Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer

Dent, R.; Oliveira, M.; Isakoff, S. J.; S. -A., Im; Espie, M.; Blau, S.; Tan, A. R.; Saura, C.; Wongchenko, M. J.; Xu, N.; Bradley, D.; Reilly, S. -J.; Mani, A.; Kim, S. -B.; Lee, K. S.; Sohn, J. H.; Kim, J. H.; Seo, J. H.; Kim, J. S.; Park, S.; Velez, M.; Dakhil, S.; Hurvitz, S.; Valero, V.; Vidal, G.; Figlin, R.; Allison, M. A. K.; Chan, D.; Cobleigh, M.; Hansen, V.; Iannotti, N.; Lawler, W.; Salkini, M.; Seigel, L.; Romieu, G.; Debled, M.; Levy, C.; Hardy-Bessard, A.; Guiu, S.; Estevez, L. G.; Villanueva, R.; Martin, A. G.; Rovira, P. S.; Montano, A.; Plaza, M. I. C.; Saenz, J. A. G.; Garau, I.; Bermejo, B.; Alonso, E. V.; Wang, H. -C.; Huang, C. -S.; Chen, S. -C.; Chen, Y. -H.; Tseng, L. -M.; Wong, A.; Ang, C. S. P.; De Laurentiis, M.; Conte, P. F.; De Braud, F.; Montemurro, F.; Gianni, L.; Dirix, L.

doi:10.1007/s10549-021-06143-5

Purpose: In LOTUS (NCT02162719), adding the oral AKT inhibitor ipatasertib to first-line paclitaxel for locally advanced/metastatic triple-negative breast cancer (aTNBC) improved progression-free survival (PFS; primary endpoint), with an enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumors (FoundationOne next-generation sequencing [NGS] assay). We report final overall survival (OS) results. Methods: Eligible patients had measurable previously untreated aTNBC. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status, and were randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8, 15) plus ipatasertib 400 mg or placebo (days 1-21) every 28 days until disease progression or unacceptable toxicity. OS (intent-to-treat [ITT], immunohistochemistry PTEN-low, and PI3K/AKT pathway-activated [NGS PIK3CA/AKT1/PTEN-altered] populations) was a secondary endpoint. Results: Median follow-up was 19.0 versus 16.0 months in the ipatasertib-paclitaxel versus placebo-paclitaxel arms, respectively. In the ITT population (n = 124), median OS was numerically longer with ipatasertib-paclitaxel than placebo-paclitaxel (hazard ratio 0.80, 95% CI 0.50-1.28; median 25.8 vs 16.9 months, respectively; 1-year OS 83% vs 68%). Likewise, median OS favored ipatasertib-paclitaxel in the PTEN-low (n = 48; 23.1 vs 15.8 months; hazard ratio 0.83) and PIK3CA/AKT1/PTEN-altered (n = 42; 25.8 vs 22.1 months; hazard ratio 1.13) subgroups. The ipatasertib-paclitaxel safety profile was unchanged. Conclusions: Final OS results show a numerical trend favoring ipatasertib-paclitaxel and median OS exceeding 2 years with ipatasertib-paclitaxel. Overall, results are consistent with the reported PFS benefit; interpretation within biomarker-defined subgroups is complicated by small sample sizes and TNBC heterogeneity.

Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer / Dent, R.; Oliveira, M.; Isakoff, S. J.; Im, S. -A.; Espie, M.; Blau, S.; Tan, A. R.; Saura, C.; Wongchenko, M. J.; Xu, N.; Bradley, D.; Reilly, S. -J.; Mani, A.; Kim, S. -B.; Lee, K. S.; Sohn, J. H.; Kim, J. H.; Seo, J. H.; Kim, J. S.; Park, S.; Velez, M.; Dakhil, S.; Hurvitz, S.; Valero, V.; Vidal, G.; Figlin, R.; Allison, M. A. K.; Chan, D.; Cobleigh, M.; Hansen, V.; Iannotti, N.; Lawler, W.; Salkini, M.; Seigel, L.; Romieu, G.; Debled, M.; Levy, C.; Hardy-Bessard, A.; Guiu, S.; Estevez, L. G.; Villanueva, R.; Martin, A. G.; Rovira, P. S.; Montano, A.; Plaza, M. I. C.; Saenz, J. A. G.; Garau, I.; Bermejo, B.; Alonso, E. V.; Wang, H. -C.; Huang, C. -S.; Chen, S. -C.; Chen, Y. -H.; Tseng, L. -M.; Wong, A.; Ang, C. S. P.; De Laurentiis, M.; Conte, P. F.; De Braud, F.; Montemurro, F.; Gianni, L.; Dirix, L.. - In: BREAST CANCER RESEARCH AND TREATMENT. - ISSN 0167-6806. - 189:2(2021), pp. 377-386. [10.1007/s10549-021-06143-5]