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P T. 2011;36(8): 508-512, 517
Meeting Highlights

2011 American Society of Clinical Oncology

Walter Alexander

This year’s annual American Society of Clinical Oncology (ASCO) meeting in Chicago hosted 32,000 attendees, including 26,000 health care professionals, from 120 countries June 3–7, 2011. Of more than 10,000 abstracts presented at the meeting, key sessions on pharmaceutical therapies are summarized for melanoma; glioblastoma; non–small-cell lung cancer; gastrointestinal, prostate, and breast cancers; and myelofibrosis. Markers for lymph node mapping and antibody response are also discussed.

Ipilimumab (Yervoy) Plus Dacarbazine (DTIC) Versus Dacarbazine Alone in Stage III or IV Melanoma: Phase 3

  • Jedd D. Wolchok, MD, Memorial Sloan–Kettering Cancer Center, New York, N.Y.

Dacarbazine (DTIC-Dome, Bayer) is currently the global standard of care in the treatment of melanoma with one-year and two-year survival rates after initiation of therapy at about 25% and 10%, respectively. In phase 3 clinical trials, monotherapy with ipilimumab intravenous (IV) injection (Yervoy, Bristol-Myers Squibb) 3 mg/kg also improved survival and durable responses, compared with gp-100 Melanoma Peptide Vaccine.

In Dr. Wolchok’s double-blind trial, 502 previously untreated patients with metastatic melanoma were randomly assigned to receive ipilimumab 10 mg/kg plus dacarbazine 850 mg/m2 or placebo plus dacarbazine 850 mg/m2 at weeks 1, 4, 7, and 10, followed by dacarbazine every week through week 22. Eligible patients, those without disease progression or dose-limiting toxicity after the 24-week induction period, received ipilimumab or placebo every 12 weeks as maintenance therapy. The primary endpoint was overall survival.

Dr. Wolchok said, “This is a poor-prognosis group of patients.”

All patients had stage IIIc N3 (unresectable) or stage IV melanoma. Mean age was 57 years (60% men), with more than half (56.2%) at stage M1c with visceral metastases and/or elevation of baseline lactate dehydrogenase (LDH), a marker of malignancy in melanoma.

Median overall survival was 11.2 months for the ipilimumab/dacarbazine group and 9.1 months for the dacarbazine/placebo group, with a hazard ratio (HR) of 0.72 (0.59–0.87; P = 0.0009). Estimated survival rates at one, two, and three years for ipilimumab/dacarbazine were 47.3%, 28.5%, and 20.8%, respectively, and 36.3%, 17.9%, and 12.2%, respectively, for dacarbazine/placebo. Median progression-free survival was 2.8 months for ipilimumab/dacarbazine and 2.6 months for dacarbazine/placebo (HR = 0.76 [0.63–0.93]; P = 0.006).

Rates of adverse events (AEs) were higher with ipilimumab/dacarbazine and were consistent with those found in previous studies. Most AEs were immune-based and were responsive to dose interruptions or discontinuations, corticosteroids, or other immunosuppressants.

Dr. Wolchok noted that although rates of diarrhea (overall, 35.4%; grade 3–4, 4%) and colitis rates (4.5%; grade 3–4, 2%) were lower than in phase 2 trials, rates for elevated aspartate transaminase (AST, 29.1%; grade 3–4, 18.2%) and alanine transaminase (ALT, 33.2%; grade 3–4, 21.9%) were higher.

Dr. Wolchok concluded, “This is the second randomized ipilimumab phase 3 trial to show significant survival improvement in metastatic melanoma.”

Adjuvant Pegylated Interferon alpha-2b (Sylatron) Or Observation in Melanoma: EORTC 18991, Phase 3

  • Alexander M. M. Eggermont, MD, EORTC Melanoma Group, Cancer Institute Gustave Roussy, Villejuif, France

In March 2011, the FDA approved pegylated interferon alpha-2b (Peg-Int, Sylatron, Schering) for use in resected stage III melanoma based on findings from the European Organization for Research and Treatment of Cancer (EORTC 18991) trial. As shown in that trial, the primary endpoint of relapse-free survival favored Peg-Int over observation (HR = 0.82; P = 0.01) in those with stage III melanoma after 3.8 years.

The current study extends EORTC 18991 follow-up to 7.6 years. Patients (n = 1,256; mean age, 50 years) were randomly assigned to receive Peg-Int induction for eight weeks at 6 mcg/kg per week plus five years of maintenance therapy at 3 mcg/kg per week of observation. The patients were stratified according to microscopic (N1) or palpable (N2) lymph node status and tumor ulceration status (ulcerated or non-ulcerated). By four to five years, only 23% of the patients remained on treatment, with median maintenance duration at 23 months in the N1 group and nine months in the N2 group.

“The N2 patients drop out rapidly because of relapses,” Dr. Eggermont said.

Benefits for Peg-Int in distant metastasis-free survival and in overall survival did not achieve statistical significance after 7.6 years, although relapse-free survival remained significantly greater in the Peg-Int group (HR = 0.87; P = 0.05).

When investigators looked at the influence of lymph node and ulceration status on relapse-free survival, they found both to be important. The Peg-Int benefit approached significance in N1 patients (HR = 0.82; P = 0.08) but not in N2 patients (HR = 0.89; P = 0.21). In the N1 patients, although nonsignificant benefits for Peg-Int were reported in distant metastasis-free survival (HR = 0.96) and overall survival (HR = 1.00), no hint of benefit was apparent in the N2 patients for either survival category.

Among patients with N1 (sentinel node) ulcerative melanomas, benefits were increased. In the 3.8-year analysis, the overall survival risk reduction was 23% (HR = 0.77) in patients with ulcerated stage III disease and 50% (HR = 0.50) in those with ulcerated stage III disease and N1 status. At 7.6 years, there was no overall survival benefit for Peg-Int in non-ulcerated tumors (HR = 1.05; P = 0.64), whereas there was a trend toward benefit in ulcerated tumors (HR = 0.81; P = 0.11).

For patients with ulcerated melanomas and N1 status, the benefit in relapse-free survival approached significance (HR = 0.72; P = 0.06) and attained full statistical significance for distant metastasis-free survival (HR = 0.65; P = 0.02) after 7.6 years. The overall survival benefit for those with N1 status and ulceration was also significant (HR = 0.59; P = 0.006).

Median overall survival was 3.7 years in the observation group with ulceration and N1 status and more than nine years in the patients with N1 melanomas and ulcerative status who had received Peg-Int.

“Basically, still at 7.6 years, the effect mediated by treatment is restricted to the sentinel node [N1] patient population. So stage and interferon interact significantly,” Dr. Eggermont said.

Temozolomide (Temodar) in Glioblastoma: Radiation Therapy Oncology Group 0525

  • Mark R. Gilbert, MD, M.D. Anderson Cancer Center, Houston, Tex.
  • Kenneth D. Aldape, MD, Trial Co-Chair, M.D. Anderson Cancer Center, Houston, Tex.

A phase 3 trial that was designed to determine whether a dose-dense schedule of adjuvant temozolomide (Temodar, Merck) would confer increased benefits among patients with newly diagnosed glioblastoma multiforme found that it did not. At the same time, O-6-methylguanine-DNA-methyl-transferase (MGMT) methylation status was found to be an important determinant of treatment response.

The randomized Radiation Therapy Oncology Group (RTOG 0525) trial, conducted in 209 centers in the U.S., Canada, and Europe, compared concomitant radiation followed by adjuvant temozolomide (the current standard therapy) with concomitant radiation followed by dose-dense temozolomide. The study was conducted in concert with the European Organization for Research and Treatment of Cancer (EORTC) and the North Central Cancer Treatment Group (NCCTG).

In earlier research, glioblastoma patients with tumors positive for MGMT methylation had demonstrated improved overall survival (46%) compared with patients with unmethylated or normally functioning MGMT (13.8%) after treatment with radiation and temozolomide.1

To test the dose-dense strategy and the effect of MGMT methylation status, participants were randomly assigned to one of two adjuvant treatment arms:

  • arm 1 (n = 411, the standard arm): temozolomide on days 1 to 5 every 28 days for up to 12 cycles or 12 months
  • arm 2 (n = 422, the dose-dense arm): temozolomide on days 1 to 21 every 28 days for up to 12 cycles or 12 months

The primary outcomes were overall survival and progression-free survival at 48 months. The analysis revealed no differences in overall or progression-free survival between standard and dose-dense schedules. Analysis by MGMT status, however, showed significantly higher overall survival rates for patients with positive MGMT methylation status (HR = 1.74; P < 0.0001) as well as higher progression-free survival for this group (HR = 1.63; P < 0.0001).

Grade 3–5 AEs were more common (194 vs. 120 patients; P < 0.001) in the dose-dense arm (arm 2), most frequently consisting of lymphopenia (107 vs. 51 patients) and fatigue (33 vs. 12 patients).

Dr. Aldape said that the study’s confirmation of a positive correlation between clinical outcomes and molecular classification of glioblastoma was an important finding. “It will enable improved future prognostic prediction, spur the development of specific therapies based on tumor biology, and ultimately lead to individualization of treatment,” he commented.

Autologous Heat-Shock Protein Vaccine (Prophage G-200) For Recurrent Glioblastoma: Phase 2

  • Andrew Parsa, MD, PhD, Associate Professor of Neurosurgery, University of California, San Francisco

Heat-shock proteins interact with receptors on the surface of antigen-presenting cells (APCs), leading to robust CD8+ and CD4+ T-cell responses with antitumor specificity. These proteins also interact with other receptors to stimulate innate immune responses. Heat-Shock Protein Peptide Complex-96 (vitespen, Prophage G-200, HSPPC-96, Agenus Inc.), a vaccine designed specifically to target cancer cells, contains glycoprotein-96 (gp-96) and associated antigenic peptides purified from a patient’s own tumor tissue.

Dr. Parsa presented results of a study that included 30 evaluable patients (mean age, 53 years) with confirmed diagnoses of glioblastoma multiforme. All patients had first undergone surgery to remove as much of the malignancy as possible. From tumor tissue sent to a laboratory, HSPPC-96 was then prepared and introduced to the patient via intradermal injection (25 mcg) once weekly for four weeks. Injections were initiated after recovery from surgery (about two to three weeks). Biweekly injections were then administered until vaccine depletion.

The most common AEs in 14 of 17 patients were injection-site reactions. No grade 3 or 4 AEs were reported.

“The safety profile of HSPPC-96 offers a great opportunity for its use in combination with other approved treatments for glioblastoma multiforme,” Dr. Parsa commented.

Among the 33 patients treated with at least four doses of HSPPC-96, progression-free survival was about 17 weeks. Median overall survival was 47.6 weeks.

“The 47.6-week overall survival rate is very good for this population,” Dr. Parsa said.

He also explained that the immune response was very robust, and both overall survival and progression-free survival rates among patients who received the vaccine compared well with outcomes observed in other trials in which various cytotoxic or targeted agents had been used to control glioblastoma. The findings, he concluded, support advancement of the vaccine to phase 3 trials.

Ganetespib as Monotherapy for Non–Small-Cell Lung Cancer: Phase 2

  • Geoffrey Shapiro, MD, PhD, Dana–Farber Cancer Institute, Boston, Mass.

Ganetespib (STA-9090, Synta Pharmaceuticals), a potent heat-shock protein-90 (Hsp90) inhibitor, is unrelated structurally to first-generation Hsp90 inhibitors, which produce hepatic or ocular toxicities. In the first 400 patients treated to date, it has been well tolerated and has shown promising activity.

Dr. Shapiro and colleagues enrolled 76 patients with advanced stage IIIb and IV non–small-cell lung cancer (NSCLC) who had not responded to an average of two to three earlier treatments. The patients received ganetespib 200 mg/m2 as a one-hour infusion once weekly for three weeks in a four-week cycle. The primary endpoint was progression-free survival at 16 weeks. Initial cohorts were stratified by mutation status:

  • cohort A (n = 16), epidermal growth factor receptor (EGFR) mutation
  • cohort B (n = 17), v-Ki-Ras-2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation
  • cohort C (n = 25), wild-type
  • cohort D (n = 37), wild-type EGFR and KRAS with adenocarcinoma histology only

Tumor response was assessed every eight weeks. Fourteen patients in cohort A, 13 in cohort B, and 48 in cohorts C and D received at least one dose of ganetespib and one follow-up scan. In most cases, therapy was discontinued because of disease progression. Five patients in the wild-type arm died.

Among 23 patients in cohorts C and D who were tested for anaplastic lymphoma kinase (ALK) translocation or rearrangement, eight had tumors that were ALK-positive in at least one assay. Six of these eight patients (75%) showed tumor shrinkage in target lesions, one patient showed no change in tumor size, and one patient achieved stable disease (defined as tumor growth of less than 20%), yielding a disease-control rate (complete response plus partial response plus stable disease [CR + PR + SD]) of 88% at the first scan and an objective response rate (CR + PR) of 50%. All patients with durable objective responses had tumors harboring ALK rearrangements.

Tumor shrinkage in cohorts C and D was reported in 15/48 patients (31%), and stable disease was noted in 24/48 patients (50%), with an objective response rate of 8% (4/48 patients) and a disease-control rate of 58% (28/48 patients). Eight patients among the 13 evaluable patients in cohort B experienced tumor shrinkage in target lesions (62%). Stable disease was noted in 5 of 13 patients (38%), and the overall disease-control rate was 38%. Among the 14 evaluable patients in cohort A, five patients (36%) experienced tumor shrinkage. The stable disease rate was 7/14 patients (50%), and the overall disease control rate was 50%. For the entire patient population tested (n = 76), progression-free survival at week 16 was 24.1%. The disease-control rate at eight weeks was 54%, and the overall objective response rate was 5.3%.

The most common grade 3 or higher AEs (in more than 5% of patients) were dyspnea (in 12.5%), fatigue (in 12.5%), diarrhea (in 9.4%), and hyponatremia (in 5.2%). Overall, diarrhea (in 78.1% of subjects), fatigue (in 50%), and nausea (in 38.5%) were the most common AEs. Dr. Shapiro noted that diarrhea was manageable with supportive care.

Ganetespib showed promising clinical activity as a single agent in NSCLC patients with actively progressing disease, Dr. Shapiro concluded. A phase 2b/3 trial of ganetespib, in combination with docetaxel (Taxotere, Sanofi-aventis), has been initiated in second-line advanced NSCLC.

Talactoferrin in Non–Small-Cell Lung Cancer: FORTIS-M, Phase 2

  • Purvis Parikh, MD, Indian Cooperative Oncology Network, Mumbai, India

Talactoferrin (Agennix), an oral investigational immunotherapy agent with antibacterial properties, appears to improve overall survival in several prognostically important subsets of patients with stage IIIb/IV non–small-cell lung cancer (NSCLC). This medication is also extremely well tolerated, according to results of a phase 2 study conducted at 11 centers.

“Talactoferrin demonstrated an apparent effect across a broad range of baseline prognostic factors, including squamous and non-squamous histology and Eastern Cooperative Oncology Group 0 (ECOG 0) and ECOG 1 performance status, among others,” Dr. Parikh said.

Dr. Parikh and co-investigators randomly assigned 100 patients with stage IIIb/IV NSCLC to receive talactoferrin 1.5 g twice daily or placebo in addition to best supportive care. All patients had failed to respond to first-line or second-line chemotherapy.

The authors noted that advances in long-term survival for NSCLC had been modest.

“In 1975, the five-year survival rate in the United States for non–small-cell lung cancer was about 13%. Currently, the five-year survival rate is roughly 16%. Thus, it’s clear that there’s an urgent need for new therapies,” he said.

Talactoferrin was given for a maximum of three 14-week cycles. Each cycle involved 12 consecutive weeks of talactoferrin treatment followed by a two-week “off” period. The study met its primary endpoint of overall survival, with a 65% increase in the talactoferrin group (6.1 months), compared with 3.7 months in the placebo group (HR = 0.68; P < 0.05).

Assessment of overall survival for all various patient subsets demonstrated a consistent effect for talactoferrin. For example, talactoferrin-treated patients with squamous histology had a 7.9-month median overall survival compared with 4.2 months for placebo-treated patients. For patients with non-squamous histology, the median overall survival was 5.8 months with talactoferrin therapy and 3.5 months with placebo.

Patients with ECOG 0 performance status who received talactoferrin had a 12.1-month median overall survival compared with four months for the placebo group. For patients with ECOG 1 performance status, the median overall survival was 5.8 months in the talactoferrin arm and 3.7 months in the placebo arm. The overall survival benefit for talactoferrin persisted regardless of the patient’s age, sex, disease stage, or line of therapy. The total number of AEs and grade 3 and 4 AEs was lower with talactoferrin than with placebo.

“If FORTIS-M is successful in extending overall survival and if the treatment is approved, talactoferrin will provide practitioners with an effective and well-tolerated immunotherapy in a setting where options are limited,” Dr. Parikh said.

Phase 3 FORTIS-M study results are expected in 2012.

Imatinib (Gleevec) for GISTs: Phase 3, Final Results

  • Heikki Joensuu, MD, Helsinki University Central Hospital, Helsinki, Finland
  • Charles D. Blanke, MD, Discussant, University of British Columbia

Although gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the GI tract, have variable malignancy potential, high-risk GIST is associated with 50% or more five-year risk of recurrence after surgery. High-risk features include a tumor larger than 5 cm and a high cell-proliferation rate. One year of adjuvant imatinib mesylate (Gleevec, Novartis) was shown to improve recurrence-free survival compared with placebo in patients with advanced GISTs.

The goal of the phase 3 Scandinavian Sarcoma Group and the German Association for Medical Oncology (SSG XVIII/AIO) study was to determine whether three years of imatinib therapy could extend recurrence-free survival. In an open-label design, 400 high-risk patients (median age, 61 years; 51% men) were randomly assigned to receive, in a 1:1 ratio, imatinib 400 mg daily for either 12 or 36 months. The primary outcome was recurrence-free survival (the time from randomization to GIST recurrence or death). At a median follow-up of 54 months, recurrences or deaths were reported in 84 patients (42%) from the 12-month imatinib group and in 50 patients (25%) from the 36-month group, with GIST deaths among 14 (7%) and 7 (4%) in the 12-month and 36-month groups, respectively.

Recurrence-free survival rates in the intent-to-treat (ITT) population were 47.9% and 65.6% in the 12- and 36-month imatinib groups (HR = 0.46; P < 0.0001). Overall survival rates in the ITT population were 81.7% and 92%, respectively, for the 12-and 36-month groups (HR = 0.45; P = 0.019).

Treatment-related AEs were reported in virtually all subjects (99% and 100% for the 12- and 36-month groups, respectively), with grade 3–4 AEs in 20% of the 12-month-therapy patients and in 33% of the 36-month patients (P = 0.006). Discontinuation rates resulting from AEs doubled in the 36-month group (13% vs. 26%, respectively; P = 0.001). Anemia and periorbital edema were the most common AEs.

Noting the three-year versus one-year improvements in recurrence-free and overall survival, Dr. Joensuu concluded: “As a treatment [for] GIST patients who have a high estimated risk of recurrence after surgery, adjuvant imatinib for three years is relatively well tolerated with few severe adverse events.”

In view of the higher AE rates with long-term treatment, Dr. Blanke recommended a threshold of “50% chance of recurrence” for selecting patients for therapy with long-term adjuvant imatinib.

Zoledronic Acid (Zometa) Versus Denosumab (Prolia) in Prostate and Breast Cancer: Two Trials

  • Marc F. Botteman, MSc, MS, Managing Partner, Pharmerit North America, Bethesda, Md.

Two analyses of cost–benefit ratios comparing zoledronic acid (Zometa, Novartis) and denosumab (Prolia, Amgen) in cancer patients show that the slight edge in reduced skeletal-related events (SREs) and quality of life conferred by denosumab comes with a high price tag.

As the author of both studies, Mr. Botteman said, “We used fairly simple mathematical modeling to try to understand the costs and benefits associated with use of these two treatments for preventing SREs in breast cancer and prostate cancer, taking into account the cumulative incidence of events over time, the cost of avoiding these events, and the impact on quality of life.”

Previous research has confirmed clinical advantages for denosumab over zoledronic acid in both tumor types. In castrate-resistant prostate cancer among men with bone metastases, median time to first on-study SRE was 20.7 months (95% CI, 18.8–24.9) with denosumab and 17.1 months (95% CI, 15.0–19.4) with zoledronic acid (HR = 0.82; 95% CI, 0.71–0.95; P = 0.0002 for non-inferiority and P = 0.008 for superiority).2

In patients with bone metastases and advanced breast cancer, denosumab was superior to zoledronic acid in delaying the time to first on-study SREs (HR, 0.82; 95% CI, 0.71–0.95; P = 0.01 superiority) and the time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66–0.89; P = 0.001).3

In the current prostate cancer study,2 a Markov model based on the published phase 3 trial data noted previously evaluated SRE incidence, quality-adjusted life-years (QALYs), SRE-related costs, and drug-related costs (acquisition, administration, and monitoring). SRE costs were obtained from a literature review, and drugs costs ($1,650 for denosumab injection; $886 for zoledronic acid infusion) were based on wholesale acquisition costs. Administration costs were $154 for zoledronic acid and $32 for denosumab.

Cumulative SREs were lower for denosumab (1.04 vs. 1.29, respectively, for a difference of −0.25), and discounted QALYs per patient were marginally higher for denosumab (0.93512 vs. 0.93080, for a difference of +0.00432). Related costs over 27 months of treatment were $7,604 for denosumab and $9,528 for zoledronic acid. Drug costs, however, were $7,314 higher for denosumab, leaving a net cost of $5,390 over 27 months to achieve the benefit. The resultant cost per QALY for denosumab (approximately $1.25 million), Mr. Botteman said, is far above what is traditionally considered to be a good value for a medical intervention in the U.S. ($50,000–$100,000 per QALY).

“This analysis raises questions about the cost–benefit ratio of denosumab in metastatic castrate-resistant prostate cancer,” Mr. Botteman stated.

The metastatic breast cancer study assessed the cost-effectiveness of denosumab compared with zoledronic acid from a managed care perspective, using a Markov model estimating SRE incidence, QALYs, SRE-related costs, and drug-related costs. Cumulative SREs per patient were higher for zoledronic acid (1.010 vs. 0.694, for a difference of −0.317), with concomitant higher costs ($7,290 vs. $5,152, for a difference of –$2,138). Drug-related costs were higher for denosumab ($15,994 vs. $25,016, for a difference of +$9,023). Those differences led to a comparative cost per QALY for denosumab of +$643,726, again far above what is customarily considered to be a good value for a medical intervention in the U.S.

“You do have a reduction in events and increase in quality of life with denosumab. But when you raise the question as to whether it is sufficient to justify the extra cost, our conclusion is that it is quite unlikely,” Mr. Botteman said.

The two studies were funded by Novartis.

Ruxolitinib in Myelofibrosis: COMFORT, Phase 3

  • Srdan Verstovsek, MD, PhD, University of Texas M.D. Anderson Cancer Center, Houston, Tex.

Myelofibrosis (MF), a life-threatening hematological cancer, is marked by bone marrow failure, an enlarged spleen, and debilitating fatigue and pain. Treatment options are limited.

COMFORT-I (COntrolled MyeloFibrosis Study with ORal JAK inhibitor Therapy-I) included 301 patients with intermediate-2 or high-risk MF, a palpable spleen (5 cm or larger), and platelet counts of 100 × 109 or greater whose status was positive or negative for Janus kinase (JAK2 V617F), a mutation associated with myeloproliferative disorders. Patients were randomly assigned to receive, in a 1:1 ratio, ruxolitinib (INCB18424, Incyte) 15 or 20 mg twice daily or placebo. The primary endpoint of the study was the proportion of patients achieving a 35% reduction or more in spleen volume from baseline at week 24. Mean age was 68 years, and 54% of the patients were men. Median spleen length was 16 cm in both groups.

During the trial, 36 placebo patients were switched to ruxolitinib, and 39% discontinued therapy (14% ruxolitinib, 25% placebo); 11% in each group withdrew because of AEs.

At 24 weeks, 41.9% of patients in the ruxolitinib group experienced a 35% or greater reduction in spleen volume, compared with 0.7% in the placebo group (P < 0.0001). Ruxolitinib-treated patients had a median 33% decrease in spleen volume, and placebo-treated patients experienced a median 8.5% increase (P < 0.0001). In addition, 45.9% of ruxolitinib-treated patients had a decrease of 50% or more in total symptom scores, compared with 5.3% in the placebo group (P < 0.0001). Overall survival favored ruxolitinib (HR = 0.67) but not significantly (P = 0.3268). Improvements with ruxolitinib treatment were similar regardless of the presence or absence of the JAK2 V617F mutation.

Ecchymosis, dizziness, and headache were more common with ruxolitinib, and abdominal pain was more common in the placebo group. Grade 3–4 anemia and thrombocytopenia, which were more common in patients with higher baseline grades, led to one discontinuation in each group. Thrombocytopenia, anemia, and transfusion rates with ruxolitinib treatment decreased over the course of the study and approached placebo levels.

Dr. Verstovsek concluded, “These results, along with those of COMFORT-II, demonstrate that ruxolitinib may become an important new option for patients with myelofibrosis.”

In COMFORT-II, also presented at ASCO, ruxolitinib demonstrated significant and sustained improvements in splenomegaly, disease-related symptoms, functioning, and quality of life.

99mTc-Tilmanocept (Lymphoseek) Versus Blue Dye In Breast Cancer and Melanoma: Phase 3

  • Vernon K. Sondak, MD, H. Lee Moffitt Cancer Center, Tampa, Fla.

For cancer surgeons, intraoperative lymph node mapping (ILNM) with a radiopharmaceutical agent identifies the first lymph nodes to receive lymphatic flow from a primary tumor site. Nodes are removed and analyzed for the presence of malignant cells, providing reliable staging without the post-surgical morbidity of a regional node dissection. Dr. Sondak stated that for intraoperative melanoma and breast cancer patients, in whom the ILNM procedure is routinely used, evaluation is critically dependent on the accuracy of the ILNM agent used in order to provide equivalence to regional node dissection.

Vital blue dye (e.g., isosulfan blue, Lymphazurin, United States Surgical Corp.) contrast medium is the only standardized pharmaceutical agent approved for ILNM use in the U.S. In two similar phase 3 trials of technetium 99m (99mTc)-tilmanocept (Lymphoseek, Neoprobe Corp.), a receptor-targeted radiopharmaceutical, the agent reliably identified not only tumor-containing nodes identified by the dye but also other disease-containing nodes not found by the dye.

In the studies, one of breast cancer and the other of melanoma, patients received injections near the tumor with 50 mcg of tilmanocept labeled with 0.5 to 2 mCi of 99mTc and underwent surgery 30 minutes to 30 hours later. Just prior to incision, the blue dye was injected in the proximity of the tumor. ILNM was performed to determine which lymph nodes had been localized by the agents. The primary efficacy endpoint was the concordance of in vivo lymph node detection rates of tilmanocept (hot nodes) versus vital blue dye (blue nodes). Vital blue dye is considered the standard.

The analysis clearly showed that tilmanocept was not inferior to vital blue dye, either on a per-node basis (total, 444 nodes) or a per-patient basis (total, 269 patients) (P < 0.0001 for both). Concordances were 0.999 (the number of blue and hot nodes divided by the number of blue nodes) for both.

Many nodes identified as hot with tilmanocept, however, were not identified as blue with the dye. Only 0.6439 of the hot nodes were also blue, and blue nodes were identified in only 0.5772 of the patients with hot nodes. As a result of the detections with tilmanocept, melanoma in two patients and breast cancer in two patients were reclassified to a higher stage. There were no clinically significant adverse events with either agent.

Dr. Sondak summarized, “Tilmanocept was superior to vital blue dye in identifying disease-containing lymph nodes, and it had a significantly lower failed detection rate. The bottom line is that the data strongly support that this agent is efficacious for sentinel node biopsy for getting good pictures and identifying tumor-containing lymph nodes.”

He added, “By locating the lymph nodes prior to surgery, a small incision can be used to remove these nodes and a smaller overall surgical dissection can be used than with blue dye alone.”

MVA-5T4 Vaccine (TroVax) in Renal Cancer: Phase 3

  • Howard L. Kaufman, MD, Rush University Cancer Center, Chicago, Ill.

A biomarker predicted antibody response to a cancer vaccine (TroVax, MVA-5T4, Oxford BioMedica) and in turn predicted treatment benefit in renal cancer patients, according to an analysis of a phase 3 study.

“If this finding is validated,” said Dr. Kaufman in an interview, “we would have a way to take patients with almost any kind of cancer that expresses 5T4—and to determine the likelihood of their responding to the vaccine or the vaccine and IL-2.”

5T4, he said, is an antigen found in almost all adenocarcinomas; most colon, prostate, and breast cancers; and in nearly 100% of clear-cell and papillary renal tumors, as well as others.

TRIST (TroVax Renal Immunotherapy Survival Trial), a phase 3 study, enrolled 733 patients with advanced or metastatic renal cell carcinoma. Patients received MVA-5T4 or placebo in combination with local interferon (IFN-α), interleukin-2 (IL-2) or sunitinib (Sutent, Pfizer). Although the primary endpoint of overall survival was not achieved, a benefit was shown over placebo in subjects who had received IL-2 and MVA-5T4. After the fourth MVA-5T4 injection, antibody response was also correlated with patient survival (P < 0.01), and each doubling of antibody levels was associated with a 20% reduction in the hazard ratio (HR).

The investigators then quantified antigen responses after the third and fourth vaccinations to see whether they could uncover baseline factors predicting antibody response. Their analysis showed that 5T4 antibody responses were predicted by baseline hemoglobin, hematocrit, and 5T4 antibody levels, allowing construction of an immune response surrogate (IRS) consisting of these factors.

Looking at the prognostic effects of IRS on overall survival, the team then reported significantly reduced HRs for the MVA-5T4 group of patients, compared with the placebo group at 12 months (HR = 0.275; P = 0.0015), 18 months (HR = 0.375; P = 0.0048), and 24 months (HR = 0.357; P = 0.0017). Using this methodology to evaluate earlier phase 1 and 2 trials in colorectal, renal, and prostate cancer, the authors found the benefits to be similar (combined P < 0.0001).

Use of an IRS, Dr. Kaufman said, could allow patients who were likely to have a survival benefit to receive treatment early in their care and those who were less likely to benefit could avoid treatment. He commented further that recent positive data for BRAF inhibitors and for ipilimumab (Yervoy) show far lower complete response rates (less than 0.1% and 0.9%, respectively) than have been seen with IL-2 (7%–8%).

“I would go to IL-2 first because the statistics are better,” he said.

He further noted that accumulating data suggest that IL-2 contributes to the benefit of vaccines.


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