In the Literature - October 2016

October 2016, Vol 7, No 9

In This Article


Inotuzumab Ozogamicin Shows Benefit in Acute Lymphoblastic Leukemia

Many patients with B-cell acute lymphoblastic leukemia (ALL) who achieve complete remission will have disease relapse. Because of the poor prognosis for adults with relapsed ALL, investigators assessed the efficacy and safety of using the investigative single-agent inotuzumab ozogamicin compared with standard intensive chemotherapy in patients with relapsed or refractory B-cell ALL. Inotuzumab ozogamicin is an anti-CD22 antibody conjugated to the cytotoxic antibiotic calicheamicin (Kantarjian HM, et al. N Engl J Med. 2016;375:740-753). This open-label, 2-group, phase 3 clinical trial randomized 326 adults with relapsed or refractory ALL to receive inotuzumab ozogamicin or standard intensive therapy in a 1:1 ratio. Inotuzumab ozogamicin was administered intravenously at a starting dose of 1.8 mg/m2 per cycle, with 0.8 mg on day 1 of each cycle, and 0.5 mg on days 8 and 15; cycle 1 lasted 21 days, and the following cycles lasted for 28 days, with treatment continued for ≤6 cycles. Among the patients who achieved complete remission with or without incomplete hematologic recovery, the dose administered on day 1 of each cycle was reduced to 0.5 mg. Standard chemotherapy consisted of the investigator's choice of fludarabine, cytarabine, and granulocyte colony-stimulating factor therapy for up to four 28-day cycles; cytarabine plus mitoxantrone for up to four 15- to 20-day cycles; or high-dose cytarabine for up to one 12-dose cycle. The primary end points were complete remission, including complete remission with incomplete hematologic recovery, and overall survival (OS). Treatment with inotuzumab ozogamicin was associated with a significantly higher rate of complete remission (80.7%) compared with standard chemotherapy (29.4%). Median duration of remission was 4.6 months in the inotuzumab ozogamicin group and 3.1 months in the standard chemotherapy group. In addition, median progression-free survival was 5 months in patients receiving inotuzumab ozogamicin versus 1.8 months in those getting standard therapy; similarly, median OS was longer in the inotuzumab ozogamicin group than in the standard therapy group (7.7 months vs 6.7 months, respectively). The safety profile of inotuzumab ozogamicin was consistent with previously reported data. The most common grade ≥3 nonhematologic adverse events were liver-related. Rates of veno-occlusive liver disease of any grade were 11% with inotuzumab ozogamicin versus 1% with standard chemotherapy. These results show that inotuzumab ozogamicin increases the rate of complete remission and improves OS for patients with relapsed or refractory ALL. Furthermore, more patients receiving inotuzu-mab ozogamicin had results below the threshold for minimal residual disease. Return to Top

Adding Daratumumab to Combination Therapy Improves Progression-Free Survival in Patients with Multiple Myeloma

Early-phase studies of daratumumab (Darzalex) in combination with proteasome inhibitors and immunomodulatory drugs showed high response rates, and the combination was well-tolerated in patients with multiple myeloma. In a recent study, researchers reported results from a prespecified interim analysis that compared the addition of daratumumab to the combination of bortezomib (Velcade) plus dexamethasone versus bortezomib and dexamethasone combination in patients with relapsed and/or refractory multiple myeloma (Palumbo A, et al. N Engl J Med. 2016; 375:754-766). This multicenter, open-label, active-controlled, phase 3 trial randomized 498 patients with relapsed and/or refractory multiple myeloma with ≥1 previous lines of therapy, at least a partial response to ≥1 of their previous therapies, and documented progressive disease. Patients were randomized to receive ≤8 cycles of bortezomib plus dexamethasone with or without daratumumab. Patients randomized to bortezomib plus dexamethasone were given 1.3 mg/m2 of bortezomib subcutaneously, and 20 mg of oral dexamethasone; patients who received daratumumab were administered daratumumab 16 mg/kg intravenously once weekly during cycles 1 to 3, once every 3 weeks during cycles 4 to 8, and then once every 4 weeks until the patient withdrew consent, experienced disease progression, or had un-acceptable toxic effects. The primary end point was progression-free survival (PFS). Secondary end points were time to disease progression, overall response rate, proportion of patients who achieved very good partial response or better, duration of response, time to response, and overall survival. The daratumumab group exhibited significantly longer PFS than the control group at 12 months (60.7% vs 26.9%, respectively), which translated to a 61.4% lower risk for disease progression in patients receiving daratumumab compared with those who did not. The median PFS was not reached in the daratumumab cohort after a median follow-up of 7.4 months and was 7.2 months in the control group. The rate of overall response was higher in patients who received daratumumab compared with those who did not (82.9% vs 63.2%, respectively). In addition, the number of patients achieving a complete response or better and a very good partial response or better was significantly in the daratumumab group compared with the control group (19.2% and 59.2% vs 9.0% and 29.1%, respectively). The daratumumab group had higher rates of grade 3 or 4 adverse events, particularly thrombocytopenia, neutropenia, and lymphopenia. Infusion-related reactions occurred in 45.3% of patients in the daratumumab group, most of which (98.2%) occurred during the first infusion. "Overall these findings are consistent with observations from phase 1 and phase 1/2 trials that showed an additive benefit of daratumumab in combination with proteasome inhibitors or immunomodulatory drugs (pomalidomide or lenalidomide) and dexamethasone and highlight the advantages of combination therapy," concluded the researchers. Return to Top

Addition of Elective Neck Dissection Reduces Overall Costs in Patients with Oral Cavity Cancer

Findings from a randomized trial showed a survival benefit among patients with early-stage, clinically node-negative oral cavity cancer who received elective neck dissection with primary surgery compared with those who received primary surgery alone. However, this additional procedure comes with greater treatment costs and patient morbidity, which led researchers to conduct a cost-effectiveness analysis of elective neck dissection for the initial surgical management of early-stage oral cavity cancer (Acevedo JR, et al. J Clin Oncol. 2016 Aug 22. Epub ahead of print). Using a Markov model to simulate primary, adjuvant, and salvage therapy; disease recurrence; and survival in patients with T1 and T2 node-negative oral cavity cancer, the researchers compared the cost-effectiveness of primary resection with elective neck dissection added to primary resection followed by watchful waiting. Transition probabilities were derived from clinical trial data, and costs and health utilities were estimated from the literature. Cost-effectiveness was measured with an incremental cost-effectiveness ratio (ICER), and treatment was considered cost-effective if the ICER fell under a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were also conducted to examine model uncertainty. Adding elective neck dissection to primary surgery was cost-effective and improved health outcomes compared with primary surgery followed by watchful waiting. The lifetime cost of treatment using the elective neck dissection strategy was $63,400 compared with $69,400 for watchful waiting. Although the upfront cost is increased with elective neck dissection, an overall reduction in cost was attributed to using less salvage therapy. When comparing effectiveness, the elective neck dissection strategy yielded 9.20 QALYs compared with 8.78 QALYs from watchful waiting. Overall, elective neck dissection lowered costs by $6000, and improved effectiveness by 0.42 QALYs compared with the watchful waiting strategy. The one-way sensitivity analysis showed that the model was most sensitive to assumptions about disease recurrence, survival benefit, and the health utility reduction from a neck dissection. At a willingness-to-pay threshold of $100,000 per QALY, the probabilistic sensitivity analyses showed that elective neck dissection was cost-effective 76% of the time. This study demonstrates that adding elective neck dissection to primary surgery reduces lifetime costs and improves outcomes for patients with early-stage oral cavity cancer, making this a cost-effective treatment strategy. Return to Top

70-Gene Signature Assists Clinicians in Breast Cancer Treatment Decision-Making

Several genomic tests have been developed to better predict clinical outcomes and determine whether adding adjuvant chemotherapy to endocrine therapy is beneficial in patients with breast cancer. The 70-gene signature test is one example that has demonstrated predictive value in patients with early-stage breast cancer. In a recent study, researchers sought to provide evidence of the clinical usefulness of adding the 70-gene signature to standard clinical−pathologic criteria when choosing patients suitable for adjuvant chemotherapy (Cardoso F, et al. N Engl J Med. 2016;375:717-729). Microarray in Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy (MINDACT) was an international, prospective, randomized, phase 3 trial that enrolled 6693 women with early-stage breast cancer, including hormone receptor positive, HER2-negative, and lymph node−negative disease. Using the 70-gene signature test and a modified version online, Adjuvant! Online, to determine genomic and clinical risks, respectively, the researchers divided patients into 4 groups. Patients with low-risk disease were advised not to receive chemotherapy, whereas patients categorized as having high-risk disease by both tests were advised to receive chemotherapy. In patients with conflicting risk results, the genomic risk or clinical risk was used to determine their use of chemotherapy. The primary end point was survival without distant metastasis at 5 years. Secondary end points were the proportion of patients who received chemotherapy according to clinical risk compared with genomic risk, overall survival (OS), and disease-free survival. A total of 1550 patients were deemed high clinical risk with low genomic risk. At a median 5-year follow-up, the rate of survival without distant metastasis in this group was 94.7% among those who did not receive chemotherapy. Furthermore, the difference in survival rate between these patients and those who received chemotherapy was 1.5%, with a lower rate for patients who did not receive chemotherapy. Similar survival rates in patients without distant metastasis were demonstrated across subgroups of patients with estrogen receptor−-positive, HER2-negative, and either node-negative or node-positive disease. In addition, no significant differences in disease-free survival and OS were observed between patients in the discordant-risk group who did or did not receive chemotherapy. Not administering chemotherapy on the basis of the 70-gene signature test led to a 5-year survival rate without distant metastasis among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence. "Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy," the researchers concluded. Return to Top

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