In the Literature – September 2014

September 2014, Vol 5, No 7 - In the Literature


Enzalutamide Extends Survival in Men with Metastatic Prostate Cancer

Prostate cancer is the sixth leading cause of cancer-related mortality in men. Suppressing androgen receptor overexpression has led to improved outcomes in men in this patient population. Enzalutamide (Xtandi), a new oral androgen receptor inhibitor, has shown promising results for men with metastatic castration-resistant prostate cancer (mCRPC) who had not received chemotherapy (Beer TM, et al. N Engl J Med. 2014;371:424-433).

PREVAIL was a multinational, double-blind, randomized, placebo-controlled, phase 3 trial. Between Sep­tember 2010 and September 2012, PREVAIL included 1717 chemotherapy-naïve patients with asymptomatic or mildly symptomatic mCRPC who progressed with androgen-deprivation therapy. A total of 1717 patients were randomized to receive 160 mg daily of enzalutamide (N = 872) or placebo (N = 845); 1715 patients received at least 1 dose of enzalutamide.

The coprimary end points were radiographic progression-free survival and overall survival (OS). Secondary end points included the time until the initiation of cytotoxic chemotherapy, the time until the first skeletal-related event, the best overall soft-tissue response, the time until prostate-specific antigen (PSA) progression, and a decline in PSA of ?50% from baseline.

The study was stopped early after an interim analysis of OS (which was conducted as planned when 540 deaths had been reported) showed a benefit of the active treatment.

The enzalutamide group had an 81% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.19; P ‹.001). At the 22-month interim analysis, treatment with enzalutamide compared with placebo resulted in a 29% decrease in the risk of death (HR, 0.71; P ‹.001).

The median OS was an estimated 32.4 months in the enzalutamide group and 30.2 months in the placebo group. Enzalutamide improved all secondary end points. For example, overall response to imaging of soft-tissue disease with enzalutamide succeeded in 59% of patients (20% complete responses and 39% partial responses) versus 5% in the placebo group (P ‹.001).

In addition, enzalutamide delayed the median time to chemotherapy initiation by 17 months. Patients receiving enzalutamide did not need to initiate chemotherapy until a median of 28 months versus 10.8 months in the placebo arm (HR, 0.35; P ‹.001).

Enzalutamide also exhibited a favorable safety profile. Grade ?3 adverse event rates were on par between the enzalutamide and placebo arms (43% vs 37%, respectively), although the safety observation period was 3 times longer with enzalutamide than with placebo (17.1 months vs 5.4 months, respectively). The most common adverse events reported with enzalutamide were fatigue and hypertension.




Lenalidomide plus R-CHOP Improves Outcomes in Patients with Lymphoma

Although intensive high-dose chemotherapy can be used as salvage therapy for some patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), the majority of them will die from this cancer. Therefore, the development of a more effective initial therapy is crucial to improving long-term outcomes in this patient population.

In a study of patients with newly diagnosed DLBCL, the addition of lenalidomide (Revlimid) to R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone; this new combination is known as R2CHOP) mitigated the negative prognostic significance of the non–germinal center B-cell (GCB) phenotype (Nowakowski GS, et al. J Clin Oncol. 2014 Aug 18. Epub ahead of print). Lenalidomide has previously shown activity in patients with relapsed or refractory DLBCL, particularly in those with the non-GCB subtype.

Researchers from the Mayo Clinic conducted a phase 2, open-label, single-arm study of 64 patients with newly diagnosed, untreated, stage II to stage IV CD20-positive DLBCL. For comparison, 87 patients with DLBCL who had received treatment with conventional R-CHOP were selected from the Mayo Clinic lymphoma database. This control group was treated during a similar time frame and met the same inclusion criteria as the patients in the active study. The DLBCL molecular subtype was determined by tumor immunohistochemistry and was classified as GCB or non-GCB.

Of the 64 patients enrolled, 60 were eligible for response evaluation. The treatment consisted of 25 mg lenalidomide daily on days 1 to 10 with standard R-CHOP every 3 weeks for 6 cycles. The primary end point was event-free survival (EFS), with secondary end points of progression-free survival (PFS) and overall survival (OS).

The overall response rate was 98%, with 80% of patients achieving a complete response. At a median follow-up of 23.5 months, the median duration of response had not yet been reached. In patients receiving R2CHOP, the EFS rate was 59% at 24 months. Because no patients received subsequent treatment for lymphoma before disease progression, the results for EFS and PFS were identical. At 24 months, the OS rate was 78%.

In the patients receiving R-CHOP, the 24-month PFS and OS rates were 28% versus 64% and 46% versus 78% in the non-GCB patients versus the GCB patients, respectively. Surprisingly, no differences in PFS or OS were seen with R2CHOP between patients who had the non-GCB phenotype and those who had the GCB phenotype (60% vs 59% and 83% vs 75%, respectively).

The R2CHOP regimen was well tolerated. The most common grade ?3 adverse events were neutropenia (87%), leukopenia (80%), and thrombocytopenia (44%). One patient had grade 5 sepsis after the first cycle of therapy.

“This study demonstrated that the addition of lenalidomide to conventional R-CHOP resulted in similar PFS rates and OS rates between sub-types,” said lead investigator Grzegorz S. Nowakowski, MD, Assistant Professor of Medicine, Mayo Clinic, Rochester, MN, in a press release. “This is intriguing as patients with the non-GCB phenotype have traditionally experienced poorer outcomes. The results of this study support further evaluation of this regimen in this sub-type of DLBCL.”




Medicaid Coverage for Hematopoietic Cell Transplantation Varies among States

Variation in Medicaid policies among states may lead to gaps in Medicaid coverage for complex treatments and procedures in oncology, and, as a result, may affect access to care and patient outcomes. Researchers used hematopoietic-cell transplantation (HCT) as a case study to highlight variations in Medicaid coverage among states (Preussler JM, et al. J Oncol Pract. 2014;10:e196-e200).

HCT, an optional benefit under Medicaid, is an example of a nondrug oncology service for which there is no specific coverage guidance. To characterize variation in coverage for HCT among state Medicaid programs, researchers reviewed coverage benefits for 2012 from state Medicaid websites and compared the data with the recommended HCT benefits developed by multiple stakeholders. The coverage was reviewed for transplantation procedure; donor search; prescriptions; clinical trials; and patient food, lodging, and transportation. The data were coded on a 3-point scale for each state; states were ranked according to the number of variables for which they met the recommended benefits criteria.

Although all states provide coverage for HCT through their Medicaid programs, the findings showed substantial variation in coverage by state. Among the 47 states for which data were available, no state provided the recommended benefits in all 5 categories, and only 4 states met at least 4 of the 5 categories.

Overall, 39 states provided the recommended prescription coverage and 35 states did not cover clinical trials. The coverage for donor search varied, with 8 states not providing coverage at all, and 20 states meeting the recommended benefits. It is not unusual for patients to relocate to be closer to their transplantation center and to stay nearby for ?3 months posttransplant. Yet, only 29 states provided the recommended coverage for patient lodging and transportation coverage.

Among the states that did not fully meet the recommended benefits, the researchers identified 3 examples of coverage restrictions that can serve as barriers to HCT access among Medicaid patients, including (1) lack of coverage for standard indications of transplantation, (2) limitations on the number of inpatient days allowed annually, and (3) the absence of coverage for searching for a donor.

This study shows considerable variation in coverage for HCT through individual state Medicaid programs. The researchers note that these findings can be extrapolated to other areas in oncology. A majority of Medicaid programs clearly define coverage guidelines for common cancers. However, coverage parameters for other cancers may not be specific, and variation in coverage may increase the disparities in access to cancer care for already medically underserved populations, especially if treatment requires a combination of several specialties and modalities.




Gemtuzumab Ozogamicin Improves Overall Survival in Patients with AML, Warrants New Considerations

Gemtuzumab ozogamicin (Mylotarg) was granted accelerated approval by the FDA in May 2000 for the treatment of patients aged ?60 years with recurrent acute myeloid leukemia (AML) who were not considered candidates for other chemotherapy. However, Pfizer voluntarily withdrew its drug from the US market in June 2010, after the disappointing results of the SWOG (Southwest Oncology Group) S0106 study, which was required for postapproval support by the FDA. The study was terminated early when no improvement in clinical benefit was observed and after more deaths occurred with gemtuzumab ozogamicin.

Because SWOG S0106 and other randomized trials have shown conflicting results, researchers conducted a new meta-analysis to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adults with AML (Hills RK, et al. Lancet Oncol. 2014;15:986-996).

The meta-analysis included data on 3325 patients from 5 randomized, open-label trials of gemtuzumab ozogamicin, given to adults in conjunction with the first course of intensive induction chemotherapy for AML compared with chemotherapy alone.

Overall survival (OS) was the primary end point for all 5 trials. Secondary end points included risk of relapse, complete remission, and 30-day mortality. In the trials, gemtuzumab ozogamicin was given at 3 mg/m2 on day 1, 6 mg/m2 on day 4, and 3 mg/m2 (up to a maximum of 5 mg per dose) on days 1, 4, and 7. The median follow-up was 60.8 months.

The addition of gemtuzumab ozogamicin to induction chemotherapy significantly improved OS at 5 years (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.82-0.98). At 6 years, the absolute survival benefit, defined by cytogenetic characteristics, was observed in patients with low risk (20.7%; OR, 0.47; 95% CI, 0.31-0.73) and intermediate risk (5.7%; OR, 0.84; 95% CI, 0.75-0.95). However, patients with adverse cytogenetic characteristics did not benefit (2.2%; OR, 0.99; 95% CI, 0.83-1.18).

Furthermore, gemtuzumab ozogamicin significantly reduced the risk for relapse (OR, 0.81; 95% CI, 0.73-0.9), despite no improvement in the proportion of patients achieving complete remission with or without peripheral count recovery (OR, 0.91; 95% CI, 0.77-1.07). Although the researchers identified no significant interaction between different dosing schedules, they noted significant interaction between gem­tuzumab ozogamicin (3 mg/m2 vs 6 mg/m2) with respect to 30-day mortality. Fewer early deaths were associated with the lower dose of gemtuzu­mab ozogamicin compared with the higher dose of the drug.

The investigators noted that these findings demonstrate significant OS benefit in patients with low-risk and intermediate-risk AML without adverse cytogenetic characteristics, and may warrant revision of its regulatory status.

In an accompanying editorial (Lancet Oncol. 2014;15:913-914), Kharfan-Dabaja concurred that the data support consideration by regulatory authorities to review their decision with the view of making this therapy available again. Although the optimal dose and dosing schedule remain elusive, Kharfan-Dabaja said that a single dose of 3 mg/m2 on day 1 or fractionated dosing of 3 mg/m2 on days 1, 4, and 7 are reasonable recommendations for prescribing guidance.