Oncologists should understand the characteristics of 7 emerging drugs and biologics that should improve patient care. At the 2012 Pharmacy Program held during the 17th Annual Conference of the National Comprehensive Cancer Network (NCCN) in Hollywood, Florida, Van Anh Trinh, PharmD, of the University of Texas MD Anderson Cancer Center, Houston, and Robert Ignoffo, PharmD, of the University of California San Francisco and the Touro University College of Pharmacy, Vallejo, California, described the appropriate use of axitinib, crizotinib, ipilimumab, and vemurafenib and previewed carfilzomib, regorafenib, and vosaroxin.
New Tyrosine Kinase Inhibitors
Axitinib was recently approved for, and carries an NCCN category 1 recommendation for, advanced renal cell carcinoma after failure of 1 prior systemic therapy, joining everolimus and sorafenib in this setting. “It’s hard to say which to use first. Selection can be guided by the toxicity profile,” Trinh suggested. In the pivotal phase 3 trial comparing axitinib with sorafenib, the most potency was seen in cytokine-refractory patients, while in patients with prior sunitinib treatment the delay in progression was a modest 1.4 months, she noted. The approved dosing schedule is 5 mg orally twice a day (PO BID), with titration (after 2 weeks) to 7 mg BID, then (after 2 more weeks) to 10 mg BID. Axitinib should not be used concurrently with CYP3A4/5 inducers.
Crizotinib is indicated for, and carries an NCCN category 1 recommendation for, locally advanced or metastatic non–small cell lung cancer with the ALK translocation. Off-label use is anticipated for anaplastic large cell lymphoma, Trinh said.
The approved dose is 250 mg PO BID, with adjustments recommended for patients with hepatic impairment or severe renal insufficiency, but not for creatinine clearance ≥30 mL/min. Drug interactions can occur with potent CYP3A inducers or CYP3A substrates with a narrow therapeutic index. Complete blood count, liver function tests, and EKG are recommended for monitoring.
Novel Melanoma Agents
“Ipilimumab and vemurafenib are long-awaited treatments for melanoma,” Trinh said. “Ipilimumab was the first drug to provide a survival improvement in a randomized phase 3 trial in melanoma.”
The approved dosing schedule for ipilimumab is 3 mg/kg IV over 90 minutes every 3 weeks for 4 doses. Premedication and prophylactic antiemetics are not needed, nor are adjustments necessary for patients with hepatic or renal dysfunction. It is unclear whether “reinduction” is effective upon progression, but ipilimumab has been shown to restore disease control in two-thirds of patients and is an option in the NCCN Guidelines. Whether it will be reimbursed beyond 4 doses is an open question, according to Trinh.
Since the drug works via the immune system, the unique clinical features of ipilimumab are a delayed onset of response and immune-related adverse effects. Inflammatory T-cell infiltrates can produce tissue necrosis within 12 weeks, which is mostly mild to moderate and reversible but can be life threatening. The skin, gastrointestinal tract, liver, and endocrine system can be affected (Table).
Patients should be instructed to report side effects promptly; clinicians should monitor for these closely and treat them immediately with steroids (1-2 mg/kg prednisone or equivalent, then tapered). Ipilimumab can be restarted when grade 1 or 2 toxicity resolves but should be stopped in the case of grade 3+ toxicity.
Vemurafenib is a kinase inhibitor of mutant BRAF (with activity against several other mutations) and is approved, with an NCCN category 1 recommendation, for unresectable or metastatic melanoma with the BRAFV600E mutation. Vemurafenib led to a 67% reduction in risk of death in the landmark phase 3 trial.
The approved dosing schedule is 960 mg PO BID; adjustments are not needed for patients with mild to moderate liver or kidney dysfunction, although vemurafenib should be used with caution in patients with severe impairment. Drug interactions are possible when used along with CYP3A4 inducers and with CYP1A2, CYP2D6, and CYP3A4 substrates with a narrow therapeutic index.
Adverse events are largely dermatologic, and more than one-third of patients may need dose modifications because of them. Clinicians should also watch for changes in liver function tests and for QT prolongation.
“There is no consensus yet about how to integrate these agents into the treatment schema for advanced melanoma,” Trinh said. A reasonable approach is to use vemurafenib first in patients with mutant BRAF and rapidly growing disease or a need for immediate relief of symptoms, since patients respond rapidly, although drug resistance also emerges soon. Ipilimumab may be a good first choice for patients with limited tumor burden who “can afford to wait 3 or 4 months for clinical benefit.”
Emerging Drugs
Ignoffo described 3 agents on the horizon that could also be game changers.
Carfilzomib is a novel irreversible proteasome inhibitor that is mechanistically distinct from, more potent than, and a more selective inhibitor of the proteasome and immunoproteasome than bortezomib. In the PX-171-004 study, in bortezomib-naive patients with relapsed/refractory disease, median progression-free survival (PFS) was 8 months, and median overall survival (OS) was not reached in myeloma patients receiving carfilzomib.1
Carfilzomib is dosed on 2 consecutive days, 1 week apart, in 28-day cycles. Its rapid plasma clearance is not affected by renal dysfunction. Proteasome inhibition occurs after 1 dose and is prolonged due to inhibition of proteasome recovery between doses. In striking contrast to bortezomib, peripheral neuropathy grade 2/3 occurs in <1% of patients. Fatigue is the dose-limiting toxicity. Approval by the FDA is “highly probable,” he predicted.
Regorafenib is an oral multikinase inhibitor against several endothelial receptor tyrosine kinases that is active in colorectal cancer. In the phase 3 CORRECT trial, median OS was significantly improved, although the difference was only 1.4 months (P=.005).2 Median PFS was improved by 1.2 months, a 51% reduction in risk (P<.000001).
“Clinically, it’s an exciting drug based on the PFS curve,” Ignoffo said. “It seems regorafenib does not so much produce tumor shrinkage as prevent progression, leading to a high disease control rate.” Vosaroxin is a first-in-class anticancer quinolone derivative that induces site-selective DNA damage by intercalating DNA and inhibiting topoisomerase II, leading to apoptosis.
Vosaroxin combined with cytarabine showed favorable clinical activity and tolerability in patients with relapsed or refractory acute myeloid leukemia, with a median OS of 7.1 months, a 29% complete remission rate, and a median leukemia-free survival of 14.4 months.3
Conclusion
Trinh concluded the session, saying “These are new and exciting drugs with efficacious and unique safety profiles. Pharmacists and oncologists need to ensure their appropriate use, educate patients, monitor for and manage adverse events, guide patients to drug assistance programs, and stay updated with emerging information.”
References
- Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naïve patients with relapsed and/or refractory multiple myeloma [published online ahead of print May 3, 2012]. Blood.
- Grothey A, Sobrero AF, Siena S, et al. Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies. J Clin Oncol. 2012;30(suppl 4). Abstract LBA385.
- Stuart RK. Vosaroxin in AML. Presented at Chemotherapy Foundation Symposium XXVIII, New York, November 10, 2010. http://www.sunesis.com/data-pdf/595/sunesis-vosaroxin-20101110-Stuart.pdf.