The Economic Value of Ipilimumab as a Second-Line Treatment in Patients With Advanced Melanoma

In early 2011, ipilimumab, an anti-CTLA- 4 monoclonal antibody with antitumor activity, was approved by the US Food and Drug Administration (FDA) for the treatment of advanced melanoma. Ipilimumab was compared with the gp100 vaccine in a clinical trial and patients survived a median of 3.7 months longer than those receiving the vaccine. In another trial, ipilimumab with dacarbazine was compared with dacarbazine in previously untreated patients with advanced melanoma. The investigators found that combination therapy yielded higher survivals at 1, 2, and 3 years.

Ipilimumab is an expensive treatment that is associated with positive clinical outcomes. Researchers from the United States and United Kingdom (and from Bristol-Myers Squibb, the manufacturer of ipilimumab) sought to evaluate the cost-effectiveness of ipilimumab compared with best supportive care in previously treated patients with advanced (unresectable or metastatic) melanoma.

Progression-free and overall survival data were used from a phase III trial of ipilimumab to model stable disease, progression, and death. Clinical outcomes, quality of life, and healthcare utilization were included in the analyses. The Markov model considered only the direct costs in patients with an average age of 55 years having advanced melanoma. A discount rate of 3% was utilized for both costs and outcomes.

Because no previous clinical trial with another therapy demonstrated a prolongation of survival, best supportive care was defined as disease management without active chemotherapy. The researchers acknowledged that this may provide a conservative cost benefit for ipilimumab, as most patients usually receive some type of chemotherapy that increases treatment costs of advanced melanoma. Both the incremental costeffectiveness ratio (ICER) and incremental cost utility ratio (ICUR) were estimated in the model. They included direct costs associated with pharmaceuticals, clinical management, and costs associated with toxicity-related events (

The model used ipilimumab clinical data from a trial comparing the agent with gp100, dacarbazine, interleukin-2, and temozolomide. Ipilimumab demonstrated benefits in both progressionfree survival and overall survival.

Those in the ipilimumab group demonstrated a mean gain of 1.88 life-years and 1.14 quality-adjusted life-years (QALYs) compared with patients receiving basic supportive care. The drug costs were higher in the ipilimumab group. They estimated the incremental cost-effectiveness ratios to be $78,000 per life-year gained and $129,000 for the incremental cost per QALY gained.

Based on their sensitivity analysis, and assuming a willingness-to-pay threshold of $113,000 per QALY, the researchers estimated a 6% chance that ipilimumab would be considered costeffective. However, if the threshold were raised to $146,000/QALY, ipilimumab would be considered cost-effective in better than 95% of the scenarios.

The investigators explained that the differences between the ICER and ICUR were expected, owing to the definitions utilized for disease progression from stable disease to progressive disease in the model. Using the costs of alternative therapies that have no shown benefit in survival would increase the cost-effectiveness of ipilimumab, as this therapy has been proved to improve survival.

 Barzey V, Atkins MB, Garrison LP, et al. Ipilimumab in 2nd line treatment of patients with advanced melanoma: a cost-effectiveness analysis. J Med Econ. 2013;16(2):202-212.

Combined BRAF and MEK Inhibition in Melanoma Improves Cytogenic Response

Vemurafenib is a valuable treatment in patients with advanced melanoma who have the BRAF V600E mutation. However, roughly half of patients treated with vemurafenib have progression-free survivals of about 7 months before melanoma activity recurs. An international group of researchers from multiple centers sought to determine if a combination of investigational BRAF and MEK inhibitors might produce a more durable response.

This investigation was part of a larger study that determined the pharmacokinetic activity, clinical activity, and safety of oral dabrafenib (a BRAF inhibitor) and trametinib (an MEK or MAPKkinase inhibitor). The trial of interest was an open-label, randomized, phase II trial that included 162 patients with advanced melanoma who were therapy- naïve or received no more than 1 chemotherapy regimen (excluding any prior treatment with BRAF or MEK inhibitors).

The patients were randomly assigned treatment with either 150 mg dabrafenib bid monotherapy (54 patients; median age, 50 years) or 150 mg dabrafenib bid plus 1 daily dose of trametinib 1 mg (combination 150/1 therapy) (54 patients; median age, 49 years) or 2 mg (combination 150/2 therapy) (54 patients; median age, 58 years). Each of the 3 study groups in this phase had similar poor prognostic attributes including brain metastases, M1c disease, and high lactate dehydrogenase levels. The frequency of cutaneous squamous-cell carcinoma (including keratoacanthoma) was 19% for the dabrafenib monotherapy group, 2% for the combination 150/1, and 7% for the combination 150/2 group (

The median follow-up time was 14.1 months (range, 10.8-17.6 mo) at the time of the planned efficacy analysis. The researchers calculated progression- free survivals (PFSs) of 9.4 months for the combination 150/2 patients, 9.2 months for the combination 150/1 patients, and 5.8 months for monotherapy patients. An independent review committee assigned a hazard ratio for progression or death of 0.55 (95% confidence interval, 0.33 to 0.93; 

= .02) for those receiving the 150/2 combination (

After 12 months, 41% of patients in the 150/2 group were still experiencing PFS compared with only 9% of monotherapy patients (

<.001). When investigators stratified patients according to BRAF V600E mutation or V600K mutation, they did not find any difference in outcome.

Seventy-six percent of the patients in the combination 150/2 group experienced a complete or partial response compared with 54% in the monotherapy group (54%; P = .03). The median overall survival rate, acknowledged the authors, could not be analyzed, because it had not yet been reached.

At 1 year, 79% of the patients in the 150/2 group and 70% in the monotherapy group were alive. When the disease progressed in patients currently receiving monotherapy with the BRAF inhibitor, 80% crossed over to the 150/2 combination therapy group.

The side effect of rash was higher in the monotherapy group (36%) versus the combination 150/1 and 150/2 populations (20% and 27%, respectively). However, the combination groups had a more widespread MEK-inhibitorassociated acneiform dermatitis than the monotherapy subjects (11% for 150/1, 16% for 150/2, 4% for monotherapy treatments).

Adverse events that were seen more frequently in the combination 150/2 group were pyrexia (all grades, 71%) and chills (all grades, 58%). In addition, other adverse events that occurred more frequently in the combination 150/2 group than in the monotherapy patients were fatigue (53% of patients), nausea (44%), vomiting (40%), and diarrhea (36%).

The investigators conclude that this combination of BRAF-MEK inhibitors is at least partly successful in mitigating the resistance in advanced melanoma to BRAF inhibition alone that occurs over time. Dabrafenib and trametinib given to patients at their full singleagent doses proved to be safe and effective when combined, the clinicians stated. This trial, they concluded, supports the effectiveness of using a combination regimen of BRAF-MEK inhibitors for treating patients with advanced melanoma.

Flaherty KT, Infante JR, Daud D, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694-1703.

The Effect of Ipilimumab on Health-Related Quality of Life in Patients With Unresectable Advanced Melanoma

Patients diagnosed with melanoma are typically affected psychologically. Treatment usually causes impaired physical functioning and fatigue. Researchers summarized health-related quality of life (HRQOL) during the 12-week ipilimumab induction period in previously treated patients diagnosed with advanced stage III or IV melanoma.

Patients in the study were randomized to receive 1 of 3 treatments: ipilimumab plus gp100 vaccine, gp100 vaccine plus placebo, or ipilimumab plus placebo. The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORT QLQ-C30) was utilized to assess HRQOL. This tool entails global health status, and physical, emotional, role, cognitive, and social functioning. Higher scores are indicative of better functioning. Differences in scores were subgrouped into 4 categories (eg, “no change” [0-5 points], “a little” [5- 10 points], “moderate” [10-20 points], and “very much” [>20 points]). A score differential of 0 to 10 points was interpreted as no or minimal impact on patient HRQOL.

The researchers reported that after 12 weeks, most patients reported that changes to HRQOL outcomes were no greater than minimal. The only statistically significant difference in score was for constipation, in a comparison of the ipilimumab plus gp100 and the gp100 alone groups. Scoring indicating “moderate” function and global health status score were role function in the ipilimumab alone group and role function and global health in the gp100 group. Symptom scoring rating a “moderate” were fatigue in the ipilimumab plus gp100 group; fatigue, sleep disturbances, and appetite loss in the ipilimumab alone group; and fatigue, pain, sleep disturbances, appetite loss, and constipation in the gp100 alone group.

Patients older than 65 years tended to have more “moderate” changes in health status than the patients younger than 65 years. The greatest differences, albeit moderate, were observed for role function, social function, global health, dyspnea, sleep disturbance, appetite loss, and diarrhea. It is difficult to fully appreciate the importance of the findings owing to the small sample size of the >65 years group, as the mean age was 55.6 years to 57.4 years across all of the study groups.

Treatment within all 3 treatment groups resulted in minimal changes in HRQOL. Therefore, the authors conclude that HRQOL changes should not be a concern for those patients with advanced melanoma and their physicians considering ipilimumab treatment.

 Revicki DA, van den Ertwegh AJM, Lorigan P, et al. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual Life Outcomes. 2012;10:66.

Is Daily Sunscreen Use Cost-Effective for Preventing Skin Cancer?

Exposure to ultraviolet radiation is an important risk factor for the development of skin cancers. A major study previously demonstrated the benefit of sunscreen as an effective strategy, both clinically and economically, for reducing the burden of squamous-cell carcinoma. However, the study did not investigate the long-term benefit of using sunscreen to prevent melanoma, the least prevalent but more often fatal skin cancer.

To evaluate the economic effects of sunscreen use to prevent melanoma, investigators evaluated data from the Nambour Skin Cancer Prevention Trial conducted in Queensland, Australia, from 1992 to 2006. In this trial, the intervention group was encouraged to apply daily a sunscreen with an SPF rating of at least 15, which was provided free of charge at designated study clinics. The study group was instructed to apply the sunscreen daily to their head, neck, arms, and hands, and the control group was instructed to apply sunscreen at their discretion. The decision model tracked multiple cohorts to examine the health and cost outcomes of participants with different profiles. Key measures included time since diagnosis, costs, number of melanomas, QALYs, and life-years lived.

All participants were melanoma free at the start of the data collection period. Individuals who developed melanoma and were diagnosed and treated were characterized further by whether they remained in remission, had a recurrence, were diagnosed with additional tumors or distant metastases, or died, as well as by an age-specific all-cause mortality risk.

Health outcomes in the model included QALYs, counts of melanomas and squamous-cell carcinoma, and melanoma-related deaths. Resources and costs included both those of government health providers (monitoring participants, cost of sunscreen, diagnosis, treating, and following suspicious skin lesions) and household members (time and out-of-pocket costs for applying sunscreen, attending clinic visits, and a discounted lifetime cost following a diagnosis of melanoma. The cost of melanoma was taken from a previous study and inflated to 2010 prices.

Articles

Evidence-Based Oncology

Literature Review: Melanoma

At SABCS 2012, experts in the field provided an update on the use of molecular testing to guide treatment selection for in situcarcinoma of the breast, early-stage intermediate-risk estrogen-receptor-positive and triple-negative breast cancer, and metastatic disease.Molecular oncology has brought a new understanding of carcinogenesis and has revolutionized the way we think about treating cancer.

Oncologists believe they are at a turning point in terms of how to use molecular assays now and in the not-toodistant future. “We are beginning to realize that we have only just scratched the surface,” said Peter Ravdin, MD, PhD, UT Health Science Center San Antonio, who chaired an educational session titled

 The Practical Use of Molecular Profiling

 at the 2012 CTCR-AACR San Antonio Breast Cancer Symposium (SABCS). “It is pretty exciting, actually.” The field is moving away from making decisions based on qualitative, descriptive prognostic information and moving toward precision medicine that is based on quantitative predictions.

Lawrence Solin, MD, Albert Einstein Medical Center, talked about molecular profiling of in situ carcinoma. Recent studies suggest that in situ disease is relatively advanced in its molecular progression to invasion, despite its distinct histologic appearance. National Comprehensive Cancer Network guidelines do not recommend molecular profiling for ductal carcinoma in situ (DCIS) or lobular carcinoma in situ, although estrogen receptor (ER) status is recognized as a tumor marker for DCIS.

Whole breast irradiation (XRT) is known to reduce local recurrence among women who undergo lumpectomy for DCIS. Randomized trial data have demonstrated that radiation plus tamoxifen reduces risk for patients with estrogen receptor (ER)-positive tumors. In practice, it is difficult to distinguish low-risk patients using clinical and pathological factors. “These are aggressive treatments for low-risk patients who rarely die of this disease,” said Dr Solin.

Researchers who have developed a 12-gene signature assay for DCIS hope their system will address the problem of who to treat with adjuvant XRT. Initial results of their findings were presented at the 2011 SABCS and are under review for publication.

 Investigators anticipate that this type of assay, once incorporated into widespread use, will support individualized treatment decision making and identification of molecular biology underlying DCIS.

Dr Solin participated in an analysis that compared the costeffectiveness of basing decisions of whether to use adjuvant XRT on the 12-gene score versus routine clinical practice. Results of the analysis were presented as a poster at the 2012 SABCS.

The average cost of the 12-gene assay was lower than that of standard clinical assessment by approximately $1000 per patient. Changing strategy from using the assay to clinical assessment was associated with an incremental cost-effectiveness ratio of approximately $95,000 per quality-adjusted life-year. Estimates assumed that XRT benefits were independent of biology and that ≥75% of patients would not receive XRT.

For early-stage breast cancer, decisions regarding the use of adjuvant chemotherapy have considered hormone status of the tumor. With respect to tumor markers for breast cancer, the American Society of Clinical Oncology recommends ER and progesterone receptor (PgR) testing for decisions on endocrine therapy, and human epidermal growth factor (HER2) testing for decisions regarding anti-HER2 and anthracycline therapy.

For prognosis, the 21- gene recurrence score (Oncotype DX breast cancer assay, Genomic Health, Inc), urokinase plasminogen activator, and plasminogen activator inhibitor for prognosis are recommended. The 21-gene recurrence score may also be used to help make treatment decisions; patients identified with a highrisk recurrence score are more likely to benefit from chemotherapy. This is not surprising, explained Antonio Wolff, MD, Johns Hopkins Kimmel Cancer Center, because nearly one-third of the non-reference genes in the assay are markers of proliferation, a trait that makes tumors particularly vulnerable to chemotherapy.

Gene expression array analyses have further refined tumor classifications. As additional molecular information is emerging, it is becoming clear that breast cancer should be viewed as a biologic continuum, not as discrete categories. “We know that [these categories] are not enough,” said Dr Wolff. The validated predictive biomarkers have a strong negative predictive value; if the markers are not expressed, targeted therapy is not indicated. With a modest positive predictive value, however, they don’t specifically ensure that patients who have receptor-positive tumor markers will benefit. “They also don’t tell us in absolute terms whether to give it. For prognostic utility, you have to incorporate clinicopathologic measures of prognosis such as tumor size and node status for baseline assessment of risk.”

At this point, clinicians and researchers are realizing that standard clinical measures and molecular assays do not provide the same information. “One assay, one method, is not necessarily better than the other,” said Dr Wolff, emphasizing that clinical context matters. “The question is whether they can be complementary. What we need now are exercises where we are able to combine both molecular and clinical standard information and try to improve on the prediction of what to do.”

To answer some questions about how to use these assays, the field is awaiting the results of 2 completed prospective randomized trials: the Trial Assigning IndividuaLized Options for Treatment (Rx) (TailoRX) and the Microarray for Node-Negative Disease may Avoid Chemotherapy (MINDACT).

 TailoRX will attempt to answer the question of whether adding adjuvant chemotherapy to endocrine therapy will improve outcomes of patients with ERpositive, node-negative breast cancer and an intermediate-risk recurrence score (by the 21-gene assay). MINDACT will examine outcomes when chemotherapy is added to endocrine therapy in patients with discordant tumor risk assessments as determined by Adjuvant! Online and the 70-gene signature (MammaPrint, Agendia).

Tumor classification will improve with continued research. Building on established molecular information, the Cancer Genome Atlas recently reported the molecular portrait of over 800 breast tumor tissue samples, incorporating a host of biological factors, including phenotype, genotype, proteomics, epigenetics, copy number variation, and mRNA expression.

 The analyses confirmed the existence of 4 major molecular subtypes of breast cancer: HER-2 enriched, luminal A, luminal B, and basal-like. “Much of the prognostic variability seems to be happening within these groups,” said Dr Wolff. Yet, the usefulness of the data set is limited without a correlation to clinical outcomes. “As we move into the era of precision medicine, I think we need to begin to correlate this kind of information with clinical outcomes so that we can begin to make decisions,” he said. Along with other studies, this study is also beginning to tease out different molecular subtypes underlying triple-negative breast cancer.

Multiple studies have been examining how and to what extent available assays are being put into practice. One of the largest of these studies used the NCCN registry database to assess the adoption of gene expression profiling (GEP) and use of chemotherapy for women with hormone-receptorpositive breast cancer at 17 centers.

 They found an absolute increase of 12% in GEP use (P <.01) from 2006 to 2008 and an absolute decrease of about 5% in chemotherapy use (

<.01) over the same time period (N = 7375). Testing was associated with lower odds of chemotherapy use (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.62- 0.80), overall. However, Dr Wolff noted an interesting observation: physicians might have ordered the 21-gene assay to help confirm their underlying intent. Patients with node-positive and large node-negative cancers were less likely to receive chemotherapy (OR, 0.11; 95% CI, 0.07-0.17) while those with small, node-negative cancers were more likely to receive chemotherapy after GEP testing (OR, 11.1; 95% CI, 5.39-22.99). This suggested an underlying assumption by the clinician that one test might be more informative than the other. Patient factors also may have influenced GEP test ordering; the odds of being tested were lower for blacks versus whites (OR, 0.70; 95% CI, 0.54-0.92) and for those with high school education or lower versus those with a higher education (OR, 0.63; 95% CI, 0.52-0.76).

Despite a great deal of exciting investigational activity on molecular profiling of metastatic disease, relatively little has carried over to actual routine clinical use. “Sadly enough, there is no genomic test that is used routinely in the management of metastatic breast cancer today,” lamented Lajos Pusztai, MD, Yale Cancer Center. More often, for metastatic breast cancer, molecular markers are being used as patient selection criteria or to enrich a specific population in clinical trials.

In some select cases, repeating ER, PgR, or HER2 tests can be justified; for example, when the diagnosis of a solitary nodule is in doubt, on technical grounds, in clinical trial, or when the clinical course of disease suggests different biology than the original receptor test result indicates. Considering test results in the clinical context is critically important. “For example, if a patient originally diagnosed with ERnegative breast cancer has recurrence 5 or more years after original diagnosis, this would be atypical,” explained Dr Pusztai. “In this setting, repeating a biopsy could be very important. If the patient turns out to be hormone receptor— positive on repeat testing, you could extend the life of that patient by years by offering hormone therapy.”

It is important to understand that a single repeat of the same test does not improve accuracy of the result. A 90% accurate test repeated twice on the same sample yields concordant results about 81% of the time (0.9 x 0.9) because 10% of the 90% of correct classifications from the first round will be misclassified in the second round and vice versa.

Because there is a cognizance bias to act on the most recent results, discordant results can be problematic and potentially dangerous, said Dr Pusztai. Yet, outside of a known technical error in the first test, there is no reason why the most recent test would be more accurate than the first. He recommends that if a patient has at least 1 positive result, at least 1 targeted agent should be tried.

Circulating tumor cells appear promising as a prognostic indicator for metastatic breast cancer, but are not of clinical utility in treatment selection. “One of the most important future challenges is to design experimental and informatics tools that could guide how to combine targeted agents to match the multiple abnormalities that individual cancers have that we can now readily measure,” said Dr Pusztai.

Clinical studies, as well as private and grant-funded entities, are now bringing high-throughput genomic analysis to cancer care with the goal of therapy tailored to a tumor’s molecular abnormalities.

 In practice, however, clinicians are faced with the problem of what to do with the results.

In an interview after the session, Dr Pusztai talked about a hypothetical scenario with a patient who has metastatic disease, has tried all available established therapies, has a molecular profile showing an epidermal growth factor receptor (EGFR) mutation, and is asking for an additional line of treatment with an EGFR inhibitor. “It would be great to know if that worked,” said Dr Pusztai. “It would be great to have a means to collect information on this— whether patients in those types of scenarios responded to a certain drug.” But, these therapies are expensive, most patients cannot afford them, and insurance companies are not likely to be willing to pay for these types of offlabel treatment.

From a systems perspective, it is currently hard to prospectively collect outcomes data of this type of molecularly directed treatment approach in academic centers, explained Dr Pusztai. “At this point, off-label use of molecularly targeted drugs is too expensive without proper funding. Individual molecular abnormalities (eg, EGFR mutation in breast cancer) are rare; access to many different off-label drugs would be needed in order to offer some therapy for most molecularly tested patients and learn from their experience,” he explained. Dr Pusztai would like to see insurance companies and the Centers for Medicare & Medicaid Services explore reimbursement for approved molecularly targeted drugs administered in the context of clinical studies that collect outcome information systematically. That type of information could provide grounds to build subsequent large definitive clinical trials to follow up on drugs that show activity in molecularly selected patient populations. “Molecular analysis of tumors to find intriguing potential targets is readily available; the real bottleneck of progress is how to prove or disprove the clinical utility of these technologies,” said Dr Pusztai.

The author reports receiving payment for involvement in the preparation of this manuscript with no associated conflicts of interest.

 Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; administrative, technical, or logistic support; and supervision.1. National Comprehensive Cancer Network. NCCN Guidelines Breast Cancer Version 3. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Published 2012. Accessed December 26, 2012.

2. Solin LJ, Gray R, Butler S, et al. A quantitative multigene RT-PCR assay for predicting recurrence risk after surgical excision alone without irradiation for ductal carcinoma in situ (DCIS): a prospective validation study of the DCIS Score from ECOG E5194 [Abstract S4-6]. Presented at: 2011 CTCR-ACCR San Antonio Breast Cancer Symposium; December 6-10; San Antonio, Texas.

3. Alvarado MD, Harrison BL, Solin LJ, Ozanne EM. Cost-effectiveness of gene expression profiling for ductal carcinoma in-situ (Oncotype DCIS Score) [Abstract P5-15-01]. Poster presented at: 2012 CTCR-AACR San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, Texas.

4. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J Clin Oncol. 2007;25(33):5287-5312.

5. Clinicaltrials.gov website. www.clinicaltrials.gov. Accessed December 20, 2012.

6. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumors [published online September 23, 2012]. Nature. 2012;490(7418):61-70.

7. Metzger-Filho O, Tutt A, de Azambuja E, et al. Dissecting the heterogeneity of triple-negative breast cancer [published online March 26, 2012]. J Clin Oncol. 2012;30(15):1879-1887.

8. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with use of chemotherapy among women with breast cancer [published online May 14, 2012]. J Clin Oncol. 2012;30(18):2218- 2226.

9. Pusztai L, Yelensky R, Wang B, et al. Use of next-generation sequencing to detect high frequency of targetable alterations in primary and metastatic breast cancer [abstract 10559]. J Clin Oncol. 2012;30(15S):670S.

10. SantarpiaL, Qi Y, Stemke-Hale K, Wang B, et al. Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers [published online April 27, 2012]. Breast Cancer Res Treat. 2012;134(1):333-343.

11. Foundation Medicine website. www.foundationmedicine.org. Accessed December 20, 2012.

12. My Cancer Genome website. www.mycancergenome.org/. Accessed December 20, 2012.

Crossroads in Breast Cancer: The Intersection of Clinical Uncertainty and Molecular Profiling

Newly Discovered Biomarkers Predict Response in AML

Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults, and most patients with AML relapse after achieving complete remission with induction therapy. Most patients with AML die from relapsed disease. Therefore, biomarkers that accurately predict outcome in AML are needed so patients can be matched to the most appropriate therapies, according to presenters at the American Society of Hematology 54th Annual Meeting.

Extensive mutational testing can be used to refine prognostication in AML and inform therapeutic approaches, said Ross L. Levine, MD, Memorial Sloan- Kettering Cancer Center, New York, NY. Novel disease alleles in AML are mutations in TET2, ASXL1, IDH1 and IDH2, PHF6, and DNMT3A. Integrated genetic analysis from 502 patients with AML enrolled in the Eastern Cooperative Oncology Group (ECOG) E1900 clinical trial revealed several genes with prognostic importance. Mutations in IDH2 R140, but not IDH2 R172 or IDH1, were associated with improved survival. Mutations in ASXL1 and PHF6 were associated with worse overall survival.

Risk can be further refined in patients with intermediate-risk AML by more extensive mutational analysis, said Dr Levine. Three distinct risk groups can be identified in FLT3-ITDnegative intermediate-risk AML based on mutational status; TET2, ASXL1, PHF6, and partial tandem duplications in MLL are poor-risk mutations associated with worse survival in the group of intermediate-risk patients with wild-type internal tandem duplications in FLT3.

In the ECOG E1900 trial, a post hoc analysis of mutational status found that high-dose daunorubicin improved outcomes markedly for patients with DNMT3A mutations. Patients with NPM1 or DNMT3A mutations, or MLL translocations, had a 3-year overall survival rate of 44% with high-dose daunorubicin induction chemotherapy compared with 25% rate when treated with standarddose daunorubicin.

Minimal residual disease (MRD) after treatment in AML predicts failure to maintain a morphologic complete response and negatively affects survival. Elisabeth Paietta, PhD, professor, department of medicine (oncology), Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, reviewed approaches to monitoring MRD, noting that the best method is still a matter of debate and that MRD assessment assays need to be standardized. They are either immunophenotypic, done by multiparameter flow cytometry, or done by polymerase chain reaction to detect recurrent gene mutations or leukemia fusion transcripts. Very sensitive assays, perhaps next generation sequencing, are needed to find minor clones present at diagnosis that may lead to relapse. Even with detection of MRD, therapeutic options at present are limited, she said. Intensive therapeutic approaches have not worked in MRD-positive patients, said Dr Paietta.

Relapsed AML remains a clinical challenge, said Jeffrey Szer, MBBS, professor/ director, department of clinical haematology and BMT service, The Royal Melbourne Hospital, Parkville, Australia. Novel approaches to the treatment of relapse include clofarabine, a novel purine analogue, with or without cytarabine; tosedotat, an orally available aminopeptidase inhibitor that has shown significant clinical activity in a phase I/ II study; and FLT3 inhibitors, which may have a role as a bridge to transplantation. Inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus and sirolimus, have potential utility given the role of the mTOR pathway in cytarabine activity. Hypomethylating agents are being studied as maintenance therapy after allo-stem cell transplant (SCT). Allo-SCT has the potential to cure relapsed or refractory disease, but only after patients have achieved a second complete remission or MRD.

Evidence-Based Approaches to Cytopenias Discussed

Diagnostic approaches to cytopenias require an understanding of their etiology, said presenters during the American Society of Hematology 54th Annual Meeting.

Neutropenia is often a secondary finding “to a far more significant underlying hematologic disorder, placing the patient at risk for infectious complications,” said Laurence A. Boxer, MD, a pediatric hematologist-oncologist at the University of Michigan Heath System, Ann Arbor.

In the case of severe congenital neutropenia (SCN), which is characterized by recurrent severe infections during the first months of life, bone marrow examination characteristically shows a myeloid “maturation arrest” at the promyelocyte-myelocyte stage of development. Mutations in the ELANE gene have been observed in 40% to 60% of patients with congenital neutropenia, and neutropenia caused by the ELANE mutation is associated with the most severe infectious complications, Dr Boxer said.

An autosomal-recessive subtype of SCN is Kostmann disease, in which mutations of the HAX1 gene are observed. Patients with both isoform A and isoform B HAX1-spliced variants can suffer from neurologic impairment that ranges from developmental delay to severe epilepsy.

Uncovering the cause of chronic anemia relies on a complete blood count (CBC), said Mark J. Koury, MD, professor of medicine, division of hematology/oncology, Vanderbilt University, Nashville. The 4 patterns encountered frequently in CBCs associated with chronic anemia are anemia with abnormal platelets and/or leukocyte counts, anemia with increased reticulocyte counts, a lifelong persistence of an abnormal CBC, and anemia with inappropriately low reticulocytes.

Diseases affecting early-stage hematopoietic progenitors, such as liver disease, will likely affect platelets and leukocytes. Underlying causes can include chronic alcohol intake and antiviral treatments for hepatitis C. The absence of an enlarged spleen usually indicates a primary bone marrow disease, including myelodysplasia or malignant invasion of the bone marrow, such as with multiple myeloma.

An increased number of reticulocytes with chronic anemia indicates lowgrade hemolysis or blood loss (possibly from upper gastrointestinal lesions or menorrhagia). Erythrocyte fragmentation on the blood smear is often associated with malignant tumors, large hemangiomas, prosthetic heart valve defects, or direct external trauma, said Dr Koury. Spherocytes suggest hereditary spherocytosis or immune hemolysis, the latter of which can be diagnosed by surface antibodies and/or complement components on erythrocytes in the direct antiglobulin test.

Bone marrow events responsible for low reticulocyte production include apoptosis of erythroid progenitor and precursor cells by intrinsic and extrinsic factors, development of macrocytosis when erythroblast DNA replication is impaired, and development of microcytosis due to heme-regulated elF2-alpha kinase inhibition of protein synthesis in iron-deficient or thalassemic erythroblasts.

Correct identification of the cause of thrombocytopenia is crucial for proper management, said Roberto Stasi, MD, PhD, department of haematology, St. George’s Hospital, London, UK. Thrombocytopenia may be the initial manifestation of infections (ie, HIV and hepatitis C virus). Examination of the peripheral blood smear remains the most important investigation to guide diagnostic approaches. Liver and renal function tests, a clotting screen with D-dimers, and measurement of lactate dehydrogenase are part of the basic laboratory evaluation.

A bone marrow aspirate and biopsy may be performed if the etiology of the thrombocytopenia is unclear, said Dr Stasi.

Primary immune thrombocytopenia (ITP) remains a diagnosis of exclusion, he said, with no consensus on the set of investigations. The role of the bone marrow biopsy and aspirate in ITP are controversial.

Thrombocytopenia in the hospitalized patient has many possible etiologies; special consideration should be given to drug-induced thrombocytopenia considering its frequency in this setting, said Dr Stasi. Heparin-induced thrombocytopenia is often a clinical emergency and typically develops after 5 to 10 days of exposure to heparin.

Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

ASH Conference Coverage 

Across specialties, prior authorization (PA) is the bane of physicians and their office staff. Once employed as a utilization management tactic primarily for more benign therapeutic classes, it is now a ubiquitous force in oncology management—one that is expected to become even more targeted beyond US Food and Drug Administration (FDA) indication alone.

Recent research conducted by HRA (Healthcare Research & Analytics, a market research consultancy based in Parsippany, New Jersey) reveals that 93% of the 47 major health plans included in its recent study routinely employ PA to manage utilization of oncology agents. Over three-fourths of these payers, which cover over 100 million lives in total, place at least some reliance on rigid PA that links approval with product efficacy at specific milestones, or rely on PA to ensure that the appropriate biomarker tests are conducted prior to approval of specific agents. In the future, the use of more stringent PA criteria is expected to increase significantly—with nearly 90% of the plans intending to link PA to specific treatment milestones and even more planning to link PA with genetic testing (

“Any specialty other than oncology, this is the way you’d do it—fairly rigid according to what the evidence has shown,” states one key opinion leader participating in the research who is employed by a major US payer organization. “Oncologists want a separate set of guidelines for how they manage patients. The problem is you’re dealing with expensive drugs, and we have a fiduciary responsibility to make sure what the employer is paying for is appropriate, and to keep the physicians honest.…When you have a third party paying for it, they have a right to a say on how it’s being spent.”

 Changing Paradigms in Managed Care— Oncology Management

, surveyed oncologists and oncology nurse navigators clearly are not pleased with the trends toward increased PA use.

“Who’s going to be calling for all these approval[s]?…I’ve got somebody that’s got metastatic cancer. They need to be treated now—not a month from now, not 3 months from now,” stated an oncologist participating in HRA’s study.

“We spend a lot of time in trying to do the best…for our patients [to get treatments] approved and it basically delays care.”

In fact, the use of more stringent prior authorization guidelines will lead about half of the 100 medical oncologists participating in the research to reconsider their first-choice oncolytic agent due to the hassle factor that PA presents (

). PA based on product efficacy at select milestones or on the number of treatment cycles, as well as step therapy requirements enforced via PA, serve as the primary deterrents, whereas oncologists are less fazed by the idea of payers requiring specific biomarker/genetic tests before approving the associated agents. Fortunately, for the oncologists and the patients they treat, widespread use of PA beyond FDA indication alone is not occurring—yet.

Although managed care is including general PA as a requirement for over two-thirds of oncology agents, on average, more stringent PA is just emerging. PA based on patient response to specific treatments, on biomarker/ genetic testing, and as a means to enforce step therapy is currently in place for one-fifth or less of agents, though significant increases in prevalence are expected over the next few years (Table).

The growing presence of step therapy poses a disadvantage for new oncology agents—logistically as well as conceptually&mdash; as oncologists maintain strong perceptions that new oncolytic agents are very likely to be subject to PA. Agreement with this concept is noted among over 80% of oncologists in the research. Further, nearly 2 out of 3 oncologist participants point to PA as a deterrent to prescribing new agents (

“[There will be] a lot more prior authorization, a lot more attempt to engage oncologists around pathway adherence, and end-of-life discussions earlier in the course of therapy,” said a key opinion leader participating in the research, “because these are felt to be the biggest variables that contribute the most to cost.”

Increased PA, the development of clinical pathways programs, and high copays/ co-insurance levels are leading oncologists toward perceptions of oncology as now being a “heavily managed” category. While over half of oncologists currently perceive payers as providing hands-on management of oncology, 8 in 10 oncologists predict that active management will be the norm 2 or 3 years from now (

). Further, those oncologists who have more negative perceptions of payers and their involvement in oncology are more inclined to suggest that payers will be more stringent in both the short and long term (

“There is a new intensity of scrutiny from the payer side, a significant increase in protocols and other management constraints on oncology,” said one of the key opinion leaders participating in the research. “Across all lines of business, saying ‘We’re not going to pay for everything, and if we are, we need to have some understanding of medical necessity, and the rationale around morbidity, mortality, and patient improvement.’”

By 2015, oncolytic agents are predicted to be the second- or third-greatest driver of total drug spend, an increase from seventh place in 2011.

 By 2020, total cancer costs are projected to reach $158 billion.

 To ensure their own fiscal survival, payers may be left with little choice but to increase controls in oncology, despite the potential backlash.

So the question remains—which direction will payers take in exerting greater control over the oncology category? Will novel approaches such as clinical pathways programs provide enough specific direction and incentive to control spend, or will payers need to resort to the more traditional mainstay of prior authorization to manage utilization? If prior authorization in oncology continues to evolve, just how far will payers be willing to go in the stringency of their requirements, without risking major repercussions among oncologists? And, will oncologist and payer affiliations in integrated delivery networks help enforce these approaches?

As one payer respondent participating in the research states, “We have a number of prior auth requirements on most of these agents, but are limited in our effectiveness by the strong public pressure and some special legal protections they enjoy.”

Balancing the need for fiscal soundness with public policy considerations as well as—most importantly&mdash;the need to provide patients with the most effective treatments is a fine line for payers, one that continues to fray with each new expensive oncology treatment that comes to market.

 From Healthcare Research & Analytics, Parsippany, NJ.

 Ms Fox reports employment with HRA—Healthcare Research & Analytics, the company that produced this research. HRA is owned by MJH & Associates, which also owns The American Journal of Managed Care.

Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

 Lisa A. Fox, Vice President, Research Strategy, Healthcare Research & Analytics, 400 Lanidex Plaza, Parsippany, NJ 07054. E-mail: lfox@hra research.com.1. Study by Express Scripts, via Real Endpoints Advisory Services. www.valueandinnovation.com/research/cancer-pathways-provide-leverage-for-payers-hurting-biopharma/. Accessed December 10, 2012.

2. Cancer’s growing burden—the high cost of care. USA Today website. www.usatoday.com/news/health/story/health/story/2012-02-27/Cancers-growing-burden-the-high-cost-ofcare/53271430/1. Published February 27, 2012. Accessed December 10, 2012.

Managed Care Restrictions: Barriers to Product Use in Cancer Care

The number of drugs to treat cancer in the drug development pipeline, reportedly exceeding 900 as of 2012,

 is both exciting and frightening to payers. Nearly half of the cancer medications currently in development are oral oncolytics, and with costs for these agents commonly exceeding $50,000 to $100,000 per patient per year, this could result in significant budgetary impacts for payers. There is no question that innovation can result in improved quality of care and reduction in morbidity and mortality rates for various cancers; however, payers struggle with ensuring that the right patient receives the right medication at the right time.

In the case of expensive self-administered medications, this also means ensuring that patients prescribed the right medication take the medication as prescribed and are adherent to the therapeutic regimen. This is easier said than done. An analysis of patients diagnosed with early-stage breast cancer showed that less than 50% of patients prescribed adjuvant hormonal therapy actually continued therapy for the full duration of the optimal schedule for treatment.

 The same analysis showed that younger patients were even more nonadherent to therapy than older patients. Reasons for nonadherence included lack of patient counseling by their physician, toxicity from the therapeutic regimen, and out-of-pocket costs associated with the prescribed therapy.

In addition to lack of adherence (failure to take the medication as prescribed), common challenges also include failure in filling the initial prescription (noninitiation) and failure to continue the prescribed duration of therapy (early discontinuation).

 Many strategies have been used to improve rates of adherence to self-administered therapies, including oral therapies, in the past. This article will shed light on a strategy requiring more frequent counseling of patients by patient care coordinators trained in oncology and the partnership they form with the patients to ensure improved adherence to potentially life-saving therapies.

Cost Trend Mitigation Strategies for Oral Oncolytics

While traditional drug cost trends are forecasted to be in the range of 0% to 5% per year over the next 2 years, specialty drug cost trends are expected to be in the range of 20% to 25% per year during the same time period.

 In response to historical and forecasted drug cost trends for specialty drugs, payers have implemented various strategies to help mitigate these cost trends.

Strategies that have been and continue to be implemented include renegotiating contracts with providers to obtain more aggressive discounts, benefit cost strategies aimed at shifting more costs to patients through increased cost sharing, formulary management strategies aimed at a low net cost goal through preferencing of lower cost agents and/or obtaining larger rebate concessions from pharmaceutical manufacturers, utilization management strategies including step therapy and/or prior authorization to ensure medications are being prescribed in accordance to best practices and consensus guidelines, channel management strategies to ensure medications are dispensed or administered in the lowest cost site of care, and drug therapy management strategies to ensure patients are taking the most appropriate therapies and remaining adherent to prescribed therapies.

Innovation in all of these areas has been experienced over the past few years. One of the most recent innovations within drug therapy management, partial fill strategies for oral oncolytics, has led to some excitement within the payer and specialty pharmacy communities due to its impact on drug cost trends as well as improved, and more frequent, direct interaction between providers and the patients they are treating.

Partial Fill Strategies for Oral Oncolytics

The first published article on partial fill strategies for oral oncolytics focused on 3 oral oncolytics, including sorafenib (Nexavar), sunitinib (Sutent), and erlotinib (Tarceva).

In this program, monthly therapies for the 3 medications were split into 14-day and 16-day batches (partial fill) and out-off-pocket cost share was also adjusted for the partial fill. In addition to the partial fill of the prescription, patients received education on the treatment regimen, the importance of adherence to therapy, and earlier identification of adverse events from the medications, and regular communication with the patients and their providers on measures to take to reduce dosages or discontinue therapy was provided.

The intervention group consisted of 1069 patients who were prescribed 1 of the 3 study medications during the time period of June 2008 through February 2010. The control group consisted of 351 patients who were prescribed 1 of the 3 study medications during the time period of January 2007 to May 2008 (before the inception of the partial fill program).

The authors demonstrated that 261 patients discontinued therapy in the first month of the program, and 7.7% could have saved at least one-half of the prescribed month of therapy. Overall, 33.8% of patients could have been prevented from wasting the prescribed oral chemotherapy medications through implementation of a partial fill program. Average savings per patient was $934.20. The study also demonstrated that hospitalizations were reduced by 2.9%, resulting in average savings of $439.87, in patients that received interventions within the partial fill program.

The results of this study have led to a rapid expansion of partial fill strategies being adopted by payers and an expansion in the number of oral oncolytics included in the partial fill programs.

Expansion of Partial Fill Strategies for Oral Oncolytics

In early 2010, Diplomat Specialty Pharmacy implemented a partial fill program for payer clients focusing on enhanced outreach, education, and intervention for patients that were prescribed sorafenib (Nexavar), sunitinib (Sutent), or erlotinib (Tarceva). Patient outreach was provided telephonically twice per month by patient care coordinators, nurses, and pharmacists with specific training in oncology. Each  phone call was provided 5 to 7 days before the next partial fill was dispensed. Dispensing was provided in 14-day and 16-day batches.

Patient outreach included initial enrollment of the patient into an oncology patient care program, education of the patient on their diagnosis and prescribed therapy which included verbal communication as well as written education materials, assessment of adverse events reported by patients and what to do to mitigate adverse events, copay assistance support provided through non-profit charitable organizations, home delivery of prescribed medications and supportive therapies, and outreach to prescribing physicians to discuss alternative treatment options for patients that could not tolerate the prescribed therapy.

Results of interventions were tracked for 12 months after the program was implemented (

). Nearly 43% of patients discontinued therapy after the first month of the prescribed therapy with nearly 25% discontinuing therapy after 1 partial fill. The primary reason for discontinuation was adverse events reported by patients.

Based on the results of the initial partial fill program rollout, the list of target medications for the program was expanded in early 2011 to include sorafenib (Nexavar), sunitinib (Sutent), erlotinib (Tarceva), everolimus (Afinitor), imatinib (Gleevec), dasatinib (Sprycel), bexarotene (Targretin), and pazopanib (Votrient). The same types of interventions were provided to patients in this phase of the program. Results of interventions were tracked for 12 months after the program was implemented (

). Fifty-two percent of patients discontinued therapy after the first month of the prescribed therapy, with more than 15% discontinuing therapy after 1 partial fill. The primary reason for discontinuation in this phase was adverse events reported by patients.

The current version of the partial fill oral oncolytic program includes 15 oral oncolytics (

). The program was expanded to include all 15 oral oncolytics in early 2012. Specific oral oncolytics were targeted for the program due to high discontinuation rate due to poor response, adverse effects, and high rates of noncompliance. Results of interventions were tracked for 9 months after the program was implemented (

). 41% of patients discontinued therapy after the first month of the prescribed therapy with approximately 20% discontinuing therapy after 1 partial fill. Again, the primary reason for discontinuation in this phase was adverse events reported by patients.

In addition to tracking discontinuation rates of therapy, potential drug cost savings has also been tracked (

). For a payer that has approximately $1M in annual spend for the targeted medications, the potential annual savings due to this program would be expected to exceed $186,000 or 19% of total spend based on the average monthly cost of the prescription and the experienced discontinuation rates.

It is important to note that the purpose of partial fill oral oncolytic programs is not to reduce access to potentially lifesaving therapies. The goal is to allow more frequent direct intervention and tracking of patients and their therapies by personnel specifically trained in oncology. The patient care coordinators, pharmacists, and nurses working within specialty pharmacies that reach out to patients regularly partner with patients and their physicians to promote high-quality care and improved adherence to therapy. While significant drug cost savings can be achieved with partial fill oral oncolytic programs, the focus must remain on the patient and ensuring that they are getting the best care possible.

In conducting these programs, there are 2 observations that require more study and understanding. One observation is related to the higher-thanexpected rate of adverse events with the therapies. The incidence reported by patients was higher than that reported in clinical trials with these therapies and this should be investigated more thoroughly. The other observation was the incidence of mortality in patients within each phase of the program, which reached over 20% of patients that discontinued therapy after the first month of treatment. This also needs further investigation to ensure that the specific medications are not being used in lieu of end-of-life care for patients. The answers to these questions will further our understanding of these important therapies and how they can impact the lives of patients diagnosed with cancer.

 From Diplomat Specialty Pharmacy, Flint, MI.

 The author reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Concept and design; acquisition of data; analysis and interpretation of data; and drafting of the manuscript.

 Atheer A. Kaddis, PharmD, Senior Vice President, Sales and Business Development, Diplomat Specialty Pharmacy, 4100 S Saginaw St, Flint, MI 48507. E-mail: akaddis@diplomatpharmacy.com.1. Medicines In Development — Cancer. 2012 Report. PhRMA. www.phrma.org/sites/default/files/1000/phrmamedicinesindevelopmentcancer2012.pdf. Accessed December 17, 2012.

2. Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. JCO.

3. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.

4. Express Scripts Drug Trend Report 2011.http://www.drugtrendreport.com/specialty/specialty-forecast. Accessed January 6, 2013.

5. Khandelwal N, Duncan I, Ahmed T, et al. Impact of clinical oral chemotherapy program on wastage and hospitalizations. Am J Manag Care. 2011;17(5 spec no.):e169-e173.

Partial Fill Strategies for Oral Oncolytics to Reduce Waste and Drive Persistency

Colorectal cancer (CRC) was the third-most common cause of cancer-related deaths in the United States in 2012, accounting for around 51,690 deaths. Approximately 143,460 people are diagnosed with CRC annually, making up 9% of all cancer diagnoses.

 Specifically, colon cancer makes up 72% of the incidence of CRC, with rectal cancers accounting for the remaining 28%. CRC is more common in males and in the African American population compared with other ethnicities. Within the last 35 years, the mortality rates have been decreasing. The 5-year overall survival (OS) of CRC, a non-curable malignancy, is around 64.3%, with stage I disease being 89.9% and stage IV disease being 11.9%.

The treatment of colon cancer depends upon the stage. For those who have operable disease, surgical resection is preferred. Patients with high-risk stage II or stage III disease should then receive adjuvant chemotherapy with 5-fluorouracil (5-FU), leucovorin (LCV), and oxaliplatin. Oral capecitabine may be substituted for intravenous 5-FU/LCV. In patients with metastatic disease, surgical evaluation should be conducted, especially in those with limited hepatic metastases. If the tumor is deemed unresectable, palliative chemotherapy with a 5-FU/LCV regimen should be offered. Potential regimens include FOLFOX (5-FU/ LCV and oxaliplatin), FOLFIRI (5-FU/LCV and irinotecan), CapeOX (capecitabine and oxaliplatin), 5-FU/LCV alone, and capecitabine alone. Biologic therapy with bevacizumab (with FOLFOX, FOLFIRI, or CapeOX), panitumumab (with FOLFOX or FOLFIRI), or cetuximab (FOLFIRI) may be added to standard regimens. KRAS is an important cellsignaling protein in the growth and progression of tumor cells. Malignancies with mutated KRAS, which occur in 40% of patients with CRC, are associated with poor response to epidermal growth factor receptor (EGFR) inhibitors, including cetuximab and panitumumab. This occurs since KRAS signaling happens downstream from EGFR. With progressive disease, regimens can be changed to another option with medications not already utilized.

 In 2012, 2 new agents were approved for use as second-line therapy. Ziv-alibercept, a vascular endothelial growth factor receptor (VEGFR) 1 and 2 inhibitor, when combined with FOLFIRI in those who had failed a previous oxaliplatinbased regimen, had an improved OS of 1.4 months compared with those who received placebo (13.5 months vs 12.1 months, 

 Regorafenib, an oral multikinase inhibitor, demonstrated an improved OS over placebo in patients who had failed standard therapy in the CORRECT trial (6.4 months vs 5 months, 

 Of note, even though this article will focus on colon cancer, patients with rectal cancers are also included in many of the clinical trials.

In stages III and IV CRC, traditional chemotherapy has been shown to improve OS. Irinotecan, a topoisomerase I inhibitor commonly used in the metastatic setting, is broken down into its active metabolite SN-38. When SN-38 binds to topoisomerase I, it prevents single-strand repair, which causes permanent single- and double-strand DNA breakage.

 Two products in phase II and III trials, etirinotecan pegol (NKTR-102) and EZN-2208, are pegylated versions of irinotecan which delay clearance and prolong the half-life of SN-38.

 Specifically, etirinotecan pegol is a pegylated prodrug of irinotecan, while EZN-2208 is the pegylated formulation of SN-38. In a phase I trial of 76 patients, including 17 patients with CRC, etirinotecan pegol was given at a maximum tolerated dose (MTD) of 115 mg/m2 dose in patients treated on days 1, 8, and 15 in a 28-day cycle, and 145 mg/m2 in patients treated once every 2 weeks or once every 3 weeks. Two patients with CRC had a partial response (PR), with 1 of those patients being unconfirmed by traditional response criteria. The dose-limiting toxicity (DLT) was grade 3 diarrhea in all dosing schemata.

 The half-life of SN-38 was 50 days compared with only 12 to 47 hours with irinotecan studies.

 EZN- 2208 has been studied as a third-line treatment in 173 metastatic colorectal cancer (mCRC) patients who had previously failed 5-FU, oxaliplatin, and irinotecan. Patients with KRAS mutations received EZN-2208 at 9 mg/m2 once daily on days 1, 8, and 15 of a 28-week cycle, while patients with KRAS wild-type received either EZN-2208 with cetuximab or irinotecan with cetuximab. No responses were seen with the first group who had received single-agent EZN-2208, but 9% of patients had a response to the second arm (EZN-2208 and cetuximab) and 14% had a response to the third arm (irinotecan and cetuximab). The most common adverse effects in all groups were gastrointestinal (GI).

TAS-102 consists of 2 components: α,α,α-trifluorothymidine (FTD), the active agent, and 5-chloro-6-(2-iminopyrrolidin- 1-yl) methyl-2,4 (1H,3H)-pyrimidinedione hydrochloride utilized to prevent first-pass metabolism and maintain therapeutic FTD concentrations with oral administration. FTD exerts its activity by inhibiting thymidylate synthase and inhibiting DNA transcription by incorporating into base pairs when phosphorylated. A phase II trial included 169 adult patients with mCRC who had failed ≥2 chemotherapy regimens, including 5-FU, irinotecan, and oxaliplatin. TAS- 102 dosed at 35 mg/m2 orally, twice daily or placebo, was given to patients on days 1 to 5 in a 28-day cycle. The median OS for the TAS-102 group was 9 months compared with 6.6 months for the placebo group (

= .001).There was a median progression-free survival (PFS) of 1 month (2 months vs 1 month) for the TAS-102 group (P <.0001). Only 1 patient in the TAS-102 group had a PR, but 43% of patients achieved stable disease (SD). Severe adverse events included bone marrow suppression, fatigue, diarrhea, and febrile neutropenia.

 A phase III trial is under way to compare the OS and toxicity of TAS-102 versus placebo in patients with refractory mCRC.

ThermoDox is a doxorubicin-based low temperature—sensitive liposome in phase II clinical trials for the treatment of recurrent or refractory unresectable liver metastases (≤4 metastases with a diameter of 2-7 cm) in patients with CRC, along with radiofrequency ablation (RFA) compared with RFA alone.

 Use of the nanoparticle ThermoDox with mild hyperthermia (41ºC-42ºC) should allow for doxorubicin to be delivered and released directly into the liver metastases and therefore avoid systemic distribution. Doxorubicin given along with hyperthermia has been shown to potentially cause a synergistic effect by increasing chemotherapy penetration into the tumor.

Tumor angiogenesis, a crucial mechaon tumor vasculature.

 Ramucirumab is a human monoclonal antibody targeting VEGF, specifically blocking the interactions between all known VEGFs and VEGFR-2.

This interaction has been shown to inhibit angiogenesis and tumor growth in preclinical studies.

 nism in cancer growth and metastasis, occurs as a result of interactions between VEGF and VEGFR. VEGF-A, an important component of tumor angiogenesis, endothelial proliferation, permeability, and survival, binds to both VEGFR- 1 and VEGFR-2, which can be found on tumor vasculature.

 This interaction has been shown to inhibit angiogenesis and tumor growth in preclinical studies.

 Because ramucirumab actually blocks the binding to these receptors, it differs in mechanism from other VEGF-directed therapies already available.

A phase I study was completed in patients with advanced solid malignancies who were receiving escalating, once-weekly doses of ramucirumab. Six of the 37 patients included in the study had CRC. Authors observed antitumor activity and antiangiogenic effects with varying doses. Two patients experienced dose-limiting toxicities (grade 3 hypertension and deep vein thrombosis) after receiving a dose of 16 mg/kg; therefore the MTD was set at 13 mg/kg.

 The primary side effects observed with ramucirumab include hypertension, vascular thrombotic events, proteinuria, and bleeding.

 A phase II study investigating if patients with mCRC have an improved PFS when treated with standard chemotherapy, standard chemotherapy plus ramucirumab, or standard chemotherapy plus icrucumab, a monoclonal antibody targeting VEGFR-1, is currently recruiting patients.

 A phase III study currently recruiting patients will compare OS in mCRC patients treated with either ramucirumab plus FOLFIRI or FOLFIRI monotherapy.

A new approach to intracellular signal blockade is noted with brivanib, a novel receptor tyrosine kinase inhibitor (TKI). In addition to VEGFR-2, which was previously discussed, fibroblast growth factor-1 (FGF-1) and -2 (FGF-2) plays a role in both angioneogenesis and tumorigenesis. In order to combat the resistance seen with bevacizumab, an FDA-approved VEGF-2 inhibitor, it has been theorized that the FGF pathway should be targeted. Brivanib works by targeting FGF and VEGF signaling simultaneously.

 Brivanib alaninate is an oral L-alanine ester pro-drug which is hydrolyzed into its active form, brivanib.

 Preclinical studies indicate that brivanib has antiangiogenic and antitumor effects in colon cancer.

January/February

Literature Review: Melanoma

Crossroads in Breast Cancer: The Intersection of Clinical Uncertainty and Molecular Profiling

ASH Conference Coverage

Managed Care Restrictions: Barriers to Product Use in Cancer Care

Partial Fill Strategies for Oral Oncolytics to Reduce Waste and Drive Persistency

From Bench to Bedside: Promising Colon Cancer Clinical Trials

The Future of Oncology? COME HOME, the Oncology Medical Home

Focusing on Clinical and Economic Outcomes-Not Guidelines

The Role of Companion Diagnostic Testing in Payer Decision Making

Literature Review: Chronic Myeloid Leukemia

Lessons From an Oncology Medical Home Collaborative