SOLAR-1 Expands the Role of Precision Medicine in Metastatic Breast Cancer: Alpelisib plus Faslodex in HR+ / HER2− PIK3CA mutant metastatic breast cancer

by Thomas Campbell | Oct 22, 2018
Co-authored by Stephanie Hawthorne

The phosphoinositide 3-kinase PI3K pathway is involved in several cellular processes central to the development of cancer, including metabolism, growth, and proliferation.1, 2 In breast cancer, activation of the PI3K pathway can result in resistance to endocrine therapy and lead to poor prognosis for patients.3 The well-established involvement of the PI3K pathway in tumor biology has served as the rationale for the clinical development of PI3K inhibitors across many tumor types, although in breast cancer it has historically met with limited success.4-6

The proteins in the PI3K pathway comprise several isoforms, including the PIK3C-alpha (PIK3CA).2 An activating tumor mutation of PIK3CA is found in roughly 40% of HR+ / HER2− breast cancer patients.7 Alpelisib (BYL719, Novartis) is the first PIK3CA-specific inhibitor to reach late-stage clinical development for breast cancer and the results of the Phase III SOLAR-1 trial (NCT02437318) were presented at the European Society of Medical Oncology (ESMO) Congress on October 20, 2018, by the study’s lead investigator, Dr. Fabrice André of Institut Gustave Roussy, Villejuif, FR.8

The SOLAR-1 trial compared alpelisib + Faslodex® (fulvestrant, AstraZeneca) to placebo + Faslodex in men and post-menopausal women with recurrence or progression on/after prior treatment with an aromatase inhibitor (with or without a CDK4/6 inhibitor). The trial enrolled 572 patients who had measurable disease or ≥1 predominantly lytic bone lesion, and an ECOG performance status ≤1, and the PIK3CA-mutation status of all patients was determined in archival or fresh tumor tissue. The patients were split into a PIK3CA-mutant cohort (341 pts) and a PIK3CA-non-mutant cohort (231 pts) and randomized 1:1 within each cohort to receive alpelisib (300 mg QD PO) + Faslodex (500 mg IM) or placebo + Faslodex.  Among enrolled patients, approximately one-half (54%) were treated on-study as first-line patients.  It is also important to note that a protocol amendment in SOLAR-1 excluded enrollment of patients who had a long (>1 year) time to recurrence following (neo)adjuvant hormone therapy, which meant that the SOLAR-1 trial heavily enrolled patients considered to be endocrine-resistant (86% of patients).

Although the trial enrolled patients regardless of their PIK3CA-mutation status, the primary endpoint of the trial was progression-free survival (PFS) in the PIK3CA-mutant cohort. In this cohort, the combination of alpelisib and Faslodex nearly doubled the median PFS compared to the control arm (per investigator assessment (the primary endpoint): 11.0 months vs. 5.7 months, HR = 0.65, 95% CI 0.50–0.85, p=0.00065; per central review (conducted for only 50% of patients): 11.1 months vs. 3.7 months, HR 0.48). Unlike the PIK3CA-mutant cohort, a significant improvement in median PFS was not observed in the PIK3CA-non-mutant cohort (7.4 months vs. 5.6 months, HR = 0.85, 95% CI 0.58–1.25).  The PFS benefit with alpelisib was evident in all reported subgroups.  In addition to PFS, the combination of alpelisib plus Faslodex also significantly increased the objective response rate compared to placebo + Faslodex in patients with a PIK3CA mutation (35.7% vs. 16.2%, p=0.0002 in patients with measurable disease). The SOLAR-1 trial continues as investigators evaluate secondary endpoints, including overall survival. But Novartis have stated that they intend to begin discussions with regulatory authorities based on these results.9

For the entire study population—including both the PIK3CA-mutant and -non-mutant cohorts—grade ≥3 adverse events (AEs) were observed in 76.0% of patients receiving alpelisib plus Faslodex compared to 35.5% in the comparator arm. The most common grade ≥3 AEs in the alpelisib arm were hyperglycemia (36.6%) and rash (9.9%); each of these grade ≥3 AEs occurred in <1% of patients in the placebo plus Faslodex arm. Overall, more patients discontinued alpelisib due to AEs (25.0%) than those who discontinued in the placebo arm (4.2%), although only 6.3% of patients discontinued alpelisib due to hyperglycemia and 3.2% due to rash, in-part due to medical intervention and dose modifications that were employed per-protocol.

The data on safety and tolerability for the SOLAR-1 trial may have been as highly anticipated as the efficacy data presented, in light of the history of PI3K inhibitors in breast cancer.  Previously, the Phase III BELLE-3 and SANDPIPER trials studied the safety and efficacy of pan-PI3K inhibitors buparlisib (Novartis) and taselisib (Genentech/Roche), respectively. Both trials demonstrated a modest improvement in PFS, but in both trials patients in the experimental arm suffered unacceptably high rates of treatment-related toxicities.5-6 In BELLE-3, 61% of patients in the buparlisib arm experienced a grade ≥3 AE, most commonly elevated alanine transaminase, elevated aspartate transaminase, and hyperglycemia; suicidal ideation was also a significant issue with five patients (2%) in the experimental arm reporting suicidal ideation and 3 suicide attempts (1%).5 The investigators of the BELLE-3 trial cited buparlisib’s poor safety profile as the basis for discontinuing its development.  In the case of taselisib, 50% of patients enrolled in the taselisib arm of the SANDPIPER trial experienced a grade ≥3 AE, leading to 17% of patients discontinuing treatment due to AEs; the most commonly reported AEs in the taselisib arm were diarrhea and hyperglycemia.  Genentech / Roche cited the modest PFS benefit and “challenging safety profile” in their decision not to seek regulatory approval of taselisib.6

In comparison to BELLE-3 and SANDPIPER, alpelisib in the SOLAR-1 trial actually appears more toxic – more patients overall experienced a grade ≥3 AE, and more patients discontinued therapy in SOLAR-1 due to AEs than occurred in BELLE-3 (2.8%) or SANDPIPER (16.8%).  For a more robust measure of patients’ tolerability for the drug, health-related quality of life is included as a secondary endpoint for SOLAR-1, but these data were not yet presented.

Unlike BELLE-3 and SANDPIPER, the SOLAR-1 trial demonstrated a clinically-meaningful magnitude of benefit in PFS, which may make its toxicity profile more acceptable for use in clinical practice.  If approved, alpelisib may become a new standard of care in a very specific patient population.  Not only will its use be limited to patients with a PIK3CA mutation, but based on the SOLAR-1 trial enrollment criteria it may also be limited to patients who have demonstrated resistance to prior endocrine therapy.  Furthermore, the appropriate line of therapy in which to use alpelisib is muddied by the fact that standard of care changed during the conduct of this trial - just 6.1% of patients enrolled in SOLAR-1 received prior treatment with a CDK4/6 inhibitor, which has now become the first-line standard of care in HR+ / HER2− metastatic breast cancer.10  Will physicians opt to use alpelisib in first-line for an endocrine-resistant patient who recurs with metastatic disease and a PIK3CA mutation, or will they delay use of alpelisib until second-line after first treating the patients with a CDK inhibitor?  Ibrance® (palbociclib, Pfizer) is fully entrenched in this market currently9, although some hope may exist if one looks at other tumor types in which new biomarker-defined populations emerge and quickly establish a new treatment paradigm.

The SOLAR-1 results are significant for bringing a new effective treatment option to patients with metastatic breast cancer, and for establishing a new biomarker segment that will further enhance the ability of precision medicine to guide treatment decisions in this disease. Additionally, PI3K mutations are found in many other tumor types. So, if the side effects of alpelisib prove to be manageable in the long term, the future may be bright for the development of this agent in other treatment settings.


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  3. Miller TW, Rexer BN, Garrett JT, Arteaga CL; “Mutations in the Phosphatidylinositol 3-Kinase Pathway: Role in Tumor Progression and Therapeutic Implications in Breast Cancer;” Breast Cancer Res, 13(224): 2011.
  4. Baselga J, Im S-A, Iwata H, et al. “Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial;” Lancet Oncol, 18: 904-916, 2017.
  5. Di Leo A, Johnston S, Seok Lee K, et al. “Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial;” Lancet Oncol, 19: 87-100, 2018.
  6. Baselga J, Dent, S, Cortés J, et al. “Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER;” J Clin Onc, 36 (suppl): Abs LBA1006, 2018.
  7. The Cancer Genome Alliance Network, “Comprehensive molecular portraits of human breast tumors;” Nature, 490(7418): 61–70, 2012.
  8. André F, Ciruelos EM, Rubovszky G, et al. “Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial;” Presented at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3.
  9. Novartis Press Release, “Novartis investigational BYL719 (alpelisib) plus fulvestrant nearly doubles median PFS in patients with PIK3CA mutated HR+/HER2- advanced breast cancer compared to fulvestrant alone;” www.novartis.com; 20 October 2018.
  10. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed 21 October 2018.


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