New Targeted Therapy Modestly Improves PFS in Advanced Breast Cancer
By Mark L. Fuerst
The targeted therapy taselisib, combined with standard hormone therapy fulvestrant, extended progression-free survival (PFS) of advanced breast cancer by 2 months longer than hormone therapy alone, according to a new study.
Taselisib targets a common genetic abnormality in breast cancer, the PIK3CA gene mutation. It is the first and most potent treatment in a relatively new class of PI3K inhibitors, according to the lead author José Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan Kettering Cancer Center in New York City.
“About 40 percent of all patients with advanced breast cancer estrogen-receptor positive have PIK3CA mutations, which means they could benefit from taselisib,” said Baselga. “Our findings are proof that targeting this pathway in breast cancer is effective. However, the benefit to patients was more modest than we had hoped for, and there is a risk of considerable side effects with the addition of taselisib.”
He presented the results of the study at a press briefing at the 2018 American Society of Clinical Oncology Annual Meeting.
PI3K signaling is involved in tumor growth, proliferation, and survival, and mutations are frequently observed in hormone receptor-positive, HER2-negative breast cancer. “In early preclinical and clinical studies, taselisib had enhanced activity in PIK3CA-mutant cell lines and more frequent tumor responses were observed in patients with PIK3CA-mutant tumors,” said Baselga. Taselisib has also shown promising clinical benefit in early trials of patients with head and neck cancer and certain gynecologic cancers.
The SANDPIPER trial (Abstract LBA1006) is the first placebo-controlled, randomized study evaluating the efficacy and safety of a mutant-selective PI3K inhibitor, taselisib, added to the endocrine agent fulvestrant in a biomarker-defined population—patients with ER-positive metastatic breast cancer with PIK3CA-mutant tumors. The trial enrolled 516 postmenopausal women with locally advanced or metastatic ER-positive, HER2-negative metastatic breast cancer that worsened or recurred despite initial hormone treatment with aromatase inhibitors. The patients were randomly assigned to receive fulvestrant and placebo (176 patients) or fulvestrant and taselisib 4 mg daily (340 patients).
Those who received taselisib and fulvestrant had a 30 percent lower chance of cancer worsening than those who received fulvestrant and a placebo. Taselisib extended PFS by a median of 2 months—7.4 months with taselisib and fulvestrant versus 5.4 months with fulvestrant and placebo. The overall response rate (ORR) more than doubled when taselisib was added to fulvestrant (28% vs. 11.9%). Overall survival (OS) data are not yet available.
The addition of taselisib to fulvestrant led to an increase in toxicity, said Baselga. “The safety profile was unexpected, but substantial,” he said.
Gastrointestinal toxicities, in particular diarrhea and hyperglycemia, were the most frequent side effects seen with the addition of taselisib to fulvestrant: diarrhea: 60.1 percent versus 19.7 percent (all grades) and hyperglycemia: 40.4 percent versus 9.4 percent (all grades). Serious side effects were 32 percent in the taselisib group versus 8.9 percent in the placebo group. Similarly, grade 3 or higher side effects were more severe with taselisib (49.5%) as compared to placebo (16.4%).
He noted that taselisib provided more benefit to study participants who received treatment in North America and Europe, where cancer worsening was delayed by a median of 3.5 months (7.9 months with taselisib plus fulvestrant vs. 4.5 months with only fulvestrant). In other countries, including Eastern Europe and Latin America, taselisib appeared to provide very little or no added benefit. More research is needed to understand the reasons for this discrepancy, he said.
“The phase III SANDPIPER study met its primary endpoint,” Baselga concluded. “The addition of taselisib to fulvestrant showed a statistically significant improvement in investigator-assessed PFS in patients with PIK3CA-mutant tumors. Secondary endpoints, including ORR, clinical benefit response, and duration of response, showed consistent improvement with the combination. OS data are immature.”
The safety profile of the combination of taselisib plus fulvestrant was generally as expected from earlier studies, with gastrointestinal toxicities and hyperglycemia being the most frequent side effects. “Overall, the efficacy observed in SANDPIPER was considered modest. The challenging tolerability of this combination led to frequent treatment discontinuations and may have limited the clinical benefit in this disease setting,” said Baselga, who added that PIK3CA-mutant tumors are “a bonafide target.”
ASCO Expert Harold Burstein, MD, PhD, Associate Professor of Medicine at Harvard Medical School, commented: “We now know that it’s possible to target this common breast cancer mutation, and it’s heartening to see that a new therapy can provide some benefits to women with advanced breast cancer. However, because the treatment has side effects, doctors will have to weigh its benefits and risks with their patients.
“We have found a lock and key, and opened it a little bit,” he stated. “This is a modest step forward, but an important one. We can target this pathway.”