Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

JHOP - December 2016 Vol 6, No 4 - From the Literature
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With Commentaries by

Robert J. Ignoffo, PharmD, FASHP, FCSHP
Clinical Professor Emeritus
University of California, San Francisco
Professor of Pharmacy
College of Pharmacy
Touro University–California
Mare Island, Vallejo, CA
Inotuzumab Ozogamicin Shows Benefit in Acute Lymphoblastic Leukemia

BACKGROUND: 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.

METHODS: 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.

RESULTS: Treatment with inotuzumab ozogamicin, an anti-CD22 antibody conjugated to the cytotoxic antibiotic calicheamicin, was associated with a significantly higher rate (80.7%) of complete remission 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 overall survival 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.

Source: Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740-753.

COMMENTARY BY ROBERT J. IGNOFFO

This international study of patients with relapsed or refractory B-cell ALL has shown significant improvements with the use of inotuzumab ozogamicin in several important outcomes, including complete response, duration of response, progression-free survival, and overall survival. These results are important, because they suggest that more patients with B-cell ALL will have the opportunity to receive another stem-cell transplant, which is considered the only potentially curative treatment for this condition. The current recommended salvage therapies produce a complete remission rate of approximately 30%. By contrast, the results of this study showed better outcomes, with an approximately 90% complete remission rate—except in those with Philadelphia-positive or t(4:11)-positive ALL. Adverse events were similar in each study group; however, inotuzumab ozogamicin was associated with significantly more cases of veno-occlusive disease. Inotuz­umab ozogamicin is still an investigational drug, but it is likely that the US Food and Drug Administration (FDA) will approve it by the end of the year.

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

BACKGROUND: 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. 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.

METHODS: 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 unacceptable toxic effects. The primary end point was progression-free survival. 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.

RESULTS: The daratumumab group exhibited significantly longer progression-free survival 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 progression-free survival 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.

Source: Palumbo A, Chanan‑Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.

COMMENTARY BY ROBERT J. IGNOFFO

Daratumumab is currently indicated for patients with multiple myeloma who have received ≥3 lines of previous therapy, including a proteasome inhibitor and an immunomodulatory agent, or patients whose disease is double-refractory to a proteasome inhibitor and an immunomodulatory drug. This clinical trial by Palumbo and colleagues brings the use of daratumumab with a standard combination (ie, a proteasome inhibitor plus dexamethasone) for the treatment of refractory disease further upfront. The results show that the addition of daratumumab improved the progression-free survival significantly, as well as the overall response rate. Grade 3 or 4 adverse events were greater among the patients receiving the 3-drug combination and included thrombocytopenia, which occurred in 45.3% of patients versus 32.9% of those receiving the 2-drug combination of bortezomib plus dexamethasone.

A recently published phase 3 randomized clinical trial by Dimopoulos and colleagues included 569 patients with relapsed or refractory multiple myeloma.1 In this study, the investigators compared the use of lenalidomide plus dexamethasone with or without daratumumab, which resulted in similar clinical outcomes and adverse events to those in the study by Palumbo and colleagues.

The results of these 2 recent studies are rigorous enough to promote the use of daratumumab in combination with an immunomodulatory agent (eg, lenalidomide) plus dexamethasone, or a proteasome inhibitor plus dexamethasone. Future treatment guidelines may include daratumumab in combination after the failure of a primary regimen.

1. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.

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Two-Drug Combination Shows Promise for Recurrent Small-Cell Lung Cancer

BACKGROUND: Patients with small-cell lung cancer (SCLC) frequently respond to first-line chemotherapy; however, disease progression is rapid, and outcomes with second-line treatments are poor.

METHODS: CheckMate 032 was a multicenter, open-label, 2-stage, multiarm, phase 1/2 clinical trial that randomized 216 patients with progressive SCLC after ≥1 platinum-based chemotherapy regimens to single-agent nivolumab (Opdivo) or to 1 of 2 arms with the combination of nivolumab plus ipilimumab (Yervoy), at 1 of 2 doses. In the monotherapy arm, patients received nivolumab 3 mg/kg intravenously every 2 weeks. In the combination arms, patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg intravenously or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg intravenously every 3 weeks. After 4 cycles, patients in the combination arms received nivolumab monotherapy 3 mg/kg every 2 weeks.

The primary end point was objective response rate. The secondary end points included overall survival, progression-free survival, duration of response, and treatment-related adverse events leading to treatment discontinuation.

RESULTS: The objective response rate was 10% in the nivolumab arm, 23% in the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg arm, and 19% in the nivolumab 3-mg/kg plus ipilimumab 1-mg/kg arm. Response generally consisted of partial responses, with 1 complete response observed in the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg arm. The median overall survival was 4.4 months in the monotherapy arm, 7.7 months in the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg cohort, and 6.0 months in the nivolumab 3-mg/kg plus ipilimumab 1-mg/kg cohort. The corresponding 1-year overall survival was 33% for the nivolumab 3-mg/kg group, 43% for the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg group, and 35% for the nivolumab 3-mg/kg plus ipilimumab 1-mg/kg group.

The median progression-free survival was 1.4 months in the monotherapy arm; in the combination arms, the progression-free survival was 2.6 months in the nivolu­mab 1-mg/kg plus ipilimumab 3-mg/kg group and 1.4 months in the nivolumab 3-mg/kg plus ipilimumab 1-mg/kg group. The median duration of response was not reached with single-agent nivolumab; in the combination arms, the median duration of response was 7.7 months and 4.4 months, respectively.

Adverse events leading to treatment discontinuation were observed in 6% of patients in the monotherapy arm, 11% of patients in the nivolumab 1-mg/kg plus ipilimumab 3-mg/kg arm, and 7% in the nivolumab 3-mg/kg plus ipilimumab 1-mg/kg arm.

Nivolumab alone and in combination with ipilimu­mab showed antitumor activity with durable responses, encouraging overall survival, and manageable safety profiles in advanced SCLC. The findings suggest a potential new treatment approach for a population of hard-to-treat patients who have limited therapeutic options.

Source: Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol. 2016;17:883-895.

COMMENTARY BY ROBERT J. IGNOFFO

The National Comprehensive Cancer Network currently recommends the use of topotecan in patients with refractory SCLC, which results in a 23% overall response rate in platinum-sensitive patients. Because ipilimumab and nivolumab are active in several cancers, the CheckMate-032 clinical trial was designed to study the activity of the combination of these 2 drugs in several metastatic cancers. In CheckMate-032, the combination of nivolumab plus ipilimumab resulted in an objective response rate of 19% to 23%, but only 1 complete response.

Unfortunately, the responses were not stratified by the patients’ previous response to platinum-based chemotherapy. Of note, adverse events were more common in the combination group, with a total of 18% of patients using the combination discontinuing therapy because of grade 3 or 4 adverse events.

Although the results of CheckMate-032 are modest, other clinical trials (CheckMate-331 and CheckMate-451) have begun to evaluate the efficacy and toxicity of nivolumab versus chemotherapy or in combination with ipilimumab in patients with refractory SCLC. The results of these trials will likely determine whether this combination receives FDA approval for the treatment of patients with relapsed or refractory SCLC.

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Ricolinostat Shows Promise in Patients with Relapsed or Refractory Multiple Myeloma

BACKGROUND: Histone deacetylase (HDAC) inhibitors are a new class of drugs investigated for multiple myeloma. Encouraging findings from preclinical trials that assessed the oral, first-in-class selective HDAC6 inhibitor ricolinostat with lenalidomide (Revlimid) led to a study that evaluated the safety and preliminary activity of ricolinostat in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma.

METHODS: This multicenter, phase 1 trial enrolled 38 patients with relapsed and/or refractory multiple myeloma who had received ≥1 previous therapies. All patients had measurable disease, a Karnofsky performance score of ≥70, adequate bone marrow reserve and hepatic function, and a creatinine clearance of ≥50 mL/min. Patients were given escalating doses of ricolinostat (from 40 mg to 240 mg once daily and up to 160 mg twice daily) according to a standard 3 plus 3 design based on 3 different regimens on days 1 to 21, with a conventional 28-day schedule of lenalidomide and dexamethasone. The median follow-up was 5.9 months.

The primary end points were dose-limiting toxicities, maximum tolerated dose of ricolinostat plus lenalidomide and dexamethasone, and the dose and schedule of ricolinostat for future phase 2 clinical trials.

RESULTS: Two dose-limiting toxicities were observed in patients receiving ricolinostat 160 mg twice daily; 1 grade 3 syncope, and 1 grade 3 myalgia adverse event in different cohorts. A maximum tolerated dose was not reached. The researchers chose ricolinostat 160 mg once daily on days 1 to 21 as the phase 2 dose. Ricolinostat was well-tolerated and its adverse events were generally mild. The most common adverse events were fatigue, diarrhea, neutropenia, upper respiratory tract infection, anemia, and thrombocytopenia. Pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low tolerable level of class I HDAC inhibition. Coadministration of ricolinostat and lenalidomide did not have an effect on pharmacokinetics.

Preliminary efficacy data showed an overall response of 55% in the 38 patients, and a median progression-free survival of 20.7 months, which was similar to findings from trials combining new agents with lenalidomide and dexamethasone.

The improved tolerability of ricolinostat suggests a potential benefit of selective inhibition of HDAC6 compared with pan-HDAC inhibition.

Source: Yee AJ, Bensinger WI, Supko JG, et al. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016 Sept 16. Epub ahead of print.

COMMENTARY BY ROBERT J. IGNOFFO

Ricolinostat falls into another new class of targeted agents that can be combined safely with an immunomodulatory agent plus dexamethasone for the treatment of patients with refractory multiple myeloma. The selective inhibitory effect of ricolinostat on HDAC6 appears to impart a much lower toxicity profile than the more toxic first-generation HDAC inhibitors.

The results of this study show that ricolinostat is indeed safe, is associated with only 2 grade 3 adverse events, and is effective in refractory disease. The overall response rate observed in this phase 1 clinical trial was similar to that of other new drugs that have been combined with lenalidomide and dexamethasone. Because this drug is administered orally, it will be a convenient regimen for patients to take. However, as with other oral agents, it will have the potential for nonadherence, which is a known problem among orally administered drugs, and the pharmacist should monitor patients for adherence. With regard to the impact of this study on the current management of refractory multiple myeloma, this was primarily a safety and dose-finding study comprising only 38 patients. Much larger phase 2 and phase 3 comparative trials will be needed before this drug receives FDA approval.

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Last modified: January 16, 2017