trial update clinical

Transcription

1 clinical trial update by John W. Mucenski, B.S., Pharm.D., director of pharmacy operations, UPMC Cancer Centers Therapies for relapsed or refractory leukemias are limited. Research into small molecules and monoclonal antibodies may lead to additional effective therapies for these populations. Title: Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapse or refractory chronic lymphocytic leukemia. Authors: Badoux XC, Keating MJ, et al. Reference: J Clin Oncol. doi: / JCO Purpose: Overall survival (OS) has improved for patients with chronic lymphocytic leukemia (CLL) since the introduction of fludarabine (Fludara)- based chemotherapy administered in the first-line setting. Once these patients relapse, second-line therapy with agents such as bendamustine (Treanda) may be effective; however, patients with short response durations have limited salvage therapy options. Therapy with monoclonal antibodies such as alemtuzumab (Campath) and ofatumumab (Arzerra) is associated with a median progression-free survival (PFS) of generally less than 12 months. Alternative therapy is needed. Lenalidomide (Revlimid) is an immunomodulatory drug that enhances T-cell and natural killer (NK) cell cytolytic activity in vivo and in vitro. It also alters the tumor microenvironment by modulating cytokine production by dendritic cells. Lenalidomide has activity in relapsed and refractory CLL, as noted in phase 2 studies. There is also a synergistic activity between lenalidomide and rituximab (Rituxan) against CLL and non- Hodgkin s lymphoma cells in vitro. This study investigates the activity of the combination in patients with relapsed or refractory CLL. Methods: All patients had active relapsed or refractory CLL, were at least 18 years of age, had received prior purine analog-based chemotherapy (with the exception of one elderly patient), had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 and adequate end-organ function at the time of enrollment. Rituximab (375 mg/m 2 ) was administered intravenously on days one, eight, 15 and 22 during cycle one and once every four weeks for cycles three to 12. Lenalidomide was started on day nine of cycle one at 10 mg orally per day and given continuously. Each treatment cycle was 28 days, with a planned treatment duration of 12 cycles. Patients deriving a clinical benefit could continue lenalidomide beyond 12 cycles. Lenalidomide dosage could be adjusted for sustained grade 3 or 4 neutropenia and/or thrombocytopenia. Response was evaluated following three, six and 12 cycles and every six cycles thereafter. The primary end point of the study was overall response rate (ORR). Secondary end points included time to treatment failure (TTF), OS and toxicity. Results: A total of 59 patients, ages 42 to 82 years, with relapsed or refractory CLL, were enrolled in the study. The median number of prior therapies was two (range one to nine); 98 percent had received prior rituximab and 98 percent had received prior fludarabine. The ORR was 66 percent -7 complete responses (12 percent), seven nodular partial responses (12 percent) and 25 partial responses (42 percent). The majority of patients achieved an objective response, partial response or better by three cycles of therapy. All complete responses were observed after 12 or more cycles of therapy. Responses correlated with prior response to fludarabine ORR of 70 percent in patients not refractory to their last fludarabinecontaining regimen compared to 33 percent among patients refractory to fludarabine (p = 0.041). TTF was 17.4 months (95 percent confidence interval [CI], months), with the median time to progression for responding patients of 27.6 months (95 percent CI, months). The median OS has not been reached, with an estimated survival at 36 months of 71 percent. A median of 15 cycles of therapy per patient was administered. As expected, hematologic toxicity was most common. Grade 3 or 4 neutropenia was noted in 73 percent of the patients, with 24 percent experiencing managedcareoncology.com 39

2 a grade 3 or 4 infection or febrile episode. Grade 3 or 4 anemia or thrombocytopenia was less common, occurring during 10 percent and 3 percent of treatment cycles, respectively. Only one venous thromboembolic event occurred during the study. Conclusion: The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation. Managed Care Implications: Oral immunomodulating agents such as lenalidomide may have a role to play in the treatment of relapsed and refractory CLL. When combined with rituximab, the response rates and duration of response are impressive. Title: Oral sapacitabine for the treatment of acute myeloid leukemia in elderly patients: a randomized phase 2 study. Authors: Kantarjian H, Faderl S, et al. Reference: Lancet Oncol. 2012;13: Purpose: Intensive chemotherapy has led to a cure rate of percent in younger patients with acute myelogenous leukemia (AML). Elderly patients do not do as well due to their poor tolerance to intensive chemotherapy, the high rates of treatment-related mortality and the high incidence of cytogenetic abnormalities. Although nearly 50 percent of this patient population achieves a complete response to initial therapy, the median survival in elderly patients treated with intensive chemotherapy is only four to six months. These numbers have not changed over the past 20 years despite variations in chemotherapy regimens and dramatic improvements in supportive care measures. Lowintensity therapy with agents such as decitabine (Dacogen), azacitidine (Vidaza), cytarabine, gemtuzumab ozogamicin (Mylotarg) and clofarabine (Clolar) has been assessed. Novel drugs with new mechanisms of action and improved antileukemic activity are needed for this patient population. Oral sapacitabine is an analog of cytarabine with a unique mechanism of action. The drug initially causes a single-strand DNA break that is only partially repaired. During a subsequent round of DNA replication, unrepaired single-strand DNA breaks are converted to double-strand DNA breaks, causing cell death. This phase 2 study investigates three dosing schedules of oral sapacitabine in elderly patients with untreated or relapsed AML. Methods: This multinational, multicenter study recruited patients ages 70 years or older with a diagnosis of AML who were either newly diagnosed or in first relapse. Additional eligibility criteria included ECOG performance status of 0-2, adequate end-organ function and recovery from previous therapy. Patients were stratified by history of prior therapy (yes vs. no) and were allocated in a 1:1:1 ratio. Three dosing regimens were evaluated: 200 mg orally twice a day for seven days (group A), 300 mg orally twice a day for seven days (group B) and 400 mg orally twice a day for seven days (group C). Courses were repeated every 28 days. Patients did not start their next cycle of therapy until any clinically significant or drugrelated nonhematological toxicity had resolved to a grade 0-1 or baseline, at which time there was a dose reduction for those patients with grade 3 or 4 toxicity. Dose reductions for hematological toxicities were guided by findings from bone marrow biopsies and aspirates and time to absolute neutrophil and platelet recovery. The primary objective of the study was the assessment of one-year overall survival. Secondary objectives included complete response (CR), complete response with incomplete platelet recovery (CRp), complete response with incomplete blood count recovery (CRi) and partial response (PR) and hematological improvement (HI) rates and toxicity. Results: A total of 107 patients were enrolled, 105 of whom received treatment. The median length of follow-up was 143 weeks. The median age of patients was 77 years (range 70-91). Eighty-six patients were previously 40 managedcareoncology Quarter

3 untreated and 19 were in first relapse. After assessment of the first 60 patients, favorable preliminary results were noted in group A and group C. The one-year overall survival was 35 percent (95 percent CI, 16-69) in group A, 10 percent (2-33) in group B and 30 percent (13-54) in group C. Additional patients were only added to groups A and C, first by adding 20 patients to group A, then expanding group C. The median one-year survival in the expanded treatment groups was 10 percent (2-33) in group A and 24 percent (10-46) in group C. Fourteen of 105 patients (13 percent) died within 30 days of the initiation of therapy and 27 (26 percent) died within the first 60 days. Of the 105 patients, 36 (34 percent) had a treatment response; 28 of these patients were previously untreated (nine CR, one CRp, three CRi, two PR and 13 HI). Those patients treated with relapsed disease had eight responses (three CR, one PR, four HI). The median overall survival of the 12 patients who achieved a CR was 525 days (95 percent CI, ). The median overall survival for the 24 patients achieving a CRp, CRi, RP or HI was 277 days (95 percent CI, ). The most common grade 3 or 4 toxicities were anemia (8/40 in group A, 12/20 in group B, 15/45 in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, one in group B, 22 in group C) and febrile neutropenia (16 in group A, nine in group B, 22 in group C). Conclusion: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations combining sapacitabine with other low-intensity therapies should be explored. Managed Care Implications: Lowintensity therapies need to be developed for elderly patients with de novo or relapsed AML. Sapacitabine may be an oral agent that can be used as the cornerstone for future studies with other chemotherapeutic agents in this patient population. Title: Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/ refractory B-cell malignancies. Authors: Advani RH, Buggy JJ, et al. Reference: J Clin Oncol. 2012;31: Purpose: B-cell proliferation, differentiation, apoptosis and cell migration are regulated by signaling from the B-cell antigen receptor (BCR) and is essential for normal B-cell development and survival. The BCR pathway is implicated in several B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia. Bruton tyrosine kinase (BTK) is a signaling molecule positioned early within the BCR signaling cascade. This makes it an attractive target for selective B-cell inhibition. Ibrutinib is a selective and irreversible small-molecule BTK inhibitor that inhibits BCR signaling in human B-cells. In vitro, it is selectively cytotoxic to DLBCL cell lines driven by chronic active BCR signaling. Due to the central role of BCR signaling, the restricted expression of BTK and promising preclinical activity of ibrutinib, it was evaluated in this phase 1, open-label, dose-escalation trial to determine dose, safety and pharmacokinetics as well as tumor response in patients with relapsed or refractory B-cell non-hodgkin s lymphoma (NHL) and B-cell CLL. Methods: Patients with relapsed or refractory, histologically confirmed NHL, CLL or Waldenström macroglobulinemia (WM) who had failed at least one previous therapy were eligible. Additional eligibility criteria included ECOG performance status 1, age 18 years, measurable disease and adequate end-organ function. Patients received ibrutinib capsules orally once a day at 1.25, 2.5, 5, 8.3 or 12.5 mg/kg per day on a 28-day on and seven-day off schedule or received a continuous daily dosing of 8.3 mg/kg or 560 mg until disease progression, unacceptable toxicity or patient or physician decision to end therapy. At least six patients were enrolled in each dosing cohort. Dose escalation continued until a maximum managedcareoncology.com 41

4 tolerated dose (MTD) was established based upon predefined dose-limiting toxicities (DLT). The MTD was defined as the highest dose at which 33 percent of patients in a cohort experienced a DLT, or in the absence of a DLT, until three dose levels above the dose level in which full BTK occupancy could be demonstrated. Response was evaluated following every two cycles. Results: Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts, of which 50 were evaluable for tumor response. The MTD of ibrutinib was not reached and only two DLTs occurred one grade 3 allergic hypersensitivity in a patient with a history of drug hypersensitivity and one dose interruption for > 7 days due to transient grade 2 neutropenia. Most adverse events (AEs) observed were grade 1 or 2 in severity. Grade 3 or 4 hematological AEs were infrequent and independent of dose. They included neutropenia (12.5 percent), thrombocytopenia (7.2 percent) and anemia (7.1 percent). From a pharmacokinetic standpoint, ibrutinib is rapidly absorbed and eliminated following oral administration. Mean peak serum concentrations occurred one to two hours after dosing; the plasma concentrations declined biphasically with an initial mean apparent terminal half-life of six to eight hours. Tumor responses were noted in 60 percent of the patients evaluable for response. Responses were observed across all histologies, including seven of nine patients with mantle cell lymphoma (78 percent with three complete responses), 11 of 16 patients with CLL/small lymphocytic lymphoma (69 percent with two complete responses), six of 16 patients with follicular lymphoma (38 percent with three complete responses), two of seven patients with DLBCL (29 percent), three of four patients with WM (75 percent) and one of four patients with marginal zone lymphoma (25 percent). Conclusion: Ibrutinib, a novel BTKtargeting inhibitor, is well-tolerated and has substantial activity in a variety of B-cell malignancies. Managed Care Implications: Ibrutinib is an orally active agent with a unique mechanism of action. It will be incorporated into the treatment of patients with CLL in combination with other agents active in this disease state. Title: Ponatinib in refractory Philadelphia chromosome-positive leukemias. Authors: Cortes JE, Kantarjian H, et al. Reference: N Engl J Med. 2012;367: Purpose: The Philadelphia chromosome (Ph-(+)), a translocation of chromosomes 9 and 22 (t(9;22)), leads to the fusion protein product BCR-ABL, an active tyrosine kinase that gives rise to chronic lymphocytic leukemia (CML) and Ph-(+) acute lymphocytic leukemia (ALL). There are presently three oral tyrosine kinase inhibitors (TKIs) (imatinib Gleevec; nilotinib Tasigna; dasatinib Sprycel) approved for the treatment of newly diagnosed chronic-phase CML. Resistance to these TKIs is a major reason for treatment failure in patients with Ph-(+) disease. Resistance to imatinib is reported in percent of patients with newly diagnosed chronic-phase CML. Dasatinib and nilotinib are available to treat patients who develop resistance or intolerance to imatinib and have been shown to induce a major cytogenetic response in percent of these types of patients. However, for patients who develop resistance to these agents, no approved therapy is available. A major mechanism of resistance is mutation of the BCR-ABL kinase domain. One of the more common mutations is the T315I substitution, which blocks access of the drug to the enzyme s adenosine-5 -triphosphate (ATP)- binding site and confers resistance to the presently approved TKIs. This mutation is seen in up to 20 percent of patients with CML. Ponatinib is a small-molecule TKI that contains a novel triple-bond linkage that avoids the steric hindrance caused by the bulky isoleucine residue at position 315 in the T315I mutant. In vitro studies have shown it to have potent activity against native BCR-ABL and against all tested mutant forms of BCR-ABL, including T315I at obtainable serum levels. Ponatinib may have clinical efficacy in the treatment of Ph-(+) disease in patients who have received previous therapy with currently approved TKIs. Methods: Patients were eligible if they were at least 18 years of age; had an ECOG performance status of 2; had adequate renal, hepatic and cardiac function; and had Ph-(+) hematologic disease, excluding 42 managedcareoncology Quarter

5 lymphoma, that had relapsed or was resistant to standard care or for which no standard care was available. The primary objective of this phase 1 trial was to establish the maximum tolerated dose (MTD) or a recommended dose of oral ponatinib administered once daily. Secondary objectives included safety, antileukemic activity and potential pharmacogenomic markers. In the dose-escalation portion of the study, patients were assigned to cohorts of at least three patients. Dose escalations in the same patients were allowed up to the dose immediately preceding the highest studied dose. Treatment continued until disease progression, an adverse event leading to cessation, withdrawal of consent or investigator discretion. Results: A total of 81 patients with resistant hematologic malignancies were enrolled in the study, including 60 with CML (43 with chronic phase, nine with accelerated phase and eight with blast phase) and five with Ph-(+) ALL. Other patients had diagnoses of myelodysplastic syndrome (n = 1), multiple myeloma (n = 1), myelofibrosis (n = 2) and acute myelogenous leukemia (n = 12); however, data for these patients is not included. Ponatinib was administered orally as a once-daily dose ranging from 2 to 60 mg. The median follow-up was 56 weeks (range two to 140). No dose-limiting toxicities were observed in patients receiving up to 30 mg of ponatinib daily. At 45 mg, grade 3 rash was the only dose-limiting toxicity reported, in one patient. At 60 mg of ponatinib daily, doselimiting toxicities were reported in six patients in two separate cohorts and consisted of clinical pancreatitis in four patients, grade 3 fatigue in one patient and a grade 3 elevation in aminotransferase and aspartate aminotransferase in an additional patient. Pancreatitis occurred in 11 patients and was a serious adverse reaction in eight patients. Elevated lipase or amylase without pancreatitis occurred in another seven patients. Grade 3 and 4 hematologic toxicities were common, with thrombocytopenia occurring in 12 patients (28 percent), neutropenia in six patients (14 percent) and anemia in 1 or 2 percent of patients. Of the 43 patients with chronic-phase CML, 98 percent had a complete hematologic response, 72 percent had a major cytogenetic response and 44 percent had a major molecular response. Of the 12 patients with chronic-phase CML with the T315I mutation, 100 percent had complete hematologic response and 92 percent had major cytogenetic response. The majority of these responses were durable. Responses were also noted in 22 patients with CML in accelerated-phase and blast-phase or Ph-(+) ALL, with 36 percent having a major hematologic response and 32 percent having a major cytogenetic response. Conclusion: Ponatinib is active in heavily pretreated patients with Ph-(+) leukemias with resistance to TKIs, including patients with the T315I mutation. Managed Care Implications: The large number of available oral TKIs for the treatment of Ph-(+) leukemias is outstanding. Ponatinib, which is active against the T315I mutation, is unique among these agents. Additional studies will reveal where it should be placed in the treatment of Ph-(+) leukemias, particularly CML. Title: Inotuzumab ozogamicin, an anti-cd22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukemia: a phase 2 study. Authors: Kantarjian H, Thomas D, et al. Reference: Lancet Oncol. 2012;13: Purpose: The use of combination chemotherapy with induction, consolidation and maintenance phases, along managedcareoncology.com 43

6 with CNS prophylaxis, has improved the survival of adult patients with ALL. Utilization of this approach leads to a response rate of 90 percent and long-term survival in percent of patients treated. Drugs such as clofarabine (Clolar), intrathecal chemotherapy and use of targeted TKIs for Philadelphia chromosome (+) ALL and rituximab (Rituxan) in CD20(+) ALL have added to the breakthroughs seen in these disease states. Intensive chemotherapy that augments the effects of nonmyelosuppressive drugs such as asparaginase (Elsapar), vincristine (Oncovin) and steroids improves survival in adults but is associated with severe side effects, especially in patients 45 years old. B-lymphocytes express CD20 in about 50 percent of cases, CD19 in more than 90 percent of cases and CD22 in more than 80 percent of cases. These markers are potential targets for new monoclonal antibodies. Inotuzumab ozogamicin is a monoclonal antibody against CD22 that is bound to calecheamicin, a toxic natural product. Calecheamicin binds to the minor DNA groove and causes breaks in double-stranded DNA, leading to cell apoptosis. The molecule is rapidly internalized and delivers the conjugated calecheamicin intracellularly. Phase 1 and 2 studies have shown encouraging activity in indolent and aggressive lymphomas. These results encouraged the investigation of the drug in patients with relapsed and refractory ALL. Methods: Adults with a confirmed diagnosis of refractory or relapsed ALL of B-cell origin were eligible. Children under the age of 16 were also allowed to enter the study after the safety of the treatment had been established by at least 10 adults having received at least one course of inotuzumab ozogamicin. Additional inclusion criteria included an ECOG performance status of 0-3 and adequate hepatic, renal and cardiac function. Inotuzumab ozogamicin was administered intravenously over one hour every three weeks. All patients received premedication with oral paracetamol (Tylenol) and intravenous diphenhydramine (Benadryl) and hydrocortisone (Solu-Cortef). The first three adult and pediatric patients received 1.3 mg/m 2 in the first course to ensure that no unexpected toxicity would be encountered. Thereafter, they received 1.8 mg/m 2. All other patients received the 1.8 mg/m 2 dosage in all treatment cycles. Bone marrow aspirates were performed on days 14, 21 and 28 after each injection until complete remission was obtained. The primary end point was overall response (complete response or marrow complete response with no recovery of platelet count or incomplete recovery of neutrophil and platelet counts). Secondary end points included overall survival and toxicity. Results: The median age of the patients treated was 36 years (range 6-80), with three patients (6 percent) age 16 or younger. CD22 was expressed in more than 50 percent of blasts in all patients. Thirty-six of the patients (73 percent) received inotuzumab ozogamicin as second or later salvage regimen. The median number of treatment courses was two (range 1-5) and the median time between courses was three weeks (range 3-6). Forty patients (82 percent) received two or more courses and 23 (47 percent) received three or more. The overall response rate was 57 percent (95 percent CI, percent) with 28 of 49 patients responding. The median overall survival was 5.1 months (95 percent CI, ). Nine patients (18 percent) had a complete response, 19 (39 percent) had a marrow complete response, 19 (39 percent) had resistant disease and two (4 percent) died within the first four weeks of starting therapy. Hematologic toxicity, primarily thrombocytopenia and neutropenia, was seen in all treatment groups and the incidence was seen to increase in patients initially treated who had lower platelet and neutrophil counts at the time of therapy. Nonhematologic toxicity included fever in 59 percent of patients, which was severe (grade 3 or 4) in 31 percent; grade 1 or 2 hypotension in 24 percent and grade 3 in 2 percent; grade 1 or 2 increases in bilirubin in 24 percent, with grade 3 in 4 percent; and grade 1 or 2 increases in liver enzymes in 55 percent of patients, with grade 3 elevation seen in 2 percent of patients treated with inotuzumab ozogamicin. Conclusion: Inotuzumab ozogamicin shows promise as a treatment for refractory and relapsed ALL. Managed Care Implications: As targeted therapy such as inotuzumab ozogamicin is developed for diseases such as refractory and relapsed ALL, new combination therapy can be developed for those whose initial response to therapy was not optimal. Title: Phase I trial of anti-cd22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. Authors: Kreitman RJ, Tallman MS, et al. Reference: J Clin Oncol. 2012;30: managedcareoncology Quarter

7 Purpose: Hairy cell leukemia (HCL) makes up 2 percent of all leukemias diagnosed. The purine analogs cladribine (Leustatin) and pentostatin (Nipent) achieve high and durable complete response rate, with most patients still in remission 10 to 15 years following treatment. However, the lack of a plateau on the diseasefree survival curves and high rate of minimal residual disease (MRD) following purine analog administration suggests a lack of curability in many, if not most, patients. This has resulted in an increasing number of patients with relapsed or refractory disease for which there is no approved therapy. Major responses, including CRs, have been documented in patients with relapsed or refractory HCL using recombinant immunotoxins. BL22 (CAT-3888), which targets CD22, achieved a CR rate of percent in patients with HCL in phase 1 and 2 trials. Toxicity limited further development of this compound. Moxetumomab pasudotox contains a different amino acid sequence than BL22, resulting in a 14 times increase in binding affinity for CD22 and therefore increased cytotoxicity. This phase 1 trial was initiated to determine the safety and efficacy of the compound in patients with relapsed or refractory HCL. Methods: Patients with a confirmed diagnosis of HCL with measurable disease and at least two prior systemic therapies, including at least two courses of a purine analog, were included in the trial. Other eligibility criteria included adequate end-organ function. Patients received moxetumomab pasudotox intravenously every other day for a total of three doses within 30 days. Hydroxyzine (Vistaril) and ranitidine (Zantac) were used to prevent allergic reactions, acetaminophen (Tylenol) was used to prevent fever and intravenous fluid was administered pre- and post-administration to prevent hypovolemia. Patients were treated with up to 16 cycles repeating at a 4-week interval if not experiencing disease progression or developing neutralizing antibodies. The end points of the study were overall response rate, toxicity and appropriate dosing schedule. Results: A total of 28 patients ages 40 to 77 years (median 59 years) were enrolled. All patients had classic HCL, except for two patients with variant HCL. Patients received one to seven prior courses of a purine analog (median of two), including cladribine in all patients and pentostatin in 11 patients. Eleven of 24 (46 percent) were refractory to the last course of purine analog, based on failure to achieve blood counts consistent with a CR for more than one year. The majority of patients received prior rituximab. Twenty-eight patients received a total of 114 cycles for a median of four cycles per patient. The dose of 50 µcg/kg was established as the appropriate treatment dose. Dose-limiting toxicities were not observed. Two patients had transient lab abnormalities consistent with grade 2 hemolytic uremic syndrome. Other toxicities included grade 1 or 2 hypoalbuminemia, aminotransferase elevations, edema, headache, hypotension, nausea and fatigue. Ten patients (38 percent) made antibodies neutralizing more than 75 percent of the cytotoxicity of the immunotoxin. The overall response rate was 86 percent, with responses seen at all dosing levels. Forty-six percent of the patients experienced a CR, with only one lasting less than one year. The median disease-free survival had not been reached out to 26 months. Conclusion: Moxetumomab pasudotoxin at doses up to 50 µcg/ kg administered every other day for three doses has activity in relapsed or refractory HCL and has a safety profile that supports further clinical development. Managed Care Implications: Hairy cell leukemia is a rare disease that usually responds nicely to the purine analogs. For those patients not responding, investigational agents such as moxetumomab pasudotoxin may offer an effective second- or third-line treatment option. Additional studies, both as a single agent and in combination, are needed. managedcareoncology.com 45