Detailed AE management plan may help reduce alpelisib discontinuations in breast cancer

Author: By Laura Cowen, medwireNews Reporter 

medwireNews: Implementation of a detailed adverse event (AE) management plan may help improve safety outcomes and reduce discontinuations among patients with advanced breast cancer undergoing treatment with alpelisib plus fulvestrant, shows an analysis of data from the phase III SOLAR-1 trial. 

The trial included patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. Participants were randomly assigned to receive the PI3K inhibitor alpelisib 300 mg/day (n=284) or placebo (n=287) each in combination with fulvestrant 500 mg on days 1 and 15 of cycle 1 and on day 1 of each subsequent 28-day cycle. In all, 341 patients carried a PI3KCA mutation. 

The primary data analysis revealed that the most common grade 3 or 4 AEs among the patients receiving alpelisib were hyperglycaemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), maculopapular rash (grade 3, 8.8%) and diarrhoea (grade 3, 6.7%), which the researchers say “are expected with PI3K inhibition”. 

The current, more detailed, safety analysis found that the median time to onset of grade 3 or worse hyperglycaemia, rash and diarrhoea was 15 days, 13 days and 139 days, respectively. The corresponding median times for each of these AEs to improve by at least one grade after reporting were 6 days, 11 days and 18 days. 

Most (87.1%) patients who experienced any-grade hyperglycaemia received an antidiabetic agent, typically metformin, while just under half (47.2%) of the alpelisib group were given anti-rash medication, most commonly steroids and antihistamines, and almost two-thirds (63.4%) were treated for diarrhoea, typically with loperamide. 

In all, 59.2% of the alpelisib group required a dose reduction and 72.2% required a dose interruption, with AEs the main reason given in both cases (57.7 and 66.5%, respectively). 

Hope Rugo, from the University of California San Francisco in the USA, and co-investigators note that when 56.6% of the planed 560 participants had been recruited, the study protocol was amended to improve monitoring and management of hyperglycaemia and skin toxicity. Specifically, the maximum permitted glycated haemoglobin level was reduced from 8.0% to 6.5% to exclude patients with uncontrolled diabetes, and consultation with a dermatologist was recommended for better assessment and management of alpelisib-induced skin toxicity.  

Following this amendment, the discontinuation rate due to any-grade AE was 20.7% compared with 29.2% before the change. The corresponding rates of discontinuations due to grade 3 or 4 AEs were 7.9% and 18.1% while those due to hyperglycaemia 3.6% and 9.0%. 

The researchers also found that the 86 patients in the alpelisib group who received preventative anti-rash medication prior to the onset of rash had a lower rate of any grade (26.7 vs 64.1%) and grade 3 rash (11.6 vs 22.7%) compared with those who received no preventative medication. 

Writing in the Annals of Oncology, Hope Rugo and co-authors say their findings “underscore the importance of education on early, prompt, and effective AE management for patients receiving alpelisib to maximize the intended clinical impact of the treatment on patients’ outcomes.” 

This statement is highlighted by the fact that individuals with alpelisib dose intensities at or above the median of 248 mg/day had longer progression-free survival (PFS) than those with lower dose intensities, at 12.5 versus 9.6 months. Median PFS with placebo was 5.8 months. 

The authors conclude that although their findings indicate that AEs of special interest associated with alpelisib “are largely manageable with concomitant medications, with or without dose modifications as needed”, observational data from real-world studies are now required to “provide insight into the impact of AE management approaches on the clinical benefit of this treatment and how this benefit can be maximized during routine clinical practice.” 

Reference  

Rugo HS, André F, Yamashita T, et al. Time course and management of key adverse events during the randomized phase 3 SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer. Ann Oncol; Advance online publication 12 May 2020. doi: 10.1016/j.annonc.2020.05.001