Clinical challenges and considerations in managing HR+/HER2- advanced breast cancer in the post-CDK inhibitor setting

31 Dec 2020

Dr. Chan, Wing-Lok Wendy

Clinical Assistant Professor,
Department of Clinical Oncology,
Li Ka Shing Faculty of Medicine,
The University of Hong Kong

Demonstrating efficacy with a nearly doubled progression-free survival (PFS) rate, cyclin-dependent kinase inhibitor (CDKi) plus endocrine therapy (ET) have now become the new standard-of-care (SOC) in the first-line treatment setting of hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC).1 In most ABC cases, however, resistance to CDKi is considered a near-inevitability and there is limited evidence available support the sequential treatment for patients who have progressed on or after CDKi treatment.1 Phosphatidylinositol 3-kinase (PI3K) is one such signaling pathway that has been implicated in mediating resistance to CDKi, and its mutation are found to be prevalent in HR+/HER2- ABC patients with a significantly reduced survival rate and increased risk of brain metastases.1-4 A case of a patient with PIK3CA-mutant HR+/HER2- ABC who received alpelisib plus fulvestrant in the post-CDK4/6i setting was presented.


Breast cancer is the most common cancer among female in Hong Kong, in which 20.2% of patients develop advanced or metastatic disease.5 In the first-line line setting, the selective CDK4/6i plus ET have recently become the standard of care in managing HR+/HER2- ABC with demonstrated benefit in approximately doubling PFS when compared to ET plus placebo.1 Similar to ET, however, resistance to CDK4/6i occurs frequently in most patients with time and there is a lack of large prospective trials available to support treatment on HR+/ HER2- ABC patients who have progressed on or after CDKi treatment.1 In fact, most treatment sequencing reports to date have been derived from small-scale retrospective data and would require further real-world data to support the appropriate treatment pathway.6

Among the mechanisms identified for CDKi resistance development, PI3K is one such signaling pathway that has been implicated in mediating resistance to CDKi.2 PIK3CA mutations have been identified in approximately 40% HR+/HER2- ABC patients.2 Compared to their PIK3CA wild-type counterpart, HR+/HER2- ABC patients with PIK3CA mutation had significantly lower response rates to chemotherapy (51% vs. 69%, p=0.005) and significantly shorter median overall survival (OS) (19.6 months vs. 23.5 months, p=0.04).3 Similarly, central nervous system (CNS) metastases are more prevalent in HR+/HER2- ABC patients with PIK3CA mutation (30.8% vs. 17.1%, p=0.0049), suggesting that PIK3CA mutation is a poor prognosis factor in HR+/HER2- ABC.4 In the phase 3 clinical trial SOLAR-1, alpelisib, an alpha-specific PI3K inhibitor, plus fulvestrant demonstrated significant benefit in prolonging PFS in HR+/HER2- ABC patients with PIK3CA mutation.7 Furthermore, the phase 2 clinical trial BYLieve illustrated the consistent efficacy of alpelisib plus fulvestrant among HR+/HER2- PIK3CA-mutation ABC patients who had disease progression after CDK4/6i, suggesting a new alternative to in part address the unmet need in the current post-CDKi treatment landscape.8

This article presented a patient with HR+/HER2- ABC with multiple liver and lymph modes metastasis, who used alpelisib after progression on CDK4/6i. The management of side effects of alpelisib is also discussed.

Case report

Madam M, a 52-year old female, was diagnosed to have left breast cancer with liver and lymph node metastasis. Her disease was dated back in 2017 when she was 48 years old and was first diagnosed to have left breast cancer. Madam M had partial mastectomy and pathology revealed invasive ductal carcinoma, pT1cN0 disease, estrogen receptors (ER)-positive, progesterone receptors (PR)-positive and HER2-. She received adjuvant radiotherapy to the left breast and started on adjuvant tamoxifen.

A year later, Madam M was found to have multiple liver and lymph node metastases. She was started on first-line hormonal therapy using aromatase inhibitor with CDK4/6i. After 19-months of CDK4/6i till August 2019, Madam M had disease progression with new and enlarging liver metastasis. In particular, she experienced distending abdomen that affected her appetite.

Next generation sequencing (NGS)-based gene panel testing confirmed that the tumor was PIK3CA-mutant. Madam M then received secondline treatment using alpelisib plus fulvestrant since September 2019. While on alpelisib, Madam M had diarrhea, rash and hyperglycemia which were consistent with common adverse events reported in the clinical trials. Her diarrhea improved after use of imodium and her rashes improved with antihistamine. Most notably, the patient’s blood glucose level reached 18mmol/L. Alpelisib treatment needed to be discontinued because of grade 3 hyperglycemia. Endocrine physician was consulted and a metformin-based regimen was introduced to stabilize the serum glucose level. Alpelisib was then continued after serum glucose normalized.

During the treatment period, Madam M had decreased in abdominal distension with improvement in appetite. Interval CT done in December 2019 showed response with decrease in size of the liver metastases. Unfortunately, disease progressed again in April 2020 and she was started on chemotherapy.


Hormonal therapy with CDK4/6i has emerged as the standard of care in first-line therapy for HR+/HER2- ABC patients with no visceral crisis. On progression after CDK4/6i, subsequent treatment depends on several clinical factors including the presence of visceral crisis, previous ET treatment duration, and the results of gene mutation testing. In cases with presence of visceral crisis, chemotherapy is preferred for rapid disease control.9 Otherwise, ET is still preferred for its relatively milder toxicity profile. Gene mutation testing is recommended, especially for ESR1/ PIK3CA, which can guide on subsequent systemic treatment. For PIK3A-wildtype patients, traditional approach with ET with or without everolimus can be considered; while for PIK3A-mutated patients, alpelisib with fulvestrant is another treatment option.

In the SOLAR-1 trial, alpelisib plus fulvestrant have significantly prolonged PFS of patients with PIK3CA-mutated HR+/HER2- ABC who had previously received ET with a median PFS of 11.0 months versus 5.7 months in patients who received placebo plus fulvestrant (HR=0.65; 95% CI: 0.50-0.85).7 Additionally, among those with measurable diseases, patients treated with alpelisib plus fulvestrant have demonstrated a significantly higher objective response rate (ORR) of 35.7% versus 16.2% in patients who received placebo plus fulvestrant.7 In the subgroup analysis with patients with lung and/or liver metastases, alpelisib plus fulvestrant demonstrated a reduction in progression or death when compared to placebo plus fulvestrant (HR=0.62; 95% CI: 0.44-0.89).7 A numerical benefit in median OS was also observed in this subgroup (37.2 months vs. 22.8 months, HR=0.68; 95% CI: 0.46-1.00) (Figure 1).10


At the time of enrollment of SOLAR-1, CDK4/6i has not yet become the standard of treatment. The number of patients with prior CDK4/6i were limited within the study. For the small subset of 20 patients previously exposed to a CDK4/6 inhibitor in SOLAR-1, the median PFS was 5.5 months versus 1.8 months in patients treated with alpelisib compared to placebo, with 44.4% of patients free of disease progression at 6 months in the alpelisib arm.

Another prospective phase 2, BYLieve study evaluated the efficacy of alpelisib plus fulvestrant in the post-CDKi setting. In this study, HR+/ HER2- ABC patients in the post-CDKi setting were treated with alpelisib plus fulvestrant. The median PFS was 7.3 months with more than 50% of patients alive without disease progression at 6 months.8 Over a median follow-up of 11.7 months, the overall response rate (ORR) was 17.4% for the total cohort and 21.0% for the 100 patients with measurable disease at baseline. The clinical benefit rates were 45.5% and 42.0%, respectively. The ORR of the alpelisib plus fulvestrant treatment in the BYLieve study was also consistent with the one observed in SOLAR-1.8 Unadjusted results showed a median PFS of 7.3 months in cohort using alpelisib plus fulvestrant versus 3.6 months in the real-world cohort, suggesting alpelisib plus fulvestrant could be a treatment option for patients with PIK3CA-mutated tumors on progression of CDK4/6i.

Genetic mutation testing is important for the identification of possible available targeted therapies for cancer patients. PIK3CA test can be performed at the time of initial diagnosis for metastatic HR+/HER2- ABC or at time of progression after first-line hormonal treatment. In the PALOMA-3 trial, only 8.2% of patients have acquired PIK3CA mutation during treatment, which suggested that PIK3CA mutation may be a truncal mutation rather than acquired and testing for PIK3CA mutation can be done upon initial diagnosis.12 The results from the SOLAR-1 trial also demonstrated consistent efficacy in the alpelisib arm regardless on tumor tissue or ctDNA for PIK3CA mutation testing. Therefore, the prognostic value of detecting PIK3CA mutation using either tissue or blood are comparable.

While targeting PIK3CA-mutated breast cancer with PI3K inhibitors is a promising strategy, treatment-related toxicities (especially hyperglycemia, rashes, and diarrhea) should be closely monitored during use of PIK3CA inhibitors. In the SOLAR-1 study, the incidence of hyperglycemia was 63.7% for any grade, 32.7% for grade 3, and 3.9% for grade 4. The median time to onset of grade ≥3 toxicity was 15 days with risk of hyperglycemia higher among patients who were overweight or obese. Strategies to manage hyperglycemia in alpelisib use include stringent HbA1c and serum glucose level monitoring before starting and during treatment and the use of antidiabetic medications as needed. It is noteworthy that insulin sensitizers (e.g. metformin) may be preferable to insulin secretagogues (e.g. sulfonylurea, meglitinides) to manage hyperglycemia in patients treated with alpelisib due to the insulin spikes and relative resistance noted with PI3K inhibitors. Incretinbased therapies and sodium-glucose co-transporter-2 (SGLT2) inhibitors were also considered for hyperglycemia management in the SOLAR-1 trial.

The incidence of all grade alpelisib-associated rash in SOLAR-1 was 35.6%, with 9.9% of those experiencing grade 3 rash or above. The median time to onset for rash was 13 days (range 7-571 days). Close monitoring together with prophylactic and early preventive measures using oral antihistamine, topical corticosteroid treatment, and lotion could help manage the observed rashes.

Lastly, all grade diarrhea was reported in 57.7% of patients with 6.7% of cases being grade 3 or above. The median time to onset for diarrhea was 139 days, a later time point compared to hyperglycemia and rashes. Use of antidiarrheal medications and dose adjustment can be initiated if there is grade 2 or above diarrhea.


While CDKi is the standard of care for first line treatment of HR+/ HER2- ABC, most patients on CDK4/6i eventually progress and require further treatment management. Due to limited evidence support, systemic treatment in the post-CDK4/6i setting remains challenging. PIK3CA-mutation is seen in approximately 40% of HR+/HER2- ABC patients, with this cohort having a worse prognosis due to resistance to chemotherapy and higher risk of brain metastases. Alpelisib plus fulvestrant demonstrated promising efficacy in prolonging PFS and improving ORR in both SOLAR-1 and the BYLieve studies. Adding alpelisib plus fulvestrant as a treatment option in HR+/HER2- ABC patients who have progressed on CDK4/6i should be considered.

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