For this month and next month, Dr Christy Russell and I will be covering some of the data from this year’s Annual Oncology Meeting. In this edition, I will review for you a number of the presentations and posters concerning hematologic malignancies, gastrointestinal (GI) cancers, lung cancer and head & neck cancers. In August, Dr Russell will cover breast cancer, genitourinary (GU) cancers, and other areas.

Presentations from the Lymphoma and Myeloma Sessions at The Annual Oncology Meeting

There were 3 presentations in the lymphoma section that I believe are worth reviewing.

Abstract 8506: A phase III trial comparing R-CHOP-14 and R-CHOP-21 for treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin’s lymphoma by Dr David Cunningham, et al

Dr Cunningham reminded everyone that previous trials had demonstrated that R-CHOP was more effective than CHOP in diffuse large B-cell (DLBC) lymphoma and that, in older patients, CHOP-14 was more effective than CHOP-21. In the German RICOVER-60 trial, R-CHOP-14 for 6 cycles was as effective as and better tolerated than R-CHOP-14 for 8 cycles, and both were more effective than CHOP-14 without rituximab. So this trial with 1080 patients was initiated in early 2005 to compare R-CHOP-14 for 6 cycles followed by 2 cycles of rituximab alone to R-CHOP-21 for 8 cycles. Patients in the R-CHOP-14 arm all received granulocyte colony-stimulating factor (G-CSF). Patients in the R-CHOP-21 arm received G-CSF as needed. Patients with bulky stage IA to IV were eligible. There was no age limit. Overall survival (OS) was the primary endpoint with failure-free survival (FFS), response rate, and safety the secondary endpoints. The 2 arms were well balanced, and patients were stratified for age, international prognostic index (IPI) score, performance status, and stage. Grade 3-4 neutropenia and febrile neutropenia were somewhat more common in the R-CHOP-21 arm. Thrombocytopenia was slightly more common in the R-CHOP-14 arm. There were also slight increases in neurological and cardiac adverse events in the R-CHOP-14 arm. The complete response (CR)/unconfirmed complete response (Cru) rates for the 2 arms were nearly identical at approximately 60%. The overall response rates (CR/CRu/partial response [PR]) were approximately 90% in each arm. Two-year OS and FFS for the entire patient population were 81% and 74%, respectively, with no significant differences between treatment arms. There were differences in the treatment endpoints of OS and FFS between IPI scores, performance status, and stage. Overall survival and FFS were significantly worse for IPI 2-3 and 4-5 compared to 0-1. Patients with World Health Organization (WHO) performance scores of 2 also fared worse, as did those patients with stage III-IV disease compared to those patients with stage I-II DLBCL. Endpoint outcomes were of borderline significance for younger patients versus those older than 60 years.

Dr Cunningham concluded that R-CHOP-14 and R-CHOP-21 were equivalent in efficacy with no differences in any subgroups. Neutropenia and febrile neutropenia were more common with R-CHOP-21, and thrombocytopenia was more common with R-CHOP-14. Final analysis will be performed when 330 deaths have occurred among the trial participants. This is expected in approximately October 2010.

Abstract 8509: R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by autologous stem cell transplantation: CORAL study by Dr Christian Gisselbrecht, et al

The second lymphoma presentation of note was by Dr Christian Gisselbrecht representing the CORAL trial group. CORAL is the Collaborative trial in Relapsed Aggressive Lymphoma. The goal of this study was to compare 2 salvage induction regimens for relapsed DLBCL followed by autologous stem cell transplant (ASCT), and then randomize responders to observation or 1 year of maintenance rituximab. Approximately 400 patients were randomized. Eighty-three percent completed 3 cycles of induction therapy and approximately 51% to 55% underwent ASCT. Sixty-five percent of the randomized patients had achieved a CR with their first-line therapy, and 20% had achieved partial response (PR). Forty-four percent of the randomized patients had relapsed less than 12 months after their first-line therapy. The response rates to salvage induction therapy were approximately 63% in each treatment arm with 36% to 40% CR/CRu rates. Response rates were lower in those patients with higher IPI scores, those with prior rituximab exposure, and also in those patients with early relapse. However, the negative effect of prior rituximab exposure was only seen in those patients who relapsed less than 12 months following their first-line therapy. Renal toxicity was higher with rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP), and platelet transfusions were more frequent with R-DHAP. Infections were seen in about 23% of patients in each arm. There were no differences between the 2 treatment arms regarding progression-free survival (PFS) or OS. Once again, event-free survival (EFS) was worse in patients with prior rituximab exposure, but only if they relapsed less than 12 months after first-line treatment. In multivariate analysis, the factors that were significantly associated with worse outcome included IPI score >1, prior rituximab exposure and early relapse. Treatment arm did not affect outcome.

Abstract 2 in the Plenary Session: Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results by Dr Stephen Schuster, et al

Dr Stephen Schuster presented the results of BV-301, a prospective, randomized phase III trial of patient-specific autologous tumor-derived idiotype vaccine in advanced stage, previously untreated patients with follicular lymphoma (FL) achieving CR from front-line chemotherapy with 4 cycles of prednisone, doxorubicin, cyclophosphamide, and etoposide (PACE). The patient specific vaccine was developed using heterohybridoma technology. One hundred seventy-seven patients were randomized to vaccine versus placebo. However, 60 patients had progression of disease (PD) within 6 months after achieving CR, and therefore did not receive treatment. One hundred seventeen patients in CR for ≥6 months were randomized 2:1 to receive vaccine plus adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo. Seventy-six patients received the vaccine, and 41 received placebo. At the median follow-up of 56.6 months, median time to relapse for the vaccine arm was 44.2 months versus 30.6 months for the placebo arm. The hazard ratio (HR) for relapse was 0.62 with a P value of .047. Overall survival at 56.6 months was 95.4% for the vaccine group and 91.2% for the placebo group. Overall, the vaccine was well tolerated with no significant differences between the vaccine group and the placebo group.

There were 4 presentations in the myeloma section that I believe are worth reviewing.

Abstract 8515: A phase III study of VMPT versus VMP in newly diagnosed elderly myeloma patients by Dr Antonio Palumbo, et al

In older, transplant ineligible patients recent studies have documented that the melphalan, prednisone, and thalidomide (MPT) and bortezomib, melphalan, and prednisone (VMP) regimens are both more effective than MP alone. Dr Antonio Palumbo presented the results of this in abstract 8515. The GIMEMA group was asking the question as to whether the combination of MP and bortezomib plus an immunomodulatory agent would increase efficacy without adding toxicity in this older population. The VMP regimen included bortezomib 1.3 mg/m² days 1, 8, 15 and 22 plus standard doses of melphalan and prednisone. The bortezomib, melphalan, prednisone, and thalidomide (VMPT) regimen included the same agents and doses as in VMP plus thalidomide 50 mg/day days 1-35 of each 5 week cycle. The 2 treatment groups were well balanced in regards to age, β2M level, hemoglobin level, serum creatinine, and serum calcium. There were approximately 220 patients in each arm. The CR rate was higher for VMPT at 35% compared to 21% for VMP, but the ≥very good partial response (VGPR) rates were not statistically different at 51% for VMPT and 42% for VMP. The time to next treatment (TTNT) at 3 years was essentially the same for both arms. The 3-year projected PFS was 71% for VMPT and 56% for VMP, but this was not statistically significant. For the VMP arm, there was no difference in PFS between the patient group <75 years of age and those older. Whereas, in the VMPT arm those patients over 75 years of age had a significantly inferior PFS compared to the younger group. Progression-free survival did appear to be significantly better in those patients with better responses. Progression-free survival for those achieving CR was greater than for VGPR, which was greater than PR. Therefore, depth of response did appear to affect outcome in this study. Subgroup analysis was also performed examining the PFS results in those patients who were considered high-risk by fluorescence in situ hybridization (FISH) analysis of cytogenetics compared to standard-risk patients. Those patients who were positive for t(4;14), t(14;16) or deletion 17p had similar outcomes to the standard-risk group. However, when the poor prognostic features of high international staging system (ISS) stage, high β2M and high-risk cytogenetics are combined, a group with a statistically-borderline worse outcome can be identified. Hematologic adverse events were very similar between the 2 arms. There were, however, higher incidences of grade 3-4 non-hematologic events including infection, sensory neuropathy, fatigue, thrombotic events and cardiac events in the VMPT arm. It should be noted that initially bortezomib was given on a day 1, 4, 8, and 11 schedule to the first 135 patients; however, the schedule was then changed to a weekly schedule with a marked decrease in peripheral neuropathy. Complete response rate was also somewhat lower with the weekly dosing schedule, but not significantly.

The authors concluded that adding thalidomide to VMP increased the CR rate significantly. Progression-free survival at 3 years showed a non-significant increase with the addition of thalidomide, but OS survival rates at 3 years were identical. The addition of thalidomide did add significantly to the non-hematologic adverse event profile.

Abstract 8517: Lenalidomide, bortezomib, pegylated liposomal doxorubicin and dexamethasone in newly diagnosed multiple myeloma: Initial results of a phase I/II MMRC trial by Dr Andrzej Jakubowiak, et al

This phase II trial was another effort to expand an induction regimen to 4 active agents combining the agents of the bortezomib, lenalidomide, and dexamethasone (VRD) and bortezomib, pegylated liposomal doxorubicin, and dexamethasone (VDD) regimens for which there has been established efficacy in front-line therapy of myeloma. Patients with significant peripheral neuropathy or serum creatinine >2.5 were excluded. Bortezomib was given on a day 1, 4, 8 and 11 schedule. Lenalidomide was given daily for the first 14 days of the 21 day schedule. The phase II doses chosen were lenalidomide 25 mg/day 1-14, bortezomib 1.3 mg/m², pegylated liposomal doxorubicin (PLD) 30 mg/m² and dexamethasone 20 mg/day the day of and day after bortezomib. Adverse events were primarily grade 1-2 with 10% grade 3-4 neutropenia. Forty patients were treated in phase I. The ORR was 97%, VGPR rate was 62%, CR was achieved by 22%. Stem cell harvesting was successful in all patients attempted. The phase II portion of this study continues.

A third myeloma presentation examined a novel 3 drug regimen. Dr Robert Orlowski has led 2 trials in relapsed/refractory myeloma and in newly diagnosed myeloma using the combination of bortezomib, PLD and dexamethasone. In addition, the combination of low-dose dexamethasone plus lenalidomide has been shown to be an effective induction regimen in the Eastern Cooperative Oncology Group (ECOG) trial E4A03 with ORR of 71% and a ≥VGPR rate of 40% as best response.

Abstract 8518: Phase II study of pegylated liposomal doxorubicin (PDL), low-dose dexamethasone (DEX), and lenalidomide (LEN) in patients with newly diagnosed (ND) multiple myeloma (MM) by Dr Rachid Baz, et al

Dr Baz presented a previous phase I/II study in relapsed/refractory myeloma with this regimen that had demonstrated an ORR of 75% and a VGPR rate of 29%. Doses included PLD 40 mg/m², dexamethasone 40 mg days 1-4 and lenalidomide 25 mg/day days 1-21 every 28 days. Aspirin 81 mg or low molecular weight heparin (LMWH) plus fluoroquinolone and acyclovir prophylaxis were recommended. Twenty-nine patients were treated. Thirty-five percent had high-risk cytogenetics. Twenty-one percent had light chain myeloma. Fifty percent had ISS stage II-III. Grade 3-4 hematologic adverse events included neutropenia 62%, anemia 21%,and thrombocytopenia 13%. The febrile neutropenia rate was low at 7%. Thirty percent had grade 3-4 infections with neutropenia. Grade 3-4 DVT/PE was seen in 10% despite prophylaxis. Thirty-four percent of patients experience grade 3-4 fatigue. There were no toxic deaths. Responses among the 28 evaluable patients included ORR of 71% and ≥VGPR of 50%. Complete response rate was approximately 10%. Fourteen patients went on to ASCT. The authors recommend that the dose of PLD be reduced to 30 mg/m² in future trials. The authors concluded that this was an active regimen with an increase in the VGPR rate after 4 cycles compared to lenalidomide–low-dose dexamethasone, but that it is too early to draw conclusions regarding the role of anthracyclines in induction therapy in myeloma.

OncoFacts™ Editor:

James Epstein, MD

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