Table 3:

FDA Risk-Benefit Analysis, SOLAR-1 (7)

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	Breast cancer is the most common cancer in women, with more than 260,000 new cases and 40,000 deaths annually. Breast cancer is rare in men, and limited data are available from clinical trials on its treatment. Advanced or metastatic breast cancer is incurable.	Advanced or metastatic breast cancer is a serious and life-threatening condition with ongoing unmet medical need in both female and male patients.
Current Treatment Options	Metastatic breast cancer is not presently curable. Treatment goals are palliative in nature and include delay of disease progression, prolongation of survival, and reduction of cancer-related symptoms. FDA approved therapies for patients with HR-positive, HER2-negative advanced or metastatic breast cancer include endocrine therapy (aromatase inhibitor [AI], fulvestrant) in combination with CDK 4/6 inhibitors (abemaciclib, palbociclib, ribociclib), everolimus with exemestane, endocrine monotherapy (AI, fulvestrant, tamoxifen), and chemotherapy (multiple agents including taxanes, capecitabine, eribulin, vinorelbine, ixabepilone, and gemcitabine.).	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.
Benefit	SOLAR-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 aromatase inhibitor, with or without a CDK 4/6 inhibitor. In patients whose tumors had a PIK3CA tumor mutation, the estimated median PFS by investigator assessment in the alpelisib plus fulvestrant arm was 11.0 months (95% CI: 7.5, 14.5) compared to 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 overall response rate (ORR) in patients with a PIK3CA tumor mutation, measurable disease at baseline, and confirmed response was higher in the alpelisib plus fulvestrant arm (36% versus 16%).	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 tumor mutated advanced breast cancer, which represents a new molecular subset in breast cancer. The companion diagnostic 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 circulating tumor DNA (ctDNA) isolated from plasma specimens. If the test is negative for PIK3CA mutations in plasma, tumor tissue should be tested.
Risk and Risk Management	Adverse reactions were common and, except for hyperglycemia and rash, predominantly grade 1-2 in severity. 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 adverse events 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 glucose increased (79%), creatinine increased (67%), diarrhea (58%), rash (52%), lymphocyte count decreased (52%), gamma glutamyl transferase (GGT) increased (52%), nausea (45%), alanine aminotransferase (ALT) increased (44%), lipase increased (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. Twenty-one percent of patients permanently discontinued alpelisib alone due to adverse reactions, and 4.6% permanently discontinued both alpelisib and fulvestrant.	Alpelisib plus fulvestrant can be used safely with appropriate labeling. No REMS is indicated.