BACKGROUNDPIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. METHODSIn a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CAmutated cancer. Secondary end points included overall response and safety. RESULTSA total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib-fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo-fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort with PIK3CA-mutated cancer was greater with alpelisib-fulvestrant than with placebo-fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib-fulvestrant group vs. 0.7% in the placebo-fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib-fulvestrant group, as compared with 0.3% of those in the placebo-fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. CONCLUSIONSTreatment with alpelisib-fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.

BACKGROUNDAcute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stemcell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODSWe conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTSA total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, nonrelapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONSRuxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.

Background: Alpelisib (a-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. Patients and methods: AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. Results: Patients were randomly assigned to receive fulvestrant plus alpelisib (n ¼ 284) or placebo (n ¼ 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade !3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade !3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of !248 mg/day and <248 mg/day, respectively, compared with 5.8 months with placebo. Conclusions: Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progressionfree survival at higher alpelisib dose intensities support the need for optimal AE management. ClinicalTrials.gov Id: NCT02437318.

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Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, present in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2—) ABC. SOLAR-1, a Phase 3 randomized, double-blind trial (NCT02437318), investigated efficacy and safety of ALP (α-specific PI3K inhibitor) + FUL in pts with HR+, HER2— ABC. ALP+FUL met the primary endpoint by significantly extending progression-free survival (PFS) vs placebo (PBO) + FUL in the PIK3CA-mutant cohort (hazard ratio [HR] 0.65; 95% CI 0.50—0.85; p=0.00065; median 11.0 vs 5.7 months). Here we report overall survival (OS), subgroup data and safety in the PIK3CA-mutant cohort, and PFS by circulating tumor (ct)DNA PIK3CA mutation status in the total population. Methods: Enrollment was open to men/postmenopausal women with PIK3CA-mutant HR+, HER2— ABC and 1 prior line of endocrine therapy. Pts were randomized (1:1) to ALP (300mg/day) + FUL (500mg every 28 days and Cycle 1 Day 15) or PBO+FUL. OS was the key secondary endpoint. PFS was analyzed by PIK3CA mutant status in ctDNA, and in important prognostic subgroups, including line of treatment in ABC and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) use. Safety was analyzed in the PIK3CA-mutant cohort. Results: 341 pts in the PIK3CA-mutant cohort received ALP+FUL (n=169) or PBO+FUL (n=172). Median follow-up from randomization to data cut-off was 20.0 months. At data cut-off, 92 deaths had occurred (52% of the total 178 pts planned for final OS analysis); 40 for ALP+FUL (24%) and 52 for PBO+FUL (30%). OS results were immature at data cut-off (HR 0.73; 95% CI 0.48—1.10; p=0.06; median not estimable vs 26.9 months). There was a 45% risk reduction in PFS for pts with ctDNA PIK3CA mutations (HR 0.55; 95% CI 0.39—0.79; n=186); 20% for pts without (HR 0.80; 95% CI 0.60—1.06; n=363). PFS treatment effect for ALP+FUL vs PBO+FUL was generally consistent across subgroups of interest, with a risk reduction of 29% for pts receiving first-line (1L) treatment (HR 0.71; 95% CI 0.49—1.03; n=177), and 39% for 2L treatment (HR 0.61; 95% CI 0.42—0.89; n=161); 52% in pts with prior CDK4/6i (HR 0.48; 95% CI 0.17—1.36; n=20) and 33% in pts without (HR 0.67; 95% CI 0.51—0.87; n=321). Most frequent all-grade adverse events (AEs; ≥40% in either arm by single preferred term; ALP+FUL vs PBO+FUL) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%), and rash (40% vs 6%). Grade 3/4 AEs in ≥10% pts in either arm were hyperglycemia (fasting plasma glucose &gt;250mg/dL; 37% for ALP+FUL vs &lt;1% for PBO+FUL) and rash (13% vs &lt;1%); discontinuations of ALP+FUL/PBO+FUL due to AEs were 3% vs 2%. Conclusions: ALP+FUL showed consistent clinically meaningful treatment benefit for pts with ctDNA PIK3CA mutant status, and across pt subgroups, including pts with/without prior treatment for ABC and prior CDK4/6i use. OS data were not yet mature at the data cut-off, but OS appeared numerically longer for ALP+FUL vs PBO+FUL after 52% of events. Key words: advanced breast cancer; PI3K; alpelisib; endocrine therapy Citation Format: Juric D, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu Y-S, Inoue K, Takahashi M, Pápai Z, Longin A-S, Mills D, Wilke C, Sellami D, Andre F. Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-08.