Critical view of CDK4/CDK6 inhibitors clinical trials

James Fleck, MD, PhD & Marco A A Azeredo, MD: Anticancerweb 08 (12), 2021

Breast cancer has recently become the leading cause of global cancer incidence, contributing to 2.3 million new cases. Despite important improvements in early diagnosis and advances in treatment, breast cancer is still the fifth leading cause of cancer mortality worldwide. Breast cancer incidence increases with advancing age. In premenopausal woman the ASR is 34.3 and 30.5 in US and Europe, respectively. In postmenopausal woman the ASR increases to 305.7 and 297.9 in US and Europe, respectively. Using absolute numbers, breast cancer is predominantly (75%) diagnosed in postmenopausal woman (≥50 years) both in US and Europe. Median age for breast cancer diagnosis in US is 61 years-old. Figure 1 shows the number (n) of breast cancer diagnosed in US according to menopausal status and the US relative distribution of breast cancer molecular subtypes. 

In US, most of the patients are luminal subtypes (68%), expressing a cluster of genes associated to hormone receptor positive (HR+) cells. Despite better prognosis, roughly a third of HR+HER2- early breast cancer patients will relapse. Historically, these patients have been treated with hormone therapy both in palliative and adjuvant scenario. More recently, CDK4/CDK6 inhibitors have been used to overcome endocrine resistance in HR+HER2- metastatic breast cancer. Seven phase III prospective randomized trials have been published evaluating the impact of CDK4/ CDK6 inhibitors in palliative first- and second-line treatments. Data are provided in table 1. 

All trials have shown significant benefit in progression free-survival. Some also demonstrated benefit in median overall survival (m-OS). Five studies were design for post-menopausal women, one for pre and peri-menopausal women (Monaleesa-7) and one for any menopausal status (Monarch-2). Improvement in clinical outcomes were observed regardless the menopausal status. A recent update of the pre-menopausal subgroup of the Monarch-2 trial showed a numerical overall survival favoring the combined use of abemaciclib + fulvestrant compared to fulvestrant alone (HR 0.69). Improvements were also observed in exploratory outcomes, like time to second disease progression, time to chemotherapy and chemotherapy-free interval. Nevertheless, these favorable results have not been uniformly transferred to the adjuvant setting. Table 2 shows data from the three major phase III adjuvant prospective randomized trials.

In early breast cancer, the combined use of standard adjuvant endocrine therapy with Abemaciclib (Monarch-E) resulted in significant and clinically meaningful improvement. However, the combined use of adjuvant hormone treatment with Palbociclib in the Pallas trial derived no benefit. Likewise, in the Penelope-B trial, Palbociclib did not show benefit after neoadjuvant chemotherapy. The conflicting outcomes could be explained by selection bias, since stage III and N2 patients were more frequent in Monarch-E than in Pallas trial. Despite both being CDK4/CDK6 inhibitors, the two drugs have important pharmacokinetic differences. But, the main challenge for all clinical trials is related to the genomic heterogeneity of HR+HER2- breast cancer patients. Although luminal A and B molecular subtypes shared some similarities, next-generation sequencing (NGS) has revealed differences in specific oncogenic drivers. The Cancer Genome Atlas (TCGA) Network initiative provided several molecular characteristics distinguishing luminal A and B breast cancer phenotypes. Luminal B tumors expresses higher frequency of TP53 mutation (29% versus 12%) and lower frequency of PIK3CA mutation (29% versus 45%) when compared to luminal A subtype. Clinical useful surrogate markers correlates Luminal B breast cancer with lower expression of hormone receptors, higher proliferative index (Ki67) and higher histologic grade, when compared to luminal A molecular subtype. These differences are responsible for luminal B worse prognosis and distinct response to hormonal treatment and chemotherapy. Gene expression signatures (Oncotype-DX and MammaPrint) usually classify luminal A tumors as low genomic risk, whereas luminal B tumors are often classified as high genomic risk. Breast cancer showing high recurrence score (RS ≥ 31) derives larger benefit from adjuvant and neoadjuvant chemotherapy and lower benefit from adjuvant hormone therapy. Additionally, cycle-dependent kinase (CDK) deregulation is associated to a higher proliferative cellular phenotype and is also linked to endocrine resistance. The encoding gene for cyclin D1 (CCND1) amplification is predominantly found in luminal B (58%) when compared to luminal A subtype (29%). Luminal B subtype also expresses cyclin E2, which is also correlated to shorter progression-free survival. 

The ebb and flow of CDK4/CDK6 inhibitors in HR+HER2- early breast cancer adjuvant trials will only stop after using more strict and selective genomic criteria in defining the target population.

ASR = Age-Standardized Risk

References:

1.     Global Cancer Observatory: International Agency for Cancer Research (IARC) of the World Health Organization, 2020

2.     Cancer Statistics Center: American Cancer Society, 2021

3.     S.-A. Im, Y.-S. Lu, A. Bardia, et al: Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer, N Engl J Med 381: 307-316, 2019

4.     Richard S. Finn, Miguel Martin, Hope S. Rugo, et al: Palbociclib and Letrozole in Advanced Breast Cancer, N Engl J Med 375:1925-36, 2016

5.     G.N. Hortobagyi, S.M. Stemmer, H.A. Burris, et al: Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer, N Engl J Med 375:1738-48, 2016

6.     Stephen Johnston, Joyce O’Shaughnessy, Miguel Martin, et al: Abemaciclib as initial therapy for advanced breast cancer: MONARCH 3 updated results in prognostic subgroups, Breast Cancer 7:80, 2021

7.     Dennis J. Slamon, Patrick Neven, Stephen Chia, et al: Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer, N Engl J Med 382:514-24, 2020

8.     Jason Harris: Palbociclib Plus Fulvestrant Combo Maintains Long-Term OS Benefit, ASCO Annual Meeting – Breast cancer, June 5, 2021

9.     George W. Sledge, Jr., Masakazu Toi, Patrick Neven, et al: MONARCH 2: Abemaciclib in Combination with Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy, J Clin Oncol 35:2875-2884, 2017

10.   Stephen R. D. Johnston, Nadia Harbeck, Roberto Hegg, et al: Abemaciclib Combined with Endocrine Therapy for the Adjuvant Treatment of HR1, HER22, Node-Positive, High-Risk, Early Breast Cancer (monarchE), J Clin Oncol 38:3987-3998, 2020

11.   Erica L Mayer, Amylou C Dueck, Miguel Martin, 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 22: 212-22, 2021

12.   Sibylle Loibl, Frederik Marmé, Miguel Martin,et al: Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial, J Clin Oncol May 10, 39 (14): 1518-1530, 2021

13.   Felipe Ades, Dimitrios Dardavas, Ivana Bozovic-Spasojevic, et al: Luminal B Breast Cancer: Molecular Characterization, Clinical Management, and Future Perspectives, J Clin Oncol 32: 2794-2803, 2014

14.   Binghe Xu, Ying Fan: CDK4/6 inhibition in early-stage breast cancer: how far is it from becoming standard of care? Lancet Oncol, Feb, 2021