Clinical relevance: The recent monarchE and NATALEE trials have both been practice-changing; they tested the efficacy of two different cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors in the adjuvant setting in patients with stage II and III breast cancer and led to ASCO releasing guideline rapid recommendation updates.
The monarchE and NATALEE trials were both complex, and the results will affect a very large absolute number of patients with breast cancer each year. Accordingly, the American Society of Clinical Oncology (ASCO) recently released a
rapid guideline recommendation update on this topic on May 20, 2024. Here, we aim to review the current status of the evidence, present the opinions of expert breast medical oncologists regarding the adoption of these drugs in the adjuvant setting, and discuss several caveats that must be considered when evaluating these important trials.
The monarchE trial
Abemaciclib (brand name Verzenio) with endocrine therapy (either an aromatase inhibitor or tamoxifen) was initially approved in October, 2021 in the adjuvant setting for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, early breast cancer at high risk of recurrence based on the results of the monarchE study. In March 2023, the indication was broadened, as the previous requirement for Ki-67s score of ≥ 20% was removed. The monarchE trial was a randomized 1:1 open-label trial that consisted of two cohorts.
- Cohort 1 included patients with ≥ 4 pathologically involved lymph nodes or 1-3 involved nodes and either tumor grade 3 or tumor size ≥ 50 mm.
- Cohort 2 included patients who were ineligible for cohort 1 with 1-3 pathologically involved nodes and Ki67 score of 20%.
Patients were randomized 1:1 to either 2 years of abemaciclib (150 mg twice daily) plus physician’s choice endocrine therapy or endocrine therapy alone. The major efficacy outcome, on which the federal drug administration (FDA) approval was based, was invasive disease-free survival (IDFS). The most recent update of the long-term outcomes from monarchE was
published in the Journal of Clinical Oncology in January, 2024 . This publication reported the 5-year efficacy results, and it also included results from a prespecified overall survival (OS) interim analysis. At a median duration of follow-up of 54 months, the previously observed IDFS benefit for abemaciclib in the intent-to-treat population persisted in this analysis with a hazard ratio (HR) of 0.68 (95% confidence interval [CI] 0.60 to 0.77). Likewise, a similar benefit for abemaciclib was seen in distant relapse-free survival (DRFS) with a HR of 0.675 (95% CI, 0.59 to 0.77). This translated to absolute benefits of 7.6% for 5-year IDFS and 6.7% for 5-year DRFS. Importantly, the benefits seen with abemaciclib were durable and persistent beyond the two-year treatment-completion date and out to the 5-year landmark. The IDFS and DRFS benefits seen with abemaciclib also persisted in multiple subgroup analyses by age, demographics, disease characteristics including Ki67, and choice of endocrine therapy (tamoxifen or aromatase inhibitors). There were fewer deaths in the abemaciclib + endocrine therapy arm than in the endocrine therapy arm (208 vs. 234), but statistical significance was not reached for OS (HR 0.90 [95% CI 0.75, 1.09). The authors commented that the lower number of deaths in the abemaciclib arm was suggestive of a possible emerging OS signal, and they also commented that previous adjuvant trials in HR+ breast cancer have shown that clinically meaningful survival signals can emerge as late as 10 years after trial entry. Abemaciclib’s main side effects include neutropenia, diarrhea, transaminase elevation, fatigue, and reduced appetite. Most of abemaciclib’s side effects are shared with other CDK 4/6 inhibitors, although it is associated with less neutropenia and more predominant diarrhea. While Abemaciclib is more toxic overall than other CDK 4/6 inhibitors, the PEARL trial showed that a different CDK /6 inhibitor (Palbociclib) was substantially less toxic than chemotherapy (https://www.annalsofoncology.org/article/S0923-7534(20)43221-1/fulltext).
The NATALEE trial
The NATALEE trial was an open-label, international phase 3 trial in which patients with HR+, HER2- stage II-III breast cancer were randomized 1:1 to riboclib (brand name Kisqali)(400 mg once daily, 3 weeks on followed by 1 week off) with a nonsteroidal aromatase inhibitor (NSAI) for ≥ 5 years vs. a NSAI alone. For patients with T2N0 disease to be eligible, they had to have either a grade 2 tumor + Ki67 of at least 20% or high genomic risk. Premenopausal women and men additionally received gonadal suppression as part of their endocrine therapy. As in the monarchE trial, IDFS was the primary outcome. The first prespecified interim analysis of the NATALEE trial was published in March, 2024 in the
New England Journal of Medicine . A total of 2549 patients were randomized to ribociclib plus an NSAI and 2552 were randomized to an NSAI alone. The median duration of follow up from randomization in this report was 28 months. The topline finding from NATALEE was that, at the 3-year landmark, IDFS was 90.4% with ribociclib plus an NSAI vs. 87.1% in patients who received an NSAI alone (3.3% absolute difference). This translated to a HR for invasive disease of 0.75 (95% CI 0.62 to 0.91, p=0.003). There was a similar-sized benefit in DDFS for ribociclib. The HR was 0.74 (95% CI 0.60 to 0.91) and 3-year DDFS rates were 90.8% vs. 88.6%. At a median follow-up of 30 months, OS did not differ significant (HR for ribocicclib 0.76 [95% CI 0.54 to 1.07]). Among patients randomized to ribociclib, 56.8% completed at least 2 years of treatment with ribociclib plus an NSAI, and 20.2% completed the planned 3 years of ribociclib. Serious adverse events were reported in 336 patients (13.3%) in the ribociclib–NSAI group and in 242 patients (9.9%) in the NSAI group. Adverse events that led to early discontinuation of ribociclib were reported in 477 patients (18.9%). The most notable adverse events were neutropenia (43.8% of patients receiving ribociclib plus an NSAI vs. 0.8%), liver-related adverse events (8.3% vs. 1.5%), QT prolongation (5.2% vs. 1.2%). Other adverse events included nausea (23% vs. 7.5%), headache (22% vs. 16.5%), and fatigue (21.9% vs. 12.7%).
ASCO guideline rapid recommendation update
The ASCO guideline rapid recommendation update published in May 2024 promoted the use of abemaciclib in patients who would have been eligible for monarchE based on that trial’s eligibility criteria. While the guideline panel noted the FDA’s approval language was broad, the recommendation nevertheless was graded as strong and as being based on high-quality evidence. Based on the results of the NATALEE trial, the panel recommended that patients meeting inclusion criterial may be offered ribociclib in addition to standard of care endocrine therapy. This recommendation was graded as conditional and as being based on high quality evidence. The panel elaborated that they believed that CKD 4/6 inhibitors may not provide a clinically meaningful benefit for all patients who were included in the two trials. In particular, they had concerns that the risks may outweigh the benefits in many node negative patients, who have lower risk of recurrence. They acknowledged that there are currently insufficient data to specify which subgroups will benefit, and recommended careful consideration benefits, risks, costs, and preferences for each patient. The committee also noted that, of the two drugs, abemiciclib has more mature follow-up data, a shorter treatment duration, and clear evidence of an increasing benefit with increasing amounts of follow up time. For this reason, they conditionally recommended abemiciclib over ribociclib in patients who would meet the inclusion criteria for both studies, reserving ribociclib for more frail patients and those with baseline contraindications to abemaciclib such as a history of clinically significant diarrhea.
Using CDK 4/6 inhibitors in adjuvant setting
SurvivorNet spoke with several breast cancer experts regarding the adoption of CDK 4/6 inhibitors into their practices in this setting. Dr. Charles Shapiro, Professor of Medicine, Hematology and Medical Oncology at the Icahn School of Medicine at Mount Sinai, told SurvivorNet that abemaciclib combined with endocrine therapy “represents a new standard of care for women with high-risk early-stage breast cancer.” Dr. Neil Vaasan, a Medical Oncologist at Columbia University Irving Medical Center also spoke with SurvivorNet about abemiciclib. "In breast cancer, we have been prescribing many of the same drugs for so many years. This is definitely going to change the way we treat women with breast cancer in this category… We all have patients with high-risk disease who need better treatment options," he explained. Dr. Vasan elaborated regarding the real-world adoption of abemaciclib: “The question in the real world is whether all women who fit the inclusion criteria from the trial are truly the best candidates for this drug, or only the highest risk women.” Dr. Eleonora Teplinsky, a Breast Medical Oncologist practicing at Valley Health System in New Jersey commented on the durability of benefit seen with abemaciclib. “The nice thing that we've seen with Abemaciclib is we have five-year data. We've shown about a 7% decrease in risk of of recurrence or disease progression or death. So we know that when you take the abemaciclib for two years, there's at least a five year benefit. So that's very important context," she said. Dr. Teplinksy, articulated that ribociclib is a welcome addition to the treatment armamentarium, but added that questions remain regarding how many patients should receive it. “What we're really trying to figure out is whether this drug is for everyone? How do we balance the benefit with the side effects? …And so we really have to think about how do we balance benefit with potential risk? How does that impact quality of life?” She then went on to discuss the importance of shared decision making. “Now for some patients, that benefit may be more important than it is for others, and that's where that shared decision making becomes really important. Having the conversation of, I'm concerned about these side effects, or I'm concerned about the cost of the medication or how I'm going to feel on it and what's the benefit?” She continued “I will have some patients that say to me, I will do everything to not experience a recurrence. So for them, that 3% improvement is worth it. And other women will say, ‘I appreciate that benefit, but I don't want to risk the toxicity’… And so that's where individual shared decision making becomes very important.” “I expect that these trial results will change practice,” added Dr. Rita Nanda, director of the Breast Oncology Program at the University of Chicago Medicine, of the NATALEE results.
Financial toxicity
The ASCO rapid guideline recommendation update also touches on another important aspect: the possibility of financial toxicity. The authors stated that a formal cost-effectiveness analysis was beyond the scope of those guideline, but they felt that future work in that space would be informative. While not a formal cost-effectiveness analysis, Haslam et al
recently estimated that the costs to prevent one IDFS event would be quite staggering: $5,700,000 for abemeciclib based on monarchE and $11,200,000 for ribociclib based on NATALEE. It is also important to also consider that these trials apply to a large absolute number of patients — Haslam et al estimated that the NATALEE results may apply to up to 35% of patients with breast cancer in the United States. Both the ASCO rapid guideline recommendation and several experts we interviewed pointed out that they will be very interested to see if the FDA approves ribociclib based on NATALEE. On this, Dr. Teplinksy said, “But for stage one through three, abemaciclib is approved by the FDA ribociclib is not yet approved by the FDA. We do have robust data. It will be very interesting to see what happens with the FDA approval. I think that when we talk to patients, it's important to tell them this and it's important to have this conversation of this is not yet FDA approved.”
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