2023 ASCO Highlights, Part 1: CDK4/6 Inhibitors

The American Society of Clinical Oncology (ASCO) held its annual meeting in early June where researchers presented updates to key cancer treatment clinical trials. In a series of Science Spotlights, NBCC will bring you the highlights from this meeting and break down what they mean for our mission to end breast cancer. The first in this series focuses on two clinical trials, NATALEE and SONIA, that involve CDK4/6 inhibitors.

What are CDK4/6 Inhibitors?

Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) are two proteins that when activated, allow tumor cells to keep growing and multiplying. CDK4/6 inhibitors block the activation of CDK4/6 and thereby help to prevent tumor cells from growing and multiplying. CDK4/6 inhibitors are used in HR+/HER2- breast cancers and include ribociclib (Kisqali), palbociclib (Ibrance), and abemaciclib (Verzenio). Importantly, research on CDK4/6 inhibitors has benefitted from NBCC’s tireless advocacy for the Department of Defense Breast Cancer Research Program (DOD BCRP).

NATALEE Trial Update 

NBCC involvement:

NBCC is currently partnering with the clinical research organization Translational Research in Oncology (TRIO) and Novartis Pharmaceuticals on the NATALEE trial, where NBCC advocates have served on the trial’s steering committee, data safety monitoring board, and its translational research committee.


The NATALEE trial evaluated the potential benefit of adding a CDK4/6 inhibitor, in this case, ribociclib to adjuvant hormonal treatment for patients with HR+/HER2- stage II or III breast cancer. As many as 30% of these patients experience a recurrence, sometimes as long as two to three decades following their primary treatment. Ribociclib has previously demonstrated overall survival benefits in advanced/metastatic HR+/HER2- breast cancer in the MONALEESA clinical trials.

Can moving this drug into the adjuvant setting result in fewer metastatic recurrences and more cures? What is the balance of benefit to risk for these patients, most of whom will not recur?

The NATALEE Trial:

Since we last wrote about ribociclib, Dr. Dennis Slamon presented detailed results from an interim analysis of the Phase III trial at ASCO.1

5,101 patients were randomized 1:1 to receive standard-of-care endocrine therapy alone (ET) or in conjunction with ribociclib (RIB + ET) for 3 years. It is important to note that the data presented at ASCO are still immature. At the time of this interim analysis, only 20.2% of the patients in the RIB + ET arm had completed 3 years of ribociclib with another 57% having completed 2 years of treatment. Notably, 19% had discontinued treatment with ribociclib due to an adverse event.


At this interim analysis, ribociclib demonstrated an improvement in invasive and distant disease-free survival, as follows:

  • A 3.3% absolute improvement in invasive disease-free survival (iDFS) (87.1% ET alone vs 90.4% RIB + ET), which was statistically significant (p = 0.0014)
  • A 2.2% absolute improvement in distant disease-free survival (dDFS) (88.6% ET alone vs 90.8% RIB + ET), which was also statistically significant (p = 0.0017)
  • Overall survival (OS) data were immature (73 events ET alone vs 61 events RIB + ET)

However, ribociclib also increased the risk of adverse events, including:

  • Grade ≥3 neutropenia (0.8% ET alone vs 43.8% RIB + ET)
  • Grade ≥3 liver-related complications (1.5% ET alone vs 8.3% RIB + ET)
  • Grade ≥3 QT prolongation (0.5% ET alone vs 1.0% RIB + ET).

NATALEE prescribed a lower dose of ribociclib (400 mg) compared to previous trials in advanced/metastatic breast cancer (600 mg). While the 400 mg dose used in NATALEE spared patients from higher rates of adverse events, the rate of discontinuation due to adverse events (4% ET alone vs 19% RIB + ET) was still notable.

Key Takeaways and Outstanding Questions:

As noted above, these data are still immature. As the ongoing analysis of NATALEE continues, will the iDFS and dDFS benefits observed diminish or strengthen, and importantly, will there be an improvement in OS? Who actually benefits from ribociclib, and are there biomarkers that can identify the patient population most appropriate in this setting? This is an important question given that the vast majority of individuals treated with ribociclib in the adjuvant setting do not receive benefit.

We will have to wait for longer term follow-up to understand the full benefits and risks of ribociclib and who exactly is benefiting in the early breast cancer setting.



Oftentimes, clinical trials do not inform us of the best sequence for a specific treatment in metastatic breast cancer. Is it best to use a drug in the first line vs second line vs third line, etc.? Where do we see the most benefit?

Many trials, by nature of their design, leave these important comparative effectiveness questions about real-world use unanswered. For example, as we explained in the context of the DESTINY Breast-03 trial of T-DXd vs T-DM1, the lack of required crossover (access to the experimental drug previously shown to be effective) after disease progression among patients in the control arm means that we can’t be sure if it is better to use T-DXd in the second line or third line. Why does that matter?

CDK4/6 inhibitors combined with endocrine therapy have been shown to improve progression free and sometimes, overall survival outcomes when used in either the first or second line setting for advanced/metastatic HR+/HER2- breast cancer, but their use in the first line is associated with longer exposure to side effects and increased cost. If delaying the use of CDK4/6 inhibitors until the second line can maintain beneficial outcomes and decrease the risk of side effects and financial burdens, should we prioritize it as the preferred treatment sequence?

This was precisely the question that the SONIA trial, an academically sponsored investigator-initiated trial in the Netherlands addressed. Primary outcomes from SONIA were presented at ASCO.2

This Phase III clinical trial randomized 1,050 patients with newly diagnosed HR+/HER2- metastatic breast cancer 1:1 to either receive a CDK4/6 inhibitor combined with endocrine therapy in the first line (first line non-steroidal aromatase inhibitor + CDK4/6 inhibitor, then second line fulvestrant) or in the second line (first line non-steroidal aromatase inhibitor, then second line fulvestrant + CDK4/6 inhibitor).

The primary endpoint was the time from random assignment at the start of the trial to the second objective disease progression or death (PFS2). Secondary endpoints included overall survival (OS), safety, quality of life (QoL), and the total cost of treatment.


First-line use of a CDK4/6 inhibitor did not improve the primary endpoint of PFS2 compared to those receiving a CDK4/6 inhibitor in the second line of treatment (PFS2=31.0 months with first line CDK4/6i use vs 26.8 months with second line CDK4/6i use; P=0.10).

Importantly, there was no improvement in overall survival with first line use of a CDK4/6 inhibitor compared to receiving it in the second line of treatment (OS=45.9 months with first line CDK4/6i use vs 53.7 months with second line CDK4/6i use; P=0.83).

While there were no differences in PFS2 or OS, there were marked differences in adverse events and costs between the two treatment approaches. Use of a CDK4/6 inhibitor in the first line of treatment for metastatic HR+/HER2- breast cancer versus second line use was associated with 16.5 month increase in CDK4/6 inhibitor exposure (24.6 months vs 8.1 months). Consequently, patients randomized to use of a CDK4/6 inhibitor in the first line experienced a 42% increase in Grade ≥3 adverse events (2,782 events vs 1,620 events) and a $200,000 increase in drug expenditure per patient.

Key Takeaways:

While comparative effectiveness trials such as SONIA are important, it must be noted that the outcome of this particular trial may be affected by the fact that palbociclib, which was the CDK4/6 inhibitor used by the majority (91%) of patients in this trial, has not been shown to extend overall survival in any population. It may well be that excluding CDK4/6 inhibitors from the first line treatment does not harm patients and in fact can spare them from adverse events and additional financial burden. We must find ways to answer these questions in order to do what is best for women.

NBCC applauds the SONIA investigators for asking important questions that are clinically relevant and impact the physical, mental, and financial well-being of breast cancer patients.


  1. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(17_suppl):LBA500-LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500
  2. Sonke GS, Van Ommen – Nijhof A, Wortelboer N, et al. Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). J Clin Oncol. 2023;41(17_suppl):LBA1000-LBA1000. doi:10.1200/JCO.2023.41.17_suppl.LBA1000