In the Journals

Capivasertib plus paclitaxel improves survival in triple-negative breast cancer

Peter Schmid
Peter Schmid

The addition of the AKT inhibitor capivasertib to first-line paclitaxel extended PFS and OS among a cohort of women with previously untreated, metastatic triple-negative breast cancer, according to results of the phase 2 PAKT trial published in Journal of Clinical Oncology.

The beneficial effect of capivasertib (AZD5363, AstraZeneca) appeared more pronounced among women with PIK3CA, AKT1 and/or PTEN-altered tumors.

“Apart from the enormous clinical need to have more effective therapies for patients with triple-negative breast cancer, we also know that the PI3K/AKT pathway is frequently activated in triple-negative disease and is associated with resistance to chemotherapy,” Peter Schmid, MD, PhD, FRCP, clinical director of St. Bartholomew Breast Cancer Centre in London and lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, told Healio.

For this reason, Schmid and colleagues sought to assess the safety and efficacy of capivasertib plus paclitaxel as first-line therapy among a cohort of women with previously untreated, metastatic, triple-negative breast cancer.

In the PAKT trial, researchers randomly assigned 140 women (median age, 54 years) to 90 mg/m² paclitaxel on days 1, 8 and 15 plus 400 mg twice-daily capivasertib (n = 70) or placebo (n = 70) every 28 days until disease progression or unacceptable toxicity. Most women (69%) had visceral involvement, and 46% had metastases in three or more organs.

The majority of women (77%) received adjuvant or neoadjuvant chemotherapy, 57% received prior taxane-based therapy and 18 women had de novo metastatic disease.

PFS served as the primary endpoint. OS, PFS and OS in a subgroup of women with PIK3CA/AKT1/PTEN alterations, tumor response and safety served as secondary endpoints.

Median follow-up was 18.2 months (95% CI, 13.5-24).

Researchers observed 51 progression events in the capivasertib group compared with 61 in the placebo group. Median PFS was 5.9 months in the capivasertib group vs. 4.2 months in the placebo group (HR = 0.74; 95% CI, 0.5-1.08). This result narrowly missed the predefined significance level (one-sided) to detect improvement in PFS with capivasertib; however, this was achieved according to central review assessments (median PFS, 5.5 months vs. 3.6 months; HR = 0.64; 95% CI, 0.43-0.95).

Median OS was 19.1 months in the capivasertib group compared with 12.6 months in the placebo group (HR = 0.61; 95% CI, 0.37-0.99).

More women in the capivasertib group experienced grade 3 to grade 4 diarrhea (13% vs. 1%), infection (4% vs. 1%), fatigue (4% vs. 0%) and rash (4% vs. 0%).

Among the subgroup of women with PIK3CA/AKT1/PTEN-altered tumors (n = 28), results showed median PFS of 9.3 months (95% CI, 3.7-17.7) with capivasertib vs. 3.7 months (95% CI, 1.9-5.9) with placebo (HR = 0.3; 95% CI, 0.11-0.79).

Results of an exploratory analysis of the interaction between PIK3CA/AKT1/PTEN-altered tumors and treatment showed a 66% (HR = 0.34; 95% CI, 0.13-0.93) reduction in risk for women with these alterations in the capivasertib group.

Median duration of response was 7.6 months (95% CI, 5.6-12.5) in the capivasertib group vs. 7.3 months (95% CI, 3.5-9.1) in the placebo group. However, among those with PIK3CA/AKT1/PTEN-altered tumors, median duration of response was 13.3 months (95% CI, 8.9 to not reached) with capivasertib and 3.5 months (95% CI, 3.5 to not reached) with placebo.

By data cutoff, 33 deaths had occurred in the capivasertib group vs. 41 deaths in the placebo group.

“Our trial clearly indicates that the addition of the AKT inhibitor [capivasertib] can improve the outcome of first-line paclitaxel chemotherapy with longer PFS and OS,” Schmid told Healio. “Most of the benefit seems to be observed in patients with certain mutations in their tumor, including AKT, PIK3CA or PTEN. The results are the basis for the phase 3 Capitell290 trial in the same setting, which is currently underway.” – by Jennifer Southall

For more information:

Peter Schmid, MD, PhD, can be reached at Barts Cancer Institute of Queen Mary University of London, Old Anatomy Building, Charterhouse Square, London EC1M 6BQ, United Kingdom; email: p.schmid@qmul.ac.uk.

Disclosures: Schmid reports honoraria from AstraZeneca, Novartis, Pfizer and Roche; consultant/advisory board roles with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Merck, Novartis, Pfizer and Puma Biotechnology; and research funding to his institution from Astellas Pharma, AstraZeneca, Genentech, Medivation, Merck, Novartis, Oncogenex and Roche. He also reports that an immediate family member is employed by Roche. Please see the study for all other authors’ relevant financial disclosures.

Peter Schmid
Peter Schmid

The addition of the AKT inhibitor capivasertib to first-line paclitaxel extended PFS and OS among a cohort of women with previously untreated, metastatic triple-negative breast cancer, according to results of the phase 2 PAKT trial published in Journal of Clinical Oncology.

The beneficial effect of capivasertib (AZD5363, AstraZeneca) appeared more pronounced among women with PIK3CA, AKT1 and/or PTEN-altered tumors.

“Apart from the enormous clinical need to have more effective therapies for patients with triple-negative breast cancer, we also know that the PI3K/AKT pathway is frequently activated in triple-negative disease and is associated with resistance to chemotherapy,” Peter Schmid, MD, PhD, FRCP, clinical director of St. Bartholomew Breast Cancer Centre in London and lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, told Healio.

For this reason, Schmid and colleagues sought to assess the safety and efficacy of capivasertib plus paclitaxel as first-line therapy among a cohort of women with previously untreated, metastatic, triple-negative breast cancer.

In the PAKT trial, researchers randomly assigned 140 women (median age, 54 years) to 90 mg/m² paclitaxel on days 1, 8 and 15 plus 400 mg twice-daily capivasertib (n = 70) or placebo (n = 70) every 28 days until disease progression or unacceptable toxicity. Most women (69%) had visceral involvement, and 46% had metastases in three or more organs.

The majority of women (77%) received adjuvant or neoadjuvant chemotherapy, 57% received prior taxane-based therapy and 18 women had de novo metastatic disease.

PFS served as the primary endpoint. OS, PFS and OS in a subgroup of women with PIK3CA/AKT1/PTEN alterations, tumor response and safety served as secondary endpoints.

Median follow-up was 18.2 months (95% CI, 13.5-24).

Researchers observed 51 progression events in the capivasertib group compared with 61 in the placebo group. Median PFS was 5.9 months in the capivasertib group vs. 4.2 months in the placebo group (HR = 0.74; 95% CI, 0.5-1.08). This result narrowly missed the predefined significance level (one-sided) to detect improvement in PFS with capivasertib; however, this was achieved according to central review assessments (median PFS, 5.5 months vs. 3.6 months; HR = 0.64; 95% CI, 0.43-0.95).

Median OS was 19.1 months in the capivasertib group compared with 12.6 months in the placebo group (HR = 0.61; 95% CI, 0.37-0.99).

More women in the capivasertib group experienced grade 3 to grade 4 diarrhea (13% vs. 1%), infection (4% vs. 1%), fatigue (4% vs. 0%) and rash (4% vs. 0%).

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Among the subgroup of women with PIK3CA/AKT1/PTEN-altered tumors (n = 28), results showed median PFS of 9.3 months (95% CI, 3.7-17.7) with capivasertib vs. 3.7 months (95% CI, 1.9-5.9) with placebo (HR = 0.3; 95% CI, 0.11-0.79).

Results of an exploratory analysis of the interaction between PIK3CA/AKT1/PTEN-altered tumors and treatment showed a 66% (HR = 0.34; 95% CI, 0.13-0.93) reduction in risk for women with these alterations in the capivasertib group.

Median duration of response was 7.6 months (95% CI, 5.6-12.5) in the capivasertib group vs. 7.3 months (95% CI, 3.5-9.1) in the placebo group. However, among those with PIK3CA/AKT1/PTEN-altered tumors, median duration of response was 13.3 months (95% CI, 8.9 to not reached) with capivasertib and 3.5 months (95% CI, 3.5 to not reached) with placebo.

By data cutoff, 33 deaths had occurred in the capivasertib group vs. 41 deaths in the placebo group.

“Our trial clearly indicates that the addition of the AKT inhibitor [capivasertib] can improve the outcome of first-line paclitaxel chemotherapy with longer PFS and OS,” Schmid told Healio. “Most of the benefit seems to be observed in patients with certain mutations in their tumor, including AKT, PIK3CA or PTEN. The results are the basis for the phase 3 Capitell290 trial in the same setting, which is currently underway.” – by Jennifer Southall

For more information:

Peter Schmid, MD, PhD, can be reached at Barts Cancer Institute of Queen Mary University of London, Old Anatomy Building, Charterhouse Square, London EC1M 6BQ, United Kingdom; email: p.schmid@qmul.ac.uk.

Disclosures: Schmid reports honoraria from AstraZeneca, Novartis, Pfizer and Roche; consultant/advisory board roles with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Merck, Novartis, Pfizer and Puma Biotechnology; and research funding to his institution from Astellas Pharma, AstraZeneca, Genentech, Medivation, Merck, Novartis, Oncogenex and Roche. He also reports that an immediate family member is employed by Roche. Please see the study for all other authors’ relevant financial disclosures.