Newly Approved Oncology Agents

Recently approved drugs for the treatment of cancer include Cyramza, Sylvant, Zykadia, Beleodaq, Zydelig, and Keytruda.

The year 2014 has proved to be a busy time for oncology-related new molecular entity approvals at the FDA. This article will review selected newly approved oncology agents including Cyramza (ramucirumab), Sylvant (siltuximab), Zykadia (ceritinib), Beleodaq (belinostat), Zydelig (idelalisib), and Keytruda (pembrolizumab).

Cyramza (ramucirumab)^1,2

Cyramza (ramucirumab) was approved by the FDA on April 21, 2014, for the treatment of patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma, which is cancer located in the region where the esophagus meets the stomach. It is indicated for use as a single agent or in combination with paclitaxel, after prior fluoropyrimidine- or platinum-containing chemotherapy. Ramucirumab is a recombinant human IgG1 monoclonal antibody that specifically binds to vascular endothelial growth factor receptor 2.

The most common adverse reactions observed in clinical trials were hypertension and diarrhea. Hypertension can be severe, so patients should undergo routine blood pressure monitoring and inform their health care provider if blood pressure is elevated or symptoms of hypertension manifest. Instruct patients to notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. Advise patients that ramucirumab can cause severe bleeding and to contact their health care provider for bleeding or symptoms of bleeding, including lightheadedness. Ramucirumab can increase risk of an arterial thromboembolic event and also has the potential to impair wound healing. Patients should not undergo surgery without addressing this issue with their health care provider. Advise patients of childbearing potential to avoid getting pregnant and to use adequate contraception during ramucirumab treatment and for at least 3 months following the last dose of therapy.

In the first pivotal clinical trial, the major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. It was found that the group treated with ramucirumab had an overall median survival of 5.2 months (95% CI, 4.4-5.7) compared with a median of 3.8 months (95% CI, 2.8-4.7) in the placebo group. In the second pivotal clinical trial, ramucirumab plus paclitaxel was compared with placebo plus paclitaxel. It was found that the group treated with ramucirumab plus paclitaxel had an overall median survival of 9.6 months (95% CI, 8.5-10.8) compared with a median of 7.4 months (95% CI, 6.3-8.4) in the placebo plus paclitaxel group.

The recommended dose of ramucirumab is 8 mg/kg every 2 weeks as an intravenous (IV) infusion over 60 minutes. Treatment should be continued until disease progression or unacceptable toxicity occurs. Prior to each infusion, it is recommended to premedicate patients with an IV histamine H₁ antagonist, such as diphenhydramine. Should infusion-related reactions occur, consider slowing the infusion rate or adding premedication with dexamethasone or acetaminophen.

Sylvant (siltuximab)^3-5

Sylvant (siltuximab) was approved by the FDA on April 22, 2014, for the treatment of multicentric Castleman’s disease (MCD) in patients who are HIV negative and human herpes virus 8 negative. MCD is a rare disorder, similar to lymphoma, which causes an abnormal overgrowth of immune cells in lymph nodes and related tissues in the body. Symptoms can include fever, night sweats, weight loss, weakness, or fatigue. Siltuximab binds human interleukin-6 (IL-6) and prevents binding to IL-6 receptors. Overproduction of IL-6 has been linked to systemic manifestations in patients with MCD. However, siltuximab was not studied in patients with MCD who are HIV positive or HHV-8 positive because the drug did not bind to virally produced IL-6 in a nonclinical study.

The most common adverse reactions seen in clinical trials were pruritus, weight gain, rash, hyperuricemia, and upper respiratory tract infection. Patients should receive the FDA-approved patient information each time treatment is given. Siltuximab may lower resistance to infections, so patients must contact their health care provider immediately when symptoms of an infection appear. Instruct patients to seek immediate medical attention if they experience any symptoms of serious allergic reaction during the infusion such as difficulty breathing, chest tightness, wheezing, severe dizziness or lightheadedness, swelling of the lips, or skin rash. Advise patients to report any signs of new or worsening medical conditions and discuss recommended vaccinations prior to treatment with siltuximab. Patients on therapy should not receive live vaccines because IL-6 inhibition may interfere with the normal immune response to new antigens. Patients of childbearing potential should avoid pregnancy during treatment and for 3 months after treatment. Monitor complete blood counts (CBCs) prior to each siltuximab dose for the first year of therapy, then every 3 dosing cycles thereafter. Prescribing information provides guidelines for dose adjustments based on CBC results.

In a pivotal trial, the major efficacy outcome was durable tumor and symptomatic response, defined as partial and complete tumor response (assessed by independent review) and complete resolution or stabilization of MCD symptoms. The durable tumor and symptomatic response of at least 18 weeks duration in the siltuximab arm was 34% compared with 0% in the placebo arm (95% CI, 11.1-54.8; P = .0012).

The approved dose of siltuximab is 11 mg/kg given over 1 hour as an IV infusion administered every 3 weeks until treatment failure. Monitor patients for infusion-related reactions and consider a rate reduction or premedication with antihistamines, steroids, and/or acetaminophen should mild to moderate infusion reactions occur.

Zykadia (ceritinib)^6,7

Zykadia (ceritinib) is a kinase inhibitor that was granted FDA approval on April 29, 2014, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

The most common adverse reactions observed in clinical trials were diarrhea, nausea, elevated transaminases, vomiting, abdominal pain, fatigue, decreased appetite, and constipation. Patients should be advised of supportive care options, such as antiemetics and antidiarrheal medications. Distribute FDA-approved patient information with each prescription. Tell patients to contact their health care provider for severe or persistent gastrointestinal symptoms, signs or symptoms of hepatotoxicity, new or worsening respiratory symptoms, new chest pain or discomfort, changes in heartbeat, palpitations, dizziness, fainting, new use of heart or blood pressure medication, or signs and symptoms of hyperglycemia. Advise patients of childbearing potential of the risk to a fetus and to use effective contraception during treatment with ceritinib and at least 2 weeks following the completion of therapy.

Ceritinib was approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. In the single-arm, open-label clinical trial, it was determined that 54.6% (95% CI, 47-62) of patients taking ceritinib exhibited an overall response for a median duration of response of 7.4 months (95% CI, 5.4-10.1) when assessed by the investigator. When assessed by a blinded, independent central review committee, the overall response rate was 43.6% (95% CI, 36-52) and the duration of response was a median of 7.1 months (95% CI, 5.6 to not estimable).

The approved dose of ceritinib is 750 mg orally once daily on an empty stomach. Ceritinib should not be taken within 2 hours of a meal. Patients should not consume grapefruit or grapefruit juice during treatment with ceritinib. If a patient misses a dose, the patient should take the dose as soon as they remember unless the next dose is due within 12 hours.

Beleodaq (belinostat)^8,9

Beleodaq (belinostat) was approved on July 3, 2014, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma, a rare and fast growing type of non-Hodgkin lymphoma (NHL).

The most common adverse reactions observed in clinical trials were nausea, fatigue, pyrexia, anemia, and vomiting. Review FDA-approved patient information with patients prior to treatment with belinostat. Patients or their caregivers should be advised to report symptoms of thrombocytopenia, leukopenia, anemia, infection, and potential symptoms of liver injury. Complete blood counts must be checked at baseline and weekly during therapy. Patients should report any nausea, vomiting, and diarrhea so that appropriate antiemetic and antidiarrheal medications can be administered. Advise patients of childbearing potential of the risk to a fetus and to use effective contraception during treatment.

Belinostat was approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial. The primary efficacy end point was response rate (complete response and partial response) as assessed by an independent review committee in an open-label, single-arm, nonrandomized pivotal trial. Of patients participating in the trial, 25.8% achieved a complete response or a partial response (n = 31; 95% CI, 18.3-34.6). The median duration of response based on the first date of response to disease progression or death was 8.4 months (95% CI, 4.5-29.4).

The recommended dosage of belinostat is 1000 mg/m2 administered over at least 30 minutes by IV infusion once daily on days 1 through 5 of a 21-day cycle. Cycles can be repeated every 21 days until disease progression or unacceptable toxicity. Treatment discontinuation or interruption with or without dosage reductions by 25% may be needed to manage adverse reactions.

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Zydelig (idelalisib)^10,11

Zydelig (idelalisib) is a kinase inhibitor approved on July 23, 2014, for 3 oncology indications. It was approved for treatment of patients with relapsed chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities; for relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least 2 prior systemic therapies; and for patients who have relapsed small lymphocytic lymphoma in patients who have received at least 2 prior systemic therapies.

The most common adverse reactions observed in clinical trials were diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Laboratory abnormalities such as neutropenia, hypertriglyceridemia, hyperglycemia, alanine transaminase elevation, and aspartate transaminase elevation were also observed. Review FDA-approved patient information with patients prior to treatment with idelalisib. Instruct patients to report symptoms of liver dysfunction including jaundice, bruising, abdominal pain, bleeding, severe diarrhea or colitis, new or worsening respiratory symptoms, skin reactions, symptoms of anaphylaxis, or a fever or signs of infection. Advise women of childbearing potential of the risk of hazard to the fetus, to avoid pregnancy during treatment with idelalisib, and to use adequate contraception during therapy and for at least 1 month after completing therapy.

For relapsed chronic lymphocytic leukemia, the pivotal trial’s primary end point was progression-free survival, as assessed by an independent review committee. The trial was stopped for efficacy following the first prespecified interim analysis and results of a second interim analysis continued to show a statistically significant improvement for idelalisib plus rituximab over placebo plus rituximab for the primary end point of progression-free survival. Accelerated approval was granted for relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma based on overall response rate. Improvement in patient survival or disease-related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials.

The recommended starting dose of idelalisib is 150 mg orally twice daily. Advise patients to take idelalisib exactly as prescribed and not to change their dose or to stop taking idelalisib unless they are told to do so by their health care provider. Idelalisib can be taken with or without food and should be swallowed whole. If a dose of idelalisib is missed by less than 6 hours, take the missed dose right away and take the next dose as usual. If a dose of idelalisib is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.

Keytruda (pembrolizumab)^12,13

Keytruda (pembrolizumab) is a human programmed death receptor—1 blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

The most common adverse reactions observed in clinical trials were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Review FDA-approved patient information with patients prior to treatment with pembrolizumab. Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of therapy. Patients should advise their health care provider if they experience new or worsening cough, chest pain, shortness of breath, diarrhea, severe abdominal pain, jaundice, nausea, vomiting, easy bruising or bleeding, unusual headache, weakness, or vision changes, signs or symptoms of nephritis, or signs or symptoms of hyper- or hypothyroidism. Patients should be advised of the importance of keeping all scheduled appointments for blood work or other laboratory testing. Patients of childbearing potential should be informed that pembrolizumab may cause fetal harm and that the use of highly effective contraception during use of pembrolizumab and for 4 months after the last dose is required.

Efficacy was assessed in a multicenter, open-label, randomized, dose-comparative trial. Patients were randomized to receive 2 mg/kg or 10 mg/kg of pembrolizumab every 3 weeks until unacceptable toxicity or disease progression. The major efficacy outcome measures were confirmed overall response rate assessed by blinded independent central review. The overall response rate was 24% (95% CI, 15-34) in the 2-mg/kg arm, consisting of 1 complete response and 20 partial responses and the results in the 10-mg/kg arm were noted to be similar in the prescribing information.

Pembrolizumab should be reconstituted and diluted prior to IV infusion and given at a recommended dose of 2 mg/kg as an IV infusion over 30 minutes every 3 weeks. SPT

References

• FDA approves Cyramza for stomach cancer [press release]. FDA website. April 21, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394107.htm. Accessed November 4, 2014.
• Cyramza [prescribing information]. Indianapolis, IN: Eli Lilly and Co; April 2014. http://pi.lilly.com/us/cyramza-pi.pdf. Accessed November 6, 2014.
• FDA approves Sylvant for rare Castleman’s disease [press release]. April 23, 2014. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394522.htm. Accessed November 4, 2014.
• Castleman disease. American Cancer Society website; July 2014. www.cancer.org/acs/groups/cid/documents/webcontent/003093-pdf.pdf. Accessed November 4, 2014.
• Sylvant [prescribing information]. Horsham, PA: Janssen Biotech, June 2014. www.sylvant.com/sites/default/files/SYLVANT(siltuximab).pdf. Accessed November 4, 2014.
• FDA approves Zykadia for late-stage lung cancer [press release]. FDA website. April 29, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm395299.htm. Accessed November 4, 2014.
• Zykadia [prescribing information]. East Hanover, NJ: Novartis; April 2014. www.pharma.us.novartis.com/product/pi/pdf/zykadia.pdf. Accessed November 4, 2014.
• FDA approves Beleodaq to treat rare, aggressive form of non-Hodgkin lymphoma [press release]. FDA website. July 3, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm403929.htm. Accessed November 4, 2014.
• Beleodaq [prescribing information]. Irvine, CA: Spectrum Pharmaceuticals; July 2014. www.sppirx.com/downloads/140703_final-beleodaq-pi-pt-info.pdf. Accessed November 4, 2014.
• FDA approves Zydelig for three types of blood cancers [press release]. FDA website. July 23, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406387.htm. Accessed November 4, 2014
• Zydelig [prescribing information]. Foster City, CA; Gilead, July 2014. www.gilead.com/~/media/Files/pdfs/medicines/oncology/zydelig/zydelig_pi.pdf. Accessed November 4, 2014.
• FDA approves Keytruda for advanced melanoma [press release]. FDA website. September 4, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412802.htm. Accessed November 4, 2014.
• Keytruda [prescribing information]. Merck; September 2014. www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed November 4, 2014.
• Non-Hodgkin’s lymphoma. LymphomaInfo.net. www.lymphomainfo.net/nhl/description.html. Accessed November 4, 2014.
• Follicular (center cell) lymphoma. Lymphomation.org. August 2014. www.lymphomation.org/type-follicular.htm. Accessed November 4, 2014.
• Leukemia—chronic lymphocytic. American Cancer Society website. April 2014. www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Accessed November 4, 2014.

About the Authors

Stacey Ness, PharmD, RPh, CSP, MSCS, AAHIVP, has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence and persistency programs, as well as chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, National Association of Specialty Pharmacy, Specialty Pharmacy Certification Board, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is a multiple sclerosis certified specialist, a credentialed HIV Pharmacist, a certified specialty pharmacist, and currently serves as the director of specialty clinical services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, New Jersey.