primeLINES CLINICAL OPINION POLL

June 2011 Issue

NEWS FROM THE 2011 ONCOLOGY ANNUAL MEETING IN CHICAGO

The 47th Annual Meeting of the American Society of Clinical Oncology (ASCO) kicked off on June 3 in Chicago. Nearly 30,000 researchers, oncology specialists, and other healthcare professionals from all over the world attended the 2011 meeting to discuss the most current achievements in oncology. The theme of this year's meeting was "Patients, Pathways, Progress" and each of these key elements was woven in educational and scientific sessions throughout the meeting. This newsletter is dedicated to summaries of the most compelling and several practice-changing abstracts presented at the ASCO Annual Meeting this year.

Breast Cancer

Exemestane Effective for Breast Cancer Prevention

Based on the results of the National Cancer Institute of Canada Clinical Trial Group (NCIC-CTG) MAP.3 trial, exemestane may provide a new option for primary prevention of breast cancer among postmenopausal women considered at risk for developing breast cancer. The potential for rare but serious side effects (endometrial cancer, blood clots, and strokes) has long deterred many high-risk women from using selective estrogen receptor modulators (SERMs), tamoxifen or raloxifene, the only drugs currently approved for breast cancer prevention. The results of the MAP.3 trial, which enrolled 4560 postmenopausal women considered at risk for breast cancer, showed that exemestane reduced the annual incidence of invasive breast cancers by 65% compared to placebo. It also reduced pre-invasive breast cancer. Over the median follow-up period of approximately 3 years, exemestane was not associated with any serious side effects and only minimal changes in health-related quality of life. Paul Goss, MD, PhD (Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States), stated that exemestane offers a new option for consideration of breast cancer prevention in postmenopausal women and, because of its safety profile, has the potential for wider-scale implementation than SERMs. However, he cautioned against extrapolating these results to premenopausal women. This conclusion was echoed by the discussant, Andrea de Censi, MD (Oncologia Medica, Ospedali Galliera, Genoa, Italy). The highly anticipated results of this landmark trial were published simultaneously in the New England Journal of Medicine.

J Clin Oncol. 2011;29(suppl): Abstract LBA504.

N Engl J Med. 2011;364(25):2381-2391.

Regional Nodal Irradiation for Breast Cancer Patients With 1-3 Positive Lymph Nodes

The NCIC-CTG MA.20 trial evaluated the addition of regional nodal irradiation (RNI) to whole breast irradiation (WBI) following breast conserving surgery (BCS) in 1832 women with high-risk node-negative (N0) or node-positive (N+) breast cancer treated with BCS, adjuvant chemotherapy, and/or endocrine therapy. All N+ patients in this study were treated with level 1 or 2 axillary dissection. Patients were randomized to WBI (50 Gy in 25 fractions +/- boost irradiation) or WBI plus RNI (45 Gy in 25 fractions) to the internal mammary, supraclavicular, and high axillary lymph nodes. Median follow up was 62 months. The results showed that addition of RNI to WBI significantly improved 5-year disease-free survival (DFS) (89.7% vs 84.0%; hazard ratio [HR] = 0.67, P = .003); 5-year isolated locoregional DFS (96.8% vs 94.5%; HR = 0.58, P = .02), and distant DFS (92.4% vs 87.0%, HR = 0.64, P = .002). There was also a trend toward improved overall survival (OS; 92.3% vs 90.7%; HR = 0.76; P = .07). However, RNI was associated with some significantly increased toxicity, primarily dermatitis, pneumonitis, and lymphedema. Timothy Whelan, BM, BCh, MSc (Juravinski Cancer Centre, Hamilton Health Sciences, Ontario, Canada), suggested that these findings could expand the pool of women who are offered RNI. The discussant, Thomas Buchholz, MD (M. D. Anderson Cancer Center, Houston, Texas, United States), commented that this is a practice-changing trial. However, he pointed out that not all patients with 1 to 3 positive nodes are at the same risk of recurrence. While he feels high-risk patients should be offered RNI based on the results of MA.20, more data are needed for patients with low risk for recurrence (eg, patients with a small volume of disease in a sentinel node). He highlighted there is an unmet need for biomarker studies to better predict recurrence risk in patients with positive axillary nodes.

J Clin Oncol. 2011;29(suppl): Abstract LBA1003.

Gastrointestinal Cancer

Sorafenib Is Safe for Patients With Advanced Hepatocellular Carcinoma and Moderate Liver Dysfunction

Currently, sorafenib is the only systemic agent approved for the treatment of advanced unresectable hepatocellular carcinoma (HCC). GIDEON (Global Investigation of Therapeutic DEcisions in Hepatocellular Carcinoma and Of its Treatment with SorafeNib) is the largest (N = ~3200), global, prospective, non-interventional study that was required as a post-approval commitment to the European Medicines Agency (EMA). The main goal is to collect real world safety and efficacy data on sorafenib in the broad population of patients with advanced HCC who are being treated in clinical practice, which often includes patients with compromised liver function from underlying hepatic cirrhosis. These patients were generally excluded from pivotal clinical trials. Jorge Marrero, MD (University of Michigan, Ann Arbor, Michigan, United States), presented the results of a planned second interim analysis of GIDEON that included 1571 patients. In this cohort, 61% of patients had Child-Pugh A, 23% had Child-Pugh B, and 2% Child Pugh C liver dysfunction. The analysis showed that the administered dose of sorafenib was similar regardless of liver function, but Child-Pugh B patients had shorter duration of therapy (median 9 weeks versus 14 weeks). With regard to safety, treatment-emergent adverse events (AEs) of all grades were similar between the treatment groups. Compared with Child-Pugh A patients, patients with Child-Pugh B disease did not have a higher incidence of drug-related AEs, but had a higher incidence of liver-associated AEs and higher discontinuations of sorafenib treatment. As expected, OS correlated with liver function, but there was no difference in time to progression between Child-Pugh A and B patients. Based on the results of this interim analysis, Dr Marrero thought sorafenib could be safely used in selected Child Pugh B patients.

For more information on this trial, please visit the prIME Oncology Clinical Spotlight from Chicago at http://primeoncology.org/chicago_2011_cs.

J Clin Oncol. 2011;29(suppl): Abstract 4001.

Genitourinary Cancer

AXIS Trial Pits Axitinib Against Sorafenib as Second-Line Therapy for Metastatic Renal Cell Carcinoma

The battle of the multitargeted tyrosine kinase inhibitors (TKIs) for the treatment of metastatic renal cell carcinoma (mRCC) continues. In this head-to-head, randomized, phase III trial, 723 patients with clear-cell mRCC and measurable disease that had progressed after 1 prior line of systemic therapy were randomized to treatment with axitinib (5-10 mg BID) or sorafenib (400 mg BID). Axitinib is a highly potent second-generation inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3, and it has demonstrated activity in sorafenib-refractory mRCC. The axitinib dose was started at 5 mg and titrated up to a maximum of 10 mg based on tolerability. Prior therapy consisted mainly of sunitinib-based (54%) and cytokine-based (35%) therapy. The results of this trial showed that axitinib is the clear winner with a median progression-free survival (PFS) of 6.7 months compared to 4.7 months for sorafenib (HR = 0.665; P<.0001), and the advantage for axitinib was observed across all subgroups regardless of prior therapy. The greatest difference was seen in the prior cytokine—treated subgroup (12.1 months versus 6.5 months; HR = 0.46; P<.0001), but the advantage in patients previously treated with sunitinib was marginal (4.8 months versus 3.4 months; HR = 0.74; P = .01). Patients treated with axitinib had a higher incidence of hypertension, fatigue, dysphonia, and hypothyroidism, whereas patients treated with sorafenib had a higher incidence of hand-foot syndrome, rash, alopecia, and anemia. In conclusion, Brian Rini, MD (Cleveland Clinic, Cleveland, Ohio, United States), stated that axitinib resulted in a clinically meaningful improvement in PFS compared with sorafenib and should be considered the reference standard for second-line treatment of advanced RCC.

For more information on how the AXIS trial is likely to influence clinical practice, please visit the prIME Oncology Daily Clinical Update from Chicago at http://primeoncology.org/chicago_2011_dcus_cme.

J Clin Oncol. 2011;29(suppl): Abstract 4503.

Cabozantinib Shows Dramatic Activity in Prostate Cancer Bone Disease

Cabozantinib (XL184) is an oral multitargeted TKI that inhibits c-MET and VEGFR-2 and has demonstrated antitumor activity in medullary thyroid cancer, ovarian cancer, and glioblastoma. c-MET, also known as the receptor for hepatocyte growth factor (HGFR), appears to be involved in the regulation of tumor invasion and metastasis. Recent studies have shown that bone metastases are associated with high levels of c-MET expression and that HGF and VEGF may participate in cross talk between tumor cells and the bone microenvironment. In prostate cancer, preclinical findings suggest that androgen deprivation therapy increases c-MET expression. Given all of these clues, perhaps it is not surprising that cabozantinib demonstrated dramatic effects on bone metastases in patients with castration-resistant prostate cancer (CRPC). When Maha Hussain, MD (University of Michigan, Ann Arbor, Michigan, United States), presented the results of a randomized phase II trial of cabozantinib in CRPC, the bone scans showing that 76% of patients had complete or partial resolution of bone lesions at 12 weeks were met with some skepticism and disbelief. The ever-present Steven Vogl, New York, asked if the results might be an artifact. Currently, the observed effects are not well understood, but further research is ongoing. Notably, however, improvements on bone scans correlated with reduced bone pain and objective measures of an antitumor effect in measurable extraskeletal target lesions. Overall, cabozantinib induced measurable tumor regression in 74% of patients, and the disease control rate at 12 weeks was 68%, but the objective partial response rate by RECIST was a modest 4%. Among 31 patients with stable disease after 12 weeks who were randomized to continued cabozantinib or placebo, median PFS was 21 weeks in the cabozantinib group and 6 weeks in the placebo group.

In his discussion of these data, Daniel George, MD (Duke University School of Medicine, Durham, North Carolina, United States), commented that the effects of cabozantinib observed on bone scans and with respect to bone pain are unprecedented and quite dramatic. It remains to be seen, however, if these endpoints will translate into improved OS and this needs to be evaluated in a randomized phase III trial.

For more information on this trial, please visit the prIME Oncology Daily Clinical Update at http://primeoncology.org/chicago_2011_dcus_cme.

J Clin Oncol. 2011;29(suppl): Abstract 4516.

Gynecologic Cancer

Role of Bevacizumab in Ovarian Cancer

Bevacizumab Improves Progression-Free Survival in Platinum-Sensitive Recurrent Ovarian Cancer

Bevacizumab, a humanized anti-VEGF monoclonal antibody has shown single-agent activity in recurrent ovarian cancer and improved PFS in combination with standard chemotherapy in two recently reported front-line phase III ovarian cancer clinical trials (GOG 218 and ICON7). Carol Aghajanian, MD (Memorial Sloan-Kettering Cancer Center, New York, New York, United States), presented the results of the OCEANS ovarian cancer trial evaluating efficacy and safety of bevacizumab and carboplatin/gemcitabine chemotherapy in recurrent ovarian cancer. In this randomized, placebo-controlled trial, 484 women with platinum-sensitive recurrent ovarian cancer were randomized to 6-10 cycles of carboplatin and gemcitabine with or without bevacizumab at a dose of 15 mg/kg every 3 weeks, followed by single-agent bevacizumab or placebo until disease progression. At a median follow-up of 24 months, median PFS was 12.4 months with bevacizumab compared to 8.4 months in the placebo group (HR = 0.48; P<.0001). Analysis according to platinum-free interval, cytoreductive surgery, age, and baseline performance status demonstrated consistent benefit of bevacizumab in all subgroups. Objective response rate increased by 21% (P = .0001) and median duration of response by 3 months with addition of bevacizumab. Although the OS analysis is not yet mature, there was a trend toward improved survival in the bevacizumab arm (35.5 months vs 29.9 months, HR = 0.75; P = .09). Patients receiving bevacizumab were more likely to develop ≥grade 3 hypertension and proteinuria, but there were no gastrointestinal perforations during treatment with bevacizumab or any unexpected toxicities. Dr Aghajanian concluded that this regimen provided clinically meaningful benefit over chemotherapy alone and should be considered a new treatment option for women with platinum-sensitive recurrent ovarian cancer.

J Clin Oncol. 2011;29(suppl): Abstract LBA5007.

Updated results of ICON7

During the same session, Gunnar Kristensen, MD, PhD (Norwegian Radium Hospital, Oslo, Norway), presented updated PFS and interim OS results from the Gynecologic Cancer InterGroup (GCIG) ICON7 trial of standard carboplatin/paclitaxel chemotherapy plus bevacizumab (7.5 mg/kg every 3 weeks for 12 months) in newly diagnosed high-risk FIGO stage I-IIA or stage IIB-IV ovarian cancer. The updated PFS data showed a continued improvement in the bevacizumab arm of 2.4 months over the control arm (19.8 months vs 17.4 months, respectively; HR = 0.87, P = .039). The intent-to-treat (ITT) analysis showed only a trend toward an improvement in OS, but patients with high-risk stage III disease (>1 cm residual tumor after debulking) or stage IV disease had a significant improvement in OS (HR = 0.64; P = .002).

The discussant for both of these abstracts, Anil Sood, MD (M.D. Anderson Cancer Center, Houston, Texas, United States), raised some provocative fundamental questions related to the optimal dose and duration of bevacizumab therapy in combination with chemotherapy in frontline and recurrent ovarian cancer.

J Clin Oncol. 2011;29(suppl): Abstract LBA5006.

Maintenance Therapy with Olaparib: Promising Strategy in Ovarian Cancer

Another agent that garnered considerable interest at the Gynecologic Cancer Oral Session is olaparib (AZD2281), a novel poly ADP ribose polymerase (PARP) inhibitor. Up to 50% of patients with high-grade serous ovarian cancer (SOC) may be deficient in homologous recombination repair due to either BRCA1 or BRCA2 germ-line or somatic mutations, epigenetic silencing of BRCA1, or other factors. Therefore, treatment with a PARP inhibitor makes sense in this population. In the randomized, placebo-controlled, phase II study presented by Jonathan Ledermann, MD (University College London, London, United Kingdom), 264 patients with high-grade SOC who had an ongoing response to their most recent platinum-based chemotherapy regimen and stable CA125 were treated with oral olaparib (400 mg BID) or placebo as maintenance therapy until disease progression. Only approximately 20% of patients enrolled had known BRCA1 and/or BRCA2 mutations; the majority had unknown mutation status. Olaparib maintenance therapy significantly prolonged PFS (median 8.4 months versus 4.8 months; HR = 0.35; P<.00001). In general, olaparib was well tolerated. The majority of AEs were grade 1 or 2, and there was a higher incidence of nausea, vomiting, fatigue, and anemia in the olaparib group. This is the first study to demonstrate that maintenance therapy with olaparib can prolong PFS in patients with platinum-sensitive, recurrent SOC, and Dr Ledermann suggested that olaparib could play an important role in this population of patients with a high incidence of defects in homologous recombination repair, but further studies are needed.

J Clin Oncol. 2011;29(suppl): Abstract 5003.

Lung Cancer

Erlotinib: A New Standard First-Line Therapy for EGFR Mutant Non-Small Cell Lung Cancer

The European Erlotinib Versus Chemotherapy (EURTAC) trial is now the second prospective, randomized, phase III trial to demonstrate conclusively what many already knew based on the IPASS and OPTIMAL studies. However, of note, EURTAC is the first prospective study of an EGFR TKI first-line treatment of EGFR mutation–positive non-small cell lung cancer (NSCLC) in a Caucasian patient population. Patients included in the study harbored exon 19 deletions or exon 21 L858R missense mutations. A total of 1227 patients were screened, and 17.5% were positive for a deletion or mutation (confirmed by both DNA sequencing and gene scan methods). Of those, 174 patients were randomized to either erlotinib (150 mg/day) or 1 of several alternative platinum-based doublet chemotherapy regimens every 3 weeks for 4 cycles. Of note, approximately 70% of patients randomized were never smokers. The updated interim analysis as of January 2011 showed that erlotinib significantly improved PFS by 63% compared to chemotherapy (median 9.7 months versus 5.2 months; HR = 0.37; P<.0001). These results were consistent across subgroups according to age, prior chemotherapy, tumor histology, and type of mutation. The interim analysis of OS did not show a difference between arms, but the analysis was not mature and significant crossover to erlotinib occurred. There were no unexpected safety findings.

In his remarks, the discussant, Tony Mok, MD (Chinese University of Hong Kong, Hong Kong, China), put these data into perspective saying that an EGFR inhibitor (either erlotinib or gefitinib) should be standard first-line therapy for NSCLC patients with an EGFR mutation. He also made some interesting comparisons with the Asian OPTIMAL trial in which 33% of the screened patients had a mutation. The question now becomes which EGFR inhibitor to use.

J Clin Oncol. 2011;29(suppl): Abstract 7503.

Impact of Crizotinib on Overall Survival in ALK-Positive NSCLC

One of the most exciting abstracts presented last year at the 2010 ASCO Annual Meeting Plenary Session was the phase II study of crizotinib in a selected subset of patients with advanced NSCLC harboring the EML4-ALK (Anaplastic Lymphoma Kinase) fusion gene. Approximately 4% of NSCLC (primarily adenocarcinomas) are ALK-positive. That study, which was recently published in the New England Journal of Medicine (N Engl J Med. 2010;363(18):1693-1703), enrolled 82 patients and demonstrated a 57% objective response rate, including 1 complete response, and another 33% of patients had stable disease. The presentation this year by Alice Shaw, MD, PhD (Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States), focused on answering the question of whether crizotinib is likely to improve OS in patients with ALK-positive NSCLC. That question is unlikely to be addressed by the ongoing, randomized, phase III trial because of extensive crossover of patients from the chemotherapy arm to crizotinib. Therefore, Dr Shaw and colleagues selected a well matched set of controls and did careful comparisons of OS between the group of patients treated with crizotinib in the phase II study and crizotinib-naïve ALK-positive patients. At a median follow-up of 18 months, median OS has not been reached for the original cohort of 82 ALK-positive patients treated with crizotinib. The 1-year and 2-year OS rates were 74% and 54%, respectively. A comparison of 30 of these ALK-positive patients who were treated with crizotinib as second-line or third-line therapy with a matched group of 23 ALK-positive patients not treated with crizotinib showed a statistically significant improvement in OS (median not reached versus 6 months; HR = 0.36; P = .004). In this subgroup, the 1-year OS rate for patients treated with crizotinib was 70% compared to 44% for their crizotinib−naïve counterparts. These results suggest that crizotinib will likely improve OS in patients with ALK-positive NSCLC.

The discussant, Ramaswamy Govindan, MD (Washington University School of Medicine, St Louis, Missouri, United States), praised Dr Shaw for her excellent work in this field and said that we now have a good understanding of this subgroup of 3% to 7% of patients with NSCLC. They are clearly younger and mostly never smokers with adenocarcinoma, and they have poor outcomes when treated with chemotherapy or EGFR inhibitors, but they respond very well when treated with crizotinib.

J Clin Oncol. 2009;29(suppl): Abstract 7507.

Melanoma

Long-Term Results of the EORTC Adjuvant PEG-Interferon Trial

Pegylated interferon-alfa2b (PEG-IFN-α2b) was approved by the US Food and Drug Administration for adjuvant treatment of resected stage III melanoma in March 2011 based on the results of the EORTC 18991 trial at a median follow-up 3.8 years. That trial randomized 1256 patients to PEG-IFN-α2b (6 µg/kg/week x 8 weeks induction and 3 µg/kg/week maintenance for up to 5 years) or observation. The analysis at 3.8 years showed a significant improvement in relapse-free survival (RFS) in the ITT population (HR = 0.82; P = .02). The data presented by Alex Eggermont, MD, PhD (Cancer Institute Gustave Roussy, Villejuif, France) at a median follow-up of 7.6 years, showed that improvement in RFS (a primary endpoint of the study) was significant and sustained with longer follow up (HR = 0.87; P = .05), but neither distant metastasis-free survival (DMFS) nor OS was significantly improved in the ITT population. The benefit seen in this trial is almost exclusively limited to the sentinel node–positive patients (N1), whereas patients with palpable nodes (N2) derive no benefit. Further subset analysis suggested that N1 patients with ulcerated primary tumors derived the most benefit from adjuvant PEG-IFN-α2b. Indeed, in this subset of patients treatment with PEG-IFN-α2b resulted in improved RFS (HR = 0.72; P = .06), DMFS (HR = 0.65; P = .02), and OS (HR = 0.59; P = .006). To further test the role of PEG-IFN-α2b in this patient population, EORTC 18081 trial has begun randomizing patients with stage II ulcerated primary melanoma for 2 years of adjuvant PEG-IFN-α2b vs observation.

J Clin Oncol. 2011;29(suppl): Abstract 8506b.

Targeted Therapy Comes of Age in Melanoma

Vemurafenib, New Treatment Option for BRAF Mutated Melanoma

Approximately 50% of melanomas carry mutations in BRAF, most frequently the V600E mutation, that lead to constitutive activation of downstream signaling through the MAP kinase pathway. Therefore, BRAF is a good therapeutic target in melanoma. Vemurafenib (better known as PLX4032) demonstrated a >50% response rate in a phase II study (BRIM-2) in selected patients with BRAF^V600E mutations (final results of that trial were reported by Antoni Ribas, et al. (J Clin Oncol. 2011;29(suppl): Abstract 8509). In addition to the BRIM-2 data, additional exciting results from the phase III open label randomized trial (BRIM-3) were presented at the ASCO Annual Meeting Plenary Session by Paul B Chapman, MD (Memorial Sloan-Kettering Cancer Center, New York, New York, United States), and simultaneously published in the New England Journal of Medicine. (2011 June 5. [Epub ahead of print] ). This trial compared oral vemurafenib (960 mg BID) with dacarbazine (1000 mg/m2 q3weeks) in 675 patients with advanced melanoma and V600E mutations. An interim analysis after 98 deaths showed a 63% reduction in the hazard for death for patients receiving vemurafenib compared to the hazard for death with dacarbazine (HR = 0.37; P<.0001), and the data safety monitoring committee stopped the trial and allowed patients on the dacarbazine arm to cross over. Analysis of PFS showed a 74% risk reduction, and the response rate was 48% for vemurafenib versus 5% for dacarbazine. In his conclusion, Dr Chapman indicated that vemurafenib is the first single-agent drug to improve response rate, PFS, and OS compared with standard chemotherapy in patients with BRAF^V600E–mutated metastatic melanoma and is the foundation upon which to build combination therapy. Although resistance to vemurafenib emerges rather quickly, and approximately 20% of patients developed benign, treatable, squamous cell lesions, Kim Margolin, MD (University of Washington School of Medicine, Seattle, Washington, United States), hailed this as a transformational trial that will fundamentally change the landscape of advanced melanoma therapy.

J Clin Oncol. 2011;29(suppl): Abstract LBA4.

Ipilimumab Improves Survival as First-Line Therapy for Metastatic Melanoma

At the same Plenary Session, Jedd Wolchok, MD, PhD (Memorial Sloan-Kettering Cancer Center, New York, New York, United States), presented the results of a randomized, phase III trial investigating ipilimumab plus dacarbazine versus dacarbazine plus placebo in 502 previously untreated patients with unresectable stage III or stage IV melanoma. This trial also demonstrated a significant improvement in median OS (11.2 months versus 9.1 months) with a hazard ratio of 0.72 (P<.001) and was also published simultaneously in New England Journal of Medicine (2011 June 6. [Epub ahead of print] ). Most impressive is the observation that 21% of patients were alive at 3 years. The types of immune-mediated AEs observed in patients treated with ipilimumab were consistent with those seen in previous studies of ipilimumab. However, the rates of elevated liver-function values were higher than expected, and Kim Allyson Margolin, MD (Fred Hutchinson Cancer Research Center, Seattle, Washington, United States), a discussant of the study, speculated that this may be related to combination with dacarbazine. This is the second positive trial for this novel immunotherapy, which stimulates the immune system by blocking CTLA4 on T lymphocytes. At last year's ASCO Annual Meeting, ipilimumab monotherapy was shown to significantly prolong OS in previously treated melanoma patients, and ipilimumab monotherapy (3 mg/kg q3weeks x 4) was approved earlier this year with a broad indication in metastatic melanoma. Dr Wolchok indicated that the investigators are keenly interested in testing ipilimumab in combination with other agents, including vemurafenib, and a trial of that combination is planned.

J Clin Oncol. 2011;29(suppl): Abstract LBA5.

In her discussion of the ipilimumab and vemurafenib trials, Dr Margolin commented on how these agents might be used in clinical practice and highlighted some of the important questions that need to be addressed in future clinical trials. For ipilimumab, it will be important to determine which subsets of patients are most likely to benefit and to better define the optimal dose and duration of therapy. Her recommendation is not to use it in combination with chemotherapy. For vemurafenib, the most important issue is resistance, and the mechanisms of resistance are being actively investigated, but this is likely to be a complex picture. With regard to their optimal use in clinical practice, vemurafenib seems ideal for symptomatic patients with large tumor burden (provided they have the V600E mutation) because of its ability to induce rapid tumor regression and symptom relief. In contrast, ipilimumab has a slower onset of action and may be best used in patients with low tumor burden and minimal symptoms with the goal of achieving long-term disease control. However, both drugs require experience and commitment to the management of their unique toxicities.

Sarcoma

Three Years of Adjuvant Imatinib, a New Standard of Care for High-Risk Resected Gastrointestinal Stromal Tumors

The TKI imatinib inhibits tyrosine kinases KIT and PDGFRα, which are frequently mutated in gastrointestinal stromal tumors (GIST). Imatinib is currently approved for first-line therapy and 12-month adjuvant treatment of advanced (GIST). The hypothesis tested in the Sarcoma Study Group (SSG) XVIII trial was whether 36 months of extended adjuvant imatinib (400 mg/day) was superior to 12 months of adjuvant treatment in KIT-positive patients at high risk of recurrence. Heikki Joensuu, MD (Helsinki University Central Hospital, Helsinki, Finland), presented results of this trial at the ASCO Annual Meeting Plenary Session. At a median follow-up of 54 months, 36 months of imatinib compared to 12 months of imatinib significantly improved RFS (65.6% vs 47.9%; HR = 0.46, P<.0001), a primary endpoint of the study, and OS (92.0% vs 81.7%; HR = 0.45, P = .019). Adjuvant imatinib was relatively well tolerated in both groups, however patients on 36-month therapy experienced more grade 3/4 adverse events and more often discontinue treatment then patients in the standard arm. In his discussion of this presentation, Charles D. Blanke, MD (University of British Columbia, Vancouver, British Columbia, Canada), stated that based on this study 3 years of postoperative imatinib treatment represents the new gold standard for patients with KIT-positive resected high-risk GIST. However, he questioned if this is the optimal duration for postoperative adjuvant therapy. An ongoing study of 5 years of imatinib may provide further evidence to help answer this important question.

For a more detailed discussion of this study, please visit the prIME Oncology Clinical Spotlight from Chicago at http://primeoncology.org/chicago_2011_cs.

J Clin Oncol. 2011;29(suppl): Abstract LBA1.

Pazopanib Significantly Improves Progression-Free Survival in Soft Tissue Sarcoma

Targeted antiangiogenic agents have shown great promise for the treatment of soft tissue sarcoma (STS). The PALETTE trial is a large, randomized, placebo-controlled, phase III trial that enrolled 369 patients with advanced STS, predominantly leiomyosarcoma and synovial sarcoma. The majority of patients enrolled in this study had received 2-4 prior lines of systemic therapy for advanced disease, including anthracyclines and ifosfamide. Results presented by Winette T.A. van der Graaf, MD, PhD (Radboud University Nijmegen Medical Centre, the Netherlands) showed that treatment with oral pazopanib (800 mg/day) significantly improved PFS compared with placebo (HR = 0.31; P<.0001), and this was seen consistently in all histologic subgroups. Median PFS was 4.6 months in the pazopanib arm compared with 1.5 months in the placebo arm. However, an interim analysis of OS showed no significant difference between treatment groups. The safety profile of pazopanib was as expected and manageable with careful monitoring of liver function.

The discussant, Shreyaskumar Patel, MD (M. D. Anderson Cancer Center, Houston, Texas, United States), reviewed the data from PALETTE along with data from a phase II trial of brivanib, another VEGFR inhibitor, and concluded that this class of agents is clearly active in STS, yet there are many unanswered questions. It is not clear if any of these agents is better than another, and it is unclear how best to use them, particularly whether they should be used as single agents or in combination with chemotherapy. He highlighted the unmet need for biomarkers to tease out which subsets of STS patients are most likely to benefit.

J Clin Oncol. 2011;29(suppl): Abstract LBA10002.

Maintenance Therapy with a Novel mTOR Inhibitor, Ridaforolimus, SUCCEEDs in Slowing Disease Progression

Based on evidence that the PI3K/AKT pathway is highly active in sarcoma, mTOR inhibitors are being actively investigated in this disease. The SUCCEED trial enrolled 711 patients with any sarcoma subtype who had received at least 4 cycles of systemic chemotherapy (either first-line, second-line, or third-line). Patients with an objective response or stable disease to their last chemotherapy were randomized to maintenance therapy with ridaforolimus (40 mg/day x 5 day each week) or placebo. The patient population consisted primarily of STS (90%), and the primary site of metastasis was the lung. Analysis of PFS by independent radiologic review showed a 28% relative risk reduction (HR = 0.72; P = .0001). Median PFS was 17.7 weeks in the ridaforolimus arm and 14.6 weeks in the placebo arm. Similar to the PALETTE trial described above, there was no improvement in OS. This is the first trial of its kind and it clearly demonstrated that maintenance therapy with an mTOR inhibitor can improve disease control and delay disease progression in patients with advanced sarcoma.

The discussant, Scott Okuno, MD (Mayo Clinic, Rochester, Minnesota, United States), praised the investigators for carrying out such a large, ground breaking study, but pointed out a major limitation—the lack of information on histologic subtypes.

J Clin Oncol. 2011;29(suppl): Abstract 10005.