Now With Survival Benefit, CDK4/6 Inhibitors in Breast Cancer

Alexander M. Castellino, PhD

September 30, 2019

BARCELONA, Spain — Final overall survival (OS) results from the MONARCH 2 and MONALEESA-3 trials show consistent OS benefits with the cyclin-dependent kinase 4/6(CDK4/6) inhibitors abemaciclib (Verzenio, Lilly) and ribociclib (Kisqali, Novartis). The new data establish the foundation for adding these drugs to endocrine therapy in the treatment of patients with hormone receptor positive, human epidermal receptor negative (HR+/HER2-) advanced breast cancer (ABC).

The new results were presented here at the European Society of Medical Oncology (ESMO) 2019 Annual Meeting and were published online September 29 in JAMA Oncology.

The results from MONARCH 2 show that after a median follow-up of approximately 4 years (47.7 months), patients with HR+/HER- ABC lived significantly longer with the combination of abemaciclib and fulvestrant. Median OS was 46.7 months with the combination and 37.3 months with fulvestrant alone (hazard ratio [HR], 0.757; 95% confidence interval [CI], 0.606 – 0.945; P = .0137).

Dr George Sledge

This is a statistically significant and clinically meaningful improvement in OS, commented first author George Sledge, MD, Stanford University School of Medicine, California.

"The main take-home message from this study ― and from other similar studies ― is that CDK4/6 inhibitors significantly prolong the time patients remain in remission and significantly improve overall survival. Therefore, it is very reasonable to think of these as standard-of-care options for patients with metastatic breast cancer," Sledge commented in an ESMO statement.

A similar benefit was seen with the combination of ribociclib and fulvestrant in MONALEESA-3. After a median follow-up of 39.4 months, median OS was not reached with the combination of ribociclib and fulvestrant; it was 40.0 months for patients who received fulvestrant alone (HR, 0.724; 95% CI, 0.568 – 0.924; P = .00455).

Dr Dennis Slamon

"This is a significant, practice-changing report, in that we are now saying that patients with advanced breast cancer will have an overall survival benefit if they get the CDK4/6 inhibitor ribociclib up front at the time of their recurrence, even if they have not had any prior endocrine therapy at the time of presenting with metastatic disease," commented first author Dennis J. Slamon, MD, PhD, from the David Geffen School of Medicine at the University of California, Los Angeles.

Commenting for ESMO, Matteo Lambertini, MD, of the IRCCS Policlinico San Martino Hospital, University of Genoa, Italy, said, "Uniquely, MONALEESA-3 is the only trial with a CDK4/6 inhibitor to include patients with endocrine-sensitive as well as those with endocrine-resistant disease. This is the first time we have seen improved overall survival with a combination of a CDK4/6 inhibitor plus fulvestrant in first line."

The two trials had different patients populations: MONARCH 2 enrolled premenopausal, perimenopausal, and postmenopausal patients, whereas MONALEESA-3 enrolled only postmenopausal patients. However, a separate study (MONALEESA-7, whih included 1400 patients) reported positive OS results for premenopausal women with HR+/HER2- ABC who received ribociclib and fulvestrant. Slamon said that together, the two MONALESSA trials demonstrated a consistent and meaningful benefit with multiple endocrine therapy partners regardless of menopausal status.

New Data Are a "Game Changer"

"These are clinically highly meaningful data and are a game changer," commented ESMO expert Nadia Harbeck, MD, of the Breast Center at Ludwig Maximillians University in Munich, Germany. She was speaking at a press briefing at which the results from both trials had been highlighted.

These data will ensure that CDK4/6 inhibitors become the standard of care in treating patients with HR+/HER- ABC and should be used first line because they substantially improve patient outcomes compared with antihormonal treatment alone, Harbeck commented.

"We can never guarantee that patients will come back for second-line therapy. We should give the best drugs first," she said.

Harbeck was optimistic that, in light of the significant OS benefits, costs of these drugs will be reimbursed and that the drugs will be available for those who need it.

Besides abemaciclib and ribociclib, palbociclib (Ibrance, Pfizer) in combination with endocrine-based therapy is also available for use in the first-line and second-line settings of ABC. However, the OS data for this agent were not statistically significant.

Choosing Which CDK4/6 Inhibitor to Use First

At the press conference, questions were raised as to whether the mechanisms of resistance of the three available CDK4/6 inhibitors overlapped, whether they can be given in sequence, and what would dictate the use of one drug over another.

Slamon indicated that although in clinical practice, physicians have been using CDK4/6 inhibitors in sequence, cross-resistance mechanisms should preclude their being used in sequence after resistance develops.

Sledge noted that not enough patients have been followed for long enough and warned that cross-trial comparisons should not be made. In addition, he pointed out that the HRs from progression-free survival (PFS) and OS are impressive and are similar in the studies. "Primary efficacy does not provide any information on the superiority of one drug over the other," he said, but he suggested that the different toxicity profiles may favor one over the other.

Medscape Medical News asked Laura M. Spring, MD, a breast cancer expert from the Massachusetts General Cancer Center in Boston, Massachusetts, for her views on these data and how she integrates CDK4/6 inhibitors in her clinical practice.

Spring explained that CDK4/6 inhibitors are now given in conjunction with endocrine therapy for HR+/HER2- ABC unless there are toxicity concerns for patients. As an example, she indicated that an older patient with only osseous disease who expresses concerns about the side effects of adding a second agent could be given CDK4/6 in the second line after progression occurs with endocrine monotherapy.

The three CDK4/6 inhibitors are similar in efficacy, but they have distinct side effect profiles, she observed. The incidence of neutropenia is higher with ribociclib and palbociclib, whereas diarrhea is a concern with abemaciclib. QTc prolongation is a possible concern with ribociclib, and patients have to be monitored routinely with electrocardiography, Spring noted.

"That is why choosing one over another may be dictated by the other medicines patients are taking as well as their comorbidities," she said. If a patient is taking medication for QTc prolongation, she would be less likely to receive ribociclib, whereas a patient with gastrointestinal problems would be less likely to receive abemaciclib, she said.

All three agents have shown similar PFS benefit in their respective trials. However, the OS benefit now reported with ribociclib and abemaciclib was statistically significant, whereas that reported for palbociclib was not, although there was a trend showing better survival. That data come from the PALOMA-3 trial, which compared the combination of palbociclib and fulvestrant with fulvestrant for patients whose disease had progressed after initial endocrine therapy.

Despite that, patients who received the combination were at a significantly 28% reduced risk for death or progression, Spring observed.

She suggested that the lack of statistical significance was a detail that would most likely be significant only to a purist, owing to the fact that the benefit of these agents as a class is established.

She also noted that OS was the secondary endpoint for all three studies, that PALOMA-3 was not powered to show significance for OS, and that longer follow-up may be needed.

In addition, the patients in PALOMA-3 were heavily pretreated, which is likely to affect clinical outcomes.

Several experts cautioned against making cross-trial comparisons. "The three studies have key eligibility differences, and cross-trial comparisons are not warranted," Spring said.

Spring told Medscape Medical News that, as a standard of care, a physician in the United States can order any of the three agents, depending on the type of insurance coverage a patient carries. The OS data may provide a boost for abemaciclib and ribociclib, she suggested.

Sledge added that at least in the United States, indications overlap for all three CDK4/6 inhibitors and all are already approved in the second-line setting; thus, reimbursement is not likely to change much. "I think it is more likely that the docs will change. When you have an OS advantage, that changes how we feel about a drug," Sledge told Medscape Medical News.

However, Spring pointed out that palbociclib was the first CDK4/6 inhibitor to be approved, and many physicians have a greater "comfort level" with its use.

Ease of dosing and ease of dose reduction are also factors to take into consideration, she added. Abemaciclib is taken twice daily on a continuous dosing schedule, whereas ribociclib and palbociclib are given once daily on a 3-week-on, 1-week-off schedule. Because of its packaging, it is easier to reduce the dose of ribociclib without writing a new prescription, she observed.

"In prescribing CDK4/6 inhibitors to patients, it is important to discuss with them the differences between the agents, which in large measure are minor," Spring said. "But sometimes a small difference makes a big difference to a patient," she added. Some patients may prefer continuous dosing with abemaciclib, whereas others may discount that factor because the drug has to be taken twice daily, she said.

Spring recommends sequencing with another CDK4/6 agent, ideally only in the context of a clinical trial. In MONARCH 2, Sledge reported that subsequent CDK4/6 therapy was provided to 5.8% of patients who experienced disease progression with abemaciclib and fulvestrant.

More Details From MONARCH 2

MONARCH 2 randomized pre-, peri-, and postmenopausal patients with HR+/HER- ABC to receive abemaciclib twice daily on a continuous dosing schedule in addition to fulvestrant (n = 446) or fulvestrant alone (n = 223). These patients were endocrine-therapy resistant but had received no more than one prior endocrine therapy, and they had received no chemotherapy for ABC.

In addition to the new results for OS, reported above, Sledge also presented updated data for PFS (the primary endpoint). Median PFS was 16.9 months with the abemaciclib combination and 9.3 months with fulvestrant. With a hazard ratio (HR) of 0.536, patients who received the abemaciclib combination were at a significantly 44% decreased risk for progression or death (P <0.0001). Three-year PFS was nearly three times higher with the abemaciclib combination: 29.9% vs 10.1% for patients who received fulvestrant.

"At three years, three times as many patients on the combination remain progression free [compared those who received fulvestrant]," Sledge said.

Time to initiation of chemotherapy was an exploratory endpoint of the study. The abemaciclib combination was associated with a 60% delay in the time to initiation of chemotherapy. Median time to initiation was 22.1 months for fulvestrant, vs 50.2 months for the combination (HR: 0.625; P <0.0001).

Sledge reported that there were no additional safety signals and that the safety profile of abemaciclib was consistent with that reported in the primary analysis.

More Details From MONALEESA-3

MONALEESA-3 randomly assigned 726 patients with HR+/HER2- ABC to receive oral ribociclib on a 3-weeks-on, 1-week-off dosing schedule in addition to fulvestrant (n = 484) or fulvestrant alone (n = 242). Slamon noted that approximately 50% of patients received these therapies in the first-line setting.

Updated data for the primary endpoint of PFS showed that median PFS was significantly longer for patients who received the combination (20.6 months vs 12.8 months for fulvestrant; HR, 0.587).

In addition to the median OS results reported above, Slamon reported that landmark 3-year OS was 67.0% for patients who received the combination and 58.2% for those who received fulvestrant. In this second prespecified analysis, the P value crossed the prespecified boundary for establishing superior efficacy, Slamon observed. The OS benefits were seen across all subsets of patients, including those distinguished on the basis of site of metastases and line of therapy.

"There was a significant delay in time to first chemotherapy," Slamon observed. The median time to first chemotherapy was not reached in patients who received the combination; it was 29.5 months for those who received fulvestrant.

No new safety signals were observed. Slamon reported on the incidence of grade 3/4 adverse events of special interest with the combination (vs fulvestrant):

  • Neutropenia: 57.1% vs 0.8%

  • Hepatobiliary toxicity: 13.7% vs 5.8%

  • Pulmonary disorders: 0.2% vs 0% (no cases of grade 3/4 pneumonitis or interstitial lung disease were reported)

  • QTc prolongation: 3.1% vs 1.2% (no episodes of torsades de pointes were observed)

Improvement in Outcomes

At the meeting, discussant Sibylle Loibl, MD, of the German Breast Group and Goethe University, Frankfurt am Main, Germany, provided some context for the new data.

She noted that each trial had slightly different patient populations. Importantly, patients in MONALEESA-3 were the least heavily pretreated, whereas those in PALOMA-3 were the most heavily pretreated. As the level of pretreatment increased across the trials, the median PFS also decreased, she noted. More heavily pretreated patients will also have a shorter median OS, she noted.

In summarizing the data, Loibl indicated that CDK4/6 inhibitors improved PFS in the first-line and second-line settings of metastatic breast cancer, which translates to an improvement in survival. Improvement in outcomes was seen irrespective of pretreatment, menopausal status, endocrine sensitivity, and site of metastases. A meta-analysis of all the CDK4/6 trials data will likely reveal potential differences in subgroups, she said.

Sledge reports relationships with Eli Lilly, Pfizer, Syndax, Symphogen, Verseau, and Tessa. Slamon reports relationships with Biomarin, Pfizer, Vertex, Lilly, and Novartis. Spring reports relationships with Novartis, Lumicell, Puma, Merck, and Tesaro. Loibl reports relationships with AbbVie, Amgen, AstraZeneca, Celgene, Eirgenix, Novartis, Pfizer, Puma; Roche, Samsung; Seattle Genetics, Teva, Vifor, Daiichi, Cepheid, Myriad, PRIME, and Chugai.

European Society for Medical Oncology (ESMO) 2019 Annual Meeting: Abstracts LBA6_PR (MONARCH 2), LBA7_PR (MONALESSA-3), presented September 29, 2019.

JAMA Oncol. Published online September 29, 2019. Full text

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