A Disappointment in Triple-Negative Breast Cancer

Liam Davenport

December 16, 2020

Adding the oral AKT inhibitor ipatasertib to paclitaxel does not improve progression-free survival (PFS) for women with PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer (aTNBC), suggests the phase 3 trial IPATunity130, despite promising data from previous trials.

The research was presented at the San Antonio Breast Cancer Symposium (SABCS) 2020 on December 10.

Harold J. Burstein, MD, PhD, associate professor of medicine, Harvard Medical School and Dana-Farber Cancer Institute, Boston, Massachusetts, who was not involved in the study, told Medscape Medical News that "the study had a very reasonable rationale."

He explained there is a "whole cascading pathway that involves PI3 kinase, mTOR, AKT signaling, and we already have commercially successful drugs in targeting those in advanced breast cancers."

There has consequently been "a lot of interest in looking at AKT inhibitors."

However, "there was no signal of clinical improvement" in the current trial, "so it's not a drug that seems ready to move forward, because either it just doesn't work in the way they'd hoped, or we haven't found the right marker to identify which patients are likely to benefit," Burstein said.

Although he hopes that further studies will be conducted, "at the moment, it doesn't look like either the response rate or the clinical benefit rate or PFS changed in any substantial way."

The study followed prior positive results from the phase 2 LOTUS trial of 124 patients with metastatic TNBC who were randomly assigned to receive either ipatasertib or placebo plus paclitaxel as first-line therapy.

The results showed that after a median of 10 months, ipatasertib was associated with significantly longer median PFS, at 6.2 months vs 4.9 months with placebo (hazard ratio = 0.60; P = .037).

The effect was more pronounced in the 42 patients with PIK3CA/AKT1/PTEN-altered tumors, at a median PFS of 9.0 months with ipatasertib vs 4.9 months with placebo (unstratified hazard ratio = 0.44; P = .041).

Consequently, the phase 3 IPATunity130 trial enrolled women with measurable aTNBC and PIK3CA/AKT1/PTEN alteration who had not previously received chemotherapy for ≥12 months and who were candidates for taxane therapy.

Study Details and a "Burning Question"

Between February 2018 and April 2020, the investigators recruited 255 patients from 187 centers in 30 countries. Participants were randomly assigned in a 2:1 ratio to receive either ipatasertib or placebo plus paclitaxel until disease progression, intolerable toxicity, or elective study withdrawal.

Analysis of the primary endpoint of investigator-assessed PFS was planned after 125 PFS events, with a target hazard ratio of 0.50.

The treatment groups were well balanced in terms of their baseline characteristics. The women's median age was around 55 years; they were recruited primarily in Europe (~41%) and the Asia-Pacific region (21%).

Approximately half of the women had previously received (neo)adjuvant chemotherapy, and between 79% and 87% had metastatic disease. The number of patients with a PIK3CA/AKT1-activating mutation was roughly the same as the number with only a PTEN alteration.

At the data cutoff of May 7, 2020, after a median of 8.3 months, 55% of patients in both treatment groups had experienced a PFS event.

Investigator-assessed median PFS with ipatasertib plus paclitaxel was 7.4 months, vs 6.1 months with placebo plus paclitaxel, at a nonsignificant stratified hazard ratio of 1.02 (P = .9237).

Further analysis indicated that there were no clinically relevant subgroups for whom a benefit with ipatasertib vs placebo plus paclitaxel was observed.

There was also no significant difference in investigator-assessed response on the RECIST version 1.1 criteria, at a confirmed overall response rate with combination treatment of 39% vs 35% with paclitaxel plus placebo.

The clinical benefit rate, defined as an objective response or stable disease for ≥24 weeks, was estimated to be 47% with ipatasertib plus paclitaxel and 45% with placebo plus paclitaxel.

There were no notable differences in treatment duration or in the number of patients who remained on treatment between the two treatment groups.

However, ipatasertib plus paclitaxel was associated with higher rates of adverse events leading to dose reductions of any drug, at 35% vs 14% in the placebo group.

In addition, among patients in the combination therapy group, the rate of diarrhea was markedly higher than among those in the placebo group. There were also higher rates of nausea, vomiting, asthenia, hyperglycemia, and decreased appetite.

Reporting the results, Rebecca Dent, MD, senior consultant and head of the Medical Oncology Department, National Cancer Center, Singapore, said that adding ipatasertib to paclitaxel in this subgroup of aTNBC patients "did not significantly improve PFS."

She noted that overall survival follow-up is ongoing and that further analyses will "explore potential biomarker of benefit from ipatasertib."

During the postpresentation debate, Hope S. Rugo, MD, professor of medicine at the Helen Diller Family Comprehensive Cancer Center, the University of California, San Francisco, asked: "Is there any future for AKT or PI3 kinase inhibitors in triple-negative breast cancer [and] what about early- stage" disease?

Dent said this a "burning question that people are probably afraid to ask."

She commented that there were "amazing data" from phase 2, with "not one but two" randomized trials with similar designs that "clearly showed an impressive improvement in overall survival and some modest PFS benefits."

Dent said, "It's important to recognize that triple-negative breast cancer is very heterogeneous, and so it's a diagnosis of exclusion." She added that it's "really just an overarching term to describe basically a breast cancer that has several pathways that are upregulated.

"Even if you just look at the control arm of this study," she continued, the median PFS "is almost double what we saw in the control arm of, let's say, KEYNOTE-355."

Dent said this really "emphasizes the issue of TNBC heterogeneity, and then there's the issue that...we have a lot of emerging molecular items that are potential confounders that we don't measure."

For Burstein, the findings underline that "triple-negative breast cancer remains a hard-to-treat population.

"Many of the tumor targets that we use in other flavors of breast cancer, especially ER+ breast cancer, where we go after the 'normal' functioning of the cancer cell...we've been effective at targeting," he said.

"But in triple-negative breast cancer, that strategy has not, to date, emerged, and we have been leaning on, essentially, chemotherapy or fancy iterations of chemotherapy...or perhaps immunotherapy in the group of tumors that are PD-L1 positive as a way to help women with more advanced TNBC.

"The more targeted things seem not to have panned out so far, so we're obviously hoping that we can do better in the future," Burstein added.

The study was sponsored by Hoffmann-La Roche. Dent has received consulting fees from AstraZeneca, Eisai, Lilly, Merck, Novartis, Pfizer, and Roche. She has also traveled to conferences with AstraZeneca, Merck, Pfizer, and Roche. Burstein has disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2020: Abstract GS3-04. Presented December 10, 2020.

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