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ASCO Study Shows Modest Efficacy of PI3 Kinase Inhibitor in Molecularly Defined Breast Cancer

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CHICAGO (GenomeWeb) – A PI3 kinase inhibitor called taselisib showed efficacy for the first time against patients with a solid tumor characterized by PIK3CA mutations.

And while the results of the trial weren't convincing enough for the drug's sponsor to continue to pursue US Food and Drug Administration approval, experts at the American Society of Clinical Oncology’s annual meeting this week said the data add to the field’s understanding of PIK3CA-mutated cancers and demonstrate that the PI3 kinase pathway is druggable in solid tumors.

"This is a very appealing target," said Harold Burstein from Dana-Farber Cancer Institute in reviewing the data from the trial. "It is a mutation that's the most common in breast cancer when you do genomic sequencing and it arises in other tumors as well."

At the ASCO annual meeting, researchers presented data from the Phase III SANDPIPER trial showing that patients receiving Genentech's PI3 kinase inhibitor taselisib plus hormone therapy fulvestrant lived two months longer without their cancer progressing compared to those receiving just fulvestrant. Patients on taselisib had a 30 percent lower chance of their cancer worsening than those receiving only fulvestrant.

However, patients on the taselisib arm experienced more serious toxicities than those in the comparator arm. "These results are positive, but I think we would all agree they are modest," Jose Baselga from Memorial Sloan Kettering Cancer Center, who led SANDPIPER, said at the meeting.

Based on the data from SANDPIPER, Genentech has decided to halt development of the drug. "The magnitude of benefit observed in SANDPIPER isn't as strong as we had hoped for, and given the challenging safety profile of this combination and the current clinical landscape, we will not be pursuing an FDA submission for taselisib based on the data presented at ASCO," a Genentech spokesperson told GenomeWeb. The company also doesn't have plans to investigate taselisib in other types of cancer, the spokesperson added.

The Phase III study compared taselisib plus fulvestrant against fulvestrant alone in 480 estrogen receptor-positive, HER2-negative advanced breast cancer patients with PIK3CA mutations. Median progression-free survival was 7.4 months in the taselisib arm and 5.4 months in the fulvestrant only arm.

In the study, 32 percent of patients receiving the PI3 kinase inhibitor experienced serious side effects, compared to around 9 percent of patients receiving just hormone therapy. Approximately 50 percent of patients on taselisib had grade 3 or higher toxicities, compared to 16 percent of patients in the comparator arm.

Gastrointestinal toxicities, in particular diarrhea, was the most common taselisib-related side effect. Close to 17 percent of patients discontinued the study due to taselisib-related toxicities, compared to 2 percent of patients receiving only fulvestrant.

"The SANDPIPER trial showed that targeting the PI3K pathway is a feasible approach and may delay HR-positive, HER2-negative MBC from worsening," the Genentech spokesperson said. "The trial provides important information that will advance our understanding of the PI3K pathway and inform future clinical development in this area."

"I think [SANDPIPER] does establish proof of principle that this is a bona fide target, for sure," Baselga said. He noted, however, that the risks of treatment related toxicities have to be weighed against the modest benefit.

There are multiple PI3 kinase isoforms, some of which, when blocked by a targeted drug, play a role in producing toxicities.Taselisib hits multiple isoforms and that's probably what makes the drug relatively tough to tolerate. At the meeting, experts noted the need for a more selective PI3 kinase inhibitor.

Although Genentech is stopping development of taselisib, it is not giving up entirely on developing a PI3 kinase inhibitor. "Hormone receptor-positive, HER2-negative metastatic breast cancer remains incurable and we are investigating new medicines for it, including other molecules that target PI3 kinase," the Genentech spokesperson said. The drugmaker is specifically investigating a more targeted small molecule PI3K inhibitor, RRG6114, in early clinical trials.

"The fact that there was some activity [in SANDPIPER] is encouraging and suggests that this is a pathway that we need to continue to try to target," ASCO Chief Medical Officer Richard Schilsky told GenomeWeb. "It's a very commonly altered pathway in many different types of cancers."

PI3K signaling is involved in breast cancer tumor growth, proliferation and survival, and mutations show up in around 30 percent of hormone receptor positive, HER2 negative breast cancer. Prior to SANDPIPER, early preclinical and clinical studies had demonstrated taselisib's activity in PIK3CA mutant cell lines, and shown that PIK3CA mutant tumors appear to respond to the drug.

Because PIK3CA mutations occur so frequently in cancers, Burstein noted that the results from SANDPIPER were a modest yet important step forward because they demonstrate that the PI3 kinase pathway can be targeted in solid tumors. "Hopefully this gives us something we can build on so we can use a targeted precision approach in this very common type of breast cancer subsets," Burstein said.

There are two drugs in the class that are already FDA approved for hematological malignancies. "This is the first time a drug in the class has shown some activity against a solid tumor," noted Schilsky.

One curious finding in the study was that patient benefit to taselisib appeared to differ based on their geographic location. For patients in North America and Europe, median progression-free survival was 7.9 months on taselisib compared to 4.5 months on fulvestrant. However, in patients in Eastern European and Latin American countries, the addition of taselisib appeared to add very little or no benefit in addition to fulvestrant.

"It's a little shocking," Baselga said, noting the need to look more deeply into the reasons for this discrepancy.

Baselga noted that his team also conducted exploratory analysis in SANDPIPER in advanced breast cancer patients without PIK3CA mutations, and saw that some patients responded to the drug. This suggests that perhaps PIK3CA mutations aren't a perfect predictive marker in this setting, Baselga suggested.

Separately at ASCO, researchers reported data from an arm of the National Cancer Institute's Molecular Analysis for Therapy Choice study, which investigated how patients with PIK3CA mutated tumors responded to taselisib. The data revealed lackluster efficacy for taselisib and no clear patterns of benefit in subsets of patients with a variety of tumor types, in different PIK3CA mutations, and alongside co-occurring mutations (see related story).

Experts at the meeting opined that the data from NCI-MATCH and other studies suggest that in many tumors PIK3CA mutations aren't the main drivers of cancer, but play a more ancillary role. As such, they believe the data to date on the role of PIK3CA mutations in cancer suggest the need for combination treatment strategies that hit multiple targets and pathways.

"It doesn't stop just with detecting a signal of activity of a drug against a pathway," Baselga said, noting that in genetically complex tumors, "there are multiple parallel pathways that are active, there are multiple redundancies, feedback loops."

"Nobody really believes that single-agent targeted therapy is really the path forward," he said. "The real question is what's the best combination and how do you decide what the best combination is for each individual person."