AKT Inhibitor May Overcome Chemotherapy Resistance in 2 Breast Cancer Subtypes

Joyce A. O’Shaughnessy, MD

A novel inhibitor that targets the AKT node in the PI3K pathway may offer a treatment option in cases of resistance to chemotherapy in 2 patient populations: triple-negative breast cancer (TNBC) or estrogen receptor (ER)— positive, HER2-negative breast cancer with certain molecular aberrations. The agent, ipatasertib, is being tested in combination with paclitaxel in the randomized phase II/III IPATunity130 clinical trial (NCT03337724).

Patients in these populations who have mutations in the PIK3CA, AKT1, or PTEN genes tend to have chemotherapyresistant disease. “The PI3K/ AKT pathway is very strongly activated in TNBC, and when you have these alterations, they send strong survival signals [to the cancer] and the cancer cells can survive the onslaught of chemotherapy that we rely on to treat patients in the metastatic setting,” said Joyce A. O’Shaughnessy, MD, a trial investigator and member of the steering committee for IPATunity130.

Investigators believe that ipatasertib (RG7440) may demonstrate the ability to overcome resistance to chemotherapy, which is a mainstay treatment for patients either with TNBC or ER—positive, HER2-negative breast cancer, according to O’Shaughnessy, who is the Celebrating Women Chair in Breast Cancer Research and chair, Breast Cancer Research Program, Baylor University Medical Center, Texas Oncology and US Oncology. She is a 2016 Giants of Cancer Care^® award winner.

The trial is randomizing patients to receive paclitaxel with either ipatasertib or placebo (FIGURE). The primary endpoint is progressionfree survival (PFS). Importantly, prior to randomization, patients will be centrally tested for alterations in the PIK3CA/AKT1/ PTEN genes, and for enrollment they must have alterations in at least 1 of these genes. This is because ipatasertib inhibits AKT, a key component of the PI3K pathway that is dysregulated by the loss of the tumorsuppressor PTEN gene.¹

Figure. Ipatasertib in Breast Cancer Subtypes

“AKT is a master regulator of survival within the cancer cell and can lead the cell to repair DNA, for example, as 1 mechanism of chemotherapy resistance. When [the patient has cancer with] a PIK3CA mutation, the odds of achieving a pathological complete response are considerably less,” O’Shaughnessy explained. Prior trial results have confirmed the value of combining ipatasertib and paclitaxel for patients who have the relevant gene alterations. The multicenter, randomized, phase II LOTUS trial looked at PFS overall and in patients with low PTEN expression, but the study also examined overall survival in patients with PI3K/AKT pathwayactivated tumors as a secondary endpoint. There was a PFS benefit observed in both subtypes favoring the combination of ipatasertib and paclitaxel.

The combination of ipatasertib and paclitaxel resulted in a median PFS in the intentionto-treat population of 6.2 months versus 4.9 months in the paclitaxel-alone arm (HR, 0.60; 95% CI, 0.37-0.98; P = .037).² “There was a statistically significant, but modest, improvement from a clinical standpoint, but when they looked at the subset with PIK3CA/AKT1/PTEN mutations, there was a much larger impact for ipatasertib in terms of improving PFS,” O’Shaughnessy said. Patients with alterations who received ipatasertib (n = 26) achieved a median PFS of 9.0 months compared with 4.9 months for those with mutated tumors who received paclitaxel alone (HR, 0.44; 95% CI, 0.20-0.99; P = .041).

If the combination proves successful in the IPATunity130 trial, it could represent an opportunity to build a new platform for treatment of patients with TNBC or ER—positive disease with PIK3CA/AKT1/PTEN mutations. For the ER–positive population, the combination of paclitaxel plus ipatasertib could become a new standard of care if it proves superior to paclitaxel alone, O’Shaughnessy said, because there is no other agent to pair with paclitaxel that would improve PFS except for another chemotherapy.

The IMpassion130 (NCT02425891) clinical trial is investigating frontline atezolizumab (Tecentriq) in combination with nabpaclitaxel compared with nab-paclitaxel and a placebo in patients with TNBC, and this could also change the landscape for patients with this disease type.

“If [the combination] is successful in a molecularly selected population, the next logical step, in my mind, would be to build a triplet of nab-paclitaxel, ipatasertib, and atezolizumab for a molecularly selected population,” O’Shaughnessy said. “It’s likely that we’re going to need triplet therapy to have durable responses in TNBC, because this is such a molecularly heterogeneous disease. I think in ER—positive patients with these mutations, this combination could become the new standard of care.”

Ipatasertib is being developed by Genentech, based in San Francisco, California.

References

1. Ipatasertib (GDC-0068, RG7440). Genentech/Biooncology website. biooncology.com/pipeline-molecules/ipatasertib.html. Accessed March 8, 2018.
2. Kim SB, Dent R, Im SA, et al; LOTUS Investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18(10):1360-1372. doi: 10.1016/S1470-2045(17)30450-3.