Adding the oral AKT inhibitor ipatasertib to paclitaxel continued to demonstrate a clinically meaningful extension in overall survival (OS) in patients with locally advanced or metastatic triple-negative breast cancer (TNBC), according to the final analysis of the phase 2 LOTUS trial presented during the 2020 ESMO breast cancer virtual meeting.
In the intention-to-treat (ITT) population, the median OS was 25.8 months with ipatasertib plus paclitaxel versus 16.9 months in the control arm of placebo plus paclitaxel (HR, 0.80; 95% CI, 0.50-1.28). The 1-year OS rates were 83% versus 68%, respectively. The analysis occurred at a median follow-up of 19 months in the ipatasertib arm and 16 months in the placebo arm.
“This is a clinically meaningful improvement of 9 months in overall survival. Which, indeed, is not too dissimilar to what we see in patients with PD-L1–positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” said lead LOTUS author Rebecca Dent, MD, head of the Department of Medical Oncology at National Cancer Center Singapore. “The median overall survival [with ipatasertib] of greater than 2 years clearly represents a meaningful outcome in metastatic TNBC.”
Dent did note, however, that, “the [hazard ratio] confidence interval does cross 1, and, therefore, we do need confirmatory phase 3 results.”
The median OS favored the ipatasertib combination across all biomarker-defined subgroups. Among patients with normal tumor IHC PTEN status, the median OS was 28.5 versus 17.1 months with ipatasertib versus placebo, respectively (HR, 0.70; 95% CI, 0.36-1.36), and the 1-year OS rates were 85% versus 68%, respectively. Among patients with low PTEN status, the median OS and 1-year OS rates also favored the ipatasertib arm at 23.1 versus 15.8 months (HR, 0.83; 95% CI, 0.42-1.64) and 79% versus 64%, respectively.
In patients with non-altered PIK3CA/ACT1/PTEN status by NGS, the median OS was 23.1 months with ipatasertib compared with 16.2 months with placebo (HR, 0.72; 95% CI, 0.39-1.33), with 1-year OS rates of 81% versus 67%, respectively. Among patients with altered PIK3CA/ACT1/PTEN status by NGS, the median OS was 25.8 months with ipatasertib compared with 22.1 months with placebo (HR, 1.13; 95% CI, 0.52-2.47), with 1-year OS rates of 88% versus 63%, respectively.
Dent said that the IHC PTEN and NGS PIK3CA/ACT1/PTEN cohorts were all too small to make any definitive conclusions; therefore, as with the ITT data, a confirmatory phase 3 trial is needed.
The phase 2 LOTUS trial included 124 patients with previously untreated measurable locally advanced or metastatic TNBC not amenable to curative resection. Patients had to be at least 6 months removed from chemotherapy.
Patient characteristics were well balanced between the 2 arms. Specifically in the ipatasertib arm, the median age was 54 (range, 44-63), 71% had an ECOG performance status of 0, 29% had an ECOG performance status of 1, and 66% had prior neo(adjuvant) therapy (50% had prior taxane). The Targos PTEN H-score was 0 in 16% of patients; 1 to 150 in 44% of patients; and more than 150 in 40% of patients. Sites of metastases included lung (44%), liver (31%), lymph nodes (58%), and bone (26%). The chemotherapy-free interval was 6 to 12 months for 29% of patients and more than 12 months for 37% of patients, with the remaining 34% of patients having no prior chemotherapy.
“What was different about this study compared to other studies in the first-line metastatic setting is that the chemotherapy-free interval was greater than or equal to 6 months. And as you know, in many studies, it’s actually 12 months. So this study included a group of patients with quite aggressive disease,” said Dent.
Patients were randomized 1:1 to paclitaxel at 80 mg/m2
on days 1, 8, and 15, with either ipatasertib (n = 62) at 400 mg/day or placebo (n = 62) on days 1 to 21 of a 28-day cycle until progression or unacceptable toxicity. The coprimary end points were progression-free survival (PFS) in the ITT and IHC PTEN-low populations. Key secondary end points included OS, overall response rate, and safety.
Dent highlighted the OS activity with ipatasertib in subgroups defined by age. Among patients aged <50 years, the median OS was 35.2 months with ipatasertib compared with 15.1 months with placebo (HR, 0.41; 95% CI, 0.20-0.85). In patients aged ≥50 years, the median OS was 21.8 months with ipatasertib compared with 20.9 months with placebo (HR, 1.21; 95% CI, 0.71-2.07).
“What you can see [in patients aged <50 years] is that we have a hazard ratio of 0.41 that does not cross 1 in the confidence interval and we see…a 20-month improvement in overall survival. Now, this is hypothesis generating and needs to be confirmed in a phase 3 study, but I think it is biologically plausible, as many of us would agree, that patients who are under 50 who are triple-negative likely represent a different subgroup of [TNBC patients] who might be particularly susceptible to AKT inhibition,” said Dent.
Previously reported data from the LOTUS trial showed that the study had met the comprimary PFS end points.2
In the ITT population the median PFS was 6.2 months in the ipatasertib arm versus 4.9 months in the placebo arm (HR, 0.60; 95% CI, 0.37-0.98; P
= .037). In the IHC PTEN-low population, the median PFS was 6.2 versus 3.7 months, respectively (HR, 0.59; 95% CI, 0.26-1.32, P
Overall, 77% of patients in the ipatasertib arm had subsequent systemic anticancer therapy compared with 90% of patients in the placebo arm. These included immunotherapy (11% in ipatasertib arm vs 18% in control arm) and chemotherapy (77% vs 89%, respectively). Regarding specific chemotherapy treatment, platinum-containing regimens were administered to 53% of the ipatasertib arm versus 52% of the placebo arm, with non-platinum regimens being administered to 77% versus 89%, respectively.
Grade ≥3 adverse events (AEs) occurred in 56% of the ipatasertib arm compared with 45% of the placebo arm. Ipatasertib specifically led to AE-related treatment discontinuation in 7% (n = 4) of patients, AE-related dose interruption in 36% (n = 22), and AE-related dose reduction in 21% (n = 13).
“This combination is extremely well tolerated, especially when we compare it to other agents targeting this pathway. [We did] see noticeable diarrhea—in this particular study there were no prophylactic antidiarrheals given. What we also saw was an increase in sensory neuropathy, which is not entirely unexpected given that patients [in the ipatasertib arm] were on therapy longer and thus were exposed to a longer duration of paclitaxel, and hence, neuropathy would increase,” said Dent.
Key ongoing phase 3 trials of ipatasertib include IPATunity130 (NCT03337724) and IPATunity170 (NCT04177108). IPATunity130 is studying ipatasertib in combination with paclitaxel in patients with PIK3CA/AKT1/PTEN-altered, locally advanced or metastatic TNBC or hormone receptor–positive, HER2-negative breast cancer. IPATunity170 is evaluating ipatasertib plus atezolizumab (Tecentriq) and paclitaxel in patients with locally advanced or metastatic TNBC.
- Dent R, Antunes de Melo E Oliveira AM, Isakoff SJ, et al. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.
- Kim S-B, Dent R, Im S-A, et al. 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