Over the past 7 years, the introduction of combined endocrine therapy with cyclin-dependent kinase (CDK) 4/6 inhibitors resulted in a dramatic improvement in outcomes for patients with metastatic, hormone receptor–positive, HER2-negative breast cancer. Early attempts to modulate the cell cycle with therapeutic intent started in the 1990s and failed because of the toxicity and lack of specificity of the drugs used in those attempts. The development of selective CDK4/6 inhibitors showed promising activity in preclinical models and pointed to the hormone receptor–positive, HER2-negative subtype as being particularly sensitive to such interventions.
“Reports based on follow-up durations of 2 to 3 years are largely premature; analyses after 8 to 10 years, or even 15 years, will provide definitive answers.”— Gabriel N. Hortobagyi, MD, MACP, FASCO
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Following the provocative results of the phase II PALOMA-1 study,1 three selective CDK4/6 inhibitors—abemaciclib, palbociclib, and ribociclib—rapidly moved to phase III trials; within a couple of years, encouraging results were reported with all three. Although trials in the first-line setting were initiated earlier, additional trials in the second- and third-line settings were completed promptly, since progression-free and overall survival events accrue faster in these previously treated and partially resistant groups of patients.
In rapid succession, the PALOMA-22, MONALEESA-2,3 and MONARCH 34 trials reported marked prolongation of progression-free survival in first-line therapy, and the PALOMA-3,5 MONALEESA-3,6 and -MONARCH 27 trials showed a similar, highly encouraging treatment benefit in progression-free survival as second- and third-line treatments. Hazard ratios (HRs) in all these trials clustered around 0.5, suggesting a 50% reduction in progression-free survival events, regardless of the endocrine partner. Soon, the second-line trials reported similarly encouraging overall survival results, with hazard ratios around 0.7, progression-free survival doubled, and overall survival increased by 6 to 9 months in resistant patients and 8 to 12 months in those previously untreated.
These outcomes exceeded expectations and were substantially superior to all previously reported controlled trials in this type of metastatic breast cancer. These results suggested that the three CDK4/6 inhibitors were highly active, reasonably well tolerated, and seemingly similar in efficacy, with just modest differences in safety profiles. With this background, there was great optimism as trials in the adjuvant setting developed. Accrual to the three main trials -(PALLAS,8 monarchE,9,10 and NATALEE) was completed rapidly, even though all three were amended during accrual to increase sample size, and therefore the power to detect a therapeutic benefit.
Early Results of Adjuvant Trials: ‘Disconcertingly Heterogeneous’
Now, we are starting to see the early results of the adjuvant trials, and they are disconcertingly heterogeneous. First to report, the PALLAS trial,8 conducted by Gnant et al and summarized in this issue of The ASCO Post, showed no benefit whatsoever in invasive disease–free survival after a median follow-up of 31 months. By then, almost all patients had completed the planned 2 years of palbociclib therapy, and two analyses had been performed. In its wake, the PENELOPE-B study11 (a postneoadjuvant chemotherapy randomized trial) was similarly negative, with no benefit after 1 year of palbociclib in a group of high-risk patients with residual disease after chemotherapy. Just a few weeks later, the very early results of the monarchE trial were clearly positive, with a 29% reduction in the risk of developing an invasive disease–free survival event.9 A second analysis, after an additional year of follow-up (median follow-up, 27 months) confirmed the benefit, with continued separation of the Kaplan-Meier curves for invasive disease–free survival.10 NATALEE has completed accrual, but it is immature for its initial analysis.
There has been much speculation regarding the interpretation of these early results. The fact that PALLAS and PENELOPE-B are negative trials is incontrovertible. Why monarchE is seemingly strongly positive leads to several hypotheses, and we are still awaiting the “tie-breaker” results of NATALEE. The baseline characteristics of -PALLAS and monarchE show some clear differences: monarchE recruited more patients with larger tumors, more positive lymph nodes, and higher-stage and higher-grade disease. However, even if the analysis of PALLAS focuses on similarly higher-risk subgroups, there is no benefit from palbociclib.
“The challenges will be to determine the best combinations and best sequences and to identify biomarkers to select the right treatment for the right patients.”— Gabriel N. Hortobagyi, MD, MACP, FASCO
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Dose reductions were frequent in both trials, exceeding 50%, although they are difficult to compare directly because the presentations and manuscripts expressed dose reductions differently. Palbociclib was discontinued prematurely by almost 45% of patients, whereas abemaciclib discontinuation was reported in just 17% of those assigned to receive it. It is tempting to point at this major discrepancy in drug exposure as being responsible for the lack of treatment benefit, but analysis of PALLAS showed no difference between those patients who completed treatment as prescribed and those who discontinued it early. Palbociclib and ribociclib are administered intermittently (3 weeks on, 1 week off) to allow for bone marrow recovery and to reduce the risk of infectious complications, whereas abemaciclib is administered continuously.
Closer Look at the Big Three and Beyond
Preclinical studies suggested that continued suppression of CDK4/6 activity is therapeutically advantageous. There are emerging reports of differences in the selectivity of action of the three drugs on CDK4 and CDK6, potency, and some variation in pharmacokinetic properties. It is possible that some of these might influence the outcomes. However, these emerging reports cannot avoid the possibility that there are real differences in the effectiveness of the three drugs. Additional follow-up, and the initial reports of the NATALEE trial, will shed more light on the similarities and differences among these three agents as well as their role in managing metastatic and early hormone receptor–positive breast cancer.
We must also remember that hormone receptor–positive/HER2-negative breast cancer tends to have an indolent course and that reports based on follow-up durations of 2 to 3 years are largely premature; analyses after 8 to 10 years, or even 15 years, will provide definitive answers. Although at this time abemaciclib appears to provide a modest benefit for high-risk early breast cancer, this field is rapidly moving to its next phase: identification of mechanisms of resistance to CDK4/6 inhibitors, development of interventions to prevent or reverse such resistance, and emphasis on novel endocrine agents and combinations.
MORE INFORMATION
For more on the use of CDK4/6 inhibitors in advanced breast cancer, see an interview with Gabriel N. Hortobagyi, MD, MACP, FASCO, on The ASCO Post Newsreels at ascopost.com/videos.
In this regard, it is worth mentioning the encouraging findings showing the superior activity of elacestrant, a selective estrogen receptor downgrader, over the standard of care, including fulvestrant. Also of note are the development of novel PI3K, AKT, and mTOR inhibitors as well as the work on novel CDK inhibitors focused on CDK7, CDK2, and other members of the cyclin/CDK family.
Cautious Optimism
There is much reason to be optimistic in this field. The median survival of patients with metastatic hormone receptor–positive/HER2-negative breast cancer exceeded 5 years in the MONALEESA-2 trial, and the early survival of patients with early-stage disease is excellent. The emerging treatment options are likely to improve these outcomes further. The challenges will be to determine the best combinations and best sequences and to identify biomarkers to select the right treatment for the right patients.
Dr. Hortobagyi works in the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.
DISCLOSURE: Dr. Hortobagyi has received research funding and personal fees from Novartis for the MONALEESA trials.
REFERENCES
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2. Finn RS, Martin M, Rugo HS, et al: Palbociclib and letrozole in advanced breast cancer. N Engl J Med 375:1925-1936, 2016.
3. Hortobagyi GN, Stemmer SM, Burris HA, et al: Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 375:1738-1748, 2016.
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5. Turner NC, Ro J, André F, et al: Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373:209-219, 2015.
6. Slamon DJ, Neven P, Chia S, et al: Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol 36:2465-2472, 2018.
7. Sledge GW Jr, Toi M, Neven P, et al: MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2– advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 35:2875-2884, 2017.
9. 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 38:3987-3998, 2020.
10. Harbeck N, Rastogi P, Martin M, et al: Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: Updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol 32:1571-1581, 2021.
11. Loibl S, Marmé F, Martin M, et al: Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer: The PENELOPE-B trial. J Clin Oncol 39:1518-1530, 2021.
