Long-term Data for CDK4/6 Inhibitors Solidify Role in Firstline HR+/HER2- Breast Cancer

Oncology Live®Vol. 23/No. 16
Volume 23
Issue 16
Pages: 32

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CDK4/6 inhibitors have carved out a substantial role in the treatment of patients with hormone receptor–positive, HER2-negative breast cancer.

Komal Jhaveri, MD

Komal Jhaveri, MD

CDK4/6 inhibitors have carved out a substantial role in the treatment of patients with hormone receptor–positive, HER2-negative breast cancer. The first approval of palbociclib (Ibrance) launched a series of trials examining the efficacy of agents in the frontline setting for these patients both as monotherapy and in combination with aromatase inhibitors (AIs).

Hope S. Rugo,  MD, FASCO

Hope S. Rugo, MD, FASCO

During the panel discussion breast cancer experts contextualized how longer-term, retrospective, and realworld data presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and the European Society for Medical Oncology (ESMO) Breast Cancer Congress 2022 are continuing to drive clinical improvements for these patients. “It’s an exciting time to hear about the advances we’re making in this most common subset of breast cancer, the most common cancer worldwide in women,” moderator Hope S. Rugo, MD, FASCO, said.

CDK4/6 Inhibitors Hold Strong In First Line

The 2022 ASCO Annual Meeting featured updates from several key trials of CDK4/6 inhibitors for the treatment of patients with advanced hormone receptor–positive, HER2-negative metastatic breast cancer. Patient selection for this therapy accounts for several factors, but Anne P. O’Dea, MD, said that most of the patients she treats in this setting will receive a CDK4/6 inhibitor. “The overwhelming totality of data that was [is available] really supports the use of a first-line CDK4/6 [inhibitor],” she said. “It’s really a very rare patient in whom I’m not using that in the first line; perhaps an elderly patient in a skilled nursing facility where it’s very cumbersome for her to have laboratory monitoring. However, outside of a situation like that, I’m using a CDK4/6 [regimen] in all my patients.”

Anne P. O’Dea, MD

Anne P. O’Dea, MD

Although, cross-study comparisons and head-to-head trials are not feasible for these agents, investigators conducted a match- adjusting indirect comparison (MAIC) study of quality-of-life (QOL) outcomes for ribociclib plus an aromatase AI vs abemaciclib plus AI in the first-line treatment of this patient population.4

“I thought this was an interesting paper because biostatisticians have always taught us not to do cross-trial comparisons, and yet they come up with this novel technique of MAICs. They can do just that using QOL data,” Mark Pegram, MD, said. “In this case, they use the EORTC QLQ-C30 [European Organization for Research and Treatment of Cancer QOL] metric as well as the BR23 [EORTC-breast-cancer specific QOL] questionnaires. Using this statistical method, they were able to compare the difference in adverse event [AE]/patient- reported outcomes with these metrics.”

Mark Pegram, MD

Mark Pegram, MD

Specifically, the trial compared outcomes from the phase 3 MONALEESA-2 (NCT01958021) and MONARCH 3 (NCT02246621) trials evaluating ribociclib and abemaciclib, respectively. Matching and weighting of individual patient data was performed and 205 and 149 patients in the ribociclib and placebo arms for MONALEESA-2 were matched to 328 and 165 patients in the corresponding arms of MONARCH-3.

Time to first symptom deterioration (TTSD) was significantly better in terms of appetite loss (HR, 0.46; 95% CI, 0.27-0.81), diarrhea (HR, 0.42; 95% CI, 0.23-0.79), fatigue (HR, 0.63; 95% CI, 0.41-0.96) and arm symptoms (HR, 0.49; 95% CI, 0.30-0.79) in those who received the ribociclib-containing regimen vs the abemaciclib regimen. These AEs have been identified by patients as having a moderate to severe effect on their QOL.

“None of this comes as any surprise,” Pegram said. “It’s gratifying to see that the patient-reported outcomes match the investigator-reported data that’s already been published and approved by the FDA for both drugs. [The results] met what I expected, having used these drugs and heard my patients tell me about their experience. That’s gratifying, and I thought the methods were very interesting and novel to allow this kind of cross-trial comparison where a head-to-head trial is simply not available.”

Rugo noted that overall survival (OS) outcomes for abemaciclib are still maturing, but that progression-free survival (PFS) data have demonstrated significant clinical benefit.

A Closer Look at Ribociclib

Updated OS results from MONALEESA-3 (NCT02422615), which evaluated ribociclib in the first line setting for postmenopausal patients with advanced hormone receptor–positive, HER2-negative advanced breast cancer, were presented at the ESMO Breast Cancer Congress 2022.5

At a median follow-up of 70.8 months, patients who received ribociclib plus fulvestrant (n = 484) had a median OS of 67.6 months vs 51.8 months among those who were given fulvestrant/placebo (n = 242; HR, 0.67; 95% CI, 0.50-0.90). The 5-year OS rates were 56.5% vs 42.1%, respectively. The experimental combination also delayed time to second disease progression and improved chemotherapy-free survival vs placebo plus fulvestrant (TABLE).5

“That [survival is] more than 5 years—an OS we’ve never seen before—as compared with the control group, which was about 51 months,” Pegram said. “This corresponded to a hazard ratio of 0.67. Clear OS advantage is seen with ribociclib plus fulvestrant in the first-line setting.” Dose reductions with ribociclib were another topic of discussion for the panel. Data from a poster presented during the 2022 ASCO Annual Meeting showed that dose modifications of ribociclib did not demonstrate a negative effect on OS in MONALEESA-2. Trial protocol allowed reductions to 400 mg or 200 mg per day to manage treatment related-AEs.6

TABLE. Outcomes in MONALEESA-3

TABLE. Outcomes in MONALEESA-3

Among the 334 evaluable patients, 125 did not require a dose reduction (37.4%), 124 patients required 1 reduction (37.1%), 76 required 2 (22.9%), and 9 required more 3 or more (2.7%). The median OS among those who had at least 1 reduction 3 months into treatment was 63.1 months compared with 65.7 months among those with 0 reductions during that time frame (HR, 0.96; 95% CI, 0.68-1.36).6

“In the poster discussion at ASCO 2022, [an audience member] asked, ‘Why don’t you just start at a lower dose? Why start at a higher dose, after all?’ ” Rugo said. “I thought: Why not just start at the full dose because you can dose-reduce so easily?”

Pegram agreed, saying, “Unless we have randomized data, 400 mg vs 600 mg, I would not start with 400 mg. I would start with 600 mg, but if a patient has an AE, particularly neutropenia, I feel comfortable reducing to 400 mg.”


Data presented at the 2022 ASCO Annual Meeting did not demonstrate a significant improvement with palbociclib plus letrozole vs letrozole alone in the phase 3 PALMOA-2 trial (NCT01740427).7

At the November 15, 2021, data cutoff, at a median follow-up of 90 months, patients who received the CDK4/6 inhibitor palbociclib plus letrozole (n = 444) had a median OS of 53.9 months (95% CI, 49.8-60.8) compared with 51.2 months (95% CI, 43.7-58.9) for patients who received placebo plus letrozole (n = 222; HR, 0.956; 95% CI, 0.777-1.777; P = .3378). However, in a post-hoc sensitivity analysis that adjusted for missing survival data, the median OS for patients treated with the combination (n = 385) was 51.6 months (95% CI, 46.9-57.1) compared with 44.6 months (95% CI, 37.052.3) for the 175 patients in the control arm (HR, 0.869; 95% CI, 0.706-1.069). The median duration of treatment was 22.0 months and 13.8 months, respectively.

“We saw the long-awaited survival data from PALOMA-2 with disappointing results. There was no difference in the OS, but there were several unique characteristics of PALOMA-2 that are worth keeping in mind,” Rugo said. “One is it’s the only trial in the first-line setting that included patients who had a disease-free interval [DFI] from early- to late-stage disease of less than 12 months. That represented about one-third of the population. In that group of patients, when you look at a forest plot and divide the numbers up, they didn’t clearly have a survival benefit, but among those with a DFI of greater than 12 months—the OS numbers are close to first-line ribociclib and an AI, being well over 60 months.” Specifically, among patients with a DFI greater than 12 months, the median OS was 64.0 months (95% CI, 49.2-73.4) vs 44.6 months (95% CI, 37.0-53.2) with letrozole alone (HR, 0.736; 95% CI, 0.551-0.982).7

Both arms of the trial had significant amounts of missing survival data, Rugo noted. Results were missing for 59 patients in the palbociclib plus letrozole arm and for 47 patients in the letrozole monotherapy. Most patients in both arms had died at the time of the analysis (62% and 60%, respectively). Patients were still alive at a rate of 25% and 19%, respectively. “A lot of patients withdrew consent for reasons that are unclear, and so they just didn’t have survival data on those patients, unfortunately,” she said.

Aditya Bardia,  MD, MPH

Aditya Bardia, MD, MPH

“PALOMA-1 [NCT00721409] opened the field of CDK4/6 inhibitors,” Aditya Bardia, MD, MPH, said. “Since then, we’ve had several studies. In terms of why the results of PALOMA-2 were negative [although] we are seeing positive results from MONALEESA-2, MONALEESA-3, MONALEESA-7 [NCT02278120], and MONARCH-2, I think this could be differences in study populations [or other causes]. The DFI [subset] was different, the results looked similar. The second possibility is what happened after the patients had disease progression on first-line therapy. That was not controlled, so there could be some imbalances in the placebo vs the palbociclib arm. The third possibility is that there are some differences in the drug; it’s just impossible to know without head-to-head trial comparison.”

O’Dea noted that in clinical practice she has observed patients exhibiting prolonged clinical benefit on palbociclib. “If we look at the entire PALOMA series, we see the dramatic efficacy of this drug; 10% of patients continue on palbociclib at 7.5 years,” she said. “I certainly have a couple of patients in my own clinic that started the drug in February of 2015 and remain on the drug today. Clearly, it’s an effective agent…. There are a lot of nuances to this.”

Bardia agreed adding that although the PALOMA-2 data were not significant, if a patient is currently on palbociclib, he would feel very comfortable continuing treatment. However, for new patients with metastatic disease, he would consider the evidence from other trials in treatment selection.

Will Real-World Outcomes Inform Future Directions?

In selecting between agents in the first-line setting, Pegram said that there are 2 vantage points when reviewing the data: clinical vs scientific. “From a clinical perspective, we have level 1 evidence from a randomized, controlled phase 3 trial of an OS benefit that’s statistically significant in the case of the first-line ribociclib plus AI. That is the gold standard for clinical decision-making. For clinical decisions, that’s impactful to me,” he said. “The other perspective I like to look at this data set from is more from a scientific point of view. From that point of view, things are a little bit less clear.”

Considering real-world data may shine a light on certain pathways forward for patients in this setting. “We talked about patient populations in clinical trials, which is always going to be contrived; there’s no way around it,” Rugo said, adding that inclusion criteria for different trials have a huge effect on outcomes. “You really are treating a different patient population [in the clinic] with a different biology of tumor in many situations. There’s quite a lot of real-world data on CDK4/6 inhibitors and then there’s also some data about how AEs are managed in routine clinical practice.”

At the ESMO Breast Cancer Congress 2022, Rugo presented a poster on the real-world outcomes for patients treated with palbociclib plus endocrine therapy.8 In a retrospective analysis 1324 patients were identified for palbociclib plus endocrine therapy vs 1564 with an AI alone. The median OS was 53.4 (95% CI, 48.7-58.6) vs 40.4 months (95%CI, 36.3-44.9), respectively (HR, 0.67; 95% CI, 0.600.76; P < .0001).

“If you look at the results, they are quite similar to the other clinical trials with ribociclib and even abemaciclib in the sense that you see an improvement in OS,” Bardia said “We must be careful in terms of interpreting real-world data. It was not a randomized trial. But at least there’s evidence that it improved OS.”

Data from another retrospective study, REACH AUT, showed that the efficacy of ribociclib was similar to outcomes observed in in the MONALEESA trials. At a median follow-up of 14.4 months, 283 patients treated with ribociclib plus endocrine therapy. The median PFS was 29.7 months, and the 12-month OS rate was 90.3%. Data for median OS were immature.9

In reviewing all the data, treatment selection in clinical practice may lean heavier on the level 1 evidence and individual patient situations for the time being. “When we look at these trials, they were powered for the primary end point of PFS and if you look at the [Kaplan-Meier] curves they are nearly identical with identical hazard ratios,” Jhaveri said. “It’s very frustrating in some ways to then go back and say OK but now we’re not seeing OS benefit in one study but we’re seeing it in other. Are there significant differences that can explain the difference between the 2 agents?”

She added that there are differences in trial structure as well as toxicity profiles, but even with early MAIC analyses, it is not clear if that can translate into a significant clinical effect in terms of the difference in OS. “For me, I will have a patient in front of me, discuss the toxicity profiles, look at their comorbid conditions, what kind of medications they’re already taking concomitantly; and assess what would result in terms toxicity [with a given treatment].”

“Ultimately, a good balance of tolerability, QOL, and the efficacy data as we have; we can have a discussion with our patient.”


  1. Verzenio. Prescribing information. Eli Lilly and Company; 2021. Accessed August 9, 2022. bit.ly/3BUraOU
  2. Kisqali. Prescribing information. Novartis Pharmaceuticals Corporation; 2021. Accessed August 9, 2022. bit.ly/3PkgEHu Ibrance. Prescribing information. Pfizer, Inc; 2019. Accessed August 9, 2022. bit.ly/3BRKiAA
  3. Rodriguez C, Kaufman JL, Laubach J, et. al. Quality of life (QOL) with ribociclib (RIB) plus aromatase inhibitor (AI) versus abemaciclib (ABE) plus AI as first-line (1L) treatment (tx) of hormone receptor-positive/ human epidermal growth factor receptor–negative (HR+/HER2−) advanced breast cancer (ABC), assessed via matching-adjusted indirect comparison (MAIC). J Clin Oncol. 2022;40(suppl 16):1015. doi:10.1200/JCO.2022.40.16_suppl.1015
  4. Neven P, Fasching PA, Chia S, et al. Updated overall survival (OS) results from the first-line (1L) population in the phase III MONALEESA-3 trial of postmenopausal patients (PTS) with HR+/ HER2− advanced breast cancer (ABC) treated with ribociclib (RIB) + fulvestrant (FUL). Ann Oncol. 2022;33(suppl 3):S194. doi:10.1016/j. annonc.2022.03.280
  5. Hart L, Bardia A, Beck T, et al. Impact of ribociclib dose modifications on overall survival in patients with HR+/HER2– advanced breast cancer in MONALEESA-2. J Clin Oncol. 2022;40 (suppl 16):1017. doi:10.1200/JCO.2022.40.16_suppl.1017
  6. Finn RS, Rugo HS, Dieras VC, et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/ HER2− ABC): analyses from PALOMA-2. J Clin Oncol. 2022;40(suppl 17):LBA1003. doi:10.1200/JCO.2022.40.17_suppl.LBA1003
  7. Rugo HS, Brufsky A, Liu X, et al. Overall survival with first-line palbociclib plus an aromatase inhibitor (AI) vs AI in metastatic breast cancer: a large real-world database analysis. Ann Oncol. 2022;33(suppl 3):S202. doi:10.1016/j.annonc.2022.03.188
  8. Singer CR, Egle D, Greil R, et al. REACH AUT: efficacy and safety of first-line (1L) ribociclib (RIB) + endocrine therapy (ET) in HR+, HER2- metastatic breast cancer (MBC) from a real-world (RW) study: 3rd interim analysis. Ann Oncol. 2022;33(suppl 3):S217. doi:10.1016/j. annonc.2022.03.214
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