Compelling Data for Tomorrow: Dr. Rosen’s Perspective
Dr. Steven T. Rosen
Studies presented at this year’s ASCO annual meeting gave us a glimpse of the future, which looks promising with regard to improved treatments for the major hematologic malignancies. Several new compounds are in preliminary trials and others are on the fast track to approval, offering some very new options for attacking a variety of these cancers.
For Hodgkin’s lymphoma, results look encouraging for the new antibody-drug conjugate SGN-25, which targets CD30. For chronic lymphocytic leukemia (CLL), the anti-CD20 monoclonal antibody ofatumumab appears effective in patients who have progressed on rituximab (Rituxan), and if results continue to be positive it could become an alternative to this now-standard agent in this and possibly other hematologic cancers. For multiple myeloma, the novel proteasome inhibitor carfilzomib has shown benefit in heavily pretreated patients.
For follicular lymphoma (FL), the National Comprehensive Cancer Network guidelines were updated this year to include the novel alkylating agent bendamustine (Treanda), with or without rituximab. Bendamustine was also recently approved for indolent non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of rituximab treatment, based on studies showing response rates up to 77% and long response durations (Friedberg J et al: J Clin Oncol 26:204-210, 2008). Recent data suggest bendamustine produces extremely high response rates as up-front therapy in indolent NHL. At ASCO 2009, a dose-finding study (abstract 8550) combining bendamustine with bortezomib (Velcade) and rituximab showed activity and tolerability, and a phase II trial will now move forward. Clearly, we will be following this agent with interest.
In cutaneous T-cell lymphoma (CTCL), the oral histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) is approved, which yields responses in 30% of advanced patients. Expanded use of vorinostat appears likely based on an oral presentation by Jabbour et al (abstract 7004). In the phase II study of 35 untreated patients with high-risk myelodysplastic syndrome or acute myeloid leukemia, vorinostat was used for induction, followed by idarubicin plus high-dose cytarabine, then vorinostat as maintenance therapy. The complete response rate was 82%, and all FLT3-positive patients achieved a complete response.
Further capitalizing on this pathway, the novel pan-HDAC inhibitor romidepsin looks promising for CTCL, based on early reports at this meeting. Yet another exciting agent for both CTCL and peripheral T-cell lymphoma is the novel oral antifolate pralatrexate, which exhibited substantial activity in the phase II PROPEL study of relapsed and refractory patients. In this heavily pretreated group, the overall response rate (ORR) was 27% and some patients maintained benefit for over 1 year.
We also anticipate seeing lenalidomide (Revlimid) expanded into additional settings. At ASCO, several studies showed benefit for this agent in indolent NHL. An international team reported (abstract 8560) durable responses and manageable side effects with oral lenolidomide as a single agent in relapsed or refractory disease. Researchers from MD Anderson Cancer Center reported (abstract 8548) activity and minimal toxicity for a combined regimen of oral daily lenalidomide plus rituximab monthly in previously untreated patients. For MM, another study (abstract 8586) combined lenalidomide with vorinostat and dexamethasone for the treatment of refractory or relapsed patients, showing activity and tolerability. These were preliminary studies, but there was a uniform message of activity that predicts for a broader role for lenalidomide.
Finally, the novel organic arsenic molecule darinaparsin showed activity in 28 advanced lymphoma patients, and was well tolerated in an ASCO study (abstract 8501). Darinaparsin is also being studied in solid tumors, and is being developed in both oral and intravenous forms.
The unmet therapeutic needs are abundant in hematology, but these and other emerging agents hold the promise of improved efficacy and tolerability. If the studies reported at ASCO can be validated in larger trials, we can look forward to having a number of new treatment options in our arsenal. The horizon is exciting.
Therapeutic Vaccine Prolongs DFS in FL
The idiotype vaccine BiovaxID is a novel therapeutic vaccine constructed with tumor-specific purified idiotype (Id) protein conjugated to keyhole limpet hemocyanin (KLH), with GM-CSF as the adjuvant. The Id-KLH vaccine, which is individually manufactured from tissue obtained from the patient’s own tumor, produces a highly specific immune response against tumor cells. An earlier National Cancer Institute (NCI)-sponsored phase II study of 20 patients with FL found that 45% of patients still had complete responses at a median follow-up of 9 years, and the majority of patients had anti-Id antibody responses and tumor-specific CD4+ and CD8+ T-cell responses.
At the ASCO Plenary Session, Schuster et al (abstract 2) reported the results of an 8-year randomized phase III trial that compared Id-KLH with the control KLH vaccine in 177 patients who had achieved a complete response to PACE (prednisone, doxorubicin [Adriamycin], cyclophosphamide, etoposide). In the intent-to-treat (ITT) analysis of all randomized patients, no statistically significant difference in disease-free survival was observed between the arms, but this included patients who never received the vaccine. In the cohort of patients who maintained a complete response to chemotherapy for ≥ 6 months and received active vaccine (n = 76) or control vaccine (n = 41), after a median follow-up of 4.7 years the median DFS in the Id-KLH arm was 44.2 months, vs 30.6 months with the control vaccine. The hazard ratio for events was 0.62 (P = .047). The vaccine appeared to be well tolerated.
This study is more complicated than it appears. Are the results really positive, and why do they differ from those of other Id vaccine trials? In the ITT analysis, the results were negative. While they were positive for the comparison of patients actually treated, this amounts to just 50% of the cohort—those who made it to randomization. We have to ask whether the arms were balanced for those patients never treated. Also, we have to be concerned about the waiting time between eligibility for the vaccine and actual treatment. Is this delay due to difficulties manufacturing the product? Does this introduce bias? The patients in the treated population may represent “the best of the best,” ie, those with complete responses to chemotherapy for up to 1 year. Other trials have been negative, showing less durable responses. The patient inclusion criteria were different, the chemotherapy regimen was unorthodox, and the vaccine products may have been inferior. We don’t know. Finally, the study was conducted before the use of rituximab in this population. We need to determine if the Id-KHL vaccine works as well in conjunction with modern regimens. Could there be a role for active vaccination in the management of FL? It’s possible, but additional evidence is needed.
Novel Antibody Conjugate Produces 48% Response Rate in Refractory HL
A defining feature of Hodgkin’s lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) is CD30 expression on malignant cells. A novel antibody-drug conjugate targeting CD30 showed promise in a multicenter phase I study reported by Barlett et al (abstract 8500). The antibody-drug conjugate SGN-35 construct comprises an anti-CD30 antibody conjugated to the antitubulin agent monomethyl auristatin E (MMAE). The compound SGN-35 causes cell cycle arrest and apoptosis by binding to CD30 on the tumor cell surface, internalizing and releasing MMAE into the cell.
At ASH 2008, these investigators reported response rate of 54% in a phase I study with every-3-week dosing. To determine if more frequent dosing might maximize the antitumor activity without increasing toxicity, they conducted this phase I dose-escalation trial in which 34 patients with refractory or recurrent HL or sALCL were given the agent weekly at doses of 0.4–1.0 mg/kg. SGN-35 appeared to have significant activity, producing complete responses in 10 patients, partial responses in 3, and stable disease in 11. Only 3 patients progressed on treatment, and 81% of patients had a reduction in tumor volume. These are encouraging findings for this novel compound, which might be useful when transplant is not an option and after relapse occurs following high-dose chemotherapy. I believe this compound has an excellent chance of becoming a new treatment option in this malignancy.