JHOP - December 2014 VOL 4, NO 4 - From the Literature
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Robert J. Ignoffo, PharmD, FASHP, FCSHP

Professor of Pharmacy
College of Pharmacy
Touro University–California, Mare Island
Vallejo, CA
Clinical Professor Emeritus
University of California
San Francisco, CA

In This Article


 

Molecular Profiling Not Cost-Effective for Adjuvant Chemotherapy Decision-Making in Patients with Node-Negative Breast Cancer

BACKGROUND
Node-negative breast cancer (NNBC) accounts for 70% to 80% of breast cancer diagnoses. Treatment decisions regarding the use of adjuvant chemotherapy are usually based on several factors, including tumor size and histology, expression of estrogen receptor (ER) and/or progesterone receptor, and expression of human epidermal growth factor receptor-2 (HER-2).

These factors are important when assessing prognosis and risk of recurrence in patients with cancer. Although the use of adjuvant chemotherapy in patients with NNBC has a negative impact on quality of life, serious side effects, and increased overall costs of therapy, it does improve survival and delays recurrence in certain subsets of patients, mainly triple-negative cases and those with tumor size >0.5 cm.

The purpose of this study was to compare the cost- effectiveness of the genomic testing (MammaPrint) to a proven risk calculator (Adjuvant! Online) for decisions regarding the use of adjuvant chemotherapy.

METHODS
Researchers analyzed the economic impact of using the genomic test MammaPrint, a 70-gene signature, versus 2 other strategies to guide the clinical decision to use adjuvant chemotherapy in patients with NNBC. The study was conducted in France and was supported by the French National Cancer Institute. Data were taken from the TRANSBIG Consortium validation study conducted with the MammaPrint genomic test. A total of 307 patients with NNBC who did not receive any systemic adjuvant therapy were included in the study. Eligibility criteria included age <61 years at diagnosis and a tumor size <5 cm. The majority (69%) of the patients had ER-positive breast cancer; 41% had a grade 2 or 3 tumor.

In the base-case analysis, 3 strategies were used to decide whether to use adjuvant chemotherapy, including; (1) the MammaPrint genomic test, (2) the prognostic diagnosis, Adjuvant! Online; and (3) using systematic chemotherapy in all patients. The time horizon for overall survival (OS) was 10 years. In the first 2 strategies, only women at high risk for recurrence were assumed to receive chemotherapy. In the systematic chemotherapy strategy, all patients were assumed to receive chemotherapy, regardless of risk for recurrence.

The costs were based on the French National Health Insurance Scheme, life-years, and quality-adjusted life-years (QALYs), and were calculated for each of the 3 strategies for the 10-year time horizon.

RESULTS
Without the use of adjuvant chemotherapy, the 10-year OS for patients with NNBC is 77% (95% confidence interval [CI], 71%-81%). The mean differences in life-years and QALYs were similar among the 3 strategies. The MammaPrint genomic test was associated with a higher cost than the other 2 strategies: the mean difference was an additional €2037 (range, €1472-€2515) for MammaPrint compared with Adjuvant! Online and €657 (95% CI, –€642 to €3130) compared with systematic chemotherapy. However, when the cost of the genomic test was reduced, the test became a more cost-effective strategy.

Based on a €50,000 per QALY willingness-to-pay threshold, the Adjuvant! Online strategy had a 92% (76% in patients with ER-positive NNBC) probability of being the most cost-effective strategy; systematic chemotherapy had a 6% (4% in the patients with ER-positive disease) likelihood of being the most cost-effective strategy; and the MammaPrint genomic test had only a 2% (20% in patients with ER-positive NNBC) probability of being the most cost-effective strategy.

DISCUSSION
These results indicate that the use of the MammaPrint test to determine which patients with NNBC are at high risk for disease recurrence and would benefit from adjuvant chemotherapy is not cost-effective. The health outcomes in this study were almost identical among the 3 strategies evaluated. The high cost of the MammaPrint genomic test renders it less cost­effective than the other 2 options for routine use to determine the benefit of adjuvant chemotherapy in patients with NNBC. If the cost of the test were lower, however, it would become more cost-effective.

Source: Bonastre J, Marguet S, Lueza B, et al. Cost effectiveness of molecular profiling for adjuvant decision making in patients with node-negative breast cancer. J Clin Oncol. 2014;32:3513-3519.

COMMENTARY BY ROBERT J. IGNOFFO
This study shows that the MammaPrint genomic test is unlikely to be cost-effective for making decisions regarding the use of adjuvant chemotherapy in patients with NNBC. The US Food and Drug Administration has approved MammaPrint to assist in assigning risk of recurrence in ER-positive and -negative breast cancer, but has not been approved for predicting benefit from adjuvant systemic therapy. This study shows that the use of this genomic test added to the cost of therapy and did not optimize decision-making in patients with NNBC. The authors cautioned that the study was limited by the small sample size and inability to calculate reliable survival predictions. Furthermore, the results may not be generalizable to other patients with breast cancer because the study population was generally younger (47 years) than the usual age for NNBC.

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Biomarker-Driven New Anticancer Drugs Reduce Toxicity and the Associated Costs

BACKGROUND
The new anticancer drugs approved by the US Food and Drug Administration (FDA) for the treatment of patients with cancer often result in prolonged survival and improved quality of life; however, increasing reports have noted rare but serious adverse events linked to new therapies, and managing these events further increases the cost of therapy. A recent study evaluated anticancer drugs approved by the FDA between 2000 and 2011 to identify grade 3 or 4 adverse events and their associated costs.

METHODS
In this meta-analysis of 41 studies related to anticancer drugs in development, researchers analyzed the frequency and costs of 12 grade 3 or 4 adverse events. They calculated the estimated incremental drug prices and the incremental costs associated with the management of these common events based on the type of new drug and target specificity. The 41 studies included a total of 27,539 patients. The studies involved 19 experimental anticancer drugs, of which 12 were targeted agents and 7 were chemotherapies.

RESULTS
Drugs that target a specific molecular mutation or a specific target on the cancer cells were associated with a lower incidence of grade 3 or 4 adverse events compared with controls (P = .22); by contrast, other drugs, including angiogenesis inhibitors and chemotherapy agents, were associated with increased toxicity compared with controls (P <.001). In the latter, the risk for toxicity increased regardless of whether the control arm contained an active or inactive treatment.

In addition, the median monthly drug cost was higher for the experimental drugs compared with the controls, regardless of the type of drug. The median incremental drug price for the experimental drugs was $6000 (range, –$620 to $32,900) per patient per month (PPPM). The PPPM median cost was lowest, at $4610 (range, –$620 to $9150), for targeted drugs with the greatest specificity; followed by chemotherapy, at $5730 (range, $2780-$7790); and highest, at $6690 (range, $2870-$32,900), for the less specific targeted agents. The median cost of managing adverse events was higher for the new drugs than for the controls using chemotherapy or drugs with less specific molecular targets. However, for those drugs with specific molecular targets, the cost of managing toxicity was lower than for the controls.

New anticancer drugs are associated with increased toxicity, which may lead to a small increase in treatment cost. Toxicity was not observed in drugs with a specific molecular target on cancer cells, the investigators noted. These results suggest that developing biomarker-driven drugs should be encouraged as a way to reduce toxicity and the associated costs and to improve overall outcomes.

Source: Niraula S, Amir E, Vera-Badillo F, et al. Risk of incremental toxicities and associated costs of new anticancer drugs: a meta­analysis. J Clin Oncol. 2014;32:3634-3642.

COMMENTARY BY ROBERT J. IGNOFFO
One of the benefits to performing a meta-analysis is that more of the rare or uncommon toxicities may be observed when they would not have been otherwise noted. In this study, the investigators were able to identify with greater frequency the serious adverse effects from experimental anticancer drugs and the costs associated with their management. Most cases of grade 3 or 4 adverse reactions came from new nonspecific targeted anticancer drugs. Gastrointestinal perforation was one of the reported serious adverse effects and likely was due to new antiangiogenesis inhibitors, which are known to cause this problem. With more than half of the new drugs falling into the class of a targeted agent, the incidence of serious adverse effects from new drugs was substantially lower compared with traditional cytotoxic chemotherapy. This is probably due to the lower incidence of chemotherapy-induced myelosuppression leading to hospitalization, which is not a common toxicity of targeted drugs. Thus, it is not surprising that many of the new drugs—especially specific targeted agents—do not substantially increase the overall cost of administering the treatment.

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Panobinostat Improves Outcomes in Relapsed/Refractory Myeloma

BACKGROUND
Panobinostat is a potent, oral histone deacetylase (HDAC) inhibitor that has shown synergistic antitumor activity when combined with bortezomib (Velcade) and dexamethasone (Decadron). HDAC inhibitors could help overcome the acquired resistance to proteasome inhibitors, such as bortezomib, by blocking the aggresome pathway (an escape route for myeloma cells as they evade the ubiquitin proteasome pathway).

METHODS
The multicenter, randomized, double-­blind phase 3 clinical trial known as PANORAMA1 compared the use of panobinostat plus bortezomib and dexamethasone with placebo plus bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma.

RESULTS
PANORAMA1 enrolled 768 patients with relapsed and/or refractory myeloma from 215 centers in 34 countries. Patients with disease refractory to bortezomib were excluded. The patients were randomized to panobinostat or to placebo, both in combination with bortezomib and dexamethasone, for a maximum of 12 cycles. Patients were followed for a median of approximately 6 months.

The primary end point was median progression-free survival (PFS), which was significantly longer in the panobinostat group (11.99 months) than in the placebo group (8.08 months), a 27% reduction in the risk for disease progression. The 2-year PFS was 20.6% with panobinostat versus 8.4% with placebo.

For patients who achieved a complete response or near-complete response, the median PFS was 19.38 months in the panobinostat group and 15.21 months in the placebo group. The addition of panobinostat to the combination of bortezomib and dexamethasone also led to longer median duration of response and longer time to first disease progression, relapse, or myeloma-related death. These results were consistent across all subgroups, suggesting a clinical benefit with the addition of the HDAC to the treatment regimen, regardless of any previous treatment or baseline patient characteristics.

At the time of this analysis, the overall survival data were not yet mature, but the median survival duration was 33.64 months with panobinostat and 30.39 months with placebo. Although this 13% mortality risk reduction was not statistically significant, the panobinostat group had significantly more complete or near-complete responses than the placebo group (27.6% vs 15.7%, respectively; P = .006).

Serious adverse events occurred in 60% of patients receiving panobinostat versus 42% of patients receiving placebo. Neuropathy was not increased in the experimental group, but that group did have more cases of diarrhea, thrombocytopenia, asthenia, and fatigue.

The investigators noted that the results with pano­binostat are better than those seen with another HDAC inhibitor, vorinostat (Zolinza), which, when added to bortezomib, did not lead to a significant increase in PFS; panobinostat is a more potent pan-HDAC inhibitor, with more potent in vitro inhibitory activity than vorin­ostat, they noted. PANORAMA1 is the first phase 3 clinical trial to show a benefit for a 3-drug versus a 2-drug combination in patients with relapsed and/or refractory myeloma.

Source: San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195-1206.

COMMENTARY BY ROBERT J. IGNOFFO

This international, phase 3, randomized clinical study uniformly showed that the addition of panobinostat improved PFS and delayed recurrence in patients with relapsed/refractory myeloma. The improvement in median PFS was 4 months, which on the surface may not appear exceedingly impressive, but in the setting of advanced disease demonstrates that panobinostat is a very active agent. It appeared to be particularly effective in patients with high-risk cytogenetic characteristics. Of note is that approximately 44% of the patients received prior bortezomib and 57% received a stem cell transplant. It is important to point out that the higher tumor response rate in the panobinostat group suggests that this drug may be useful in the first-line setting by allowing more patients to undergo potentially curative stem cell transplants.

Although the panobinostat combination produced a higher incidence of grade 3 or 4 toxicities, it is noteworthy that it did not cause additive neurotoxicity. Diarrhea and asthenia were more frequent adverse effects in panobinostat 3-drug combination. This study shows that panobinostat may be an important new second-line agent for treating relapsed/refractory myeloma. Further studies using panobinostat as a first-line agent are warranted.

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Last modified: January 17, 2018