Practical Treatment Questions Surface in HR-Positive Metastatic Breast Cancer

Joyce A. O’Shaughnessy, MD

Novel and emerging agents are creating exciting new options for patients with hormone receptor (HR)—positive metastatic breast cancer (MBC), resulting in the need to consider how best to introduce and sequence these agents into the treatment timeline, experts say.

Two breast cancer experts, Joyce A. O’Shaughnessy, MD, and Andrew D. Seidman, MD, joined in an OncLive Peer Exchange^® discussion of pending issues that confront oncologists in daily interactions with patients in this population.

O’Shaughnessy said their goal was to address practical questions oncologists grapple with, such as, “Does everybody need combination therapy, leading off with endocrine therapy, in the metastatic setting? How do we sequence our therapy options? And when do we introduce chemotherapy into our ER [estrogen receptor]—positive metastatic patients?” In particular, the experts examined how CDK4/6 inhibitors have changed the treatment paradigms and discussed promising novel chemotherapy agents for ER-positive MBC.

Such questions are of vital importance to a large proportion of patients with breast cancer. HR-positive breast cancer is the most common subtype of the disease, accounting for at least two-thirds of cases.^1,2 Most HR-positive breast cancers are highly responsive to endocrine therapy, and an endocrine-based regimen is standard first-line therapy for HR-positive, HER2-negative MBC in patients not experiencing visceral crisis.^2,3 Endocrine therapy is rarely curative, however, and primary or acquired endocrine resistance is frequent.³

Incorporating CDK4/6 Inhibitors

Although chemotherapy is generally recommended for patients with endocrine resistance or visceral crisis, the toxicities of current regimens must be weighed against their limited survival benefit (Table).^2,3 The only option for patients with disease progression or poor performance status after multiple lines of chemotherapy is supportive care.³The FDA has approved 3 oral CDK4/6 inhibitors for HR-positive, HER2-negative MBC: palbociclib (Ibrance),⁴ ribociclib (Kisqali),⁵ and abemaciclib (Verzenio).⁶ Although the CDK4/6 inhibitors have slightly different indications, all are typically administered with an aromatase inhibitor (AI) in the first-line setting or with fulvestrant (Faslodex), an injectable selective ER modulator, in the second-line setting. Ribociclib is the only CDK4/6 inhibitor indicated for first-line therapy in pre- or perimenopausal women in addition to postmenopausal women.⁵

“It’s hard to make a strong argument against leading with endocrine therapy and a CDK4/6 inhibitor,” Seidman said. In randomized clinical trials, adding a CDK4/6 inhibitor to an AI greatly prolonged progression-free survival (PFS) in women with untreated HR-positive, HER2-negative advanced breast cancer.⁷ Based on consistent findings across multiple studies, Seidman said he is comfortable assuring these patients they will likely be able to continue endocrine-based therapy for years before their disease progresses.

O’Shaughnessy said she was reluctant to combine a CDK4/6 inhibitor with an AI for the subset of women with de novo MBC and a low-tumor burden until results of the phase III MONALEESA-2 trial, which were updated last year, showed especially pronounced improvement in PFS for this population when ribociclib was added to letrozole.⁸ “I thought, ‘Whoa, how could I not offer someone that?’” said O’Shaughnessy, who was among the key investigators on the original study. Although O’Shaughnessy and Seidman agreed fulvestrant is an effective first-line therapy for advanced HR-positive breast cancer administered alone or with a CDK4/6 inhibitor, both typically reserve it for second-line therapy because most patients prefer oral agents. Fulvestrant is administered via intramuscular injection.

Seidman said the “$64,000 question” is which CDK4/6 inhibitor to pair with an AI when selecting a first-line regimen. He said hazard ratios with all the CDK4/6 inhibitors are consistently around 0.55 and that “in terms of efficacy, it’s hard to argue that we’re seeing any big differences.” He said the decision may come down to differences in ease of use and toxicity. Abemaciclib causes more gastrointestinal issues than palbociclib and ribociclib, whereas palbociclib and ribociclib are more likely to induce neutropenia than abemaciclib.⁹ The risk of febrile neutropenia, however, is low with all the approved CDK4/6 inhibitors compared with the incidence seen with cytotoxic chemotherapy.⁷ Only ribociclib increases the risk of QT interval prolongation and requires patients to undergo periodic electrocardiograms.⁵ Seidman recommended clinicians “gain experience with all these drugs and let that experience guide them.”

Unlike abemaciclib, which is taken continually, palbociclib and ribociclib are administered in 21-day cycles, with 7 treatment-free days between cycles. O’Shaughnessy said the way proliferation rebounds when patients with highly proliferative disease permanently discontinue CDK4/6 inhibitors makes her more likely to choose abemaciclib for first-line therapy.

Getting Closer to an Oral Taxane

Both oncologists share that they rarely continue CDK4/6 inhibitor therapy after disease progression. “I’m not continuing the CDK4/6 inhibitor that there’s been progression on even if there’s been a lovely response…We have no clinical data,” O’Shaughnessy said. She added that ongoing randomized trials are assessing different approaches, including “continuing the CDK4/6 or switching to another CDK4/6 or even adding a checkpoint inhibitor.” Other trials are evaluating different classes of agents, such as PARP and PI3K inhibitors, which O’Shaughnessy said may one day allow patients to prolong time to chemotherapy even further.For HR-positive, HER2-negative breast cancer, the National Comprehensive Cancer Network recommends using sequential single-agent chemotherapy for patients who are endocrine refractory.³ Seidman said oral capecitabine is typically his first choice but that he often uses paclitaxel or another taxane if the patient has a heavier tumor burden or is symptomatic. Some chemotherapy agents, including taxanes, cause anasarca, neuropathy, skin rash, and hair loss, a development O’Shaughnessy described as particularly distressing to patients. Chemotherapy doublets are typically reserved for patients with numerous metastatic sites, rapid progression, or visceral crisis.³ Often, capecitabine is combined with a taxane such as paclitaxel or docetaxel, which can lead to permanent nail loss.

Tesetaxel

O’Shaughnessy said since the FDA’s approval of paclitaxel almost 25 years ago, researchers have strived to develop less toxic oral taxanes. One is tesetaxel, which is being combined with low-dose capecitabine in the phase III CONTESSA trial.¹⁰ CONTESSA plans to enroll 600 patients with HR-positive, HER2-negative MBC whose treatment history includes a taxane and endocrine therapy. O’Shaughnessy, one of the study’s primary investigators, explained that tesetaxel is not reformulated paclitaxel and is instead a unique molecule. “It has the same taxane structure, but it has 2 moieties that are nitrogen-based…to help with oral bioavailability,” she said. Because tesetaxel is not a substrate for P-glycoprotein (PGP), she said it has efficacy against tumor cells dependent on PGP overexpression to resist cytotoxic therapies.

According to O’Shaughnessy, tesetaxel has an 8-day half-life, which is significantly longer than the 11-hour half-life of paclitaxel and docetaxel and allows a dosing interval of once every 3 weeks. The dosing regimen was assessed in a phase II study of single-agent tesetaxel in patients with pretreated HER2- negative MBC. The confirmed response rate among 38 patients in the efficacy analysis was 45% (95% CI, 29%-62%), including stable disease in 37% and tumor shrinkage in most partipants.¹¹ “The waterfall plot is very, very impressive because very few patients progressed,” she said. “It was very, very highly active.”

Seidman, a lead investigator for the phase II trial, said alopecia was minimal: 29% of patients had grade 1 alopecia, and 21% had grade 2.¹¹ Neutropenia was the most common adverse event of grade ≥3 severity and occurred in 29% of patients (febrile neutropenia, 4%). No one experienced peripheral neuropathy of grade ≥3.¹¹

O’Shaughnessy said the hope of tesetaxel investigators is to “build a more effective, longeracting, durable drug without treatment-limiting toxicities” for patients with endocrine resistance who would normally receive capecitabine monotherapy. Another benefit is that it would be an all-oral regimen.

Other Novel Oral Taxanes

Table. NCCN Guidelines for Treatment of Recurrent or Stage IV Disease: ER- and/or PR-Positive, HER2-Negative Breast Cancer^3,a

Conclusions

Oraxol is another oral taxane in development for MBC. Seidman said it consists of an oral formulation of paclitaxel and an oral PGP inhibitor, which are administered separately. Oraxol showed activity in a small phase I/II trial and is now being compared with intravenous paclitaxel in a phase III trial of women with MBC.¹² Other investigative oral taxanes include DHP107, a lipid formulation of paclitaxel; ModraDoc001, an oral formulation of docetaxel; and ortataxel, an oral paclitaxel analogue designed to overcome PGP resistance. None of these are currently being investigated for breast cancer, however.Chemotherapy for HR-positive MBC is associated with adverse effects that some patients dread the most, like alopecia and nail loss, and time without chemotherapy is an important endpoint for them when considering treatment options. Seidman said many patients have asked him, “How much of my life can I live with MBC before I need to cross that bridge to chemotherapy?”

The incorporation of CDK4/6 inhibitors into first-line endocrine therapy for HR-positive, HER2-negative advanced breast cancer, which O’Shaughnessy called “a major sea change in practice,” has allowed many patients to delay starting chemotherapy by months or even years compared with endocrine therapy alone. She and Seidman agreed that eventually they would like to see chemotherapy replaced with less toxic targeted agents. A more immediate goal is to make chemotherapy more effective and less toxic, and novel oral taxanes, such as tesetaxel, have shown promise on that front in clinical trials. As new agents become available, however, more data are needed to help clinicians determine how and when to use them.

References

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10. O'Shaughnessy J, Piccart-Gebhart MJ, Schwartzberg LS, et al. Contessa: a multinational, multicenter, randomized, phase 3 registration study of tesetaxel in patients (Pts) with HER2-, hormone receptor + (HR+) locally advanced or metastatic breast cancer (MBC). J Clin Oncol. 2018;36(supple 15):TPS1106. doi: 10.1200/JCO.2018.36.15_suppl.TPS1106.
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