From the Journals

Meta-analysis supports hormone therapy-targeted therapy combo for advanced breast cancer

View on the News

CDK4/6 inhibitors may give chemotherapy the boot

“This meta-analysis solidifies an increasingly accepted role for CDK4/6 inhibitors in the upfront treatment of postmenopausal women with hormone receptor–positive, HER2-negative metastatic breast cancer,” Azadeh Nasrazadani, PhD, MD, and Adam M. Brufsky, MD, PhD, wrote in an editorial published in Lancet Oncology. “These agents are starting to displace more toxic chemotherapy agents as frontline treatments for estrogen receptor–positive metastatic breast cancer in general practice because of, to some extent, their similar efficacy with substantially more favorable side-effect profiles.”

Nonetheless, chemotherapy still has a role in this population, typically in the later-line setting and in patients experiencing a visceral crisis, they noted. However, the better overall response rate seen with a chemotherapy regimen (paclitaxel plus bevacizumab), compared with a combination targeted and hormonal therapy regimen (palbociclib plus letrozole), may hinge on the specific CDK4/6 inhibitor. “Future studies are needed to identify the appropriate setting and sequence for chemotherapy in these patients,” they maintained.

Outcomes were similar for comparable regimens containing the three currently approved CDK4/6 inhibitors, but individual resistance mechanisms have yet to be elucidated, according to Dr. Nasrazadani and Dr. Brufsky. In addition, it is unclear how these agents may affect duration of response to subsequent therapies, as evidence of a broad overall survival benefit is lacking.

“With the ever-increasing range of targeted therapies gaining approval for metastatic breast cancer, the clinical and research community continues to move further away from a monotherapy approach,” they concluded. “Trials are currently in progress evaluating the role of inhibitors of phosphoinositide 3-kinase, mammalian target of rapamycin, and MEK, among others. How these agents will compare to previously frontline chemotherapy, and whether we will gain more success with the combinations of these targeted therapies in addition to CDK4/6 inhibitors remains to be seen.”

Dr. Nasrazadani is a fellow in the division of hematology/oncology at the University of Pittsburgh Medical Center–Magee-Women’s Hospital. Dr. Brufsky is associate chief of the division of hematology/oncology and codirector of the Comprehensive Breast Cancer Center at Magee-Women’s Hospital. Dr. Brufsky reported receiving personal fees from numerous pharmaceutical companies; Dr. Nasrazadani reported no conflicts of interest.



Combined hormone therapy and targeted therapy should be the first choice for most postmenopausal women with recently diagnosed hormone receptor–positive, HER2-negative metastatic breast cancer, new data suggest.

Although guidelines support use of hormone therapies with or without targeted therapies in this population, up-front chemotherapy is still commonly used even in the absence of a visceral crisis, noted lead investigator Mario Giuliano, MD, PhD, of the department of clinical medicine and surgery at the University of Naples (Italy) Federico II, and colleagues.

The investigators undertook a systematic review and network meta-analysis of 140 randomized, controlled trials among 50,029 postmenopausal patients with hormone receptor–positive, HER2-negative metastatic breast cancer treated in the first- and/or second-line setting.

Study results, reported in Lancet Oncology, showed that relative to standard hormone therapy alone, the combination of hormone therapy with a targeted therapy – a CDK4/6 inhibitor, an mammalian target of rapamycin inhibitor, or an indicated phosphoinositide 3-kinase inhibitor – had significantly better efficacy, reducing the risk of progression-free survival events by more than half. In addition, no chemotherapy regimen, with or without targeted therapy, significantly outperformed the combination of hormone therapy with a CDK4/6 inhibitor.

Meanwhile, the hormone therapy–targeted therapy combinations had manageable toxicity, with the severity of adverse effects intermediate between that of hormone therapy alone and that of chemotherapy with or without targeted therapies.

“This study is, to our knowledge, the first to compare the efficacy and activity of all currently available chemotherapy and hormone therapy regimens, in combination with or without targeted therapies,” Dr. Giuliano and coinvestigators wrote. “[O]ur results corroborate the treatment algorithms recommended by the official oncology guidelines, supporting the use of new combinations of hormone therapies plus targeted therapies in the first-line or second-line setting in patients with hormone receptor-positive, HER2-negative metastatic breast cancer without visceral crisis.”

For the study, the investigators identified relevant phase 2 and phase 3 randomized, controlled trials published between 2000 and 2017, with the addition of several recently reported trials such as BOLERO-6 (JAMA Oncol. 2018;4:1367-74). Of the 140 trials ultimately included, 114 were used in the analysis of progression-free survival and time to progression, and 135 were used in the analysis of overall response.

Study results showed that when anastrozole (Arimidex) alone was the comparator, progression-free survival was significantly better with palbociclib (Ibrance) plus letrozole (Femara) (hazard ratio for events, 0.42); ribociclib (Kisqali) plus letrozole (HR, 0.43); abemaciclib (Verzenio) plus anastrozole or letrozole (HR, 0.42); palbociclib plus fulvestrant (Faslodex) (HR, 0.37); ribociclib plus fulvestrant (HR, 0.48); abemaciclib plus fulvestrant (HR, 0.44); everolimus (Afinitor) plus exemestane (Aromasin) (HR, 0.42); and, in patients with a PIK3CA mutation, the PI3K inhibitor alpelisib (Piqray) plus fulvestrant (HR, 0.39).

Several chemotherapy-based regimens, including anthracycline- and taxane-containing regimens, were also superior to anastrozole alone (hazard ratios, 0.41-0.47).

When palbociclib plus letrozole was the comparator, no chemotherapy or hormone therapy regimen yielded significantly better progression-free survival.

For the outcome of overall response, paclitaxel (Taxol) plus bevacizumab (Avastin) was the only clinically relevant regimen that significantly improved the likelihood of response relative to palbociclib plus letrozole (odds ratio, 8.95).

Dr. Giuliano reported that he receives honoraria from Amgen, AstraZeneca, Celgene, Eisai, Eli Lilly, Novartis, Pfizer,and Roche. The study did not receive any funding.

SOURCE: Giuliano M et al. Lancet Oncol. 2019 Sep 4. doi: 10.1016/S1470-2045(19)30420-6.

Next Article: