On behalf of the SONIA study team
Background: why?
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a valuable addition to the treatment armamentarium for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Indeed, several phase III trials have shown that adding a CDK4/6 inhibitor to endocrine therapy prolongs progression-free survival (PFS) in this breast cancer subtype.
In the first-line setting, combining CDK4/6 inhibitors with a non-steroidal aromatase inhibitor (NSAI) approximately doubles PFS compared to a NSAI plus placebo (see here, here, and here). In the second- and subsequent-line settings, adding CDK4/6 inhibition to fulvestrant after prior treatment with endocrine therapy and/or chemotherapy also approximately doubles PFS compared with fulvestrant plus placebo (see here, here, and here). Currently, three CDK4/6 inhibitors have been FDA- and EMA-approved for use in HR-positive/HER2-negative advanced breast cancer: palbociclib, ribociclib, and abemaciclib.
Optimal strategy: when?
There are currently no clinical data to guide clinicians in deciding whether CDK4/6 inhibitors need to be used in the first-line setting or whether their use can be delayed to subsequent lines of endocrine therapy. The following considerations require thought and further investigation:
Efficacy
In terms of efficacy, there is no evidence that CDK4/6 inhibitors are superior in first compared to second or subsequent lines. The relative gain in PFS is very similar in both settings, as expressed by nearly identical hazard ratios in all pivotal clinical trials. No direct comparison of PFS in first- versus second-line exists, but some inferences can be made from the available data. The addition of a CDK4/6 inhibitor to endocrine therapy in the first-line setting led to a median PFS of approximately 25 months, compared with around 15 months with endocrine monotherapy. When used in the second line, the addition of a CDK4/6 inhibitor yielded a median PFS of approximately 9–16 months, compared with 5–9 months with endocrine monotherapy. These data suggest that the addition of CDK4/6 inhibitors to endocrine therapy, regardless of which line, leads to a PFS of approximately 30 months after two lines of therapy. While these cross-trial comparisons must be interpreted cautiously, there is no clear benefit of administering CDK4/6 inhibitors routinely in the first-line setting.
While improvement in PFS is often the primary endpoint in clinical trials, overall survival (OS) and quality of life (QoL) are more important endpoints from a patient perspective. So far, the addition of CDK4/6 inhibitors to endocrine therapy has not resulted in a statistically significant improvement in OS. Neither the PALOMA-1 study (phase II, first-line setting) nor the PALOMA-3 study (phase III, second-line setting) showed statistically significant improvement in OS with the addition of palbociclib, although the non-significant 6.9 months difference in median OS in PALOMA-3 is hopeful. The OS results of other trials of CDK4/6 inhibitors are still awaited.
Toxicity and quality of life
Almost 70% of patients experience CTCAE grade 3–4 toxicity with the combination compared with 20% of those on endocrine therapy alone. As a result, the use of CDK4/6 inhibitors requires more frequent control visits and laboratory evaluations. Since the average duration of use of CDK4/6 inhibitors is substantially longer in first compared to second or subsequent lines, patients are subjected to potential side effects and more frequent hospital visits for a longer period of time when the drugs are used as first line treatment. This might be part of the reason why adding a CDK4/6 inhibitor to endocrine therapy as first line treatment does not clearly result in improved QoL, despite the clear benefit in PFS. Health-related QoL, as assessed by validated questionnaires, did not differ between treatment arms in the PALOMA-2 and MONALEESA-2 trials.
Financial considerations
In the USA, the monthly wholesale price of all three CDK inhibitors is over US$ 13,500, compared with less than US$ 50 for endocrine monotherapy. The price of CDK4/6 inhibitors varies for each drug and between countries, but it is safe to say that they are much more expensive than endocrine therapy. Therefore, using CDK4/6 inhibitors as a default first-line treatment for all patients with advanced, HR-positive/HER2-negative breast cancer, would have an immense impact on healthcare budgets. Yet, cost-effectiveness analyses with palbociclib in Canada, the USA, and Switzerland concluded that it is very unlikely that palbociclib in the first line is cost-effective at current pricing. A Novartis-led cost-effectiveness analysis that compared ribociclib plus endocrine therapy, palbociclib plus endocrine therapy, and endocrine therapy alone, concluded that the use of ribociclib in the first-line setting is cost-effective, albeit at the very high willingness-to-pay threshold of US$ 198,000.
Looking forward
The Dutch SONIA study addresses the question of when to use CDK4/6 inhibitors. In this study, patients are randomly allocated to either strategy A (NSAI plus CDK4/6 inhibition in the first line followed by fulvestrant in the second line) or strategy B (NSAI in the first line followed by fulvestrant plus CDK4/6 inhibition in the second line). The aim of this study is to investigate whether strategy A is superior to strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include OS, cost-effectiveness and QoL. The SONIA study started in October 2017 and aims to include 1,050 patients from 73 hospitals in the Netherlands over a period of 3.5 years. On 1st February 2019, 289 patients were randomized.
SONIA study overview (click to enlarge)
Optimal strategy: who?
Given the uncertainty of the current position of CDK4/6 inhibitors, predictive biomarkers to select patients who will or will not benefit from the addition of these drugs upfront are highly sought after. CDK4/6 inhibitors interfere with the cyclin D-CDK4/6-retinoblastoma (Rb) pathway and, as a result, proteins and genes involved in this pathway have been extensively studied as potential biomarkers. Although preclinical data suggested that elevated levels of RB1 and cyclin D1 may be associated with improved response to palbociclib, these findings could not be confirmed in clinical trials. Analysis of baseline circulating tumor DNA (ctDNA) as part of the MONALEESA-2 study found no genes predictive for response to ribociclib. In addition, gene expression levels in tumor samples of the same study did not differ between responders and nonresponders. Early dynamics in PIK3CA mutations in ctDNA did predict response to palbociclib in the PALOMA-3 study, but only 20% of patients in this study harbored a PIK3CA mutation at baseline. The applicability of this biomarker is therefore limited and findings are not consistent with data from the MONALEESA-2 study. Thus far, the only consistent biomarker for response is estrogen receptor (ER) positivity.
Future directions
Several other potential applications of CDK4/6 inhibitors in breast cancer are currently under investigation. In the advanced breast cancer population, several studies investigate the feasibility of combining CDK4/6 inhibitors with other targeted therapies such as PI3Kinhibitors in an effort to overcome resistance. Recent studies suggest that CDK4/6 inhibitors not only exert a direct effect on the cyclin D-CDK4/6-Rb pathway (and thereby inhibit cell cycle progression), but also exhibit immunomodulatory properties. This might provide clues for combination therapies with immune checkpoint inhibitors. Continuing CDK4/6 inhibitors beyond progression following one line of endocrine therapy is another interesting research subject. To expand the use of CDK4/6 inhibitors to other subtypes of breast cancer, their efficacy as part of combination therapy in HER2-amplified or triple-negative breast cancer patients is under investigation. Finally, the impressive results of CDK4/6 inhibitors in the advanced breast cancer population have led to several trials investigating their application in the (neo)adjuvant setting.
Conclusion
CDK4/6 inhibitors have improved the treatment of women with HR+/HER2-negative advanced breast cancer, but important unanswered clinical questions are: when do we give CDK4/6 inhibitors, and to which patients? The SONIA study aims to determine the optimal treatment sequence by directly comparing first- versus second-line use of CDK4/6 inhibitors. Several other clinical trials are investigating the application of CDK4/6 inhibitors in combination with other therapies, in other breast cancer subtypes and in the (neo)adjuvant setting.