the AIs [aromatase inhibitors], we have to decide how we’re going to give the drugs,” she said, indicating that other factors may also come into play, such a dosing schedule and toxicities.

“Somebody who can’t really keep track of their pills—that’s somebody on capecitabine [Xeloda] now&mdash;giving them continuous dosing with abemaciclib is good. For somebody who has a lot of neutropenia or bone marrow dominant disease, where they have low counts, abemaciclib is a really good choice. And maybe what you’re parsing out would be more visceral disease for abemaciclib or bone-only disease for palbociclib, but I’m not totally convinced that there’s differential benefit,” she said.

Treating Patients Beyond Progression: Alpelisib

For subsequent treatment of hormone receptor—positive, HER2-negative metastatic disease, the choices include keeping patients on hormonal therapy alone or in combination with the mTOR inhibitor everolimus (Afinitor) before proceeding to chemotherapy.

On May 24, the FDA expanded the armamentarium with the approval of alpelisib (Piqray), a PI3K inhibitor, in combination with fulvestrant (Faslodex) for patients with this subtype who harbor a PIK3CA mutation and have progressed on or after endocrine therapy. The agency also approved the therascreen PIK3CA RGQ PCR Kit as a companion diagnostic.¹²

Although the Peer Exchange program took place before the FDA’s decision, the panelists were eagerly anticipating alpelisib’s approval. In the pivotal SOLAR-1 trial (NCT02437318), treatment with alpelisib among patients with PIK3CA mutations resulted in a median PFS of 11.0 months versus 5.7 months for those who received placebo plus fulvestrant (HR for progression or death, 0.65; 95% CI, 0.50-0.85; P <.001). Approximately 40% of patients with hormone receptor—positive, HER2-negative breast cancer harbor PIK3CA mutations, according to SOLAR-1 investigators.¹³

Rugo, who is among the leading investigators into alpelisib, said she would check patients in this population for PIK3CA mutations while they were being treated with a CDK4/6 inhibitor or via tumor biopsy upon progression. She would then treat those with the mutation with alpelisib plus fulvestrant once they progressed. Those without mutations, Rugo said, may be candidates for clinical trials or treatment with everolimus.

The panelists noted that only 20 of the 341 patients with PIK3CA mutations in the SOLAR-1 study previously received a CDK4/6 inhibitor in addition to endocrine therapy.¹³ Although this small subset of patients showed benefit with alpelisib and fulvestrant (HR, 0.48; 95% CI, 0.17- 1.36), data from a larger cohort are needed for confirmation. Rugo said that she is conducting the BYLieve trial, which will provide some answers.

BYLieve (NCT03056755) is a phase II, multicenter, open-label, 3-cohort, noncomparative study that is enrolling men and pre- and postmenopausal women with PIK3CA-mutant, hormone receptor—positive, HER2-negative locally advanced or metastatic breast cancer that has progressed on or after prior CDK4/6 use in combination with an AI (cohort A) or with fulvestrant (cohort B) or following prior systemic chemotherapy or endocrine therapy (cohort C). Patients in cohorts A and C will receive alpelisib 500 mg orally plus fulvestrant 500 mg intramuscularly and those in cohort B will receive alpelisib 300 mg orally plus letrozole 2.5 mg orally.¹⁴

O’Shaughnessy said that although alpelisib’s initial indication is for patients with PIK3CA-mutant disease, there are other ways to activate the PI3 kinase pathway. “Perhaps it’ll be useful across the board in CDK4/6 inhibitor-resistant patients, but we’re going to need more data on that,” she said.

Many CDK4/6 trials are currently underway, including those assessing other CDK4/6 strategies in patients who have progressed following previous CDK4/6 therapy; those assessing CDK4/6 inhibitors for other breast cancer subtypes, including HER2-positive disease; and those assessing novel CDK4/6 combinations, such as the addition of immune checkpoint blockade. It is hoped that as more data become available in the coming years, CDK4/6 inhibitors will become cancer game-changers for even larger subsets of patients.

References

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13. André F, Ciruelos E, Rubovszky G, et al; SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929- 1940. doi: 10.1056/NEJMoa1813904.
14. Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutation With Advanced Breast Cancer Who Have Progressed on or After Prior Treatments (BYLieve). clinicaltrials.gov/ct2/show/NCT03056755. Updated July 18, 2019. Accessed July 18, 2019.