今年的美国癌症研究学会年会上，礼来公司的CDK4/6抑制剂类药物LY2835219引起了业界的广泛关注。礼来公司表示，目前研究人员正在进行这种药物的三期临床研究实验设计，相信很快就能进入三期研究阶段。
 

近年来以抑制CDK4/6为原理的抗癌药物受到了各方面的关注，也成为了各大医药巨头竞相开发的领域。例如辉瑞公司的palbociclib就在临床二期研究中表现出了不俗的效果。另外诺华公司也在进行自己的类似药物LEE011的研发，并也即将进入临床三期研究。而此次礼来公司对LY2835219取得进一步的研究成果也意味着公司拉近了与辉瑞公司的差距。

近年来礼来公司也因为其药物研发过于缓慢而广受质疑。这一次礼来公司能否凭借LY2835219打一个漂亮的翻身仗还需要时间的检验。
 

CDK4/6 Inhibitor LY2835219 Shows Promise in Early Study

Amita Patnaik, MD

The CDK4/6 inhibitor LY2835219 demonstrated promising single-agent activity in heavily pretreated patients with hormone receptor (HR)-positive me-tastatic breast cancer, according to a phase I expansion cohort analysis presented at the 2014 AACR Annual Meeting.

The phase I study eva1uated LY2835219 in 132 patients with glioblastoma, melanoma, lung cancer, colorectal cancer, and breast cancer. The study specifically enrolled 47 heavily pretreated patients with me-tastatic breast cancer, 36 of which were HR-positive. In these patients, the median progression-free survival (PFS) was 9.1 months, the overall response rate (ORR) was 25%, and the meaningful clinical benefit rate (CBR) was 61%.

“Although our study was not designed to compare patient outcomes based on HR status, the clinical benefit rate was 61% in our patients with HR-positive breast cancer, which means patients had disease control for longer than 24 weeks or had their tumors reduce in size by more than 30%,” said the study’s lead author Amita Patnaik, MD, an associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, Texas.

In the study, LY2835219 was administered continuously at doses ranging from 150 mg to 200 mg every 12 hours in a 28-day cycle. In the breast cancer cohort, patients had received a median of 7 prior systemic therapies.

In the 36 patients with HR-positive breast cancer, 9 achieved a partial response (PR) with no complete responses for an ORR of 25%. Altogether, 20 patients (56%) had stable disease (SD), 13 of which lasted ≥ 24 weeks. The overall CBR was 81% and was 61% specifically in patients who experienced longer durations of SD.

The PFS was 9.1 months for patients with HR-positive breast cancer with 50% of patients remaining on LY2835219 therapy at the time of the analysis. Across all 47 patients with breast cancer, 9 (19%) achieved a PR and 24 (51%) had SD for a CBR of 70%. 

The median PFS was 5.8 months.

The most common grade 3/4 treatment-related adverse events across the full study (n=132) were neutropenia (11%), diarrhea (5%), nausea (3%), fatigue (2%), and vomiting (2%).

“This is very encouraging, and warrants the initiation of future clinical trials in this setting where treatments are needed,” said Patnaik. “When tested on various breast cancer types in preclinical studies, HR-positive cells were found to be highly sensitive to this drug. Approximately 80% of breast cancers are HR-positive.”

Blocking CDK 4 and 6 acts on the cell cycle by stopping DNA synthesis through the prevention of progression from G1 to S phase. Preclinical models have demonstrated preferential activity for these agents in HR-positive breast cancer, resulting in a number of agents being investigated in early and late stage trials.

In the final analysis of the phase II PALOMA-1 study, the CDK4/6 inhibitor palbociclib improved PFS by 20.2 months compared with 10.2 months for letrozole alone in HR-positive, HER2-negative me-tastatic breast cancer (HR = .488; P = .0004). The median overall survival was 37.5 months with palbociclib compared with 33.3 months with letrozole alone. However, this advantage was not statistically significant (HR = 0.813; P= .2105).

Palbociclib is under investigation in a number of phase III clinical trials for patients with HR-positive, HER2-negative advanced breast cancer. The PALOMA-2 study follows the same design as PALOMA-1. The PALOMA-3 trial will explore palbociclib in combination with fulvestrant following prior endocrine therapies.

In another analysis presented at the AACR Annual Meeting, the CDK4/6 inhibitor LEE011 added to letrozole or fulvestrant elicited an improved tumor response in HR-positive mouse models. This study also demonstrated that a regimen of LEE011, an anti-estrogen, plus a PI3K inhibitor (BKM120 or BYL719) resulted in even more robust tumor regression, representing an area for future clinical studies.

A phase III clinical trial is currently enrolling patients to explore LEE011 in combination with letrozole for patients with untreated HR-positive, HER2-negative, me-tastatic breast cancer. The primary outcome measure will be PFS with secondary endpoints including OS and ORR.

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