Table 3.

FDA risk-benefit analysis, SOLAR-1 (7).

DimensionEvidence and uncertaintiesConclusions and reasons
Analysis of conditionBreast cancer is the most common cancer in women, with more than 260,000 new cases and 40,000 deaths annually.Advanced or metastatic breast cancer is a serious and life-threatening condition with ongoing unmet medical need in both female and male patients.
Breast cancer is rare in men, and limited data are available from clinical trials on its treatment.
Advanced or metastatic breast cancer is incurable.
Current treatment optionsMetastatic breast cancer is not currently curable. Treatment goals are palliative in nature and include delay of disease progression, prolongation of survival, and reduction of cancer-related symptoms.All currently available treatment options are palliative. There is an unmet medical need to improve outcomes of female and male patients with HR-positive, HER2-negative advanced or metastatic breast cancer.
FDA-approved therapies for patients with HR-positive, HER2-negative advanced or metastatic breast cancer include endocrine therapy (AI and fulvestrant) in combination with CDK 4/6 inhibitors (abemaciclib, palbociclib, and ribociclib), everolimus with exemestane, endocrine monotherapy (AI, fulvestrant, and tamoxifen), and chemotherapy (multiple agents including taxanes, capecitabine, eribulin, vinorelbine, ixabepilone, and gemcitabine).
BenefitSOLAR-1 enrolled 572 postmenopausal women and men with HR-positive, HER2-negative advanced or metastatic breast cancer whose disease had progressed or recurred on or after an AI, with or without a CDK 4/6 inhibitor.The SOLAR-1 trial met its primary endpoint with a statistically significant and clinically meaningful improvement in PFS. This is also the first drug approved specifically for the treatment of patients with PIK3CA-mutated tumor, advanced breast cancer, which represents a new molecular subset in breast cancer.
In patients whose tumors had a PIK3CA tumor mutation, the estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11 months (95% CI, 7.5–14.5) compared with 5.7 months (95% CI, 3.7–7.4) in the placebo plus fulvestrant arm (HR, 0.65; 95% CI, 0.50–0.85; two-sided P = 0.001).The CDx test therascreen PIK3CA RGQ PCR Kit (QIAGEN Manchester, Ltd.) will be used to select patients who have PIK3CA mutations in tumor tissue specimens and/or in ctDNA isolated from plasma specimens. If the test is negative for PIK3CA mutations in plasma, tumor tissue should be tested.
The overall response rate in patients with a PIK3CA tumor mutation, measurable disease at baseline, and confirmed response was higher in the alpelisib plus fulvestrant arm (36% vs. 16%).
Risk and risk managementAdverse reactions were common and, except for hyperglycemia and rash, predominantly grade 1–2 in severity.Alpelisib plus fulvestrant can be used safely with appropriate labeling. No Risk Evaluation and Mitigation Strategies (REMS) is indicated.
The majority of adverse reactions were managed with dose reductions, temporary treatment discontinuations, supportive care treatments, and/or standard therapy, but 21% of patients discontinued alpelisib due to AEs.
Severe hypersensitivity, severe cutaneous reactions, hyperglycemia, pneumonitis, diarrhea, and embryo-fetal toxicity are labeled as warnings and precautions.
The most common adverse reactions on the alpelisib plus fulvestrant arm were increased glucose (79%), increased creatinine (67%), diarrhea (58%), rash (52%), lymphocyte count decreased (52%), increased gamma glutamyl transferase (52%), nausea (45%), increased alanine aminotransferase (44%), increased lipase (42%), and fatigue (42%).
Serious adverse reactions occurred in 35% of patients who received alpelisib plus fulvestrant, including hyperglycemia, rash, diarrhea, acute kidney injury, abdominal pain, and anemia.
21% of patients permanently discontinued alpelisib alone due to adverse reactions, and 4.6% permanently discontinued both alpelisib and fulvestrant.