Key Questions Surround CDK4/6 Inhibitors in HR+ Breast Cancer

Debu Tripathy, MD

The introduction of CDK4/6 inhibitors has changed the treatment landscape for hormone receptor (HR)—positive, HER2-negative breast cancer, and the challenge now is to determine how best to individualize the use of these drugs for the optimal benefit of patients, according to leading breast cancer experts.

HR-positive/HER2-negative breast cancers are the most common subtype of the malignancy, making up about 67% of cases.¹ Endocrine therapy and chemotherapy have been mainstays of treatment, with CDK4/6 inhibitors being integrated into the paradigm for recurrent or stage IV disease, according to the National Comprehensive Cancer Network guidelines.²

During a recent OncLive Peer Exchange^®, a panel of experts sought to answer several key questions regarding the management of advanced, HR-positive breast cancer, particularly with CDK4/6 inhibitors.

Three CDK4/6 inhibitors have received FDA approval thus far: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). All are approved for postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy or with fulvestrant (Faslodex) in patients with disease progression following endocrine therapy. Beyond that, there are several differences in their indications (Table).^3-5

Frontline Chemotherapy: Yea or Nay?

Although chemotherapy remains an important treatment for HR-positive metastatic breast cancer, its continued use as frontline therapy in this setting is in question. In the United States, many patients are still receiving chemotherapy as their first-line metastatic treatment for estrogen receptor (ER)—positive disease, noted Ian E. Krop, MD, PhD. However, the panelists agreed that the data indicate that these patients should receive hormonal therapy first, except in the setting of true visceral crisis when a quick response or rapid debulking is needed.

“With the advent of CDK4/6 inhibitors, we have a relatively less toxic combination therapy with these dramatic survival benefits that we’ve seen in 2 different major meetings in 2019,” Hope S. Rugo, MD, FASCO, said.

The panelists discussed the Young-PEARL study (NCT02592746), which was presented at the 2019 American Society of Clinical Oncology Annual Meeting, with updated findings later published in Lancet Oncology, and its larger counterpart, the PEARL study (NCT02028507), which was presented at the 2019 San Antonio Breast Cancer Symposium.^6-8

The Young-PEARL study randomly assigned 184 premenopausal women with HR-positive, HER2-negative metastatic breast cancer to chemotherapy with capecitabine (n = 92) or a triplet regimen with palbociclib plus endocrine therapy consisting of exemestane and the gonadotropinreleasing hormone agonist leuprolide (n = 92). Patients were allowed to have received up to 1 line of previous chemotherapy for metastatic breast cancer, with approximately half of participants being treatment naïve.⁶

Table. CDK4/6 Indications in Breast Cancer^3-5 (Click to Enlarge)

What this relatively small study showed was that patients actually did better on the triplet therapy with palbociclib, the aromatase inhibitor, and ovarian suppression, and subsequently they showed that there was better quality of life in those patients as well,” Rugo said.

The PEARL study included postmenopausal women who progressed on chemotherapy or other lines of treatment. It had 2 successive cohorts, with the first randomly assigning patients to exemestane plus palbociclib versus capecitabine and the second assigning patients to fulvestrant plus palbociclib versus capecitabine. Investigators added the second cohort after data showed that ESR1 mutations may induce resistance to AIs but not to fulvestrant.⁸

At a median follow-up of 13.5 months, the median PFS was better with capecitabine than with palbociclib/ fulvestrant (10.0 vs 7.5 months, respectively). After a median follow-up of 19.0 months, the median PFS was also better with capecitabine than with palbociclib/exemestane (10.6 vs 8.0 months, respectively).⁸

“For some reason, people did really well on capecitabine,” Rugo said. She noted that the 10-month survival observed with capecitabine in pretreated metastatic disease does not match any other trial data. “The interesting thing is the patients treated with fulvestrant and those treated with exemestane did about the same. It didn’t really matter whether they were ESR1 wild-type or not,” she said.

Rugo noted that although these findings were unexpected, the data are comparable to those of PALOMA-3 (NCT01942135), in which patients previously treated with chemotherapy in the metastatic setting (34%) had a much shorter median PFS on fulvestrant alone compared with palbociclib/ fulvestrant plus placebo (3.5 vs 7.7 months, respectively; hazard ratio favoring placebo, 0.43).⁹ Although the PEARL data did not show a statistically superior PFS for palbociclib-treated patients, palbociclib/exemestane was generally better tolerated than capecitabine.

“My take-home from these [studies] is that a CDK4/6 inhibitor and an aromatase inhibitor, or fulvestrant, is a really good treatment. We should do it before chemotherapy, and there’s no clear benefit for doing chemotherapy first,” Rugo said, unless visceral crisis exists. She suggested that using chemotherapy up front may even generate resistance mechanisms.

Can ctDNA Testing Identify Mechanisms of Resistance?

Use of CDK4/6 inhibitors has led to an approximate doubling of PFS in patients with ER-positive, HER2- negative advanced breast cancer; however, eventual resistance to these agents is nearly universal.¹⁰ The panelists discussed whether molecular testing, particularly circulating tumor DNA (ctDNA), might help identify resistance mechanisms and guide treatment decision making to improve outcomes.

The experts reviewed the plasmaMATCH trial (NCT03182634), a multicohort platform trial that evaluated ctDNA testing in approximately 1000 patients with advanced breast cancer and then used those results to assign patients to the most appropriate molecularly targeted therapy data.^11,12 Investigators tested participants using digital droplet polymerase chain reaction techniques and the Guardant360 liquid biopsy nextgeneration sequencing (NGS) assay.

“The first good news was there was good concordance between [these tests],” Joyce A. O’Shaughnessy, MD, said. Individual gene level agreements between tests ranged from 95.5% to 99.4%.¹² “Secondly, looking at the ctDNA results, vis-à-vis the metastatic tissues, also with NGS [there] was good concordance, which was quite encouraging because I think there have been a lot of questions there about the reproducibility of these findings,” she said.

In women with HR-positive, HER2-negative disease, the most frequently identified mutations were ESR1, PIK3CA, and GATA3.¹¹ Patients with ESR1 mutations received fulvestrant, those with HER2 mutations received neratinib (Nerlynx) with or without fulvestrant, and those with AKT1 mutations received capivasertib plus fulvestrant.

The investigators concluded that ctDNA testing provides accurate tumor genotyping and that clinicians can use it to identify patients with rare HER2 and AKT1 mutations, a subset that has shown clinically relevant response rates with matched targeted therapies.¹¹

Although the plasmaMATCH trial did not examine mechanisms of primary resistance to CDK4/6 inhibitors, which O’Shaughnessy indicated affects approximately 20% of patients, it provides proof of concept that ctDNA can be useful to direct targeted therapies. Subsequently, once markers of primary and acquired resistance to CDK4/6 inhibitors are identified, ctDNA may help identify patients with those markers.

“The 1 marker that I think has the most evidence but probably still needs to be validated prospectively is cyclin E overexpression,” moderator Debu Tripathy, MD, said, noting that downregulation of the tumor suppressor RB has also been observed, although not frequently.

However, Tripathy clarified that most mechanisms of resistance remain undefined, and Rugo indicated that they are likely to be heterogeneous. She also explained that even if ctDNA cannot yet be used to identify resistance mechanisms to CDK4/6 inhibitors, it is an important testing modality for patients. “[For] a lot of people with ER-positive disease, it’s really tough to get tumor. You’re biopsying bone. People are decalcifying it and missing all the receptors,” she said.

How Should Patients With Progression Be Treated?

The determination of treatment following progression on CDK4/6 inhibitors poses a significant challenge. “We have a lot of patients in this situation,” Tripathy said.

Adam M. Brufsky, MD, PhD, said he uses ctDNA testing such as Guardant360 to guide next steps. “If there’s a PIK3CA mutation, I think that we probably would use fulvestrant-alpelisib [Piqray], based on the SOLAR-1 trial,” he noted. SOLAR randomly assigned 572 patients with HR-positive, HER2-negative breast cancer, including 341 with PIK3CA mutations, to alpelisib plus fulvestrant or placebo plus fulvestrant.¹³ All patients had previously received endocrine therapy, with 5.9% of patients with PIK3CA-mutated cancer also having received CDK4/6 inhibitor therapy.

At a median follow-up of 20 months, the PFS in the cohort with PIK3CA mutations was 11.0 months (95% CI, 7.5-14.5) with alpelisib plus fulvestrant compared with 5.7 months (95% CI, 3.7-7.4) with placebo plus fulvestrant (hazard ratio for progression or death, 0.65; 95% CI, 0.50-0.85; P <.001).¹³ In the cohort without PIK3CA-mutated cancer, the PFS was 7.4 months (95% CI, 5.4-9.3) in those receiving alpelisib plus fulvestrant and 5.6 months (95% CI, 3.9-9.1) in those receiving placebo plus fulvestrant (hazard ratio, 0.85; 95% CI, 0.58-1.25; posterior probability of hazard ratio <1.00, 79.4%).

Brufsky noted that even patients who had previously received CDK4/6 inhibitors showed benefit. Prior to the SOLAR-1 trial, he said, he would have used fulvestrant plus everolimus (Afinitor), based on the PrE 0102 study (NCT01797120), whose results showed a PFS of 10.3 months (95% CI, 7.6-13.8) with this combination versus 5.1 months (95% CI, 3.0-8.0) with fulvestrant plus placebo in postmenopausal women with AI-resistant metastatic breast cancer (hazard ratio, 0.61; 95% CI, 0.40-0.92; stratified log-rank P = .02).¹⁴

However, Brufsky also said he would use fulvestrant, possibly in combination with everolimus, in patients with an ESR1 mutation. Rugo also said she would use fulvestrant in these patients but would consider abemaciclib as a monotherapy when her patients have been through all endocrine partners.

“I think data are emerging [and showing] that if patients have an ESR1 mutation, their chance of benefiting from any endocrine therapy, including fulvestrant, is quite low…. But I would also say the good news is that when you partner these agents, which is what we’re increasingly doing, they seem to be more agnostic to the ESR1 mutations,” O’Shaughnessy said.

The panelists noted that another strategy after progression an a CDK4/6 inhibitor might be to switch to another CDK4/6 inhibitor. Brufsky said that he and several other investigators, including O’Shaughnessy, conducted a case series evaluation of clinical outcomes in patients with ER-positive, HER2-negative metastatic breast cancer who received abemaciclib after progression on palbociclib. Patients who received abemaciclib sequentially (n = 20) had a median PFS of 8.1 months (95% CI, 3.9—not reached).¹⁵ “Clearly, you’re getting a benefit from that,” he said.

Krop said results of a similar study also showed benefit from switching CDK4/6 inhibitors after prior progression. In that study, approximately 20% of patients who received abemaciclib after prior palbociclib had PFS rates ranging from 7 to 13 months.16 This patient population was heavily pretreated, including with multiple lines of chemotherapy. “What we need to do is establish who are the patients who benefit [from continued treatment],” he said.

Does a Role Exist for Neoadjuvant CDK4/6 Inhibitors?

The panelists said neoadjuvant hormonal therapy has been shown to be comparable to neoadjuvant chemotherapy in aggregate and unselected HR-positive breast cancers in terms of clinically important outcomes such as increased rates of breast conservation; however, whether the addition of CDK4/6 inhibitors provides additional benefit is still under investigation.

The experts discussed one trial examining this issue, SOLTI-1402/CORALLEEN (NCT03248427), a phase II study comparing neoadjuvant ribociclib plus letrozole with chemotherapy in patients with luminal B early breast cancer using the Prosigna Breast Cancer Prognostic Gene Signature Assay, formerly called the PAM50.

The study’s primary end point was rate of relapse among patients with a low PAM50 risk of relapse (ROR) at surgery; results showed the ROR was equivalent between arms (46.9% in the ribociclib/letrozole arm and 46.1% in the chemotherapy arm). Additionally, the toxicity profile was better with the ribociclib-containing regimen than with chemotherapy, with lower rates, respectively, of adverse events (AEs) leading to discontinuation (15.7% vs 19.2%) and dose reduction or temporary interruption (58.8% vs 82.7%) and of serious AEs (3.9% vs 15.4%).^17,18

“I think these data are certainly supportive of this idea that for patients with ER-positive breast cancer, neoadjuvant hormonal therapy can be a very effective approach,” Krop said. However, he added that the study’s end point of ROR is somewhat problematic because it was generated and validated in pretreated patients and not as a posttreatment end point.

Subsequently, although the data are encouraging, Krop emphasized the need for longer-term outcomes data and assessment of other end points. Nevertheless, he mentioned that results of other preoperative studies have shown that combining hormonal therapy with CDK4/6 inhibitors leads to a drop in Ki-67 protein, a marker of cellular proliferation, providing further evidence that incorporating CDK4/6 inhibitors has benefit in the neoadjuvant setting.

“What we need to do now is really try to focus on which patients with ER-positive disease benefit most from chemotherapy and which patients can get by very well with neoadjuvant hormonal therapy,” Krop said. “My guess is for the vast majority, hormonal therapy is going to be fine, but there probably are patients who still benefit from chemotherapy, and it will be nice to figure that out.”

During a median of 17 months of follow-up, the median progression-free survival (PFS) was 20.1 months (95% CI, 14.2-21.8) in the triplet arm compared with 14.4 months (95% CI, 12.1-17.0) in the chemotherapy arm (hazard ratio, 0.659; 95% CI, 0.437-0.994; 1-sided log-rank P = .0235).⁷

References

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18. Gavilá J, Saura C, Pascual T, et al. Primary results of SOLTI-1402/CORALLEEN phase 2 trial of neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: an open-label, multicenter, two-arm, randomized study. Abstract presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Abstract GS2-06. abstractsonline.com/pp8/#!/7946/presentation/1908.