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What’s New in Breast Cancer Research?

February 1, 2021

Early-stage hormone-receptor positive, HER2 negative (HR+/HER2-) breast cancer is the most commonly diagnosed type of breast cancer. While the majority of individuals with this diagnosis will not recur, approximately 20-30% will within 10 to 20 years of their initial diagnosis, and often as incurable distant metastatic disease. The FDA has approved three CDK4/6 inhibitors in advanced and metastatic HR+/HER2- breast cancer: palbociclib [IBRANCE], abemaciclib [Verzenio], and ribociclib [Kisqali]. Long-term follow-up in the clinical trials indicate that overall survival (OS) is improved in the metastatic setting with the use of ribociclib (median OS not yet reached; 70.2% vs. 46.0% at 42 months) and abemaciclib (median OS benefit, 9.4 months; 46.7 vs. 37.3 months), but not as of yet, for palbociclib.

These findings have led to a number of trials exploring the potential clinical value of these drugs in the early breast cancer setting, and the results of some of these trials are beginning to surface. Studies to date reveal mixed findings in early breast cancer, with two trials (PALLAS, PENELOPE-B) of palbociclib demonstrating no benefit and very early results in monarchE (abemaciclib) showing a preliminary benefit of 3.5% absolute reduction in IDFS. The results from NATALEE (ribociclib) are not yet out.

There are key questions being discussed among the scientific and advocate community about these mixed results. In the meantime, advocates should look for longer-term follow up data for all trials, and in monarchE to confirm the continued benefit in IDFS of abemaciclib and if this will translate to an overall survival benefit in the long run.  In addition, we should focus on the results from the ongoing NATALEE trial, which is studying the addition of 3 years (rather than 1 or 2 years) of ribociclib, at a lower dose than used in the metastatic setting, to standard-of-care endocrine treatment in high-risk early-stage HR+/HER2- breast cancer, which has not yet been reported.

Below are high-level summaries and emerging results of trials for each of the three CDK4/6 inhibitors in the early setting.

monarchE trial (abemaciclib)[iv]

  • Design: International, multicenter, phase 3, open-label trial in high-risk early HR+/HER2- breast cancer (N= 5,637)
  • Eligibility: high risk status—stage 2 or stage 3; (59% of patients had ≥4 involved nodes and 73% were stage 3)
  • Treatment: Patients randomized after treatment (e.g., surgery, radiotherapy, and/or adjuvant/neoadjuvant chemotherapy) to standard-of-care adjuvant endocrine therapy (5-10 years) with or without 2-years of abemaciclib.
  • Dose: 150 mg twice daily (same dose used in advanced/metastatic breast cancer), continuously for 2 years.
  • Primary Outcome: invasive disease free-survival (IDFS)

Results: In the second preplanned interim analysis (median follow-up 15.5 months), IDFS was improved in the treatment (abemaciclib) arm compared to the control arm (endocrine therapy alone), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. A total of 16.6% patients in the treatment arm discontinued abemaciclib early as a result of adverse events, and 68.1% of patients in the treatment arm of monarchE required a dose reduction.

PALLAS (palbociclib)[v]

  • Design: International, multicenter, phase 3, open-label trial in high-risk early HR+/HER2- breast cancer (N= 5,760)
  • Eligibility: High risk status—stage 2 (no more than 1000) and stage 3; (58.7% had high clinical risk defined as ≥4 involved nodes or 1-3 nodes with either T3/T4 and/or grade 3 disease; 48.6% stage 3)
  • Treatment: Patients randomized after treatment (e.g., surgery, radiotherapy, and/or adjuvant/neoadjuvant chemotherapy) to standard-of-care adjuvant endocrine therapy (5-10 years) with or without 2-years of palbociclib.
  • Dose: The starting dose of palbociclib was 125 mg daily for days 1-21 in a 28-day cycle (same dose used in advanced/metastatic breast cancer), for 2 years.
  • Primary Outcome: IDFS

Results: In the second preplanned interim analysis (median follow-up 23.7 months), with results published on January 15, 2021 in the Lancet (Mayer et al., 2021), investigators reported no improvement in IDFS (88.2% and 88.5% with and without palbociclib, respectively), and the discontinuation of the trial for futility. Notably, 42.2% of patients in the treatment arm discontinued palbociclib earlier than intended as a result of adverse events, and 55% required dose reduction.

PENELOPE-B (palbociclib)[vi]

  • Design: German, multicenter, phase 3, double-blind trial in high-risk early HR+/HER2- breast cancer (N= 1,244)
  • Eligibility: High risk status—Women without pathological complete response after neoadjuvant chemotherapy, defined as high risk with a CPS (pretreatment clinical stage [CS] and post-neoadjuvant treatment pathologic stage [PS] in hormone positive disease) score of 3-6
  • Treatment: Patients randomized after neoadjuvant therapy to standard-of-care adjuvant endocrine therapy (5 years) with or without 1-year of palbociclib.
  • Dose: The starting does of palbociclib was 125 mg daily for days 1-21 in a 28-day cycle (same dose used in advanced/metastatic breast cancer), for 1 year.
  • Primary Outcome: IDFS

Results: The PENELOPE-B trial of palbociclib was different in design to both monarchE and PALLAS, focusing specifically on patients with HR+/HER2- breast cancer who had residual disease at surgery after neoadjuvant chemotherapy. This trial, launched in November 2013, also randomized patients to receive only 1-year of palbociclib or placebo. Mature results (median follow-up 42.8 months) were released on October 9, 2020 (Pfizer Press Release) reporting no improvement in IDFS among patients in the treatment arm. Interestingly, results presented in December 2020 at the 2020 San Antonio Breast Cancer Symposium revealed that at an earlier time point in the trial (2 and 3 years follow-up), there did appear to be a ~3-4% benefit in IDFS, but this difference disappeared by 4 years follow-up.

NATALEE (ribociclib)

  • Design: International, multicenter, phase 3, open-label trial in high-risk early HR+/HER2- breast cancer (target N=4000)
  • Eligibility: High risk status—stage 3 or stage 2.
  • Treatment: Patients randomized after treatment (e.g., surgery, radiotherapy, and/or adjuvant/neoadjuvant chemotherapy) to standard-of-care adjuvant endocrine therapy with or without 3-years of ribociclib.
  • Dose: The starting dose of ribociclib is 400 mg daily for days 1-21 in a 28-day cycle (reduced dose compared to that used in advanced/metastatic breast cancer), for 3 years.
  • Primary Outcome: IDFS

Results: This is an ongoing trial and results are not yet available.

Summary

Studies to date reveal mixed findings of the addition of CDK4/6 inhibitors in the early breast cancer setting, with two trials of palbociclib demonstrating no benefit and very early results in monarchE with abemaciclib showing a preliminary benefit of 3.5% absolute reduction in IDFS. The results from NATALEE (ribociclib) are not yet out.

Key questions being discussed among the scientific and advocate community about these mixed results currently revolve around the length of time patients need to be on a CDK4/6 inhibitor, what the optimal dose is in early, but high-risk breast cancer setting, whether or not there are differences in the clinical efficacy of the three FDA-approved CDK4/6 inhibitors, and specifically which patients, if any, with early breast cancer may benefit.[vii]

It’s clear from the high discontinuation rate in PALLAS, and the high dose reductions rates in both PALLAS and monarchE, these drugs have adverse events that may not be acceptable in the early breast cancer setting. Moreover, is a 3.5% absolute reduction in IDFS meaningful for the $7K to $13K per month cost of the addition of CDK4/6 to treatment?

In the meantime, here is what advocates need to look for:

  • Longer follow-up data from monarchE that confirms the continued benefit in IDFS of abemaciclib and whether or not this will translate to an overall survival benefit in the long run.
  • The results from the ongoing NATALEE trial, which is studying the addition of 3 years (rather than 1 or 2 years) of ribociclib, at a lower dose than used in the metastatic setting, to standard-of-care endocrine treatment in high-risk early-stage HR+/HER2- breast cancer which have not yet been reported.

References 

[i] Im SA, Lu YS, Bardia A, et al. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. doi: 10.1056/NEJMoa1903765. Epub 2019 Jun 4. PMID: 31166679.

[ii] Sledge GW Jr, Toi M, Neven P, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2019 Sep 29;6(1):116–24. doi: 10.1001/jamaoncol.2019.4782. Epub ahead of print. PMID: 31563959; PMCID: PMC6777264.

[iii] Curigliano G. CDK4/6 inhibitors for HR+HER2- early stage breast cancer – when to escalate treatment? Nat Rev Clin Oncol. 2020 Nov 24. doi: 10.1038/s41571-020-00453-1. Epub ahead of print. PMID: 33235325.

[iv] Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE). J Clin Oncol. 2020 Dec 1;38(34):3987-3998. doi: 10.1200/JCO.20.02514. Epub 2020 Sep 20. PMID: 32954927; PMCID: PMC7768339.

[v] Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021 Jan 15:S1470-2045(20)30642-2. doi: 10.1016/S1470-2045(20)30642-2. Epub ahead of print. PMID: 33460574.

[vi] https://www.pfizer.com/news/press-release/press-release-detail/penelope-b-trial-ibrancer-palbociclib-early-breast-cancer

[vii] Curigliano G. CDK4/6 inhibitors for HR+HER2- early stage breast cancer – when to escalate treatment? Nat Rev Clin Oncol. 2020 Nov 24. doi: 10.1038/s41571-020-00453-1. Epub ahead of print. PMID: 33235325.