Posted: Monday, March 20, 2017
On March 13, 2017, the FDA approved ribociclib (Kisqali), an oral cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with an aromatase inhibitor (AI), for treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.1
Ribociclib is only the second agent in this class to be approved in this setting (palbociclib was approved in combination with letrozole in February 20151 and with fulvestrant in February 20162) and, although practitioners are becoming more comfortable with the class, there are several commonsense recommendations gleaned through clinical use that can help patients tolerate therapy well, stay on therapy, and thus derive optimal benefit from it.
The approval of the first CDK 4/6 inhibitor (palbociclib) for treatment of hormone-receptor-positive, HER2-negative newly diagnosed metastatic breast cancer together with letrozole in 20152 (and with fulvestrant in 20163) heralded a new perspective on systemic therapy for this most common breast tumor subtype. Although most breast cancers are hormone-receptor positive and HER2-negative, until recently, the lack of a discernible “target”—aside from the hormone receptors estrogen and progesterone—rendered them less treatable than more aggressive malignant types with specific (ie, targetable) molecular alterations. However, with the development of the CDK 4/6 inhibitor class of agents, the oncology community is once again energized to seek novel ways to attack tumor cells in hormone-positive disease.
Now that a number of breast cancer teams across the country and abroad have significant experience with this class, the time is ripe for sharing clinical pearls that comprise the “art” of medicine—how to administer, monitor, tweak, and modify these regimens to allow patients to derive maximal benefit.
With ribociclib newly approved and available for use,1 oncologists will be faced with questions about whether and in whom to prescribe a CDK 4/6 inhibitor, how to distinguish among agents, and how to administer them safely and effectively.
The breast cancer team at the Sarah Cannon Research Institute in Nashville, Tennessee, has been involved in trials of the CDK 4/6 inhibitor class for several years and so has a great deal of hands-on experience. JNCCN 360 was fortunate to get to speak with Howard A. (Skip) Burris, III, MD, Chief Medical Officer at Sarah Cannon and one of the coauthors on the New England Journal of Medicine report on the phase 3 ribociclib trial.4 Dr. Burris graciously shared his clinical perspective on ribociclib and the clinical nuances that can help extend progression-free survival in eligible patients with metastatic breast cancer, using an all oral, endocrine-directed regimen.
When asked what he would like to convey to community practitioners, Dr. Burris emphasized the efficacy that was seen across (mostly asymptomatic) patient populations in the phase 3 MONALEESA-2 trial.4 “The results in the ribociclib trial were as impressive in patients with visceral metastases as in those with bone-only metastases, he pointed out. “So I wouldn’t shy away from this drug and move to chemotherapy because the patient has liver or lung metastases. Results were good in all types of patients.” [Editor’s note: Both the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer5 and ASCO Guidelines6 indicate that chemotherapy may be considered for symptomatic patients in visceral crisis, when rapid and robust responses are required.]
Neutropenia: A Numerical Adverse Effect
As a first-line treatment regimen, the all-oral combination of ribociclib plus letrozole can be very attractive to both patients and practitioners. The primary concern associated with ribociclib (and other agents in the CDK 4/6 class) is neutropenia, which is not generally an adverse effect of endocrine therapies when the latter are used alone.
“The biggest challenge with this type of drug is the neutropenia,” Dr. Burris stated. The question for the clinician is how much should be tolerated before you feel the need to dose reduce or take a break.” Dr. Burris explained that the neutropenia tends to be numerical rather than symptomatic, and is not associated with fatigue. “We didn’t see low platelets or anemia; it is purely numerical,” he said. He also pointed out that the oral regimen is not associated with the usual portals of entry for infection. “We don’t see mucositis, colitis, diarrhea, dermatitis—no additional risk factors for having a febrile episode—so decisions about dose modification or holding therapy become more of a judgement call.”
Dr. Burris pointed out that, in an attempt to prevent neutropenia, some colleagues have tried to use growth factor support in this setting, but “it doesn’t provide much benefit.” Mixing growth factor support with chronic oral dosing seems to yield an increase in immature neutrophils and “a roller coaster effect. It doesn’t really smooth things out,” he said.
Broad-Spectrum Antibiotics, Just in Case
Noting that in real life, crises often occur late at night or on weekends, Dr. Burris described the protocol followed at Sarah Cannon. “For patients who are asymptomatic, ie, those who feel well but are neutropenic at the grade 3 level, we give them an antibiotic to have on hand. We’ve used a quinolone (eg, ciprofloxacin or levofloxacin) or, if a patient is intolerant of quinolones, another broad-spectrum antibiotic, such as amoxicillin clavulanate.” Dr. Burris observed that grade 4 neutropenia—a neutrophil count of 500 cells/µL or less—is the point at which treatment must be stopped. Dr. Burris said, “as we gain experience with these drugs, it will be interesting to see whether oncologists will continue treatment in patients with grade 3 neutropenia, as long as they are asymptomatic.”
Asked about how he might approach an asymptomatic patient with grade 3 neutropenia, Eric P. Winer, MD, director, Breast Oncology Center, Susan F Smith Center for Women’s Cancers and professor of medicine, Harvard Medical School, Boston, explained that all neutropenia is not the same. “Grade 3 could be a neutrophil count as low as 510 cells/µL or as high as 990 cells. If the count is at the higher end, I might not change the dose. It’s possible, even likely, that during the week off therapy, the levels will come up.” Dr. Winer also pointed out that a patient’s baseline health status is important, and that more caution should be exercised in anyone with existing marrow compromise. Moreover, he said, “older women may be more prone to develop myelosuppression.” With ribociclib being newly approved, Dr. Winer observed, clinicians will be guided first by recommendations provided in the prescribing information, but will make modifications in practice as they gain experience.
Monitoring and Dose Adjustments
The MONALEESA-2 study protocol required patients to come back for weekly monitoring, with twice weekly visits if they developed neutropenia. In retrospect, Dr. Burris noted, “That was probably too frequent.” He explained that as long as patients are well informed and have a good rapport with the nurses, “it seems much more reasonable to have patients come back 2 weeks after they start the 3-weeks on/1 week-off regimen.” Dr. Winer agreed that 7 days may not be long enough to fully evaluate the patient’s response, in terms of myelosuppression, and that a follow up at 2 weeks makes more sense.
If everything checks out and the patient feels well, Dr. Burris suggested that monthly visits would be appropriate. “That check up after 15 days on drug,” he said, “is a good time to make any dose adjustments, if they are necessary. For instance, if the neutrophil count is down, the dose can be cut back from 600 mg to 400 mg—that’s a useful strategy and that’s a good time to do it. Or, I might choose to keep up the dose intensity (ie, 600 mg) but instead of completing the third week of treatment, cut it off a bit early, so it’s closer to 2 weeks on, 2 weeks off.” Dr. Burris indicated that when neutropenia became an issue numerically, it usually occurred during that third week of dosing.
A Cardiology Consult?
Because breast cancer providers are well aware of the cardiac effects of some breast cancer therapies, such as trastuzumab, they may wonder whether and what kind of cardiac monitoring is recommended with a ribociclib regimen. Dr. Burris explained that “when we start a patient on hormonal therapy, we don’t usually look at QT intervals, unless a patient has a family history of cardiac disease or is being treated by a cardiologist and is on medication. Any time there’s a concern, which would include patients with significant cardiac history, it’s always best to ask for a cardiology consult.” Nevertheless, on the basis of the mechanisms for these CDK 4/6 inhibitors plus hormonal therapies, “cardiac toxicity doesn’t worry me too much,” Dr. Burris said.
That check up after 15 days on drug is a good time to make necessary dose adjustments. If the neutrophil count is down, the dose can be cut back from 600 mg to 400 mg. Or, the dose intensity (ie, 600 mg) can be maintained, but instead of completing the third week of treatment, the patient can discontinue a bit early—so dosing is closer to two weeks on, two weeks off.
Patients Need a Good Doctor, but a Great Nurse
It is generally believed that adherence to oral drug therapy is less of an issue in the metastatic cancer setting than in the adjuvant setting. Nevertheless, “even in the setting of a clinical trial (and even in intense early-phase studies),” Dr. Burris claimed, “some patients run out of pills too early whereas others still have pills left at the end of a cycle.” With ribociclib, “if there is any confusion or doubt about whether you took a pill already, you are better off skipping and taking it as directed the next day. Patients should not try to ‘catch up’ by taking another pill too soon.” With these kinds of therapies, Dr. Burris emphasized the key role of the oncology nurse: “Patients need a good doctor and a great nurse to help them stay on therapy.”
Other Hormonal Therapies
Although the current label specifies letrozole as the endocrine partner for ribociclib, ongoing trials are looking at other hormonal blockers, such as fulvestrant.7,8 “In practice,” Dr. Burris said, “if you give fulvestrant once every 4 weeks, it should be fairly convenient to schedule those injections with monthly check ups.” Dr. Burris also noted that a potential benefit of fulvestrant is that it may be helpful for the roughly 10% of patients who experience severe arthralgia, myalgia, and arthritic pain from AIs. “Anecdotally, we sometimes try switching patients from a nonsteroidal AI like letrozole to fulvestrant or exemestane to get around those symptoms. So, it would be helpful to have labeling that includes all of those hormonal therapy options.”
Don’t Assume New Symptoms Are Treatment Related
Dr. Burris commented that this oral combination endocrine regimen is fairly easy for patients, particularly compared with chemotherapy. The excellent safety profile and low toxicity of ribociclib are important, Dr. Winer added, because “we still do not know whether these regimens are associated with a survival advantage. For many women, hormone treatment alone, which usually is quite tolerable, can be effective. We do not want to add drugs in the first line that will make patients feel worse.”
Because there aren’t many other toxicities associated with CDK 4/6 inhibitors, patients should not assume that new symptoms are treatment related. “So, although we instruct patients to be vigilant about elevated temperature and other signs of infection, other symptoms may be unrelated to the new therapy,” Dr. Burris said. New bowel or respiratory issues, for instance, should be brought to a physician’s attention because they are rarely, if ever, associated with this type of treatment. “The bottom line is that you need to be able to sort out side effects of ribociclib, which are few, from those associated with the AIs. When we did single-agent ribociclib trials, for instance, we didn’t see any of the arthritic, bony pain typical of treatment with the AIs.”
Another Step Toward Personalized Therapy
When asked to speculate about how the CDK 4/6 inhibitors will likely be used in 2017 and beyond, especially now that there are 2 available agents in the class, with others expected in the coming months and years, Dr. Burris said that some clinicians might explore switching from one drug to the other. “Although there are no data,” he stressed, “if someone is deriving benefit from treatment with palbociclib but is having ongoing issues with neutropenia, a switch to ribociclib could be tried. We don’t know whether there would be less neutropenia, but this is a strategy that has been commonly used with other classes of drugs. It’s exciting to be able to use a potent oral drug like ribociclib along with hormonal therapy for patients with hormone-receptor-positive disease, which comprises the vast majority of breast cancers,” Dr. Burris concluded.
- Ribociclib (Kisqaliâ) [with letrozole]. U.S. Food & Drug Administration. U.S. Department of Health and Human Services. http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf Accessed March 13, 2017
- U.S. Food & Drug Administration. Palbociclib [with letrozole]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207103s004lbl.pdf Accessed February 7, 2017.
- U.S. Food & Drug Administration. Palbociclib (IBRANCE capsules) [with fulvestrant]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207103s004lbl.pdf Accessed February 7, 2017.
- Hortobagyi G, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375:1738–1748.
- Gradishar WJ, Anderson BO, Balassanian R, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Breast Cancer. Version 1.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 17, 2017.
- Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone-receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guidelines. J Clin Oncol 2016;34:3069–3103.
- Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer. (MONALEESA-3). Available at at: https://clinicaltrials.gov/show/NCT02422615. Accessed February 8, 2017.
- Fasching PA, Jerusalem GHM, Pivot X, et al. Phase III study of ribociclib (LEE011) plus fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) who have received no or only one line of prior endocrine treatment (ET): MONALEESA-3 [abstract]. J Clin Oncol 2016;34 (suppl). Abstr TPS624