YEAR IN REVIEW

A Look Back at 2011: A Banner Year for Solid Tumor Oncology

The year 2011 was a great year for oncology with a significant number of new drugs for patients with solid tumors gaining approval from both the US Food and Drug Administration (FDA) and the European Medical Agency (EMA). Furthermore, the results of several phase III clinical trials were reported that will likely lead to additional drug approvals in the near future. 2011 was a particularly exciting year for new molecularly targeted therapies that are paving the way for more personalized cancer care, and, most importantly, new treatments became available for cancers with limited or no treatment options.

• Melanoma: In advanced disease, previously with very limited treatment options, two new targeted therapies, vemurafenib (for patients with BRAF+ tumors) and ipilimumab (a novel anti-CTLA-4 immunotherapy) were granted FDA approval. These are the first new drugs to be approved for melanoma in 13 years and the first drugs to demonstrate an overall survival (OS) benefit in this disease. Pegylated interferon alfa-2b was also granted approval as adjuvant therapy in patients with node-positive melanoma.
  
  
• Castration-resistant prostate cancer (CRPC): The therapeutic armamentarium for metastatic CRPC, which currently includes sipuleucel-T, abiraterone, and cabazitaxel, all of which have shown an OS benefit in phase III trials, may soon be expanded with the addition of radium-223 chloride. Radium-223 chloride improved survival in patients with bone metastases and is currently fast-tracked for FDA approval in mid-2012.
  
  
• Thyroid cancer: Vandetanib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), became the first drug approved for patients with advanced medullary thyroid cancer ineligible for surgery and who have progressive symptomatic disease.
  
  
• Pancreatic neuroendocrine tumors (pNET): Both sunitinib and everolimus were granted regulatory approvals for this rare family of neuroendocrine cancers based on evidence that showed a significant improvement in progression-free survival (PFS) compared with best supportive care.
  
  
• Non-small cell lung cancer (NSCLC): It became clear in 2011 that mutation testing is a must for selecting first-line therapy for patients with advanced NSCLC, that patients with activating mutations in EGFR benefit from treatment with the EGFR TKIs gefitinib and erlotinib, and that selected patients with tumors harboring an ALK fusion gene benefit from treatment with crizotinib.
  
  
• Breast and ovarian cancer: Although the FDA withdrew approval of bevacizumab for metastatic breast cancer (MBC), the EMA issued a contrary opinion reaffirming both the bevacizumab/capecitabine (for selected patients) and the bevacizumab/paclitaxel combinations for treatment of first-line MBC. In advanced ovarian cancer, the PFS benefit of bevacizumab was confirmed in two large phase III trials (ICON-7 and GOG 0218), and in December 2011 bevacizumab was approved in the EU for newly diagnosed ovarian cancer. Eribulin, a novel chemotherapy agent previously approved in the US, became available in the EU for patients with previously treated MBC. However, perhaps the most exciting MBC news in 2011 came from the groundbreaking results of the BOLERO-2 and CLEOPATRA trials, which will likely lead to approval of everolimus plus exemestane for endocrine resistant MBC and the combination of dual HER2-targeted antibodies pertuzumab plus trastuzumab and chemotherapy for HER2-positive MBC. Clearly the therapeutic landscape for MBC will continue to evolve in 2012.
  
  
• Colorectal cancer: The recently presented phase III VELOUR trial demonstrated that the combination of the novel antiangiogenic agent aflibercept (VEGF-trap) and FOLFIRI significantly improved PFS and OS compared with chemotherapy alone when used as second-line treatment for colorectal cancer. Approval of this regimen is expected in the coming year.
  
  
• Head and neck cancer: Although approved since 2006 for advanced head and neck cancer as a single agent and in combination with radiation therapy, cetuximab finally garnered an expanded indication in the US for the first-line treatment of advanced squamous cell carcinoma of the head and neck. This expanded approval was based on evidence that it improved OS when combined with platinum-based chemotherapy.
  
  
• Bone-targeted therapy: Last but not least, the bone-targeted agent denosumab, a RANK ligand inhibitor, was approved for patients with solid tumors and bone metastases and to reduce bone loss in women receiving adjuvant aromatase inhibitors for early breast cancer. It was also approved for men receiving androgen-deprivation therapy for nonmetastatic prostate cancer.

CONFERENCE NEWS FROM THE 2011 HEMATOLOGY ANNUAL MEETING IN SAN DIEGO

The 53^rd American Society of Hematology (ASH) Annual Meeting and Exposition kicked off on December 10 in San Diego, California, United States. More than 20,000 researchers, hematologists, oncologists, and other healthcare professionals from around the globe convened to discuss state-of-the-art research and clinical advances in hematology. This issue of the newsletter will highlight some of the most compelling oncology news from the 2011 ASH Annual Meeting.

Lymphoma

R-CHOP Followed by Rituximab Maintenance Improves Outcomes in Elderly Patients with Mantle Cell Lymphoma

This 2-stage randomized trial that enrolled 560 elderly patients (age >60 years) with stage II-IV mantle cell lymphoma (MCL) demonstrated that standard rituximab (R)-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) was safer and significantly more effective than rituximab plus fludarabine/cyclophosphamide (R-FC), and addition of rituximab maintenance significantly prolonged remission duration compared with interferon alfa. An intergroup trial was initiated in this challenging patient population to evaluate whether 6 cycles of a fludarabine-based regimen (rituximab 375 mg/m² day 1 plus fludarabine 30 mg/m² and cyclophosphamide 250 mg/m² days 1-3 on a 28 day cycle) could improve remission rate compared to 8 cycles of standard R-CHOP, and whether rituximab maintenance could prolong remission duration and OS. The results presented by J.C. Kluin-Nelemans, MD (University Medical Center Groningen, Groningen, the Netherlands), showed that standard R-CHOP was less toxic and significantly improved both overall remission rate (87% versus 78%; P = .051) and median OS (77 months versus 43 months; P = .002) compared with R-FC. In the second stage of the trial, addition of rituximab maintenance in comparison with interferon significantly prolonged remission duration after either R-CHOP or R-FC (P<.001), but an OS benefit was only observed after R-CHOP (P = .006). The authors concluded that induction therapy with R-FC is not suitable for elderly patients with MCL, and that R-CHOP induction followed by rituximab maintenance is an effective and safe treatment option in this patient population and warrants further study.

Blood. 2011;118: Abstract 439.

Obinutuzumab (GA101) Takes on Rituximab in Head-to-Head Comparison

In a randomized phase II trial (GAUSS study) comparing the efficacy and safety of obinutuzumab versus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (NHL), obinutuzumab produced a higher overall response rate (ORR) then rituximab. Laurie Sehn, MD, MPH (British Columbia Cancer Agency, Vancouver, British Columbia, Canada), presented the results of this study. Among patients with follicular lymphoma, the ORR (primary endpoint) was 44.6% for obinutuzumab vs 33.3% for rituximab (P = .08). The complete remission rate was also higher with obinutuzumab (12.2%) than with rituximab (5.3%). Surprisingly, central review showed significantly better response with obinutuzumab compared to rituximab (43% vs 28%; P = .01). The safety profile of the two antibodies was quite similar. Although obinutuzumab was associated with a higher incidence of mild-to-moderate infusion-related reactions, there was no difference in the rate of discontinuations due to these adverse events. Obinutuzumab is the first type II glycoengineered anti-CD20 monoclonal antibody, and it appears to enhance direct cell death and increase antibody-dependent cellular cytotoxicity (ADCC) compared to other anti-CD20 antibodies.

Based on the positive results from this and other trials, large phase III trials have been initiated evaluating obinutuzumab in previously untreated patients with indolent NHL, diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL), and in patients with indolent NHL refractory to rituximab.

Blood. 2011;118: Abstract 269.

Brentuximab Vedotin Continues to Show Impressive Activity in CD30-Positive Lymphoma

Two studies presented at the ASH Annual Meeting demonstrated that the anti-CD30 antibody conjugate, brentuximab vedotin (SGN-35), has promising activity both as single-agent therapy for relapsed/refractory CD30-positive lymphoma and in the first-line setting in combination with chemotherapy. Brentuximab vedotin contains the potent antimicrotubule agent monomethyl auristatin E (MMAE) and is currently under investigation for the treatment of CD30-positive hematologic malignances, including Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL). It recently received FDA approval for relapsed Hodgkin lymphoma and ALCL. Ranjana Advani, MD (Stanford University Medical Center, Stanford, California, United States), presented updated results from a phase II study investigating brentuximab vedotin (1.8 mg/kg every 3 weeks for up to 16 cycles) in patients with relapsed or refractory systemic ALCL. The updated results showed an ORR of 86% with a median duration of 13.2 months, a complete response (CR) rate of 59% with a median duration not reached, and median PFS of 14.5 months. Median OS had not been reached, and the estimated 1-year OS rate was 70%. These data demonstrate the durability of response to brentuximab vedotin and show that responses can be achieved in patients with refractory disease. The most common side effect of brentuximab vedotin was peripheral neuropathy, which typically resolved with dose delays or reductions.

Anas Younes, MD (The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, United States), presented results from a phase I dose-escalation study investigating the addition of brentuximab vedotin to standard chemotherapy regimens ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or AVD in patients with newly diagnosed advanced-stage Hodgkin lymphoma. The most common grade ≥3 adverse events included neutropenia (77%), anemia (14%), febrile neutropenia (11%), pulmonary toxicity (11%), dyspnea (9%), syncope (9%), and pulmonary embolism (7%). Pulmonary toxicity was most significant and prompted 7 patients in the ABVD arm to discontinue bleomycin. Three patients discontinued brentuximab vedotin due to peripheral neuropathy. All 15 of 25 patients who completed planned treatment with brentuximab vedotin plus ABVD achieved a CR; however, brentuximab vedotin plus AVD appeared to be better tolerated. Based on these results, a phase III study comparing front-line brentuximab vedotin plus AVD with ABVD alone is planned.

Blood. 2011;118: Abstract 443.

Blood. 2011;118: Abstract 955.

Multiple Myeloma

Elderly Multiple Myeloma Patients Benefit From Lenalidomide Maintenance Therapy

The subset analysis of the MM-015 trial reported by Antonio Palumbo, MD (University of Torino, Torino, Italy), showed that patients age 65-75 years (n = 349) with newly diagnosed multiple myeloma (MM) derived a significant PFS benefit from lenalidomide maintenance therapy following induction with melphalan, prednisone, and lenalidomide (MPR). This 3-arm study compared outcomes in patients treated with MP alone, MPR alone, or MPR followed by continuous lenalidomide maintenance therapy (MPR-R). In patients 65-75 years of age, ORRs were 79%, 73%, and 47% in the MPR-R, MPR, and MP arms, respectively, and MPR-R reduced the risk of disease progression by 70% compared with MP (hazard ratio [HR] = 0.30, P<.001) and by 38% compared with MPR (HR = 0.62; P = .005). The median time to progression was 31 months with MPR-R, 15 months with MPR, and 12 months with MP (P<.001). A preplanned landmark analysis from the time patients entered maintenance therapy also showed that patients 65-75 years of age derived a significant PFS benefit from lenalidomide maintenance therapy (HR = 0.35, P<.001) compared to no maintenance therapy, a similar benefit to that seen in the overall patient population. Lenalidomide maintenance therapy was well tolerated. These findings suggest that the MPR-R regimen is a viable treatment option for elderly patients with MM.

Blood. 2011;118: Abstract 475.

Bortezomib Plus Melphalan/Prednisone (VMP) Yields Long-Term Survival Benefit in Multiple Myeloma

Mature results from the VISTA trial demonstrated that first-line use of VMP maintained a significant OS benefit at 5 years median follow-up compared with MP. Jesús San-Miguel, MD, PhD (Hospital Clinico Universitario, Salamanca, Spain), presented the final analysis of the VISTA trial, including an exploratory analysis of the risk of secondary primary malignancies (SPM). First-line treatment with VMP significantly reduced the risk of death by 31% (HR = 0.695, P = .0004) and improved median OS by more than 1 year (56 months versus 43 months) compared with MP alone. The 5-year OS rates were 46% and 34%, respectively, and there was no increased risk of SPM with addition of bortezomib to MP. Moreover, patients who received VMP, regardless of subsequent therapy, had superior OS compared with patients who received MP on study followed by bortezomib at relapse (median 56 months versus 45 months; HR = 0.714, P = .003), indicating that second-line use of bortezomib following conventional MP is not an optimal treatment approach. These results further demonstrated that the OS benefit associated with VMP was maintained despite considerable use of salvage therapies, and subgroup analysis demonstrated that the significant OS benefit extended to older patients and those with moderate renal dysfunction (creatinine clearance <60 mL/min), but not to patients with high-risk cytogenetics.

Blood. 2011;118: Abstract 476.

Vorinostat/Bortezomib Combination for Relapsed/Refractory Multiple Myeloma

Initial results of the VANTAGE 088 trial demonstrated that bortezomib plus vorinostat, a histone deacetylase inhibitor, significantly improved ORR (56% versus 41%; P<.0001) and PFS (HR = 0.77; P = .01) compared with bortezomib alone in patients with relapsed/refractory MM. Meletios Athanasios Dimopoulos, MD (University of Athens, Athens, Greece), reported top-line results of this large, global, randomized, placebo-controlled phase III trial. A total of 637 patients were randomized 1:1 to receive 21-day cycles of intravenous bortezomib (1.3 mg/m² on days 1, 4, 8, and 11) combined with oral vorinostat (400 mg/day) or placebo on days 1 to 14. The OS analysis is not yet mature with approximately 60% of patients in both arms alive at the time of the analysis. Overall, the combination of bortezomib plus vorinostat was generally well tolerated. Side effects were as expected and clinically manageable, and discontinuation rates were similar in both arms. These results suggest that vorinostat combined with bortezomib may provide a new treatment option for patients with relapsed/refractory MM.

Blood. 2011;118: Abstract 811.

Proactive Therapy Improves Outcomes in Patients with High-Risk Smoldering Multiple Myeloma

This randomized, phase III trial showed that patients with high-risk smoldering multiple myeloma (SMM) who received active treatment with lenalidomide and dexamethasone (len/dex) followed by lenalidomide maintenance had delayed disease progression and improved OS compared with patients receiving no treatment. The criteria for defining high-risk SMM was ≥10% plasma cells in the bone marrow and M protein ≥30 g/L. Patients in the treatment arm received lenalidomide (25 mg/day, days 1-21) plus dexamethasone (20 mg/day, days 1-4 and days 12-15) as induction followed by lenalidomide maintenance therapy (10 mg on days 1-21) every 28 days. María-Victoria Mateos, MD, PhD (Hospital Clinico Universitario, Salamanca, Spain), reported that time to progression to active disease was significantly delayed in patients receiving len/dex (median not reached versus 23 months; HR = 6.0; P<.0001), and the 3-year OS rate from study enrollment was significantly improved among patients who received len/dex (93% versus 76%; P = .04). Some patients receiving len/dex developed grade 3 neutropenia, anemia, thrombocytopenia, asthenia, rash, diarrhea, or infection during induction therapy. Prior to this study, it was unknown if patients with SMM might benefit from early therapeutic interventions, and the current standard of care is to defer treatment until patients develop symptomatic disease. Therefore, the results of this study are potentially practice changing for patients with high-risk SMM.

Blood. 2011;118: Abstract 991.

Myeloproliferative Neoplasms

Ruxolitinib Improves Survival, Spleen Size, and Symptoms Across Subgroups of Patients With Myelofibrosis

Patients with myelofibrosis (MF) receiving ruxolitinib in the COMFORT-I trial had higher response rates compared to the response rates in the placebo group—based on reductions in spleen volume and improvements in total symptom score (TSS) at week 24 regardless of baseline subgroup. Srdan Verstovsek, MD, PhD (The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, United States), presented efficacy results of ruxolitinib across different patient subgroups (defined by MF disease subtype, age, International Prognostic Scoring System risk group, presence or absence of JAK2^V617F mutation, hemoglobin level, and palpable spleen length), as well as updated OS results from the COMFORT-I trial. The updated OS analysis showed that ruxolitinib therapy was associated with a significant 50% reduction in the risk of death compared with placebo (P = .04). Importantly, this survival benefit extended to all patient subgroups, including patients with or without a V617F mutation. Ruxolitinib therapy resulted in a 66% and 44% reduction in the risk of death in patients with V617F-negative and V617F-positive disease, respectively. These results demonstrate that ruxolitinib therapy both improves symptoms and provides a survival advantage in myelofibosis.

Blood. 2011;118: Abstract 278.

Acute Myeloid Leukemia

Combination of Gemtuzumab Ozogamicin and Chemotherapy Improved Survival in Acute Myeloid Leukemia

Fractionated doses of gemtuzumab ozogamicin (GO) combined with standard induction chemotherapy significantly improved event-free survival (EFS) and OS in older patients with newly diagnosed acute myeloid leukemia (AML). Sylvie Castaigne, MD (Hopital de Versailles. UVSQ, Le Chesnay, France), reported the results of the randomized, multicenter, phase III, Acute Leukemia French Association (ALFA) 0701 trial designed to evaluate the efficacy and safety of adding a fractionated GO schedule (3 mg/m²/day on days 1, 4, and 7) to standard front-line chemotherapy with daunorubicin plus Ara C (DA) in AML patients 50-70 years of age. The trial enrolled 280 patients. At 2 years, EFS was 41% among patients treated with DAGO compared to 16% among those who received DA alone (P = .002). Even more impressive was the 10-month improvement in median OS. Patients receiving DAGO had a median OS of 25 months vs 15 months for those treated with DA alone (P = .037). The primary toxicity associated with GO was prolonged thrombocytopenia, which occurred in 19 (14%) patients, and 3 patients treated with DAGO developed hepatic veno-occlusive disease. Overall, this regimen was well tolerated and did not result in increased treatment-related mortality (6% in the DAGO group versus 4% in the DA group) or hospitalizations. Gemtuzumab ozogamicin is an anti-CD33 monoclonal antibody linked to a cytotoxic agent, calicheamicin, and it binds to CD33, which is expressed on AML cells but not on normal hematopoietic stem cells. Gemtuzumab ozogamicin was previously approved by the FDA for relapsed AML patients over 60 years old, but approval was later withdrawn due to lack of evidence of clinical benefit and toxicity. However, based on current results is it possible that GO was not studied in the right patient population and with the appropriate dosage?

Blood. 2011;118: Abstract 6.

Chronic Myeloid Leukemia

Is It Safe to Discontinue Treatment With Second-Generation Tyrosine Kinase Inhibitors?

This analysis of 33 patients with chronic-phase chronic myeloid leukemia (CML) and stable undetectable molecular residual disease (UMRD) who discontinued treatment with either nilotinib or dasatinib demonstrated a 24% rate of relapse, defined as loss of major molecular response (MMR). This study was designed to test whether selected patients with CML who achieve UMRD can safely discontinue treatment with these second-generation TKIs without rapid disease relapse and to compare the results with those from the STIM trial—STop IMatinib trial (Mahon FX, et al. Lancet Oncol. 2010;11(11):1029-1035. Mahon FX, et al. Blood. 2011;118: Abstract 603). As reported by Delphine Rea, MD (Hopital Saint Louis, Paris, France), the 33 patients (15 nilotinib and 18 dasitinib) included in this analysis had to be PCR-negative for at least 24 months, and were then followed for a minimum of 6 months after discontinuing treatment. Bcr-Abl transcripts were quantified monthly during the first 6 months and every 2 months to 3 months thereafter; TKI therapy was restarted upon loss of MMR. Eight patients (24%) had loss of MMR within 6 months off therapy, and both MMR and UMRD were rapidly regained with retreatment. At a median follow-up of 11 months, the remaining 25 patients (76%) maintained UMRD, which was substantially more than the 40% reported in the STIM trial. Although the sample size was small and the follow up short, the authors concluded that treatment with these second-generation TKIs can be safely discontinued in CML patients with a long-lasting UMRD, but under strict molecular monitoring conditions. They also recommended a larger study be conducted to verify these results.

Blood. 2011;118: Abstract 604.

Chronic Lymphocytic Leukemia

Addition of Alemtuzumab to FC Chemotherapy Improves Efficacy, But May Be Too Toxic

Early results of the randomized phase III HOVON68 CLL trial demonstrated that low-dose subcutaneous alemtuzumab (30 mg/day) plus fludarabine/cyclophosphamide (FCA) significantly improved ORR and PFS compared with fludarabine/cyclophosphamide (FC) alone in patients with previously untreated high-risk CLL. Christian Geisler, MD, PhD (Rigshospitalet, Copenhagen, Denmark), presented an early analysis of this trial based on data from 272 evaluable patients. Those treated with FCA achieved a significantly higher ORR compared to FC alone (89% versus 80%; P = .048), and significantly more patients treated with FCA achieved minimal residual disease–negative CR (29% versus 17%; P = .014). Treatment with FCA also extended median PFS by 7 months (37 months versus 30 months; P = .04). However, these benefits came at a cost of higher toxicity. Opportunistic infections, flu-like syndrome, and organ toxicity were all significantly higher in patients treated with the FCA regimen. Based on these preliminary results, the authors concluded that the addition of low-dose alemtuzumab to FC appears to improve clinical outcomes, but it is too early to tell if OS will be improved, and the immunosuppressive effects of this regimen might be of considerable concern.

Blood. 2011;118: Abstract 290.

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