FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer

Abstract

Background: This hypothesis-generating trial evaluated neoadjuvant ipatasertib-paclitaxel for early triple-negative breast cancer (TNBC).Patients and methods: In this randomized phase II trial, patients with early TNBC (T ! 1.5 cm, N0-2) were randomized 1 : 1 to receive weekly paclitaxel 80 mg/m 2 with ipatasertib 400 mg or placebo (days 1-21 every 28 days) for 12 weeks before surgery. Co-primary end points were pathologic complete response (pCR) rate (ypT0/TisN0) in the intention-to-treat (ITT) and immunohistochemistry phosphatase and tensin homolog (PTEN)-low populations. Secondary end points included pCR rate in patients with PIK3CA/AKT1/PTEN-altered tumors and pre-surgery response rates by magnetic resonance imaging (MRI).Results: pCR rates with ipatasertib versus placebo were 17% versus 13%, respectively, in the ITT population (N ¼ 151), 16% versus 13% in the immunohistochemistry PTEN-low population (N ¼ 35), and 18% versus 12% in the PIK3CA/AKT1/PTEN-altered subgroup (N ¼ 62). Rates of overall and complete response (CR) by MRI favored ipatasertib in all three populations (CR rate 39% versus 9% in the PIK3CA/AKT1/PTEN-altered subgroup). Ipatasertib was associated with more grade !3 adverse events (32% versus 16% with placebo), especially diarrhea (17% versus 1%). Higher cycle 1 day 8 (C1D8) immune score was significantly associated with better response only in placebo-treated patients. All ipatasertib-treated patients with low immune scores and a CR had PIK3CA/AKT1/PTEN-altered tumors.Conclusions: Adding ipatasertib to 12 weeks of paclitaxel for early TNBC did not clinically or statistically significantly increase pCR rate, although overall response rate by MRI was numerically higher with ipatasertib. The antitumor effect of ipatasertib was most pronounced in biomarker-selected patients. Safety was consistent with prior experience of ipatasertib-paclitaxel. A T-cellrich environment at C1D8 had a stronger association with improved outcomes in paclitaxel-treated patients than seen for baseline tumor-infiltrating lymphocytes. This dependency may be overcome with the addition of AKT inhibition, especially in patients with PIK3CA/AKT1/PTEN-altered tumors. ClinicalTrials.gov: NCT02301988.

Mutational Diversity and Therapy Response in Breast Cancer: A Sequencing Analysis in the Neoadjuvant GeparSepto Trial

“…For therapeutic strategies involving AKT inhibitors, currently tested in TNBC, it might be promising to combine PIK3CA mutations with other alterations, such as AKT and PTEN, the combination of these 3 genes has been linked to response to AKT inhibitors in the Lotus and Manta studies (29,30), and a similar approach was investigated in the neoadjuvant Fairlane study (31). The rate of PIK3/AKT pathway alterations ranged from 23% to 43%, which was higher than the 8% in our study, which did not include PTEN loss.…”

Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling

“…To develop an AKT-targeting heterobifunctional degrader, we designed compounds based on GDC-0068, the most advanced AKT inhibitor in clinical trials (Oliveira et al, 2019). The cocrystal structure of GDC-0068 bound to AKT1 (PDB ID: 4EKL) revealed that the isopropylamine is solvent-exposed, suggesting that the amine could serve as a suitable attachment site for linkers without adversely affecting affinity to AKT (Figure 1A).…”

“…Current strategies to target AKT have focused on ATP-competitive, allosteric, and covalent inhibitors. Several ATP-competitive inhibitors, such as ipatasertib (GDC-0068) and capivasertib (AZD5363), are currently under clinical investigation in phase II and III studies (Oliveira et al, 2019;Turner et al, 2019). However, these inhibitors suffer from a lack of selectivity among the AGC kinase family, and this may limit their clinical efficacy or tolerability (Huck and Mochalkin, 2017).…”

Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44

“…Recently an orally available PI3K alpha specific inhibitor termed Alpelisib has been approved for treatment of PIK3CA-mutated, hormone receptorpositive advanced breast cancer [3]. Akt inhibitors Capivasertib [4] and Ipatasertib [5] are in late stage clinical trials for breast cancers bearing PI3K or Akt mutations. However, studies to date indicate that despite encouraging initial responses, the majority of tumors display inherent resistance or develop acquired resistance to PI3K/Akt pathway inhibitors through diverse mechanisms [6,7].…”

“…This targets SGK3 to endosomal membranes, where a large pool of PtdIns(3)P is generated by the Class III PI3K family member, known as hVps34 [17,19,20]. Activation of Class I PI3K can also contribute to the pool of PtdIns(3)P at the endosomal membrane through the sequential degradation of PtdIns (3,4,5)P3 via SHIP2 and INPP4A/4B inositol phosphatases [21,22]. Studies undertaken with selective class 1 and class 3 PI3K inhibitors indicate that both PI3K family members contribute to the activation of SGK3 by growth factors [22].…”