Lead Investigator Discusses Ipatasertib Potential in TNBC

Rebecca Dent, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Rebecca Dent, MD

Adding the AKT inhibitor ipatasertib to paclitaxel improved median overall survival (OS) by 5 months for patients with locally advanced or metastatic triple-negative breast cancer (TNBC), according to results presented at the 2018 ASCO Annual Meeting.

In interim survival data from the intent-to-treat (ITT) population of the randomized, placebo-controlled phase II LOTUS trial (NCT02162719), ipatasertib improved median OS to 23.1 months compared with 18.4 months with paclitaxel and placebo (stratified HR, 0.62; 95% CI, 0.37-1.05). The 1-year OS rate increased from 70% to 83% with the addition of ipatasertib.

These results represent about 50% of OS events in both arms.

“The OS results show us that, when you look at weekly paclitaxel alone versus in addition to ipatasertib, we see a 5-month improvement in median OS, from 18 months to 23 months,” said lead author Rebecca Alexandra Dent, MD, MSc, senior consultant at the National Cancer Centre Singapore and associate professor at Duke-NUS Singapore. “We almost have a 2-year survival in TNBC, which has never been documented previously.”

Ipatasertib is an ATP competitive inhibitor of AKT1, AKT2, and AKT3. The PI3K/AKT/mTOR pathway is activated in about 40% of TNBCs, and the PI3K/AKT survival pathway is activated in response to chemotherapy. Increasing exposure to docetaxel induces increasing phosphorylation of AKT. In PI3K-mutant cell lines in TNBC, the addition of ipatasertib to docetaxel is synergistic in causing cell death.

For LOTUS, eligible patients had previously untreated locally advanced or metastatic TNBC that was not amenable to curative resection. They must have been at least 6 months removed from chemotherapy in the adjuvant setting. Archival or newly obtained tumor tissue was contributed for central PTEN assessment. Patients were randomized 1:1 to paclitaxel at 80 mg/m² on days 1, 8, and 15, with either ipatasertib at 400 mg/day or placebo on days 1 to 21 of a 28-day cycle until progression or unacceptable toxicity.

The primary endpoint was progression-free survival (PFS) in the total population and as stratified by PTEN status; OS was a secondary endpoint. Final OS results are expected in 2019.

PFS favored the experimental arm in the ITT population (6.2 vs 4.9 months; HR, 0.60; 95% CI, 0.37-0.98) and the PIK3CA/AKT/PTEN-altered tumor population (9.0 vs 4.9 months; HR, 0.44; 95% CI, 0.20-0.99).

Ipatasertib improved the overall response rate in the ITT population from 32% to 40%; in the PTEN-low subgroup from 26% to 48%; and in the PIK3CA/AKT/PTEN-altered tumor population from 44% to 50%.

OncLive: Can you discuss the results from LOTUS?

In an interview with OncLive^®, Dent spoke about identifying which patients will derive the most benefit with ipatasertib, whether the agent can fill the unmet need for patients with PIK3CA-mutated TNBC, and what she hopes to learn from the results of the ongoing phase III IPATunity130 trial (NCT03337724).Dent: [Looking at the biomarker-positive subgroup], this is the most exciting part of our study because some of the early data and some of the preclinical data show us that if we block AKT, it's not just important for patients with AKT mutations. It is important for patients who have mutations upstream in oncogenes and tumor-suppressor genes, such as PIK3CA mutations and patients with PTEN loss. Those are the patients we thought might derive more benefit from AKT blockade. These are critical survival pathways in breast cancer. Up to 40% of patients with breast cancer have aberrations in either AKT, PIK3CA, or PTEN. It's not a small number of TNBCs.

The data show us that in terms of PFS, which was the primary endpoint, we saw modest improvement in the ITT population in terms of PFS. Where we really saw impact was when we looked at PFS in the biomarker-positive group.

This was a panel done by Foundation Medicine either on the archived or fresh tissue looking at PIK3CA, AKT, or PTEN. In those patients, we saw a 4- to 5-month improvement in PFS. In TNBC, that's a fairly profound improvement.

In terms of secondary efficacy endpoints, we looked at response, duration of response, and clinical benefit rate. In all 3, we saw trends toward improved outcomes with ipatasertib, but where we saw some benefit was in duration of response.

Anybody who treats [patients with] TNBC knows that often we can get responses, but are these responses sustained? We saw almost a doubling in duration of response, from about 6 to 11 months with the addition of ipatasertib in the biomarker-positive population.

This particular presentation focused on the OS data. This was a hypothesis-generating randomized trial. Thankfully, it was placebo-controlled study, which gives it some credence. There was also a companion study performed by AstraZeneca that showed similar results. Even though these were small phase II studies, we can be cautiously optimistic that there is definitely a reason to do the phase III study, which is ongoing.

How was the toxicity?

When we look at the subgroups, we have to be cautious because these were small numbers of patients and small numbers of events. The curves all look very similar, but we're all anxiously awaiting the phase III data because we'll be collecting a lot more tissue and blood and getting to the bottom of it. We're conducting the phase III study in the biomarker-positive only population. However, studies will likely expand to include all-comers so we will get a better sense for the patients who potentially benefit.Ipatasertib is an oral AKT inhibitor. This is unlike some of the older AKT inhibitors, which are allosteric inhibitors and have a lot more toxicity. This is an ATP-competitive inhibitor of AKT, so it has much better tolerability.

This is sort of blocking the PI3K pathway, where we do see a lot of gastrointestinal toxicity. Fortunately, with AKT inhibition and certainly with this particular compound, we see a lot less toxicity than we saw with some of the other compounds. However, the most notable AE was diarrhea.

Diarrhea is something that we didn't anticipate with this particular dose level—there was no prophylactic measure in place. When patients did take treatment for their diarrhea, it resolved. Diarrhea usually happened in the first cycle.

What are the remaining unanswered questions with ipatasertib?

In terms of dose adjustments and reductions, there were small differences between the 2 groups. We were able to maintain dose intensity even with the addition of ipatasertib. We can be cautiously optimistic that we have something here that certainly warrants further evaluation in the phase III IPAtunity trial. It's the same design as the phase II trial, but with a 2:1 randomization in the biomarker-positive group. There are other studies looking at all-comers because it is an interesting compound.Can we combine it with other chemotherapies? We know that under selective pressure of chemotherapy, you have upregulation of AKT. It's not just for patients who have PI3KCA mutations or PTEN and AKT, it may just be that chemotherapy primes the system to upregulate this pathway where chemotherapy facilitates combinations with ipatasertib. The question is, “Is it just taxanes?” Most of the data we have are with taxanes, but there are accumulating data looking at other combinations that potentially could continue for longer.

Second, what is the patient population? The phase I trial included a broad number of patients, but it probably extends beyond TNBC. Certainly, the prostate program is looking very exciting—they're into registration in the phase III setting, as well.

How could an agent like this address the unmet need in PIK3CA-mutant patients?

Third, we would like to see if there is any activity when we combine it with other agents, such as immunotherapy. There is an ongoing phase I program combining ipatasertib with paclitaxel with atezolizumab (Tecentriq). There is potential there, but because they have some but not completely overlapping toxicities, we'll have to see how those studies pan out.We know that PIK3CA mutations are very common in breast cancer and in TNBC. We didn't present these data, but when we looked at PIK3CA mutations specifically, these patients appeared to derive the most benefit from AKT inhibition. The curves are quite astounding, but we had such small numbers that it wasn’t appropriate to present a subgroup of a subgroup.

Is there anything else you would like to add?

Needless to say, that's why we're hoping to get more of these patients in the phase III trial, so we can see if this was just a small signal in a randomized phase II trial or if this is something that's real. I do think there's something there and we're excited to get a broader phase III study so we can look at this further.We had a lot of patients at my own center in this trial. We had a fairly modest PFS benefit, so to see a trend toward improved survival in 2 small and similar randomized phase II trials is very reassuring because that's what we were seeing clinically—patients were doing well. We didn't see super long PFS, but patients were around to get second-, third-, fourth-line therapy. In TNBC, these patients are often very sick, so that they were well enough to go on to other medications or trials was very reassuring.

We were also able to collect data on subsequent therapy after progression and it did appear to be similar between the 2 groups.

Dent R, Im S-A, Espie M, et al. Overall survival (OS) update of the double-blind placebo (PBO)-controlled randomized phase 2 LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for locally advanced/metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2018;36 (suppl; abstr 1008).