Significant Improvement in Outcomes for Chronic Lymphocytic Leukemia: The First of Many?
| Jun 4, 2013
Co-authored by Stephanie Hawthorne, PhD, Director
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age of diagnosis at 71 in the United States and nearly 40% of patients are older than 75 at the time of diagnosis1. Standard treatment for “fit” patients is aggressive chemotherapy, but existing co-morbidities in elderly patients often precludes the use of these highly toxic regimens. Limited treatment options exist for these patients and the most common choices include chlorambucil and Rituxan® (rituximab, Genentech/Roche) – alone or in combination. More recently the combination of Rituxan with Treanda® (bendamustine, Teva) has emerged as a common option in the U.S., although it is not approved for this setting. With few treatment options, there has been a rapid increase in the number of novel agents entering development for CLL in elderly newly-diagnosed patients as a niche target population. Phase III trials are ongoing for Arzerra® (ofatumumab, GlaxoSmithKline), ibrutinib (BTK inhibitor, Pharmacyclics/Johnson & Johnson), obinutuzumab (anti-CD20 monoclonal antibody, Genentech/Roche) and Revlimid® (lenalidomide, Celgene). The first of these agents to report pivotal results is obinutuzumab, which were presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting in an oral session on June 42.
The Phase III CLL11 trial (NCT01010061) was a three-arm study that randomized 589 newly-diagnosed “unfit” patients to treatment with chlorambucil alone, chlorambucil plus obinutuzumab, or chlorambucil plus Rituxan. The definition of “unfit” in this trial wasn’t based on patient age, but was defined by the level of co-morbidities; patients were included if their total Cumulative Illness Rating Scale (CIRS) score was >6 and/or creatinine clearance <70 ml/min. The first stage of this trial is meant to compare the efficacies of each combination arm with the chlorambucil monotherapy arm; the second-stage (for which an additional 190 patients were enrolled) is meant to compare the efficacies of the two combination arms, and was designed to show superiority of obinutuzumab over Rituxan. The results presented at ASCO 2013 were for Stage I, and we will have to wait until later this year for the results of Stage II.
The results presented today showed clear and robust activity for obinutuzumab in combination with chlorambucil compared to chlorambucil alone, with improvements in complete response (CR) rate, overall response rate (ORR), and a high rate of minimal residual disease (MRD)-negativity (see Table 1). Progression-free survival (PFS; the primary endpoint) was significantly improved, with an 86% reduction in the risk of progression or death and a 23 month median PFS. The level of benefit was very impressive, although perhaps not surprising since chlorambucil is not a very active agent. Rituxan plus chlorambucil also showed a strong level of benefit compared to chlorambucil alone, with improvements in ORR and a 68% reduction in the risk of progression or death and a 16.7 month median PFS. Rituxan plus chlorambucil produced a modest CR rate and few patients were MRD-negative. In both combination arms, there was an increase in grade 3/4 neutropenia and infusion-related reactions, with rates appearing to be higher in the obinutuzumab arm; thrombocytopenia was also increased only in the obinutuzumab arm, and slightly more patients in this arm withdrew from the study due to adverse events. While these adverse events are of course concerning, the large magnitude of efficacy benefit means that these toxicities are unlikely to sway physicians away from use of the drug, especially since they are easily monitored and resolvable.
The results from this Stage I of the trial will initiate regulatory filings for obinutuzumab in newly-diagnosed CLL patients with comorbidities that make them unfit for standard chemotherapy. These Stage I results were extremely positive and certainly support approval, but the real story (and the one everyone is waiting for) is the result of Stage II – how does obinutuzumab compare statistically to Rituxan? We have to wait a while longer for those official results, but it is certainly tempting to compare by eye the results for both arms in Stage I. The three biggest measures that stand out are the CR rate, the number of patients who achieve negative MRD (in both the peripheral blood and the marrow), and PFS. All of these measures appear to strongly favor obinutuzumab. CR and MRD-negativity speak to the depth of response that is achieved, and previous data has established that MRD can independently predict for PFS and OS in CLL3. When we look at the PFS results as presented (which were based on investigator assessment), there is a 7.3 month difference at the median and a 21% difference in one-year PFS in favor of the obinutuzumab arm, although the Hazard Ratios suggest a slightly more moderate level of benefit (again, we have to stress that this type of comparison bears no statistical meaning). Somewhat concerning is the high number of censored patients “above the median” when we view the Kaplan-Meier curve for obinutuzumab; this leaves potential for the curve to change dramatically with further follow-up. Assessment of PFS by independent review was not presented, but noted to be “consistent” with the investigator assessment, although it would have been nice to see those curves and judge for ourselves. Nevertheless, the data certainly suggests that the results of Stage II have a good chance of proving obinutuzumab to be superior to Rituxan. This would be the first step of many to improve upon the efficacy of Rituxan and ultimately displace it as the standard of care in B-cell malignancies (conveniently coinciding with rituximab patent expiration).
Within chemo-ineligible/“unfit” newly-diagnosed CLL, where will obinutuzumab fit? As mentioned, development in this indication is crowded with promising new agents all seeking to transform the treatment paradigm. GlaxoSmithKline recently announced that the COMPLEMENT-1 trial of Arzerra plus chlorambucil versus chlorambucil monotherapy in previously untreated chemo-ineligible CLL patients met its primary endpoint by extending PFS from 13.1 months to 22.4 months (HR 0.57), which looks similar to the obinutuzumab results at the median, although the Hazard Ratios favor obinutuzumab (cross-trial comparisons with caveats). With this data, CLL will soon have three anti-CD20 antibodies to choose from. In addition, dinaciclib, ibrutinib and Revlimid are all seeking approval in this same patient population, and based on early trial results all have a good chance at being successful. A natural inclination would be to combine these agents with an anti-CD20 antibody, or potentially with each other, as well as bring these agents into the broader CLL population. CLL is very likely to be transformed in the next few years, with potentially more options than physicians know what to do with. We’ve encountered this problem before (renal cell carcinoma (RCC) comes to mind), but unlike RCC the influx of new agents in CLL have a large variety of mechanisms of action – an exciting turn of events!
- Kantar Health, CancerMPact® Patient Metrics United States, accessed June 4, 2013.
- Goede et al., Abstract 7004, ASCO 2013.
Böttcher et al., J Clin Oncol, 30(9):980-8, 2012.