Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer The New england journal of medicine JULY 16, 2015 Nicholas C. Turner, M.D., Ph.D., Jungsil Ro, M.D., Fabrice André, M.D., Ph.D., Sherene Loi, M.D., Ph.D.,Sunil Verma, M.D., Hiroji Iwata, M.D., Nadia Harbeck, M.D., Sibylle Loibl, M.D., Cynthia Huang Bartlett, M.D., Ke Zhang, Ph.D., Carla Giorgetti, Ph.D., Sophia Randolph, M.D., Ph.D., Maria Koehler, M.D., Ph.D.,and Massimo Cristofanilli, M.D. 내과 R3 문정락/IH prof. 백선경 수요저널 발표를 시작하겠습니다. 본저널은 2015년 7월 16일 NEJM 에 실린 논문으로 hormone receptor positive advanced breast cancer 에서 palbociclib 의 safety 와 eficacy 에 대해 연구한 논문입니다.

Back Ground Approximately 80% of breast cancers express estrogen receptors, progesterone receptors, or both. Endocrine therapies are the mainstay of treatment for these hormone receptor–positive cancers, substantially reducing the relapse rate after presentation with early-stage cancer. Despite advances in endocrine therapy, many women have a relapse during or after completing adjuvant therapy. Back round 보시겠습니다. 80%의 breast cancer 에서 estrogen 이나 progesterone receptor 하나 또는 둘 모두가 양성으로 나타납니다. 이러한 hormone receptor positive breast cancer 에서 endocrine therapy 는 가장 main 이 되는 치료이며 주로 early stage cancer 에서 relapse rate 를 줄여주는데 큰 역할을 한다고 알려져 있습니다. 그러나 이러한 치료에도 불구하고 endocrine therapy 도중이나 후에 cancer 가 relapse 되는 경우가 많이 나타나서 이러한 여성들의 endocrine therapy 후에 치료에 대해서는 아직 연구가 진행중에 있습니다.

The selective estrogen-receptor degrader fulvestrant has modest activity in this population of patients and the development of effective therapies that can reverse resistance to endocrine therapy is of clinical importance. Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which are activated by D-type cyclins, promote cell-cycle entry by phosphorylating Rb (retinoblastoma protein), among other proteins, to initiate transition from the G1 phase to the S phase Estrogen receptor 의 selective antagonist 인 fulvestrant 는 이러한 환자들에게 어느정도의 효과가 있는 것으로 알려져있고 endocrine therapy 에 대해 reverse resistance 를 가지는 효과적인 therapy 를 개발하는 것은 매우 중요한 사안입니다. CDK4,6 는 Rb protein 을 phosphorylating 해서 cell cycle 의 entry 를 promote 시키는 으로 D-type 의 cyclin 을 activation 시켜 cell cycle 의 G1 phase 에서 S phase 로의 진행을 하게 하는 역할을 합니다.

Multiple oncogenic signals in hormone receptor–positive breast cancer converge to promote expression of cyclin D1 and activation of CDK4 and CDK6 to drive breast-cancer proliferation. In vitro evidence suggests that breast cancer that has developed resistance to prior endocrine therapy remains dependent on cyclin D1–CDK4 to promote proliferation. Hormone receptor positive breast cancer 에서 multiple oncogenic signal 들은 모두 이러한 CDK4-6 의 활성화나 cyclin D1 의 expression 에 집중되어 있습니다. 그리고 endocrine therapy 에 대해 resistance 를 보이는 것은 proliferation 을 증진 시키는 cyclin D1- CDK4 에 달려 있다고 실험적으로 증명되었습니다.

Palbociclib (Ibrance, Pfizer) is an orally bioavailable small-molecule inhibitor of CDK4 and CDK6, with a high level of selectivity for CDK4 and CDK6 over other cyclin-dependent kinases. It has high activity in hormone-receptor–positive breast cancer cell lines and is synergistic in combination with endocrine therapies Palbociclib 이라는 약재는 CDK4-CDK6 를 inhibition 시키는 경구로 복용할 수 있는 약으로 CDK4-6 에 대해서 selectivity 가 높습니다. 그래서 hormone receptor positive breast cancer 에서 endocrine therapy 와 synergistic effect 가 기대되었습니다.

The PALOMA3 trial assessed the safety and efficacy of the combination of palbociclib and fulvestrant in premenopausal or postmenopausal women with hormone-receptor–positive advanced breast cancer that progressed during prior endocrine therapy. 본 PALOMA3 trial 에서는 이러한 palbociclib 과 fulvestrant 의 combination 이 hormone receptor positive 인 advanced breast cancer 환자에서 endocrine therapy 중 progression 되었을 때 Efficacy 와 safety 에 대해 연구하였습니다.

Methods Patients Advanced breast cancer 521 patients with hormone-receptor–positive, HER2–negative that had relapsed or progressed during prior endocrine therapy Regardless of menopausal status Prior exposure to fulvestrant or everolimus was no allowed Pts with uncontrolled brain meta or symptomatic visceral spread were excluded

Phase3 study ,Double blind Study Design Phase3 study ,Double blind Randomly assigned in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. - palbociclib : 125mg/day orally for 3weeks followed by 1 week off fulvestrant: 500mg IM every 14days for first 3 injection and then every 28days Premenopausal or perimenopausal patients received goserelin for the duration of study treatment, starting at least 4 weeks before randomization and continuing every 28 days

Procedures Imaging (CT, MRI, or both) was performed at screening within 4 weeks before randomization, then repeated every 8±1 weeks until disease progression. Biochemical and hematologic laboratory tests were performed on days 1 and 15 of the first two cycles and then on day 1 of subsequent cycles. Vital signs were assessed on day 1 of every cycle

End point Primary end point : Secondary end points : Investigator-assessed progression –free survival Secondary end points : Overall survival Survival probability at 1,2 and 3years Objective response Duration of response Rate of clinical benefit Patient-reported outcomes Pharmacokinetics Safety

N=521 Result 결론 보시겠습니다. 총 521명을 대상으로 연구가 진행되었으며 palbociclib-fulvestrant 347명과 plaebo 군 174 명을 대상으로 시행되었습니다. 두군간 age, race, hormone receptor status, disease free interval, menopausal status 등은 두군간에 큰 차이를 보이지 않았습니다. 타장기에 대한 metastasis 및 prior endocrine therapy 의 종류에 있어서도 비율의 큰 차이는 보이지 않았습니다

Result - Characteristic of patients

Safety -Adverse Events Serious adverse event occurred 9.6% in Palbociclib-Fulvestrant 14.0% in placebo-Fulvestrant

Efficacy- Progression free Survival

Subgroup Analysis of Progression-free survival

Conclusion In conclusion, the PALOMA3 study showed that Among patients with hormone-receptor–positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone. Neutropenia was the most common adverse event in patients receiving palbociclib, but a very low incidence of febrile neutropenia was observed in both treatment groups. 결론적으로 PALOMA3 study 는 hormone receptor positive metastatic breast cancer 환자에서 앞서 시행한 endocrine therapy 중에 disease progression 이 있을 때 palbociclib 과 fulvestrant 를 병용 사용하였을 경우 Fulvestrant 를 단독으로 사용하는 경우보다 progression fress survival 에서 확연히 긴 결과를 보여주었습니다. Neutropenia 는 가장 큰 adverse event 였지만 양쪽 treatment group 에서 febrile neutropenia 가 나타나는 경우는 매우 드물었습니다.