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LOTUS was the small trial that made the AKT-blocking tablet ipatasertib look promising in triple-negative breast cancer: added to paclitaxel it delayed progression by about six weeks. The larger IPATunity130 trial then failed to confirm it.
LOTUS (NCT02162719) randomised 124 women with measurable, untreated inoperable locally advanced or metastatic triple-negative breast cancer between September 2014 and February 2016 to paclitaxel 80 mg/m2 on days 1, 8 and 15 with ipatasertib 400 mg or placebo daily on days 1 to 21 of 28, stratified by prior neoadjuvant or adjuvant therapy, chemotherapy-free interval and PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat and PTEN-low populations. Median progression-free survival was 6.2 versus 4.9 months (stratified hazard ratio 0.60, 95 percent confidence interval 0.37 to 0.98, p 0.037) overall and 6.2 versus 3.7 months in the 48 patients with PTEN-low tumours (hazard ratio 0.59, 0.26 to 1.32, p 0.18); the largest effect was in tumours with PIK3CA, AKT1 or PTEN alterations, the group IPATunity130 then selected. Grade 3 or worse diarrhoea occurred in 23 percent of ipatasertib-treated patients against none on placebo. Its result, with PAKT for capivasertib, launched the two phase 3 AKT-inhibitor trials (IPATunity130, CAPItello-290) that both failed, so LOTUS is now read as an example of a phase 2 signal in a biomarker subgroup that did not replicate.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
124 enrolled.
| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Progression-free survival, intention to treatprimary | Ipatasertib + paclitaxel | 62 | 6.2 months | 0.6 (0.37 to 0.98) | 0.037 | link |
| Placebo + paclitaxel | 62 | 4.9 months | ||||
| Progression-free survival, PTEN-low tumoursprimary | Ipatasertib + paclitaxel | - | 6.2 months | 0.59 (0.26 to 1.32) | 0.18 | link |
| Placebo + paclitaxel | - | 3.7 months |
Shares IPATunity130, Capivasertib+Paclitaxel as First Line Treatment for Patients With Locally Advanced or Metastatic TNBC, Ipatasertib, AKT.
Shares Ipatasertib, PTEN, AKT, PI3K / AKT / mTOR.
Shares PTEN, AKT, PIK3CA / PI3K-alpha, PI3K / AKT / mTOR.
Shares Capivasertib+Paclitaxel as First Line Treatment for Patients With Locally Advanced or Metastatic TNBC, AKT, PI3K / AKT / mTOR, Paclitaxel / nab-paclitaxel.
Shares AKT, PIK3CA / PI3K-alpha, PI3K / AKT / mTOR.
Shares PTEN, AKT, PIK3CA / PI3K-alpha, PI3K / AKT / mTOR.
Shares PTEN, PIK3CA / PI3K-alpha, Triple-negative breast cancer (TNBC).
Shares Ipatasertib, Roche / Genentech, Paclitaxel / nab-paclitaxel.