How to PIK? A Review of Current PI3K Inhibitors

Jessica Lewis-Gonzalez, PharmD
PGY-2 Oncology Pharmacy Resident
Duke University Medical Center
Durham, NC

Heather Moore, PharmD BCOP
Clinical Oncology Pharmacist, Breast Oncology
Duke University Medical Center
Durham, NC

The integration of phosphatidylinositol 3-kinase (PI3K) inhibitors in clinical oncology practice was initiated with the 2014 approval of idelalisib, a PI3K-delta inhibitor, for the treatment of relapsed chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma, and small lymphocytic lymphoma (SLL). Since the time of idelalisib’s approval, other PI3K inhibitors have been approved, including copanlisib, a PI3K-alpha and -beta inhibitor, for relapsed follicular lymphoma; duvelisib, a PI3K-delta and -gamma inhibitor, for refractory CLL and SLL; and most recently, alpelisib, a PI3K-alpha inhibitor, for metastatic hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) nonamplified breast cancer. The use of PI3K inhibitors for other indications continues to be investigated in clinical trials.

The PI3K/AKT/mTOR signaling pathway is important for the regulation of growth, survival, metabolism, and angiogenesis. This pathway is dysregulated in many cancers, including breast, colorectal, and hematologic malignancies. Currently approved PI3K inhibitors are small-molecule inhibitors of specific isoforms (p110-alpha, p110-beta, p110-delta, and p110-gamma) of PI3K that inhibit downstream signaling, resulting in reduced tumor growth and apoptosis. While PI3K-alpha and PI3K-beta are commonly found, PI3K-delta and PI3K-gamma expression is primarily seen only in hematopoietic cells, which is significant when one is considering drug targets and on-target toxicities.^1,2

Given the oral availability and the toxicities seen with PI3K inhibitors, pharmacists play a unique role in patient and provider education as well as in appropriate monitoring and toxicity management.

Current PI3K Inhibitors

Idelalisib
Idelalisib received approval by the U.S. Food and Drug Administration (FDA) in 2014 for CLL on the basis of data from the phase 3 RETRO-Idel trial. This trial evaluated 220 CLL patients with relapsed disease and disease progression within 24 months from the last treatment with either a CD20-antibody-based regimen or a minimum of two prior cytotoxic regimens. Patients were randomized to receive either idelalisib (150 mg by mouth [PO]) twice daily with rituximab (375 mg/m² intravenously [IV]) once, followed by 500 mg/m² every 2 weeks for four doses, then every 4 weeks for three doses or placebo PO twice daily with rituximab. Patients who received idelalisib had significant improvement in progression-free survival (PFS) at 24 weeks compared to those receiving placebo: 93% versus 46%, respectively (adjusted hazard ratio [HR] 0.15; 95% confidence interval [CI] 0.08–0.28; p < .001). A benefit in overall survival at 12 months of 92% with idelalisib compared to 80% with placebo was also observed (HR 0.28; 95% CI 0.09–0.86; p = .02).³ Idelalisib has since gained approval for treatment of relapsed follicular B-cell lymphoma and relapsed lymphocytic lymphoma.

Copanlisib
The CHRONOS-1 trial led to the accelerated FDA approval of copanlisib in 2017. This phase 2 trial assessed efficacy and safety of copanlisib (60 mg by IV route on days 1, 8, and 15 of 28-day cycles) in 142 patients with relapsed or refractory indolent B-cell lymphomas, the majority of which were follicular lymphomas, after two or more lines of therapy consisting of rituximab and alkylating agents. The objective response rate (ORR), defined as a complete or partial response, surpassed the predefined study threshold of 40% and was found to be 59% (95% CI, 51%–67%; p < .001).⁴ Though the trial included numerous indolent B-cell lymphomas, 73% of patients in the trial had a diagnosis of follicular lymphoma, which led to the FDA approval of copanlisib in this setting.

Duvelisib
In 2018, duvelisib received FDA approval for treatment of relapsed or refractory CLL and SLL. The DUO trial was a phase 3 trial comparing duvelisib (25 mg PO twice daily) with ofatumumab (300 mg IV on day 1; 1,000 mg on day 8 of cycle 1; and then 1,000 mg on day 1 of subsequent 28-day cycles) monotherapy. In total, 319 patients who had disease progression or a relapse after at least one prior line of therapy were evaluated in this trial. Significant improvements in PFS were observed in patients receiving duvelisib compared to ofatumumab: 13.3 months versus 9.9 months (HR 0.52; p < .0001), respectively. Differences were also observed in the overall response rate in favor of duvelisib: 73.8% compared to 45.3% with ofatumumab (p < .0001).⁵ The improvement in PFS and overall response rate observed in this trial in patients on duvelisib led to FDA approval. Following the initial FDA approval, duvelisib has also been approved for use in treating relapsed or refractory follicular lymphoma.

Alpelisib
FDA approval was obtained in 2019 for alpelisib for PIK3CA-mutated, hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer in combination with fulvestrant on the basis of results of the SOLAR-1 trial. This trial randomized 572 patients to receive either alpelisib (300 mg PO once daily) with fulvestrant (500 mg by intramuscular route on days 1 and 15 of cycle 1, and day 1 of subsequent 28-day cycles) or placebo (PO once daily) with fulvestrant. Of note, this study included patients from both the PIK3CA-mutated and nonmutated subgroups, though the primary endpoint and key secondary endpoint specifically evaluated the PIK3CA-mutated subgroup. The primary endpoint of PFS in the PIK3CA-mutated cohort demonstrated significant improvement at 20 months with alpelisib and fulvestrant compared to placebo and fulvestrant: 11 months with the use of alpelisib compared to 5.7 months with placebo (HR 0.65; 95% CI 0.50–0.85; p < .001).⁶ Alpelisib is the first PI3K inhibitor to receive FDA approval for a nonhematologic malignancy indication.

Safety

Three of the current PI3K inhibitors (idelalisib, duvelisib, and alpelisib) are orally administered either once daily or twice daily. Copanlisib is the only IV PI3K inhibitor on the market. This class of drugs has the potential to cause gastrointestinal (GI) toxicity, hyperglycemia, cutaneous reactions, infection, fatigue, and elevations in serum creatinine and transaminase levels.

All four PI3K inhibitors are major substrates of CYP3A4, and as a result, careful attention should be paid to patients’ medication and supplement lists to minimize the potential for significant drug interactions. Copanlisib in particular has specific dose reduction recommendations when it is co-administered with a strong CYP3A inhibitor; these cannot be ignored. In comparison to other PI3K inhibitors, idelalisib is not only a substrate of CYP3A4 but also a strong CYP3A4 inhibitor, and it may have an impact on other medications that are major substrates of CYP3A4.

Gastrointestinal Toxicity^7-11
Many patients receiving a PI3K inhibitor experience GI toxicities, of which diarrhea is the most common. Diarrhea can develop as early onset (typically within the first 8 weeks of therapy initiation), is self-limited, and responds well to antimotility agents. Late-onset diarrhea typically presents 6 months after initiation, responds poorly to antimotility agents, is thought to be immune-mediated, and may require the use of steroids, including budesonide or prednisolone, for management. Workup for severe diarrhea should include Clostridium difficile testing and stool culture, as well as colonoscopy for atypical cases. The incidence of diarrhea (any grade) varies between agents, with higher incidences among oral agents idelalisib, duvelisib, and alpelisib (47%, 50%, and 58%, respectively) compared to the IV PI3K inhibitor, copanlisib (36%). Of note, all three oral PI3K inhibitors have warnings in their package inserts regarding development of severe diarrhea (grade 3 or higher) as a potential adverse event to monitor for, and this should be included in patient education. The development of diarrhea should prompt initiation of antidiarrheal agents and maintenance of adequate fluid intake to help prevent dehydration.

Nausea and vomiting can also occur in patients receiving PI3K inhibitors. Among these agents, alpelisib has the highest reported incidence of nausea and vomiting (any grade) at 45% and 27%, respectively. Idelalisib, copanlisib, and duvelisib have an incidence of approximately 25%–30% for nausea and approximately 15% for vomiting. The use of antiemetics as needed can be used to help manage this adverse effect.

Hyperglycemia^8,10,11
Hyperglycemia seen with PI3K inhibitors is an on-target effect secondary to inhibition of the PI3K-alpha subunit that is involved in insulin signaling and glucose homeostasis. With copanlisib, blood glucose generally peaks 5–8 hours postinfusion before returning to baseline, though blood glucose levels remain elevated for approximately 18% of patients 1 day postinfusion. Most patients in clinical trials were asymptomatic and were managed with adequate hydration of oral fluids. Although hyperglycemia with copanlisib is more transient, hyperglycemia secondary to alpelisib is continuous, with elevations in blood glucose seen by day 8 and 15, and thus requiring weekly fasting blood glucose (FBG) monitoring for the first 2 weeks of therapy. Patients should have their hemoglobin A1c and FBG drawn prior to initiation of alpelisib. In clinical trials, approximately 80% of patients experienced hyperglycemia, with 87% of those patients requiring management with antihyperglycemics, including treatment with metformin as a single agent or in combination with other antihyperglycemics. Metformin and other insulin-sensitizers are recommended for hyperglycemia management. Given that alpelisib is a CYP2C9 inducer, agents such as glipizide, glyburide, and glimepiride may not be as effective in controlling blood glucose. When treatment with antihyperglycemics is required, patients should monitor FBG weekly. Patients with type 2 diabetes mellitus should be treated only following adequate glucose control and should be closely monitored. In the SOLAR-1 study, patients were included only if they had an A1c of 6.4% or less. Of note, grade 3 or 4 hyperglycemia occurred in 41% of patients receiving copanlisib and in 37% of patients receiving alpelisib; two cases of diabetic ketoacidosis were reported with alpelisib. All patients should receive education regarding diet modifications prior to initiation of therapy, as well as adequate education and monitoring for antihyperglycemics. Alpelisib dose modifications and hyperglycemia management should be followed in accordance with the package insert.

Cutaneous Reactions^7-11
Severe cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in as many as 3% of patients receiving PI3K inhibitors. Pruritis, dry skin, and rash are more common and typically occur within the first 2 months. Treatment includes topical corticosteroids, oral antihistamines, and low-dose oral corticosteroids. Topical and oral antibiotics may be considered if skin lesions remain uncontrolled. Of note, it is recommended that patients start an antihistamine prior to the initiation of alpelisib for rash prevention.

Infection^7,9
Both idelalisib and duvelisib contain black-box warnings for risk of infection, including diarrhea or colitis, serious cutaneous reactions, and pneumonitis. Most common infections included pneumonia, sepsis, febrile neutropenia, and lower respiratory infections. Infection onset was typically seen within 3 months of therapy initiation with duvelisib. Fatal or serious infections occurred in 31% of patients treated with duvelisib and in 21% of patients who received idelalisib. Prophylaxis for Pneumocystis jirovecii pneumonia should be given during duvelisib and idelalisib treatment. Monitoring and prophylactic antivirals to prevent cytomegalovirus infection or reactivation should also be considered.

Fatigue^7-10
Fatigue can occur in up to 42% of patients on PI3K inhibitors, which can affect patients’ quality of life. Fatigue was listed as the reason for discontinuation of therapy in up to 2.5% of patients in the approval trials. Fatigue should prompt greater discussion with patients to determine any potential underlying causes that should be addressed.

Elevations in Serum Creatinine^7-10
The use of duvelisib and alpelisib has been associated with elevations in serum creatinine. If serum creatinine elevation occurs during treatment, other potential contributing causes should be assessed, such as dehydration and the use of nephrotoxic medications. No dose modifications are listed for any PI3K inhibitors, though it should be noted that these drugs have not been studied in the setting of renal impairment.

Elevations of Transaminase Levels^7-11
Elevations in transaminase levels should be monitored carefully because incidences of severe hepatotoxicity have occurred in 18% of patients receiving idelalisib and in 10% of patients receiving duvelisib. Severe autoimmune transaminitis has been seen with the use of idelalisib. Although elevations in transaminases have been observed in patients receiving alpelisib, grade 3 or 4 elevations were observed in only 3.5% of patients. Transaminases should be monitored to assess the need for dose reduction or discontinuation. Patients receiving idelalisib should be counseled to avoid concurrent use of hepatotoxic drugs.

Future Directions

Numerous ongoing trials are evaluating the use of PI3K inhibitors in solid tumors, which will likely lead to more approvals in the future. Ongoing trials include the SAFIR trial comparing alpelisib and fulvestrant to chemotherapy for maintenance therapy in PIK3CA-mutated advanced breast cancer; a phase 1 trial evaluating the combination of a PI3K-beta inhibitor (AZD8186) and docetaxel to treat advanced breast and pancreatic cancers with phosphatase tensin homologue (PTEN) or PIK3CB mutations; and the BYLieve trial, a phase 2 study evaluating the role of alpelisib in treating patients with advanced HR-positive breast cancer following disease progression after treatment with a CDK4/6 inhibitor.¹² Pharmacists are well-positioned to play an integral role in educating patients and providers about the safe use and monitoring of PI3K inhibitors.

References

1. Dienstmann R, Rodon J, Serra V, Tabernero J. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther. 2014;13(5):1021-1031.
2. Curigliano G, Shah RR. Safety and tolerability of phosphatidylinositol-3-kinase (PI3K) inhibitors in oncology. Drug Saf. 2019;42(2):247-262.
3. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
4. Dreyling M, Santoro A, Mollica L, et al. Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol. 2017;35(35):3898-3906.
5. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446-2455.
6. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940.
7. Zydelig (idelalisib) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2014. Revised October 2018.
8. Aliqopa (copanlisib) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2017. Revised May 2019.
9. Copiktra (duvelisib) [package insert]. Needham MA: Verastem, Inc.; 2018.
10. Piqray (alpelisib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.
11. Esposito A, Viale G, Curigliano G. Safety, tolerability, and management of toxic effects of phosphatidylinositol 3-kinase inhibitor treatment in patients with cancer: a review. JAMA Oncol. 2019. doi:10.1001/jamaoncol.2019.0034 [Epub ahead of print].
12. U.S. National Library of Medicine. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/. Accessed September 30, 2019.