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JHOP - March 2014 VOL 4, NO 1
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Obinutuzumab versus Rituximab for the Treatment of Older Patients with Chronic Lymphocytic Leukemia

Background: The anti-CD20 antibody rituximab, combined with chemotherapy agents, has been shown to prolong overall survival (OS) in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL), but not in patients with comorbidities. In a recent head-to-head, randomized, phase 3 trial of older patients, researchers investigated the benefit of the anti-
CD20 antibody obinutuzumab plus chlorambucil compared with rituximab plus chlorambucil in patients with previously untreated CLL and coexisting conditions.

Methods: In this open-label study, 781 patients were randomized in a 1:2:2 ratio to receive six 28-day cycles of obinutuzumab plus chlorambucil (N = 333), chlorambucil alone (N = 118), or to rituximab plus chlorambucil (N = 330). Patients were required to have a Cumulative Illness Rating Scale (CIRS) score of >6 and/or a creatinine clearance (CrCl) of 30 mL/min to 69 mL/min. The groups receiving obinutuzumab and rituximab were well-balanced. The patients had a median age of 73 years, a CrCl of 62 mL/min, and a CIRS score of 8 at baseline. Most of the patients (82%) had more than 3 coexisting conditions, such as hypertension, coronary artery disease, and diabetes. Chlorambucil was administered orally at 0.5 mg/kg of body weight on days 1 and 15 of each cycle. Obinutuzumab was administered intravenously at a dose of 1000 mg on days 1, 8, and 15 of cycle 1, and on day 1 of cycles 2 through 6. Rituximab was administered intravenously at doses of 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2 through 6.

Results: Patients in the obinutuzumab plus chlorambucil group had a significant increase in median prolonged progression-free survival (PFS) and a higher response rate than the rituximab plus chlorambucil group. The median PFS was 26.7 months in the obinutuzumab group and 15.2 months in the rituximab group (hazard ratio [HR], 0.39; 95% confidence interval, 0.31-0.49; P <.001). The complete response rates were 20.7% and 7%, respectively. The median PFS in patients receiving chlorambucil monotherapy was 11.1 months, which was shorter than the obinutuzumab plus chlorambucil group (HR, 0.18) or the rituximab plus chlorambucil group (HR, 0.44).

Grades 3 to 5 adverse events ranged from 11% to 14% and did not differ significantly among treatment groups. The main difference was in infusion-related reactions. In the obinutuzumab plus chlorambucil group, 20% of the patients experienced infusion-related reactions compared with 4% of patients in the group receiving rituximab plus chlorambucil. In the group receiving obinutuz-
umab plus chlorambucil, the researchers noted that the reaction occurred during the first infusion, and no deaths were associated with infusion-related reactions.

The researchers concluded that the combination of obinutuzumab or rituximab with chlorambucil improves outcomes in patients with previously untreated CLL and coexisting conditions. In this patient population, obinutuzumab plus chlorambucil showed an OS advantage over chlorambucil monotherapy. Furthermore, obi-
nutuzumab plus chlorambucil induced prolonged PFS and a higher complete response rate than rituximab plus chlorambucil.

Source: Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Jan 8 [Epub ahead of print].

COMMENTARY BY ROBERT J. IGNOFFO

Although obinutuzumab is an anti-CD20 monoclonal antibody similar to rituximab, its mechanism differs in that it binds to a different epitope on CD20 that enhances immune effector functions, especially antibody-dependent cell-mediated cytotoxicity. It also has been shown to produce greater B-cell depletion compared with rituximab.1 Phase 2 studies were very promising in highly refractory non-Hodgkin lymphoma.

This phase 3 study by Goede and colleagues provides high-level evidence that obinutuzumab is a very active drug in CLL. Although OS with the combination of obinutuzumab plus chlorambucil was not significantly better than rituximab plus chlorambucil, PFS was better by approximately 75%. The 20% incidence of infusion-related reactions is greater than that reported for rituximab and may be somewhat more problematic for oncology nurses to handle. Fortunately, most of the reactions occurred during the first cycle.

The average wholesale cost for 1000 mg is $6192. A monthly cycle consists of three 1000-mg doses, making the cost of a typical treatment $18,576, which varies as a result of differences in purchasing methods.

The FDA has approved obinutuzumab as a breakthrough therapy and as an orphan drug. It is likely that this drug will be added to standard algorithms for both the initial and refractory treatments of symptomatic CLL.

1. Mossner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010;115:4393-4402.


Adverse Events Reporting Suboptimal in Oncology Publications

Background: Transparent and comprehensive reporting of adverse events (AEs) in published results of oncology-related clinical trials is crucial for the treatment of patients with cancer. In efforts to improve reporting clinical trials results, the Consolidated Standards of Reporting Trials (CONSORT) extension group developed 10 recommendations in 2003 for reporting AEs.

Methods: A new study of 175 publications assessed the degree to which the publication of phase 3 trials in oncology adhered with CONSORT recommendations. The researchers also evaluated characteristics associated with AE reporting completeness score using regression analysis.

Results: The findings from this analysis showed that the reporting of AEs is suboptimal in published studies and is characterized by significant selectivity of the data. The researchers reviewed PubMed, Medline, and EMBASE citations to identify randomized, phase 3 trials in metastatic solid malignancies published between January 2009 and December 2011. Publications were assessed for 14 AE reporting elements taken from the CONSORT harms extension statement, with a completeness score of 0 to 14 being calculated. Data on 96,125 patients were included in the analysis. The median completeness score was 8 (range, 3-12). The majority of publications (96%) only reported AEs occurring above a particular threshold rate or severity. Another 37% of publications did not specify the criteria for determining which AEs were reported, and 88% grouped AEs of varying severity.

The findings showed that 91% of the articles analyzed had a title or an abstract stating whether AEs were addressed, and 58% had introductions stating whether AEs were addressed in the study. For methods, 93% specified an instrument or scale used to categorize AEs, 65% specified whether the reported AEs encompassed all recorded events or a select sample, and 62% specified a surveillance time frame. For the results, 77% of articles reported absolute numbers of AEs, 75% reported if there were deaths related to AEs, 71% reported whether patients were evaluable for toxicity, and 65% reported reasons for treatment discontinuation.

The regression analysis used to assess characteristics associated with the AE reporting completeness score revealed that trials without a specified funding source and with an earlier year of publication were associated with significantly lower completeness scores. This analysis shows substantial selectivity and heterogeneity in the reporting of AEs in oncology publications, which may affect the results used to guide clinical practice. The researchers cited potential factors for the observed variability in AE reporting and poor adherence with the recommendations, including the authors’ awareness of these recommendations and a lack of compliance with guidelines imposed by journals as a prerequisite. This study further illustrates the importance of developing oncology-specific standards for AE reporting to ensure consistency in the reporting of AEs to provide oncologists with the information required to determine treatment recommendations and to facilitate shared decision-making.

Source: Sivendran S, Latif A, McBride RB, et al. Adverse event reporting in cancer clinical trial publications. J Clin Oncol. 2014;32: 83-89.

COMMENTARY BY ROBERT J. IGNOFFO

The article by Sivendran and colleagues illustrates the variability in reporting the results of AEs in phase 3 clinical trials of anticancer drugs. The journals included for review were those considered to be important to obtaining clinical information about new treatment strategies. The journals include Annals of Oncology, Breast Cancer Research and Treatment, British Journal of Cancer, Cancer, European Journal of Cancer, Journal of Clinical Oncology, Lancet, Lancet Oncology, New England Journal of Medicine, and others. Of the 175 journals, most articles appeared in the Journal of Clinical Oncology.

It is apparent from the article by Sivendran and colleagues that more stringent criteria should be used by editorial boards requiring that an article about a phase 3 clinical therapeutics trial reach a particular level of completeness before being published. Certain reporting elements should probably always be included, such as a statement in the abstract about whether AEs occurred, the percentage of patients who discontinued therapy as a result of toxicities, and whether any grade 4 or 5 toxicities occurred.


Combination of Bortezomib and Thalidomide Used as Maintenance Improves Overall Survival in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma

Background: Patients with multiple myeloma (MM) who are not fit to undergo stem-cell transplantation typically receive melphalan plus prednisone in combination with either thalidomide or bortezomib. Recent studies are exploring the clinical benefit of the 4-drug induction regimen of bortezomib, melphalan, prednisone, and thalidomide, followed by maintenance with bortezomib plus thalidomide (VMPT-VT).

Methods: In this recent phase 3 trial, a total of 511 patients with newly diagnosed MM who were not candidates for stem-cell transplantation were randomized to receive VMPT-VT (N = 254) or bortezomib, melphalan, and prednisone (VMP; N = 257). The patients’ median age was 71 years, and 27% of the patients were aged >75 years.

Results: After a median follow-up of 54 months, the progression-free survival (PFS) was 35.3 months for patients receiving VMPT-VT and 24.8 months for patients receiving bortezomib, melphalan, and prednisone VMP (hazard ratio [HR], 0.58; P <.001). Of note, the overall survival (OS) was significantly prolonged with VMPT-VT compared with VMP; the 5-year OS rates were 61% with VMPT-VT and 51% with VMP (HR, 0.70; P = .01). A multivariable analysis revealed that treatment with VMPT-VT, age <75 years, female sex, and disease stages I and II were associated with the significantly longer OS. In addition, the difference between median PFS and time to next therapy was approximately 1 year with VMPT-VT, but only 3 months with VMP. Researchers suggested that the significant tumor reduction and ongoing treatment with maintenance therapy delayed disease progression in patients treated with VMPT-VT.

The most common adverse events (AEs) were hematologic and included grade 3 to 4 neutropenia and grade 3 to 4 thrombocytopenia; neutropenia was reported in 38% of patients in the VMPT-VT arm and in 28% of patients in the VMP arm, whereas thrombocytopenia was reported in 22% of patients in the VMPT-VT arm and in 20% of patients in the VMP arm. The most common nonhematologic AEs in both treatment arms included infections, cardiologic events, and peripheral neuropathy. Of the patients in the VMPT-VT arm, 28% discontinued treatment and required dose reduction because of AEs; the same was true for 16% of patients in the VMP arm.

The researchers concluded that the VMPT-VT regimen was superior to the VMP regimen in terms of PFS, OS, and time to next therapy in patients with newly diagnosed MM who are not eligible for stem-cell transplantation. Although these follow-up results are encouraging, an important question remains to be answered: is the clinical benefit observed with the VMPT-VT attributed to the 4-drug induction combination or to the maintenance treatment with bortezomib and thalidomide? Overall, researchers believe these results provide the foundation for newer, less toxic combinations of immunomodulatory agents and proteasome inhibitors.

Source: Palumbo A, Bringhen S, Larocca A, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014;32:
634-640.

COMMENTARY BY ROBERT J. IGNOFFO

The phase 3 study by Palumbo and colleagues combines all of the first-line chemotherapy drugs for the treatment of advanced MM for patients who are unable to undergo stem-cell transplant. The 4-drug combination of bortezomib, melphalan, prednisone, and thalidomide with maintenance significantly prolongs PFS and OS, as well as delays the time to next therapy. This regimen was very effective in the 65- to 75-year-old age-group. The overall complete response rate to the 4-drug combination with maintenance was an impressive 14%. Unfortunately, the study did not include a third arm to assess if the benefit was a result of the 4-drug induction therapy or the maintenance therapy. The 4-drug regimen produced more toxicity than the 3-drug combination of bortezomib, melphalan, and prednisone, in particular neutropenia and thrombocytopenia. Expectantly, patients aged >75 years were more susceptible to toxicity and required greater dose reduction and discontinued therapy more often than younger patients. The thalidomide plus bortezomib maintenance therapy utilized once-weekly bortezomib rather than the usual twice-weekly schedule, and decreased the incidence of peripheral neuropathy substantially. The authors noted that the study was limited by not having a predefined salvage regimen and a second randomization in the maintenance arm versus the control arm.

The 4-drug combination is a reasonably effective and low-toxicity regimen for the treatment of advanced MM in patients who are ineligible for stem-cell transplant.


Nintedanib plus Docetaxel an Effective Combination in Patients with Advanced Lung Cancer

Background: The current US Food and Drug Administration (FDA)-approved second-line treatments for non–small-cell lung cancer (NSCLC) include monotherapy with docetaxel, erlotinib, or pemetrexed. A recent trial explored the safety and efficacy of nintedanib—a potent oral angiokinase inhibitor—in combination with docetaxel, as a second-line treatment in patients with NSCLC.

Methods: In this phase 3 LUME-Lung 1 trial, 1314 patients were randomized to receive nintedanib and docetaxel (ie, the treatment group; N = 655) or docetaxel and placebo (ie, the placebo group; N = 659). The primary end point was progression-free survival (PFS) as assessed by the central independent review. The key secondary end point was overall survival (OS). The OS was assessed in the following order: first in patients with adenocarcinoma who progressed within 9 months of starting first-line therapy, next in all patients with adenocarcinoma, and, finally, in all patients, regardless of histology.

Results: After a median follow-up of 7.1 months, the median PFS was 3.4 months in the treatment group compared with 2.7 months in the placebo group (P = .001). After a median follow-up of 31.7 months, the OS of patients with adenocarcinoma who progressed within 9 months of starting first-line therapy was 10.9 months in the treatment group versus 7.9 months in the placebo group (P = .007). Furthermore, in all patients with adenocarcinoma, the OS was 12.6 months in the treatment group and 10.3 months in the placebo group (P = .035). Although treatment with nintedanib plus docetaxel had a significant effect on OS in patients with adenocarcinoma who progressed within 9 months of first-line treatment and in all patients with adenocarcinoma, there was no difference in OS between the 2 groups when all patients, independent of histology, were assessed.

Adverse events (AEs) that were more common in the treatment group than in the placebo group included diarrhea, increases in alanine aminotransferase, nausea, increases in aspartate aminotransferase, decreased appetite, and vomiting. Most of these AEs were managed with supportive care or with dose reduction.

The investigators suggest that nintedanib plus docetaxel may be an appropriate second-line treatment option for all patients with NSCLC and is particularly effective in patients with an adenocarcinoma histology.

Source: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15:143-155.

COMMENTARY BY ROBERT J. IGNOFFO

Nintedanib is not yet approved by the FDA for clinical use in patients with NSCLC. The LUME-Lung 1 study evaluated this drug in combination with the standard second-line agent, docetaxel. The benefit appears to be minimal, with only a 3-month improvement in PFS and a 2-month improvement in OS in patients with adenocarcinoma. However, the authors noted that this is the first study combining a targeted agent with chemotherapy in the second-line setting that has produced a median OS greater than 1 year. OS was not improved in patients with squamous-cell histology. Other antiangiogenic agents that have been combined with chemotherapy include vandetanib, sunitinib, and aflibercept, and none have improved OS in patients with NSCLC. The efficacy of nintedanib is apparent in both squamous-cell carcinoma and adenocarcinoma histologies. Although AEs were substantially higher with the combination, these were primarily diarrhea and elevations in hepatic enzymes. This is notably different from other antiangiogenic drugs, which generally cause hypertension, bleeding, perforation, and thromboembolism.

Reck and colleagues noted that further studies should be performed to determine if biomarker analyses correlate with response to nintedanib in patients with refractory adenocarcinoma. This study did not analyze tissue samples for potentially useful biomarkers.


Statin Therapy Lowers Mortality in Patients with Prostate Cancer

Background: Statin use has been shown to improve lipid profiles and to reduce cardiovascular morbidity and mortality. A 2012 study found that statins may have antitumor effects in various cancer types, including prostate cancer. Observational studies have investigated the association between statin use and different prostate cancer outcomes, but the findings were inconsistent. Also, these studies did not specifically assess whether the use of statins before the diagnosis of prostate cancer modified the association regarding the use of statins after diagnosis. In a new study, researchers examined the correlation between the use of statins after a prostate cancer diagnosis and the risk of cancer-related and all-cause mortality.

Methods: The data come from a large, population based electronic database of 11,772 men in the United Kingdom. The cohort focused on patients newly diagnosed with nonmetastatic prostate cancer between April 1, 1998, and December 31, 2009, who were followed until October 1, 2012. The mean age at study entry was 71.3 years.

Results: During a mean follow-up of 4.4 years, the researchers identified 3499 deaths, and 1791 (approximately 52%) of those deaths were specific to prostate cancer. The postdiagnostic use of statin therapy was associated with a 24% risk reduction in prostate cancer mortality (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66-0.88). The results also showed a 14% decreased risk of all-cause mortality (HR, 0.86; 95% CI, 0.78-0.95), with the HRs gradually decreasing with longer cumulative durations of use and higher cumulative doses. For patients who used statins before their diagnosis, these decreased risks were more pronounced (HR, 0.55; 95% CI, 0.41-0.74, and HR, 0.66; 95% CI, 0.53-0.81, respectively). However, weaker effects were observed in patients who started statins after diagnosis (HR, 0.82; 95% CI, 0.71-0.96, and HR, 0.91; 95% CI, 0.82-1.01, respectively).

Results: Overall, these findings indicate that statin use after a diagnosis of prostate cancer is correlated with a reduced risk of cancer-related mortality and all-cause mortality. This effect, however, was stronger in patients who also used statins before their diagnosis of prostate cancer, suggesting a possible effect of longer cumulative duration of use and higher cumulative doses. Although the study results provide evidence that statin use may be associated with a decreased risk of prostate cancer mortality, the researchers cautioned that additional well-conducted, observational studies are needed to validate these findings before initiating randomized controlled trials to evaluate the effects of statins in the adjuvant setting.

Source: Yu O, Eberg M, Benayoun S, et al. Use of statins and the risk of death in patients with prostate cancer. J Clin Oncol. 2014;
32:5-11.

COMMENTARY BY ROBERT J. IGNOFFO

The basis for the large number of studies evaluating statins and prostate cancer stems from research demonstrating that they have antitumor properties through their effects on lipid metabolism.1,2 This large cohort study suggests that statins may reduce the risk of prostate cancer death and all-cause mortality. In an accompanying editorial, Mucci and Stampfer state, “From the perspective of etiology and prevention, we propose that lethal prostate cancer is the optimal disease end point for epidemiologic investigations. Given the long natural history of prostate cancer, such studies require long-term and complete follow-up of large cohorts of men.”3 Mucci and Stampfer mention that the Yu study provides important new information on the use of statins. The benefit was seen primarily in men who were taking statins before their diagnosis of prostate cancer. This result suggests that statins need to be given over a specific time or exposure period to have a chemopreventive effect. Considerations include what the optimal exposure time is and when a statin should be started. An extremely large and unfeasible study would be required to answer these questions. This study may, however, convince some clinicians to institute statin therapy in a high-risk family member with borderline cardiovascular disease.

1. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367:1792-1802.
2. Pelton K, Freeman MR, Solomon KR. Cholesterol and prostate cancer. Curr Opin Pharmacol. 2012;12:751-759.
3. Mucci LA, Stampfer MJ. Mounting evidence for prediagnostic use of statins in reducing risk of lethal prostate cancer. J Clin Oncol. 2014;32:1-2.

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