Novel Therapies: R2-GDP-GOTEL and Smart Start

Julio Chavez, MD, MS: R2-GDP-GOTEL is a phase 2 clinical trial that combined lenalidomide with a very well-known regimen for salvage chemotherapy, R-GDP, which consists of rituximab, cisplatin, dexamethasone, and gemcitabine. The patients were to receive lenalidomide from day 1 to day 14, in addition to the standard dose of R-GDP [rituximab, cisplatin, dexamethasone, and gemcitabine], up to 6 cycles. Patients who completed the regimen and had at least a PR [partial response] or complete remission [CR], they went on to receive lenalidomide as maintenance. They enrolled 79 patients, 78 patients were evaluated for efficacy and toxicity. The overall response rate was 59%, with a CR rate of 32%. The adverse events were mainly related to the chemotherapy, like thrombocytopenia and neutropenia, patients had rashes, also febrile neutropenia of course, reported in about 14% of patients. Further biomarker analysis showed that there was no difference in responses according to the cell of origin, and also the regimen was active in primary refractory lymphoma. Unfortunately, there were 4 toxic deaths in the study. That’s important to know when we add a new agent into our salvage regimen.

The conclusion is that this is an active regimen, it’s a phase 2. The question is whether this is better than the standard GDP [gemcitabine, dexamethasone, cisplatin]. The reported efficacy of gemcitabine, dexamethasone, cisplatin, the overall response rate is about 45%, with CR rates in the range of 13% to 15%. Keep in mind that the earlier studies didn’t include a PET [positron emission tomography] scan as mandatory to assess for CR rates, so we don’t really know the true CR rates in the earlier studies. That’s just to keep in consideration. Also, I would say that long-term follow-up is needed to see whether that matches the long-term efficacy of this regimen in these patients. Until we know whether we need to add lenalidomide to the gemcitabine, dexamethasone, cisplatin regimen in real life, I think it’s early to say. There were some toxicities and 4 deaths in a relatively small study. I think we should be careful. Whether we need to add it, I think the decision has to be made based on a larger study, or a phase 3 randomized study.

The Smart Start study is a single-center, phase 2 clinical trial that was presented by Jason Westin, MD, and colleagues from The University of Texas MD Anderson Cancer Center. It’s a trial that consisted of 2 phases. There was a lead-in phase of rituximab, lenalidomide, and ibrutinib for 2 cycles, followed by the combination plus chemotherapy. Whether it was R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] or EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, hydroxydaunorubicin], it was physician discretion to decide which regimen the patient would go on. The overall response rate was 86%, with a CR rate of 36%, which is expected for lenalidomide and ibrutinib. There is not a high CR rate. But once the patients completed the chemotherapy part, up to 6 cycles, the overall response rate was 100%, with a CR rate of 95%. The 1-year PFS [progression-free survival]—the study has a short follow-up—was 95%.

The adverse events were expected as related to the chemotherapy agents used. There were some toxicities that we typically don’t see in patients who receive chemotherapy, like Aspergillosis. There was a patient who had CNS [central nervous system] Aspergillosis, and 1 patient who died of Aspergillosis, probably systemic Aspergillosis. That underscores the fact that adding another agent into a chemotherapy regimen could be complicated. There are descriptions of fungal infections with ibrutinib, especially in combination with steroids and cytotoxic agents, so that’s something physicians have to keep in mind.

The other interesting thing about this study is the time to initial treatment, that was about 24 days. The reason I’m pointing this out is it’s a little unusual for patients to wait 3 weeks or almost 4 weeks to start therapy, especially with an aggressive lymphoma. That tells us about a possible selection bias. You’re probably selecting the best patients, the more stable patients to do these therapies, whereas the sickest patients, the patient who was in the hospital with aggressive disease, probably is not eligible for this trial.

Overall, I think the combination showed activity in DLBCL [diffuse large B-cell lymphoma], it’s promising activity. Whether that will implicate a change in the standard of care, I think it’s early. We need to sort out this question in a randomized clinical trial, phase 3. Finally, we have to consider the cost, because you’re adding lenalidomide and ibrutinib, and that can easily be a costly therapy over 6 months. I think it’s a study that showed very interesting activity. Tolerability was acceptable. Some of the infections that we typically don’t see with the standard chemotherapy, such as Aspergillosis or fungal infections, were shown in this study, so that’s something we have to keep in mind when we decide whether to do this treatment. I wonder whether patients need to complete 6 cycles of chemotherapy. That’s something that needs to be studied. Probably fewer cycles of chemotherapy would be more convenient and may not impact efficacy. I believe there will be a follow-up study with fewer cycles of therapy to see whether that will be feasible.

Transcript edited for clarity.