Discussion
TNBC, tumors, mTNBC
TUMORS
The results of the current trial provide evidence that combining ipatasertib with continuous daily dosing with weekly carboplatin or carboplatin/paclitaxel is safe and has modest clinical activity in patients with mTNBC. In addition, ipatasertib (21 days on and 7 days off) combined with capecitabine and atezolizumab is safe and showed clinical activity. In patients with PIK3CA/AKT/PTEN alteration, ORR was 33% (5/15, including 1 CR). In AR+ TNBC, ORR was 40% (4/10). Due to limited sample size, these results are hypothesis-generating. The KEYNOTE-355 trial already established ICI plus chemotherapy for standard management of first–line patients with PD-L1+ TNBC.ICI plus chemotherapy combinations are now standard of care for PD-L1 positive mTNBC. Atezolizumab was initially granted FDA approval in March 2019 based on significant PFS benefit when atezolizumab was combined with nab–paclitaxel vs nab–paclitaxel alone seen in from IMpassion130 trial (HR, 0.60; 95% CI, 0.48-0.77; In LOTUS trial, ipatasertib added to first–line paclitaxel for mTNBC improved PFS with an enhanced effect in patients with PIK3CA/AKT1/PTEN–altered tumors.TNBC is molecularly heterogeneous with at least 4-6 molecular subtypes defined by mRNA expression. Among these, approximately 10% are luminal androgen receptor positive (LAR).Other AKT inhibitors are currently undergoing vigorous clinical investigation. In the PAKT trial, the addition of the pan-AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in longer PFS and OS. The median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50-1.08; 1-sided There are several limitations of this study including early discontinuation due to withdrawal of funding, limited enrollment per arm, variation of chemotherapy backbone, lack of randomized Phase II design, and underlying molecular heterogeneity of mTNBC. An appropriately designed randomized Phase II trial may facilitate better understanding the role of ipatasertib in treating patients with TNBC who have specific molecular alterations or phenotypes.