Breast Cancer February Journal Scan

INTRODUCTION

In this month's journal scan, our panel reviews:

  1. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer
  2. Biomarker Evaluation in the Phase 3 ASCENT Study of Sacituzumab Govitecan Versus Chemotherapy in Patients With Metastatic Triple-Negative Breast Cancer
  3. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder)

Panel

member photo
Sara Tolaney, MD, MPH

Associate Director, Susan F. Smith Center for Women’s Cancers
Director, Clinical Trials, Breast Oncology
Dana-Farber Cancer Institute
Associate Professor of Medicine
Harvard Medical School

member photo
Bhuvaneswari Ramaswamy, MD, MRCP

Professor and Section Chief- Breast Medical Oncology
The Ohio State University Comprehensive Cancer Center

Publications

Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer
San Antonio Breast Cancer Symposium. 2020 Dec 8-11. Virtual: Abstract GS1-01.

Expert Review

Sara Tolaney, MD, MPH

Title: Primary outcome analysis of invasive disease-free survival for monarchE: Too soon to tell?

Background: Hormone receptor-positive (HR+) breast tumors account for the majority of breast cancer cases. Most patients with HR+ breast cancer are diagnosed with early-stage disease, and are successfully treated with surgery and radiation therapy (sometimes with the addition of chemotherapy), followed by 5-10 years of adjuvant endocrine therapy (ET). Despite this, approximately 20% of patients will experience disease recurrence within the first 10 years after diagnosis.1 Certain clinical and pathologic characteristics have been used to identify patients at high-risk of recurrence, who might benefit from additional adjuvant treatment beyond ET.

Abemaciclib is an oral inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6). In patients with advanced HR+/HER2- breast cancer, abemaciclib in combination with ET has produced significant improvements in progression-free survival (PFS) as well as overall survival (OS) 2,3,4. Accordingly, abemaciclib is FDA approved in combination with ET and as monotherapy for the treatment of advanced HR+/HER2- breast cancer. However, the efficacy of abemaciclib in the adjuvant setting has remained largely unexplored.

Study Design: The open-label, randomized phase III monarchE study5 was designed to investigate the efficacy of adjuvant abemaciclib plus ET in HR+ breast cancer patients at high-risk of recurrence. The trial recruited patients with stage II-III HR+/HER2- breast cancer who were pre- or post-menopausal, with or without prior (neo)adjuvant chemotherapy. High-risk was defined as four or more positive axillary lymph nodes or 1-3 positive axillary lymph nodes along with one of the following features: tumor size > 5 cm, histologic grade 3, or centrally assessed Ki-67 ≥ 20%.

Patients were randomized 1:1 to receive abemaciclib (150 mg twice daily) plus ET or ET alone. Protocol therapy was administered for two years (the treatment period) or until participants met the criteria for discontinuation. After the treatment period, patients continued ET for a total of five or ten years as clinically indicated. The primary study endpoint was invasive disease-free survival (IDFS) according to STEEP criteria.6 Secondary endpoints included distant relapse-free survival (DRFS), OS, safety, pharmacokinetics, and patient-reported outcomes.

The study was powered at approximately 85% to detect the superiority of abemaciclib with ET versus ET alone in terms of IDFS, assuming a hazard ratio (HR) of 0.73 at a cumulative two-sided alpha of 0.05, with a five-year IDFS rate of 82.5% in the ET arm. The threshold for detection was 390 IDFS events in the ITT population at the time of the primary analysis. There were two pre-planned efficacy interim analyses at approximately 50% and 75% of the total required events.

Results: From July 2017 to August 2019, 5,637 patients were recruited into the study. At the second pre-planned interim analysis,5 707 patients (12.5%) had completed the two-year treatment period and 4,101 patients (72.8%) were still in the two-year treatment period. The median follow-up time was approximately 15.5 months in both arms. The 2-year IDFS was significantly higher in the abemaciclib plus ET arm (92.2%) than in the ET arm (88.7%; p = 0.01; HR: 0.75; 95% CI: 0.60-0.93). DRFS was also significantly higher in the abemaciclib plus ET arm (93.6%) than the ET arm (90.3%; nominal p = 0.01; HR: 0.72; 95% CI: 0.56-0.92).

At SABCS 2020, Dr. Priya Rastogi7 presented the results of the primary efficacy analysis, which was triggered by the occurrence of 395 IDFS events in the ITT population (with a data cutoff of July 8, 2020). After a median follow-up of 19.1 months, 1,437 patients (25.5%) had completed the two-year treatment period, and 3,281 patients (58.2%) were still within the two-year treatment period. The 2-year IDFS was 92.3% in the abemaciclib plus ET arm versus 89.3% in the ET arm (nominal 2-sided p = 0009; HR: 0.713; 95% CI: 0.583-0.871). The 2-year DRFS was 93.8% in the abemaciclib plus ET arm versus 90.8% in the ET arm (nominal 2-sided p = 0.0009; HR: 0.687; 95% CI: 0.551-0.858). The 2-year IDFS in the Ki-67-high (≥ 20%) population was 91.6% for patients on abemaciclib plus ET versus 87.1% for ET (2-sided p = 0.0111; HR: 0.691; 95% CI: 0.519-0.920). Safety was consistent with the known profile of abemaciclib and the results from the second interim analysis.5

Conclusions: At the pre-planned primary outcome analysis, the addition of abemaciclib to standard adjuvant ET significantly improved IDFS and DRFS for patients with high-risk HR+/HER2- breast cancer.

Discussion: The positive results from the monarchE trial stand in contrast to two other studies of adjuvant CDK4/6 inhibitors plus ET in HR+/HER2- breast cancer: PALLAS and PENELOPE-B. PALLAS8 is an open-label randomized phase III trial of adjuvant palbociclib plus ET versus ET alone in 5,600 patients with high-risk stage II-III HR+/HER2- breast cancer. The treatment duration was two years, after which patients received standard adjuvant ET. The primary efficacy endpoint was 3-year IDFS in the ITT population. The planned second interim analysis occurred at a median follow-up of 23.7 months, at which point the 3-year IDFS was 88.2% in the palbociclib plus ET arm versus 88.5% for ET alone (log-rank p = 0.51; HR: 0.93; 95% CI: 0.76-1.15). Moreover, the DRFS was 89.3% in the palbociclib plus ET arm versus 90.7% in the ET arm (HR: 1.00; 95% CI: 0.79-1.27; p = 0.9997).

The phase III PENELOPE-B trial9 recruited 1,250 patients with early-stage HR+/HER2- breast cancer without a pathologic complete response (pCR) after neoadjuvant chemotherapy, and at high-risk of recurrence (CPS-EG score ≥ 3 or 2 with one or more positive lymph nodes). Patients were randomized 1:1 to receive one year of palbociclib or placebo plus adjuvant ET, followed by standard adjuvant ET. After a median follow-up of 42.8 months, there were 152 IDFS events in the palbociclib plus ET group versus 156 events in the ET group, for a stratified HR of 0.93 (95% CI: 0.74-1.17; p = 0.525).

There are several factors that could explain the different results between these trials. Abemaciclib is a more potent inhibitor of CDK4 and CDK6 than palbociclib.10 Moreover, abemaciclib is dosed continuously versus a 21-day on, 7-day off schedule for palbociclib. The continuous dosing of abemaciclib might provide an advantage in the form of constant cell cycle inhibition. However, abemaciclib and palbociclib demonstrated fairly similar efficacy in metastatic trials when combined with endocrine therapy, so it is unknown why their activity would be different in the adjuvant setting.10

The discontinuation rate for abemaciclib was 27.7% in monarchE (17.2% due to AEs), which was higher than the discontinuation rate of 19.5% for palbociclib in PENELOPE-B (5.2% due to AEs). In comparison, the PALLAS trial had a much higher palbociclib discontinuation rate of 42.2%.8 This might suggest that a shorter duration of CDK4/6 inhibitor therapy, whether by design (one year of therapy in PENELOPE-B) or early discontinuation (PALLAS), could partially explain the lower efficacy of palbociclib in these two trials. However, additional PALLAS results presented at SABCS 2020 by Dr. Erica Mayer demonstrated a slight but non-significant positive association between palbociclib dose exposure and IDFS.11 This analysis indicates that duration of exposure is not sufficient to explain the lack of efficacy of palbociclib in PALLAS.

The definition of high-risk disease also varies between the studies. For instance, only 58.7% of the patients in the PALLAS trial met the eligibility criteria for inclusion in the monarchE trial. However, palbociclib plus ET did not produce any additional benefit in this high-risk subgroup in the PALLAS trial, which suggests that patient selection does not entirely explain the differences between studies. Moreover, the PENELOPE-B trial uses different criteria to define high-risk (no pCR and the CPS-EG score), which makes it difficult to directly compare these patients to the study populations of monarchE and PALLAS.

The duration of follow-up must also be considered. In the PENELOPE-B trial, at a follow-up of two years, there was a significant difference of 4.3% in IDFS between the palbociclib plus ET arm (88.3%) and the ET arm (84.0%). However, by three years of follow-up the differences were no longer significant, and by four years the IDFS curves had almost completely merged (73.0% for palbociclib plus ET; 72.4% for ET).  At 19.1 months of follow-up, the IDFS difference between the two groups in monarchE is 3.0%, and while it is possible that these curves may remain separated given the perhaps more potent inhibition of cdk4 and the longer duration of treatment, longer follow-up is needed to determine if abemaciclib will have sustained long term benefits even after abemaciclib has been discontinued.12 

References

  1. Early Breast Cancer Trialists' Collaborative G. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet 2015; 386(10001): 1341-52.
  2. Sledge GW, Jr., Toi M, Neven P, et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial. JAMA Oncol 2019.
  3. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017; 35(32): 3638-46.
  4. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 2019; 5: 5.
  5. 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 2020: JCO2002514.
  6. Hudis CA, Barlow WE, Costantino JP, et al. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol 2007; 25(15): 2127-32.
  7. Joyce A. O'Shaughnessy SJ, Nadia Harbeck, Masakazu Toi, Young-Hyuck Im, Mattea Reinisch, Zhimin Shao, Pirkko Liisa Kellokumpu Lehtinen, Chiun-Sheng Huang, Alexey Tryakin, Matthew Goetz, Hope S Rugo, Elzbieta Senkus, Laura Testa, Michael Andersson, Kenji Tamura, Guenther G. Steger, Lucia Del Mastro, JoanneCox, Tammy Forrester, Sarah Sherwood, Xuelin Li, Ran Wei, Miguel Martin, Priya Rastogi. Abstract GS1-01: Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. San Antonio Breast Cancer Symposium; 2020; Virtual; 2020.
  8. Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2021.
  9. Sibylle Loibl FM, Miguel Martin, Michael Untch, Herve Bonnefoi, Sung-Bae Kim, Harry Bear, Nicole Mc Carthy, Mireia Mele Olive, Karen Gelmon, Jose Garcia Saenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Sabine Seiler, Valentina Nekljudova, Carsten Denkert, Michael Gnant, Andreas Makris, Nicole Burchardi, Gunter von Minckwitz. Abstract GS1-02: Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B. San Antonio Breast Cancer Symposium; 2020; Virtual; 2020.
  10. Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer 2019; 5: 27.
  11. Mayer EL FC, Dueck A, Martin M, Burstein H, Prat A, Rubovsky G, Miller K, Pfeiler G, Winer E, Zdenkowski N, Anderson D, Nowetzki Z, Goetz M, Loibl S, Fohler H, Metzger O, Fumagalli D, Theall K, Hlauschek D, Gnant M, DeMichele A. Treatment exposure and discontinuation in the PALLAS trial: PALbociclib CoLlaborative Adjuvant Study of palbociclib with adjuvant endocrine therapy for HR+/HER2- early breast cancer.  San Antonio Breast Cancer Symposium; 2020; Virtual; 2020.
  12. Foldi J, O'Meara T, Marczyk M, Sanft T, Silber A, Pusztai L. Defining Risk of Late Recurrence in Early-Stage Estrogen Receptor-Positive Breast Cancer: Clinical Versus Molecular Tools. J Clin Oncol 2019; 37(16): 1365-9.

 

Biomarker Evaluation in the Phase 3 ASCENT Study of Sacituzumab Govitecan Versus Chemotherapy in Patients With Metastatic Triple-Negative Breast Cancer
San Antonio Breast Cancer Symposium. 2020 Dec 8-11. Virtual: Abstract GS3-06.

Expert Review

Sara Tolaney, MD, MPH

Title: Sacituzumab govitecan versus chemotherapy in metastatic triple-negative breast cancer (ASCENT): how important is Trop-2 expression? Background: Metast...

First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder)
San Antonio Breast Cancer Symposium. 2020 Dec 8-11. Virtual: Abstract GS3-00.

Expert Review

Bhuvaneswari Ramaswamy, MD, MRCP

Can we forgo chemotherapy in select node-positive hormone receptor positive, HER2 negative breast cancer patients? Title: RxPONDER: A Clinical Trial Rx for ...

Additional Breast Cancer February Publications

A comprehensive literature review of patient-reported outcome measures (PROMs) among common breast reconstruction options: What types of breast reconstruction score well?
CONCLUSIONS: In this comprehensive systematic review, oncoplastic surgery showed the most favorable PROMs when compared to other reconstructive modalities. Autologous was preferred over implant-based reconstruction, and prepectoral was preferred over subpectoral implant placement.

Impact of Facility Surgical Volume on Survival in Patients With Cancer
CONCLUSIONS: Patients treated surgically at higher-volume facilities consistently had improved overall survival compared with those treated at low-volume centers, although the magnitude of difference was cancer-specific.

Time Trends in Receipt of Germline Genetic Testing and Results for Women Diagnosed With Breast Cancer or Ovarian Cancer, 2012-2019
CONCLUSION: A testing gap persists for patients with ovarian cancer (34.3% tested v nearly all recommended), whereas adding more genes widened a racial or ethnic gap in VUS results. Most PVs were in 20 breast cancer-associated genes or ovarian cancer-associated genes; testing other genes yielded mostly VUS. Quality improvement should focus on testing indicated patients rather than adding more genes.

Association between BRCA mutational status and survival in patients with breast cancer: a systematic review and meta-analysis
CONCLUSION: BC patients with BRCA 1 or BRCA 2 mutations had poor survival outcomes and hence screening patients with BC for BRCA mutations might help in strategizing their treatment and improving their survival.