University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
Hope S. Rugo , Mafalda Oliveira , Sacha Jon Howell , Florence Dalenc , Javier Cortes , Henry Leonidas Gomez , Xichun Hu , Hiroji Iwata , Komal L. Jhaveri , Sibylle Loibl , Serafin Morales Murillo , Meena Okera , Yeon Hee Park , Joohyuk Sohn , Lyudmila Zhukova , Jill Logan , Ken Twomey , Mahmuda Khatun , Celina M. D'Cruz , Nicholas C. Turner
Background: In the CAPItello-291 trial in eligible pts with AI-resistant HR+/HER2– ABC, the addition of C (a potent, selective pan-AKT inhibitor) to F significantly improved PFS (primary endpoint) compared with placebo (P) in the overall (HR 0.60; 95% CI 0.51–0.71; p<0.001) and AKT pathway-altered population (HR 0.50; 95% CI 0.38–0.65; p<0.001). We report a detailed analysis of AEs. Methods: Pts were randomized 1:1 to receive F (500 mg IM on days 1 and 15 of cycle 1, and day 1 of each subsequent 28-day cycle) with either P or C (400 mg BID; 4 days on, 3 days off). Pts with HbA1c <8.0% and diabetes not requiring insulin were eligible. Incidence, management, and time to onset were summarized for common AEs (>10% any grade and >2.0% grade ≥3; CTCAE v5.0). Results: Overall, 708 pts were randomized to C+F (n=355) vs P+F (n=353); safety population C+F (n=355) vs P+F (n=350). Baseline risk factors potentially associated with hyperglycemia were a history of diabetes in 34 pts (10%) in the C+F arm vs 20 pts (6%) in the P+F arm (baseline median [range] HbA1c 5.4% [4.0–8.3] vs 5.4% [3.9–7.7]), median weight 65.0 kg (34–150) vs 66.5 kg (37–147) and 54% vs 53% of pts overweight/obese in the C+F vs P+F arms, respectively. Common AEs were diarrhea, rash, and hyperglycemia; maximum AE grade was mostly 1/2 and led to low rates of discontinuation. In the C+F arm, medications for the management of AEs were used in 151/257 pts (59%) with diarrhea (mostly loperamide; n=135), 109/135 pts (81%) with rash (mostly antihistamines; n=75/topical corticosteroids; n=64), and 28/60 pts (47%) with hyperglycemia (mostly metformin; n=18). Conclusions: Diarrhea, rash, and hyperglycemia, the most commonly reported AEs associated with AKT pathway inhibition, occur early in treatment with C+F, are generally low grade and manageable, and are associated with low rates of dose modifications/discontinuations. Clinical trial information: NCT04305496.
Diarrheaa | Rasha | Hyperglycemiaa | |||||
---|---|---|---|---|---|---|---|
C+F | P+F | C+F | P+F | C+F | P+F | ||
Any grade; n (%) | 257 (72.4) | 71 (20.3) | 135 (38.0) | 25 (7.1) | 60 (16.9) | 14 (4.0) | |
Maximum grade; n (%) | 1 | 164 (46.2) | 61 (17.4) | 57 (16.1) | 19 (5.4) | 26 (7.3) | 8 (2.3) |
2 | 60 (16.9) | 9 (2.6) | 35 (9.9) | 5 (1.4) | 26 (7.3) | 5 (1.4) | |
3 | 33 (9.3) | 1 (0.3) | 43 (12.1) | 1 (0.3) | 7 (2.0)b | 1 (0.3) | |
Median (interquartile range) time to onset, days | 8.0 (2.0–22.0) | 22.0 (10.0–57.0) | 12.0 (10.0–15.0) | 48.0 (22.0–108) | 15.0 (1.0–51.0) | 47.5 (28.0–120.0) | |
AE leading to dose change; n (%) | Reduction | 28 (7.9) | 0 | 16 (4.5) | 0 | 2 (0.6) | 0 |
Interruption | 35 (9.9) | 3 (0.9) | 42 (11.8) | 0 | 9 (2.5) | 3 (0.9) | |
Discontinuation | 7 (2.0) | 0 | 16 (4.5) | 0 | 1 (0.3) | 1 (0.3) |
aGroup terms (preferred terms): diarrhea (diarrhea, frequent bowel movements, gastrointestinal hypermotility); rash (rash, rash macular, maculopapular rash, rash papular, rash pruritic) and hyperglycemia (blood glucose increased, hyperglycemia). bOne additional pt (0.3%) had grade 4 hyperglycemia.
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