Overview of Year-to-Date 2015 Oncology Approvals

New drug approvals include therapies for patients with breast cancer, thyroid cancer, neuroblastoma, and multiple myeloma.

The first third of 2015 has proven to be a busy time for oncology-related approvals at the FDA. This article will review expanded oncology indications for already approved drugs and newly approved oncology agents including Ibrance (palbociclib), Lenvima (lenvatinib), Farydak (panobinostat), and Unituxin (dinutuximab) (see Table).

Newly Approved Oncology Agents

On February 3, 2015, the FDA granted accelerated approval for Ibrance (palbociclib) to treat advanced (metastatic) breast cancer. It is indicated for postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have not yet received an endocrine-based therapy. Palbociclib works by inhibiting cyclin-dependent kinases 4 and 6, which are involved in promoting cancer cell growth, and it is indicated for use with the anti-estrogen letrozole, as this combination demonstrated increased tumor growth inhibition compared with either agent alone.

The recommended dose of palbociclib is a 125-mg capsule taken orally once daily with food for 21 consecutive days, followed by 7 days off treatment to encompass a complete cycle of 28 days. Letrozole 2.5 mg should be administered once daily throughout the 28-day cycle. Patients should be encouraged to take their dose at approximately the same time each day.

If the patient misses a dose or vomits, an additional dose should not be taken that day and the next prescribed dose should be taken at the usual time. Patients should be advised to avoid grapefruit and grapefruit products during treatment. Palbociclib is available in 125-mg, 100-mg, and 75-mg capsules.

Neutropenia can occur with palbociclib, and it is recommended that complete blood count be monitored prior to the start of therapy, at the beginning of each cycle, on day 14 of the first 2 cycles, and as clinically indicated. Clinicians and patients should monitor for signs and symptoms of infection. The most common adverse effects (AEs) seen in the clinical trials were neutropenia, leukopenia, fatigue, anemia, upper respiratory infections, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, loss of strength, peripheral neuropathy, and nosebleeds. Management of some adverse reactions may require a dose adjustment, treatment interruption, or permanent discontinuation. Dose modification recommendations are included in the prescribing information.

Palbociclib was granted an accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Palbociclib was evaluated in a randomized, open-label, multicenter study of 165 postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their advanced disease. Eighty-four patients were randomized to receive palociclib at a dose of 125 mg daily for 21 consecutive days, followed by 7 days off treatment, in combination with letrozole 2.5 mg daily for 28 days, while 81 patients received only letrozole 2.5 mg daily. Of the palbociclib plus letrozole patients, 48.8% experienced disease progression during the study period compared with 72.8% of the patients who took letrozole alone. The median PFS was 20.2 months (95% CI, 13.8-27.5) for the group that took palbociclib plus letrozole compared with 10.2 months (95% CI, 5.7-12.6) for the group that took letrozole alone.^1,2

On February 13, 2015, the FDA approved Lenvima (lenvatinib) to treat patients with progressive, differentiated thyroid cancer (DTC) whose disease progressed despite radioactive iodine therapy. Lenvatinib is a receptor tyrosine kinase (RTK)-inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression.

The recommended daily dose is 24 mg (two 10-mg capsules and one 4-mg capsule) orally once daily, with or without food. In patients with severe renal or hepatic impairment, the dose is 14 mg once daily. Lenvatinib should be taken at the same time each day. If a dose is missed and cannot be taken within 12 hours, patients should skip that dose and take the next dose at the usual time of administration. Lenvatinib is available in 4-mg and 10-mg capsules.

When taking lenvatinib, patients should be monitored for hypertension, signs and symptoms of cardiac failure, arterial thrombotic events, hepatotoxicity, proteinuria, renal failure, gastrointestinal perforation and fistula, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy, hemorrhagic events, impairment of thyroid stimulating hormone suppression, and embryo-fetal toxicity. The most common AEs seen in clinical trials include hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. Recommended dose modifications for AEs and laboratory abnormalities are included in the prescribing information.

Lenvatinib’s efficacy was demonstrated in a multicenter, randomized, double-blind, placebo-controlled trial with 392 participants diagnosed with progressive, radioactive iodine-refractory DTC who were randomly assigned to receive either lenvatinib or a placebo. Study results showed lenvatinib-treated participants had a median PFS of 18.3 months (95% CI, 15.1-not estimable) compared with a median of 3.6 months (95% CI, 2.2-3.7) for placebo-treated patients. Of patients on lenvatinib, 41% experienced an event indicating disease progression compared with 86% of patients who received a placebo. Upon confirmation of progression, 83% of patients randomly assigned to receive the placebo crossed over to take levatinib in an open-label portion of the study.^3,4

Farydak (panobinostat) was approved by the FDA on February 23, 2015. It is a histone deacetylase inhibitor that is given in combination with bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent.

The recommended starting dose of panobinostat is 20 mg orally once every other day for 3 doses per week in week 1 (days 1, 3, and 5) and week 2 (days 8, 10, and 12) of each 21-day cycle, for up to 8 cycles. Clinicians can consider continuing treatment for an additional 8 cycles for patients with clinical benefit who do not experience unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks).

Panobinostat is administered in combination with bortezomib and dexamethasone; for cycles 1 through 8, bortezomib is given on days 1, 4, 8, and 11 of the 21-day cycle and dexamethasone is given on days 1, 2, 4, 5, 8, 9, 11, and 12. For cycles 9 through 16, bortezomib is administered on days 1 and 8 and dexamethasone is given on days 1, 2, 8, and 9. The recommended dose of bortezomib is 1.3 mg/m2 given as an injection. The recommended dose of dexamethasone is 20 mg taken orally on a full stomach.

Panobinostat includes a boxed warning advising of severe diarrhea occurring in 25% of treated patients. Patients should be monitored for symptoms and started on an antidiarrheal treatment while interrupting the dosing regimen and subsequently reducing the dose or discontinuing panobinostat. The boxed warning also indicates a risk of severe and fatal cardiac ischemic events, severe arrhythmias, and electrocardiograph (ECG) changes that have occurred in patients receiving panobinostat. Arrhythmias may be exacerbated by electrolyte abnormalities. Clinicians should obtain ECG and electrolyte results at baseline and periodically during treatment, as clinically indicated. When taking panobinostat, patients should also be monitored for hemorrhage and hepatotoxicity. Panobinostat may cause fetal harm, so patients should be advised to avoid becoming pregnant while on this medication and for 1 month after their last dose. The most common nonhematologic laboratory abnormalities observed in clinical trials were hypophosphatemia, hypokalemia, hyponatremia, and increased creatinine. The most common hematologic laboratory abnormalities observed were thrombocytopenia, lymphopenia, leukopenia, neutropenia, and anemia. Other common AEs observed include diarrhea, fatigue, nausea, peripheral edema, decreased appetite, pyrexia, and vomiting. Dose adjustments and modifications for toxicity are included in the prescribing information.

Safety and efficacy were assessed in a randomized, double-blind, placebo-controlled, multicenter trial. A total of 768 patients were randomized in a 1:1 ratio to receive either the combination of panobinostat, bortezomib, and dexamethasone (n = 387) or placebo, bortezomib, and dexamethasone (n = 381), stratified by prior use of bortezomib and the number of prior lines of antimyeloma therapy. The primary end point was PFS as assessed by the investigators.

In the overall trial population, the median PFS was 12 months (95% CI, 10.3-12.9) in the panobinostat, bortezomib, dexamethasone arm and 8.1 months (95% CI, 7.6-9.2) in the placebo, bortezomib, dexamethasone arm. Overall survival was not statistically different between arms at the time of the interim analysis. Therefore, the approval of panobinostat was based upon the efficacy and safety in a prespecified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an immunomodulatory agent and a median of 2 prior therapies, as the benefit:risk ratio appeared to be greater in this more heavily pretreated population than in the overall trial population.

In the subgroup of 193 study patients who had received prior treatment with both bortezomib and an immunomodulatory agent, the overall response rate (those who saw their cancer shrink or disappear after treatment) was 59% (95% CI, 47.9-68.6) in the panobinostat, bortezomib, dexamethasone arm and 41% (95% CI, 31.6-51.8) in the placebo, bortezomib, dexamethasone arm. The PFS in the panobinostat-treated arm was 10.6 months (95% CI, 7.6-13.8) compared with 5.8 months (95% CI, 4.4-7.1) in participants treated with bortezomib and dexamethasone.^5,6

{Click image to enlarge}

On March 10, 2015, the FDA approved Unituxin (dinutuximab) as part of first-line therapy for pediatric patients with high-risk neuroblastoma. It is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid, for the treatment of pediatric patients with high-risk neuroblastoma who achieved at least a partial response to prior first-line multiagent, multimodality therapy. Dinutuximab induces cell lysis by binding to the glycolipid GD2, which is expressed on neuroblastoma cells and on some normal cells, including those in the central nervous system and peripheral nerves.

The recommended dose of dinutuximab is 17.5 mg/m²/day administered as an intravenous (IV) infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles. Cycles 1, 3, and 5 are 24 days in length and dinutximab is administered on days 4, 5, 6, and 7 of the cycle. Cycles 2 and 4 are 32 days long and dinutuximab is administered on days 8, 9, 10, and 11 of the cycle. Infusion-related reactions have been reported with dinutuximab, so treatment should be initiated at an infusion rate of 0.875 mg/m2/hour for 30 minutes. The infusion rate can be gradually increased, as tolerated, to a maximum rate of 1.75 mg/m2/hour. Prior to each course of dinutuximab, the clinician should verify that patients have adequate hematologic, respiratory, hepatic, and renal function. In addition, IV hydration, an analgesic protocol, an antihistamine, and an antipyretic should be ordered prior to each infusion as detailed in the prescribing information.

Dinutuximab includes a boxed warning detailing infusion reactions and neuropathy. Serious and potentially life-threatening infusion reactions occurred in 26% of patients treated with dinutuximab. Clinicians should administer required prehydration and premedication, including antihistamines, prior to each infusion. Patients should be monitored closely for signs and symptoms of an infusion reaction during and for at least 4 hours following completion of each infusion. Immediately interrupt treatment for severe infusion reactions, and permanently discontinue dinutuximab for anaphylaxis. In addition, dinutuximab caused severe neuropathic pain in the majority of patients in clinical trials.

Administer IV opioids prior to, during, and for 2 hours following completion of the infusion. Discontinue treatment for severe unresponsive pain, severe sensory neuropathy, or moderate to severe peripheral motor neuropathy. Patients should also be monitored for capillary leak syndrome and hypotension, infection, neurological disorders of the eye, bone marrow suppression, electrolyte abnormalities, and atypical hemolytic uremic syndrome.

Dinutuximab may cause fetal harm, so women should be advised to use effective contraception during treatment and for 2 months after the last dose. The most common AEs observed in clinical trials were pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. The most common serious AEs observed were infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. Modifications and dosing adjustments are detailed in the prescribing information.

The safety and efficacy of dinutuximab were evaluated in a randomized, open-label, multicenter clinical trial of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Participants were randomly assigned to receive either isotretinoin or dinutuximab in combination with IL-2 and GM-CSF, (which are thought to enhance the activity of dinutuximab by stimulating the immune system), plus isotretinoin. Thirty-three patients (29%) in the dinutuximab plus isotretinoin arm experienced a disease progressive event while 50 patients (44%) in the isotretinoin arm progressed in the study.^7,8

Expanded Oncology Indications

On January 29, 2015, Imbruvica (ibrutinib; Pharmacyclics and Janssen Biotech, Inc) received an expanded indication for the treatment of patients with Waldenström’s macroglobulinemia, a rare form of cancer that begins in the body’s immune system. Ibrutinib, which was initially approved on November 13, 2013, is an inhibitor of Bruton’s tyrosine kinase. Ibrutinib has been approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia (CLL), and for patients with CLL who carry a deletion in chromosome 17, which is typically associated with a poor response to standard treatment for CLL.⁹

On February 18, 2015, the FDA expanded the existing indication of Revlimid (lenalidomide; Celegene Corp) for combination use with dexamethasone to include patients with newly diagnosed multiple myeloma. Lenalidomide plus dexamethasone was originally approved in June 2006 for use in multiple myeloma patients who had received at least 1 prior therapy. Lenalidomide, a thalidomide analogue, is also indicated for the treatment of patients with MCL whose disease had relapsed or progressed after 2 prior therapies, one of which included bortezomib, and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.^10,11

Opdivo (nivolumab; Bristol-Myers Squibb) received an expanded indication on March 4, 2015, for treatment of patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Nivolumab was first approved on December 22, 2014, for the treatment of unresectable or metastatic melanoma. It is a programmed death receptor-1 blocking antibody indicated for patients who have been previously treated with Yervoy (ipilimumab) and, if BRAF V600 mutation—positive, a BRAF inhibitor.¹²

Cyramza (ramucirumab; Eli Lilly and Company) was originally approved on April 21, 2014, as a single agent to treat patients with advanced stomach cancer or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine or platinum-containing chemotherapy. On November 5, 2014, it received an expanded indication to treat patients with advanced gastric or GEJ adenocarcinoma in combination with paclitaxel. Furthermore, on December 12, 2014, it was approved for treatment of metastatic NSCLC with disease progression on or after platinum-based chemotherapy in combination with docetaxel. It received its fourth indication on April 24, 2015, and is now indicated in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) chemotherapy for the treatment of patients with metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.¹³ SPT

The above information is a selective summary of publicly available information and is accurate as of the date of writing. Please consult the sources for complete reference information. The views expressed in this article are those of the author alone and not of Managed Health Care Associates, Inc.

References

• FDA approves Ibrance for postmenopausal women with advanced breast cancer [press release]. FDA website; February 3, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432871.htm. Accessed May 7, 2015.
• Ibrance [prescribing information]. New York, NY: Pfizer; February 2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=2191. Accessed May 7, 2015.
• FDA approves Lenvima for a type of thyroid cancer. FDA website; February 13, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm434288.htm. Accessed May 7, 2015.
• Lenvima [prescribing information]. Woodcliff Lake, NJ: Eisai; February 2015. www.lenvima.com/pdfs/prescribing-information.pdf. Accessed May 7, 2015.
• FDA approves Faydak for treatment of multiple myeloma [press release]. FDA website; February 23, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435296.htm. Accessed May 7, 2015.
• Farydak [prescribing information]. East Hanover, NJ: Novartis; February 2015. www.pharma.us.novartis.com/product/pi/pdf/farydak.pdf. Accessed May 7, 2015.
• FDA approves first therapy for high-risk neuroblastoma [press release]. FDA website; March 10, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm437460.htm. Accessed May 7, 2015.
• Unituxin [prescribing information]. Silver Spring, MD: United Therapeutics; March 2015. www.accessdata.fda.gov/drugsatfda_docs/label/2015/125516s000lbl.pdf. Accessed May 7, 2015.
• FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma [press release]. FDA website; January 29, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm. Accessed March 11, 2015.
• Revlimid [prescribing information]. Summit, NJ: Celgene Corp; February 2015. www.revlimid.com/wp-content/uploads/2013/11/PI.pdf. Accessed March 22, 2015.
• FDA expands indication for Revlimid (lenalidomide) in combination with dexamethasone to include patients newly diagnosed with multiple myeloma [press release]. Celgene Corp website; February 18, 2015. http://ir.celgene.com/releasedetail.cfm?releaseid=896912. Accessed March 22, 2015.
• FDA expands approved use of Opdivo to treat lung cancer. FDA website; March 4, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm. Accessed March 22, 2015.
• FDA approves Cyramza (ramucirumab) for use with FOLFIRI in second-line treatment of metastatic colorectal cancer [press release]. Eli Lilly and Company; April 24, 2015. www.drugs.com/newdrugs/fda-approves-cyramza-ramucirumab-folfiri-second-line-metastatic-colorectal-cancer-4206.html. Accessed May 7, 2015.

About the Author

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.