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CHICAGO -- An experimental drug that targets a common mutation in breast cancer slowed progression of the disease but with "substantial" toxicity that might rule it out as a treatment, a researcher said.

The PI3K inhibitor taselisib combined with the hormonal therapy fulvestrant (Faslodex) delayed progression by 2 months compared with fulvestrant alone in women with advanced estrogen receptor (ER)-positive breast cancer, according to José Baselga, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.

The benefit was statistically significant although clinically "modest" and proves that PIK3CA mutations in breast cancer can be successfully targeted, Baselga told reporters at the American Society of Clinical Oncology (ASCO) annual meeting.

Two other PI3K inhibitors -- idelalisib (Zydelig) and copanlisib (Aliqopa) -- are approved to treat hematologic cancers, but the SANDPIPER study is the first placebo-controlled randomized trial to test a member of the class in breast cancer, Baselga said.

But he suggested that it will not get much further consideration because of off-target effects that led to the toxicity. "I do think that in the case of breast cancer what we need to do is to work on more specific ... inhibitors," he said.

Mutations of PIK3, which are involved in growth, proliferation, and survival of tumors, are a "very appealing target," commented ASCO expert Harold Burstein, MD, PhD, of Dana-Farber Cancer Institute in Boston.

And the value of the study is that it shows "we finally have a lock and a key that can open the door," he said. Unfortunately, the toxicity is a "latch-lock with a chain" that prevents the door from opening completely, he said.

PIK3 mutations have several isoforms, dubbed alpha, beta, delta, and gamma, Baselga noted. Taselisib has a good affinity for the alpha isoform, which is responsible for much of its role in tumor growth and proliferation, but he said it also hits delta and gamma -- the isoforms linked to the toxicity.

The SANDPIPER trial enrolled women with ER-positive and locally advanced or metastatic breast cancer, with biomarkers showing they had mutations with the alpha isoform, or PIK3CA.

They were randomly assigned in a 2:1 fashion to get fulvestrant with taselisib (340) or a placebo (176). The primary endpoint of the study was investigator-assessed progression-free survival; secondary endpoints included objective response rate, complete response rate, and duration of response.

The analysis showed that patients getting taselisib had a longer period without progression, Baselga said, at 7.4 months compared with 5.4. The difference yielded a hazard ratio for progression of 0.70.

The secondary endpoints with consistent with those results, he said, adding that overall survival data are still immature.

But the crucial data involved toxicity:

• 60% of women taking taselisib reported diarrhea and 40.4% reported hyperglycemia, compared with 19.7% and 9.4%, respectively, of those on placebo.
• 32% of women taking taselisib and 8.9% of those on placebo had serious side effects.
• 49.5% and 16.4%, respectively, of the side effects were grade 3 or higher.

Finally, 16.8% of women taking taselisib stopped therapy because of adverse events, compared with 2.3% of those on placebo.

The bottom line for the compound is that "women are going to vote with their feet," commented Dawn Hershman, MD, of New York Presbyterian Columbia University Medical Center in New York City.

Hershman, who was not involved in the study, told 乌鸦传媒 that modern hormonal therapy is so tolerable that many women "can really live their lives without a lot of side effects" even if they have advanced breast cancer.

"When you add an agent, you want to know that it is efficacious, but you have to have side effects that are controllable," she stated.

She noted that diarrhea -- affecting six of 10 women on taselisib -- would be a "rate-limiting factor" for many women.

"In order for somebody to put up with that much of a side effect, they want to know they are getting a substantial benefit," she said.

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