Abemaciclib/Tamoxifen Shows OS Benefit in HR+, HER2- Metastatic Breast Cancer


The addition of tamoxifen to abemaciclib resulted in an improvement in overall survival compared with abemaciclib monotherapy in in patients with hormone receptor–positive, HER2-negative metastatic breast cancer, with benefit observed across all patient subgroups.

Erika Hamilton, MD

Erika Hamilton, MD

The addition of tamoxifen to abemaciclib (Verzenio) resulted in an improvement in overall survival (OS) compared with abemaciclib monotherapy in in patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer, with benefit observed across all patient subgroups, according to results from the final OS analysis of the nextMONARCH trial presented during the 2020 ESMO Virtual Congress.1

The OS analysis was performed 24-months after the last patient entered treatment, with a median follow-up time of 27.2 months. Despite not being powered for testing OS superiority with strong Type 1 error control, results showed a median OS of 24.2 months with the combination versus 17.0 months with 200 mg of abemaciclib (HR, 0.62; 95% CI, 0.40-0.97; P = .0341). The 150-mg dose of abemaciclib showed a longer median OS than the 200-mg dose of the agent, at 20.8 months versus 17.0 months, respectively (HR, 0.96; 95% CI, 0.64-1.44; P = .8321).

“The final OS analysis showed a 7.2-month improvement in OS with the addition of tamoxifen to abemaciclib—24.2 months compared to 17.0 months—when compared to 200 mg of abemaciclib monotherapy,” Erika Hamilton, MD, principal investigator and director of Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon Research Institute said in a presentation during the congress.

The updated median progression-free survival (PFS) was determined to be 9.07 months in the combination therapy arm compared with 7.43 months with the 200-mg dose of abemaciclib (HR, 0.81; 95% CI, 0.56-1.16; P = .2493). The median PFS was 7.2 months with the 150-mg dose versus 7.43 months with the 200-mg dose (HR, 1.06; 95% CI, 0.74, 1.53; P = .7400). The median PFS, although longer in the combination arm, was not determined to be statistically significant.

The addition of CDK4/6 inhibitors to endocrine therapy has emerged as the current standard of care for patients with HR-positive, HER2-negative advanced/metastatic breast cancer, said Hamilton. Currently, abemaciclib is the only continuously-dosed CDK4/6 inhibitor monotherapy drug in its class to be approved by the FDA for patients who have progressed after endocrine therapy or chemotherapy in the metastatic setting.2

In the randomized, open-label phase 2 trial, investigators set out to evaluate abemaciclib, either as a monotherapy or in combination with tamoxifen in heavily pretreated patients with HR-positive, HER2-negative metastatic breast cancer. Additionally, they wanted to examine how effective the combination would be in overcoming endocrine resistance. In a randomized setting, investigators assessed 2 monotherapy doses as well as the use of prophylactic loperamide to reduce the incidence and severity of diarrhea and dose adjustments.

The study population was the same as that of the MONARCH1 study,3 but without prior taxane mandation. To be eligible for participation, patients needed to have previously received 2 or more chemotherapy regimens and 1 or 2 of these therapies must have been received in the metastatic setting. Patients also needed to have measurable disease and an ECOG performance status of 0 or 1. Patients were stratified based on the presence of liver metastases or previous treatment with tamoxifen in the advanced or metastatic setting.

A total of 234 patients were enrolled on the study and they were randomized 1:1:1 to receive either abemaciclib at 150 mg every 12 hours plus tamoxifen at 20 mg once daily (arm A; n = 78), 150 mg of abemaciclib every 12 hours (arm B; n = 79), or 200 mg of abemaciclib every 12 hours plus prophylactic loperamide (arm C; n = 77).

The primary end point of the study was investigator-assessed PFS, and key secondary end points included response rates, OS, and safety. Additional exploratory end points of the trial included understanding the association between biomarkers and clinical outcomes, as well as the relationship between tamoxifen and abemaciclib exposure and response. The time of the data cutoff was June 28, 2019.

Additional results showed that the overall response rate (ORR) was consistent with what had been observed in the primary PFS analysis of the trial. In arm A, the confirmed ORR was 34.6% and the clinical benefit rate was 61.5%. In arm B, these rates were 24.1% and 49.4%, respectively; in arm C, they were 33.8% and 51.9%, respectively.

OS by prespecified subgroup analyses showed a clear trend favoring the combination arm, according to Hamilton. Two arms, however, weren’t shown to favor either regimen or were roughly equal; these included those without liver metastases and those who had less organs involved at baseline.

“I also want to call out that prior tamoxifen in advanced breast cancer, whether that was present or absent, seemed to favor the combination of tamoxifen with abemaciclib,” Hamilton added.

Of the patients who received the combination therapy, 93.6% (n = 73) experienced any grade of treatment-related adverse effects (TRAE), with 43.6% (n = 34) experiencing grade 3 toxicities and 9% (n = 7) experiencing grade 4. Slightly fewer TRAEs were observed in those who received the combination arm compared with those who were given the 150-mg dose of abemaciclib (any grade, 97.5%; grade 3, 45.6%; grade 4, 5.1%) and those given the 200-mg dose plus prophylactic loperamide (any grade, 98.7%; grade 3, 61.0%; grade 4, 10.4%).

The most common any-grade TRAE reported in the combination arm was diarrhea (53.8%; n = 42), although no grade 4 diarrhea was reported across the arms. Additionally, neutropenia was commonly reported in the combination arm (any grade, 42.3%; n = 33), with 20.5% (n = 16) of patients experiencing grade 3 toxicity and 2.6% (n = 2) experiencing grade 4. Patients also experienced anemia on the combination regimen (any grade, 43.6%; grade 3, 12.8%; grade 4, 1.3%).

TRAEs of special interest included venous thromboembolism, a known AE of tamoxifen; this toxicity was experienced at any grade in 10.3% (n = 3) and at grade 3/4 5.1% (n = 4) in the combination arm. These rates were 5.1% and 2.5%, respectively, in the 150-mg abemaciclib arm, as well as 3.9% and 2.6%, respectively, in the 200-mg abemaciclib arm.

Pneumonitis, which has been widely recognized as a risk associated with CDK4/6 inhibitors, was another TRAE of special interest. While no patients in the combination arm experienced this AE, incidences of any grade (1.3% and 1.3%) and grade 3/4 (0% and 1.3%) were reported in the 150 mg cohort and 200 mg cohorts, respectively.

“AEs were consistent with those observed in the primary analysis of the trial and the known safety profile of abemaciclib in practice,” concluded Hamilton. “Incidence and severity of treatment-emergent diarrhea was improved in nextMONARCH, with 9% grade 3 toxicities reported compared with 20% grade 3 toxicity previously reported in MONARCH-1.”


  1. Hamilton E. nextMONARCH : Final overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with HR+, HER2-metastatic breast cancer. Virtual 2020 ESMO Congress; September 19-21, 2020; virtual. Accessed September 19, 2020. Abstract 273O.
  2. Rugo, HS. Achieving improved survival outcomes in advanced breast cancer. N Engl J Med. 2019;381(4):371-372. doi:10.1056/NEJMe1906236
  3. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, A phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218-5224. Doi: 10.1158/1078-0432.CCR-17-0754
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