Addition of Capivasertib to Paclitaxel Fails to Improve OS in Metastatic TNBC

"CAPItello-290 did not meet the predefined threshold for improving overall survival in either the overall population or in the altered population, although PFS numerically favored first-line capivasertib with paclitaxel over placebo in metastatic triple-negative breast cancer,” according to Heather McArthur, MD, MPH.

The addition of capivasertib (Truqap) to paclitaxel, compared with placebo plus paclitaxel, in the first-line treatment of metastatic triple-negative breast cancer (TNBC) did not improve overall survival (OS) in the overall population and those with PIK3CA/AKT1/PTEN alterations, according to data from the global phase 3 CAPItello-290 trial (NCT03997123) presented at the 2024 European Society for Medical Oncology Congress (ESMO).¹

“CAPItello-290 did not meet the predefined threshold for improving overall survival in either the overall population or in the altered population, although PFS numerically favored first-line capivasertib with paclitaxel over placebo in metastatic triple-negative breast cancer,” Heather McArthur, MD, MPH, professor of internal medicine at UT Southwestern Medical Center in Dallas, Texas, said during a presentation at the congress.

In the overall population, median OS was 17.7 months (95% CI, 15.6-20.3) with the addition of capivasertib, compared with 18.0 months (95% CI, 15.3-20.3) with placebo (HR, 0.92; 95% CI, 0.78-1.08; P = .3239). In the PIK3CA/AKT1/PTEN-altered population, median OS was 20.4 months (95% CI, 15.7-23.4) and 20.4 months (95% CI, 14.6-26.9), respectively (HR, 1.05; 95% CI, 0.77-1.43; P = .7602). “The overall survival result in the overall population was not attributable to any specific subgroup,” McArthur noted.

In the overall population, median progression-free survival (PFS) was 5.6 months (95% CI, 5.4-7.1)with the addition of capivasertib, compared with 5.1 months (95% CI, 3.9-5.4) with placebo (HR, 0.72; 95% CI, 0.61-0.84). In the PIK3CA/AKT1/PTEN-altered population, median PFS was 7.5 months (95% CI, 5.6-9.3) and 5.6 months (95% CI, 5.3-5.7), respectively (HR, 0.70; 95% CI, 0.52-0.95). “The treatment effect was consistent across all subgroups that were interrogated,” McArthur added.

In the overall population, the overall response rate (ORR) was 50.1% with capivasertib, compared with 37.6% with placebo (OR, 1.68; 95% CI, 1.27-2.23). Among those who received capivasertib, investigators observed 9 (2.2%) complete responses (CRs), 192 (47.9%) partial responses (PRs), 107 (26.7%) with stable disease (SD), and 68 (17.0%) with progressive disease (PD). A total 6.2% of patients (n = 25) were not evaluable. In the PIK3CA/AKT1/PTEN-altered population, the ORRs were 54.1% and 41.9%, respectively, with 3 CRs (2.5%), 63 PRs (51.6%), 30 with SD (24.6%), and 19 with PD (15.6%) observed with capivasertib; 7 patients (5.7%) were not evaluable.

In the capivasertib arms, diarrhea was the most common adverse event (grade 3 or higher, 12.7%). In addition, McArthur pointed out the rate of grade 1/2 hyperglycemia (22.1%) with the agent.

“The frequency of adverse events leading to discontinuation was low across all subgroups. However, interruptions and reductions were more common in the capivasertib-treated populations,” McArthur said.

In the double-blind, randomized, phase 3 CAPItello-290 trial, investigators aimed to evaluate the efficacy and safety of capivasertib plus paclitaxel, vs placebo in combination with paclitaxel, in the first-line treatment of patients with locally advanced or metastatic TNBC.

Rationalization for the phase 3 trial was based on results from the randomized, double-blind phase 2 LOTUS trial (NCT02162719), designed to evaluate ipatasertib plus paclitaxel vs placebo plus paclitaxel in metastatic TNBC; and the phase 2 PAKT trial (NCT02423603) of capivasertib plus paclitaxel vs placebo plus paclitaxel as frontline therapy in patients with advanced TNBC, including those with PIK3CA/AKT1/PTEN-altered tumors. McArthur noted that both trials showed favorable PFS and OS with an AKT inhibitor, with a potential PS benefit in those with or without PIK3CA/AKT1/PTEN tumour alterations.

In the trial, 812 patients were randomized 1:1 to receive either 400 mg capivasertib (overall population, n = 404; PIK3CA/AKT1/PTEN-altered population, n = 124) or placebo (overall population, n = 408; PIK3CA/AKT1/PTEN-altered population, n = 125) twice daily (days 2 through 5 of weeks 1 through 3), both in combination with 80 mg/m2 paclitaxel (day 1 of weeks 1 through 3 of each 4-week cycle).

Inclusion criteria comprised patients with locally advanced or metastatic TNBC; men and pre-/postmenopausal women; eligible for taxane monotherapy; no prior (neo)adjuvant chemotherapy within 6 months (12 months for taxanes); no prior systemic therapy for inoperable locally advanced or metastatic disease; ECOG performance status 0 or 1; HbA1c less than 8.0% (63.9 mmol/mol) and diabetes not requiring insulin allowed; and formalin-fixed paraffin-embedded tumor sample from the primary/recurrent cancer available for retrospective central molecular testing.

Stratification factors included visceral vs non-visceral disease, receipt of curative intent chemotherapy, and region of enrollment.

OS in the overall and the PIK3CA/AKT1/PTEN-altered populations served as the dual primary end points. Secondary end points included PFS in the overall and the PIK3CA/AKT1/PTEN-altered populations, as well as safety.

With a planned number of 520 events in the overall population and 160 events in the PIK3CA/AKT1/PTEN-altered population, the assumed OS HR was 0.75 in the overall population and 0.65 in the PIK3CA/AKT1/PTEN-altered population.

McArthur noted that the median age of participants was approximately 54 years, and all participants were female. Approximately two-thirds of the participants were postmenopausal, and the median body mass index was just over 26 kg/m².

Further, over two-thirds of patients had visceral metastases, and approximately 40% had de novo metastatic disease. Fifty percent of patients received prior curative intent chemotherapy. McArthur also noted that 15% of patients had PD-L1-positive tumors, “although notably, 40% of patients did not have PD-L1 status available for assessment. And one question I would imagine is, how many patients got the [phase 3] KEYNOTE-522 [NCT03036488] regimen [of neoadjuvant pembrolizumab plus chemotherapy].” Lastly, 4 patients overall received prior immunotherapy.

PIK3CA and PTEN alterations were the most commonly identified, seen in 12.5% and 11.8% of patients overall.

“Despite modest advances, triple-negative breast cancer remains one of the most challenging forms of disease to treat due to the lack of known actionable biomarker targets, and chemotherapy-based regimens continue to be the mainstay of treatment,” principal investigator Peter Schmid, MD, Barts Cancer Institute, London, said in an AstraZeneca-issued release.² “While the CAPItello-290 trial results have not shown what we hoped, they provide important information to further understand this aggressive form of breast cancer where patients are in urgent need of new treatments.”

Disclosures: McArthur cited advisory board roles with AstraZeneca, Bristol Myers Squibb, Crown Bioscience, Daiichi Sankyo, Eli Lilly, Genentech, Gilead Sciences, Immunomedics, Merck, Novartis, Pfizer, Biotechnology, Roche, and Seattle Genetics; and institutional research funding from AstraZeneca, Bristol Myers Squibb, Medimmune, and Merck.

References

1. Schmid P, McArthur H, Cortes J, et al. Capivasertib + paclitaxel as first-line treatment of metastatic triple-negative breast cancer: the CAPItello-290 Phase 3 trial. Presented at: ESMO Congress 2024; September 12-16, 2024; Barcelona, Spain. Abstract LBA19.
2. AstraZeneca News Release. Update on the CAPItello-290 phase III trial for Truqap plus chemotherapy in advanced or metastatic triple-negative breast cancer. Published: June 18, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/update-on-capitello-290-phase-iii-trial.html. Accessed: September 13, 2024.