Palbociclib, one of the hottest CDK4/6 inhibitors in breast cancer in recent years, was approved by the U.S. Food and Drug Administration (FDA) in February 2015 for the treatment of breast cancer. Current approved indications include.
- In combination with letrozole for the first-line treatment of postmenopausal patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer;
- In combination with fulvestrant for second-line treatment of hormone-receptor-positive, HER2-negative advanced or metastatic breast cancer that has progressed after endocrine therapy.
In August 2018, piperacillin was approved for marketing in China in combination with an aromatase inhibitor for the first-line treatment of hormone-receptor-positive, HER2-negative advanced or metastatic breast cancer.
The use of this drug in breast cancer has been recommended by several breast cancer guidelines, which shows that it has taken its place in the treatment of breast cancer. How has piperacillin performed in the treatment of breast cancer?
How does the world’s first CDK4/6 inhibitor work?
How does the world’s first CDK4/6 inhibitor work?
Piperacillin is the world’s first inhibitor of CDK4/6, the full Chinese name for cell cycle protein-dependent kinases (CDK) 4 and 6. CDK is an essential catalyst in the ongoing cycle of cell division and proliferation.
By preventing CDK from functioning, the cell cycle can be interrupted and cells cannot continue to proliferate. This is how CDK inhibitors work to kill cancer cells.
However, selective inhibition of CDK can also affect normal cells. Piperacillin is a selective CDK inhibitor and, as the name implies, acts selectively only on CDK 4 and 6. Hormone-receptor-positive breast cancer cells are such CDK 4/6-active cells, so piperacillin can be more targeted in its anti-cancer effects.
Hormone receptor-positive advanced breast cancer: both first- and second-line wins
Piperacil can be used in combination with endocrine therapy as an initial regimen in hormone-receptor-positive, HER2-negative advanced or metastatic breast cancer, or in patients who have progressed after endocrine therapy.
In combination with letrozole for first-line treatment at the time of launch
The pivotal study below led to the accelerated approval of piperacillin by the FDA in 2015.
This phase II clinical study, code-named PALOMA-1, enrolled 165 postmenopausal hormone receptor-positive, but HER2-negative patients with advanced breast cancer who had not been previously treated with other breast cancer drugs.
The results showed that the median progression-free survival of breast cancer was almost doubled in patients treated with piperacillin in combination with letrozole compared with letrozole alone (10.2 months and 20.2 months, respectively).
In terms of adverse effects, neutropenia, leukopenia, anemia and fatigue were common, with no particular side effects seen with the addition of piperacillin.
In the absence of serious adverse reactions, piperacillin delayed the progression of breast cancer by 10 months, making it a successful drug marketing approval based on the results of the phase II clinical trial alone.
Advancing to second line, combined with fulvestrant to slow tumor progression
The PALOMA-3 phase III clinical trial provides evidence for piperacillin in second-line therapy. The study was conducted in hormone receptor-positive, HER2-negative advanced breast cancer in patients whose tumors had recurred or progressed after failure of prior endocrine therapy.
In 521 patients, median progression-free survival was 9.2 months with piperacillin + fulvestrant, compared with 3.8 months with fulvestrant alone. Piperacillin delayed tumor progression by 5.4 months, which was significant.
Although the addition of piperacillin may have increased the side effects of the drug, overall the patients tolerated it reasonably well.
Watch and explore in more breast cancers
Many tumor cells are overactive for CDK4/6, so the indications for piperacillin in breast cancer are expected to continue to expand. The following explorations are of interest.
- Moving toward early-stage breast cancer. Researchers are gradually moving from advanced breast cancer to early breast cancer. One study used piperacillin as adjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative early-stage breast cancer.
- A combination of different drugs. In addition to letrozole and fulvestrant, investigators have looked at the effects of combining piperacillin with another endocrine drug, tamoxifen.
- Comparison with other therapies. Investigators will compare piperacillin with other therapies (such as chemotherapy) to find more appropriate dosing regimens and combinations. For example, they will compare the difference in efficacy between piperacillin + endocrine therapy and capecitabine chemotherapy.
- Focus on Asian populations. The number of breast cancer patients in Asia, especially in China, is large, and investigators are also focusing on the benefits of treatment in this population.
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What is the status of piperacillin research in China?
Currently, piperacillin is available in China. The Chinese Society of Clinical Oncology breast cancer guidelines encourage patients to participate in clinical research and include CDK4/6 inhibitors as an optional endocrine combination for advanced breast cancer.
Summary
Piperacillin may be used in advanced or metastatic breast cancer that is hormone receptor-positive and HER2-negative.
- In first-line therapy, co-trimoxazole may extend progression-free survival by 10 months.
- For patients with progressive disease after endocrine therapy, fulvestrant in combination with piperacillin in second-line therapy prolonged progression-free survival by 5.4 months.
More exploration of piperacillin is underway, and it is expected that these studies will yield solid evidence.