Multiple Myeloma has had significant new advances in the past year, with the U.S. Food and Drug Administration (FDA) approval of Kyprolis® (carfilzomib, Onyx/Amgen) and the U.S. and European approvals of Pomalyst® (Imnovid® in Europe, pomalidomide, Celgene), both in the relapsed/refractory setting. The relapsed/refractory setting is poised for further evolution with the recently announced success of the PANORAMA-2 Phase III trial of panobinostat (LBH589, Novartis)1 and ongoing Phase III trials with numerous other promising agents. Although these developments in the management of relapsed/refractory disease are significant, there is still a high unmet need to delay relapse among newly-diagnosed patients. In the first-line setting, several standard options exist, and choice of therapy varies by patient characteristics (most notably by their eligibility for stem cell transplantation) and by geography. In the United States, transplant eligible patients most commonly receive a triplet regimen, RVD [Revlimid® (lenalidomide, Celgene), Velcade® (bortezomib, Millennium/Janssen), dexamethasone] whereas in Europe the standard of care remains a Velcade-based doublet2. In transplant-ineligible patients, Velcade- or Revlimid-based regimens are both commonly used in the U.S., while in Europe Velcade again remains the predominant choice of therapy2. The reason for the discordance, in part lies with the data-and compendia-supported off-label use of Revlimid in newly-diagnosed patients in the U.S., while in Europe (where Velcade has a frontline label that Revlimid does not) off-label utilization is much less common.
To support regulatory approval of Revlimid for newly-diagnosed patients in both markets, Celgene and various cooperative groups have conducted multiple studies of Revlimid in newly-diagnosed patients. The MM-015 trial (NCT00405756) was reported at the American Society of Hematology (ASH) 2012 annual meeting (Abstract 944)3, and showed that a significant improvement in progression-free survival (PFS) was obtained in transplant-ineligible patients who received the MPR-R regimen (melphalan, prednisone, Revlimid induction followed by Revlimid maintenance) compared to patients who received MP alone or MPR induction only (PFS: 31 months vs. 13 months vs. 14 months; HR 0.40, p<0.001); there was, however, no improvement in overall survival at the interim analysis. A companion study, FIRST (MM-020, NCT00689936), also evaluated the efficacy of Revlimid in newly-diagnosed transplant-ineligible patients, but with a different regimen and comparator: FIRST randomized patients to continuous RevDex until progression versus RevDex for a fixed 18 cycles (72 weeks) vs. MPT (melphalan, prednisone, thalidomide) for a fixed 12 cycles (72 weeks). A first look at the FIRST data came in the plenary session on December 8 at the 2013 ASH conference4. There was a significant improvement in PFS for patients treated with continuous RevDex compared to MPT and compared to RevDex18 (see Table 1). The Kaplan-Meyer curves for all three arms overlapped for the first 18 months of treatment, after which the continuous RevDex curve quickly separated from the curves of the other two arms. Other secondary endpoints significantly favored the continuous RevDex arm as well, most importantly that of overall survival: there was a 22% reduction in the risk of death in the continuous RevDex arm compared to the MPT arm at this interim analysis (35% of ITT events).
Treatment with RevDex was associated with some increases in adverse events (higher rates of infection, deep vein thrombosis and/or pulmonary embolism, and cataracts); the RevDex arms had markedly lower rates of neutropenia and peripheral sensory neuropathy compared to MPT. Perhaps even more important was the analysis of secondary primary malignancies (SPM). At this latest follow-up, there is no significant difference in the SPM rate among the three arms; in fact, there was a slightly lower rate of hematologic SPM in the continuous RevDex arm compared with the MPT arm. The lack of increased SPM in the RevDex arms may support the hypothesis that the worrisome SPM observed in the MM-015 trial was due to the melphalan used in that regimen rather than attributable to Revlimid.
With a significant PFS and OS benefit favoring continuous RevDex along with a safety profile that may alleviate some prior concerns regarding SPM, the FIRST trial is certainly a positive study that will have significant market impact. But just what will that market impact be? This study establishes RevDex as superior to MPT in newly-diagnosed transplant-ineligible patients. The most significant impact will be that the results are likely to support regulatory approval of Revlimid in the first-line setting in both the U.S. and Europe. As noted earlier, the lack of European approval in first-line has limited Revlimid’s utilization in this setting in Europe, so gaining this label expansion will be critical for its further success. But how will treatment patterns change? Although MP-based regimens have long been considered the standard of care for transplant-ineligible patients, in reality they have very little use in the modern day: in 14% of U.S. patients and 21% of Western Europe patients2; dexamethasone-based doublets or triplets have evolved to become the preferred regimen in both transplant-eligible and -ineligible patients in recent years. So while a change in practice from MPT to RevDex is unlikely to emerge from this study and its approval, a more likely outcome is a shift in the balance between use of Velcade-based regimens and Revlimid-based regimens in newly-diagnosed patients. As mentioned above, Velcade-based regimens are heavily utilized in Europe, due to the OS benefit as demonstrated in multiple Phase III trials5,6. With Revlimid now able to claim an OS benefit in frontline, a shift in treatment patterns may emerge, with RevDex posing a new competitive threat to VelDex in Europe and posing a renewed competitive threat to VelDex in the U.S. How do the two regimens compare? VelDex has not been extensively studied in transplant-ineligible patients, so a comparison of efficacy and safety outcomes between these two regimens is not possible. In the Phase III VISTA trial in newly-diagnosed transplant- ineligible patients, Velcade + MP (VMP) resulted in a 24 month median time to progression (TTP) and 69% 3-year OS5. The 32.5 month median TTP of RevDex in the FIRST trial4 and the 31 month PFS of MPR-R in the MM-015 trial3 (TTP was not reported) compare favorably with the 24 months reported for VMP; OS may be comparable or slightly favoring RevDex (~75% if we extrapolate 3-year OS from the Kaplan-Meyer curve presented by Dr. Facon4) and is comparable for MPR-R (70%)3. Acknowledging the weaknesses in these cross-trial comparisons, they do at least suggest the possibility for RevDex to become adopted as a new standard of care in newly-diagnosed transplant-ineligible myeloma, and most certainly will support regulatory approval by the European Medicines Agency and the FDA. Regulatory approval for Revlimid in the first-line setting will not only impact its utilization, but also that of several agents and new regimens in development that build off of a Revlimid-based backbone in first-line. Advancements may be making greater leaps and bounds in the relapsed/refractory setting, but first-line treatments continue to progress at a slow and steady pace, and in the end, it’s the patients who reap the rewards.
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age of diagnosis at 71 in the U.S. and nearly 40% of patients older than 75 at the time of diagnosis.1 Standard treatment for “fit” patients is aggressive chemotherapy, but existing comorbidities in elderly patients frequently preclude use of these highly toxic regimens. Limited treatment options exist for “unfit” 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 the combination is not approved for this setting. To fill the unmet need for treatment options, a number of novel agents have recently entered clinical development for CLL in elderly, newly diagnosed patients. Phase III trials are ongoing or recently completed for Arzerra® (ofatumumab, GlaxoSmithKline), ibrutinib (BTK inhibitor, Pharmacyclics/Johnson & Johnson), and Gazyva® (obinutuzumab, Genentech/Roche). Results from Stage I of the Phase III trial of Gazyva were presented at the ASCO 2013 in June2, and on December 8 during the plenary session final results from Stage II of this pivotal trial were reported at the American Society of Hematology (ASH).3
The Phase III CLL11 trial (NCT01010061) was a three-arm study that randomized 781 newly diagnosed “unfit” patients to treatment with chlorambucil alone, chlorambucil plus Gazyva, or chlorambucil plus Rituxan. The definition of “unfit” in this trial wasn’t based on patient age but was defined by the level of comorbidities; patients were included if their total Cumulative Illness Rating Scale (CIRS) score was above 6 and/or creatinine clearance was less than 70 ml/min. The first stage of this trial compared the efficacies of each combination arm with the chlorambucil monotherapy arm; the second stage compared the efficacies of the two combination arms and was designed to show superiority of Gazyva versus Rituxan. Results for Stage I were updated and final results of Stage II were presented for the first time.
Updated Stage I results continued to showed clear and robust activity for Gazyva in combination with chlorambucil compared with chlorambucil alone. PFS (the primary endpoint) was significantly improved, with an 82% reduction in risk of progression or death and a 26.7-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 with chlorambucil alone, with a 66% reduction in risk of progression or death and a 16.3-month median PFS. Results of Stage II, which compared efficacy and safety of the combination arms, showed that Gazyva plus chlorambucil is significantly superior to Rituxan plus chlorambucil with regard to the primary endpoint of PFS (26.7 versus 15.2 months), with a 61% reduction in the risk of progression or death. The overall response rate (ORR), complete response (CR), and high rate of minimal residual disease (MRD) negativity (see Table 1) also all favored the Gazyva arm. Overall survival favored the Gazyva arm as well, although this interim analysis is very premature (<15% of events) and the difference did not reach statistical significance when comparing Gazyva-chlorambucil versus Rituxan-chlorambucil (HR 0.66, p=0.0849). Notably, however, the OS benefit was significant when comparing Gazyva-chlorambucil versus chlorambucil (HR 0.41, p=0.0022). A greater incidence of Grade 3/4 adverse events (AEs) was reported in the Gazyva-chlorambucil arm (70% of patients) versus the Rituxan-chlorambucil arm (55%). Infusion-related reactions (20% versus 4%, respectively), neutropenia (33% versus 28%) and thrombocytopenia (10% versus 3%) represented the major differences in Grade 3/4 AEs. While these AEs 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.
Results from Stage I of the trial served as the basis for regulatory filings for Gazyva in newly diagnosed CLL patients with comorbidities that make them unfit for standard chemotherapy and on November 1, 2013, the FDA approved Gazyva for use in combination with chlorambucil for the treatment of patients with previously untreated CLL. Now with the Stage II results in hand, the measures that clearly 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 strongly favor Gazyva. CR and MRD-negativity speak to the depth of response that is achieved. Results of the CLL11 trial and the approval of Gazyla represent an improvement upon the efficacy of Rituxan and the first step toward the eventual displacement of Rituxan as a standard of care in B-cell malignancies (conveniently coinciding with rituximab patent expiration).
Within chemo-ineligible/“unfit” newly diagnosed CLL, where will Gazyva fit? As mentioned, development in this indication is crowded with promising new agents seeking to transform the treatment paradigm. Results from the COMPLEMENT-1 trial of Arzerra plus chlorambucil versus chlorambucil monotherapy in previously untreated chemo-ineligible CLL patients will be presented at ASH on Monday December 9, 20134, although it was previously announced via press release to have met its primary endpoint by extending PFS from 13.1 months to 22.4 months (HR 0.57). With this data, CLL will soon have three anti-CD20 antibodies to choose from. In addition, Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) is also seeking approval in this same patient population, and the relapsed/refractory CLL setting is rife with development by Imbruvica, idelalisib (Gilead), and ABT-199 (GDC-199, Abbvie/Genentech/Roche), all of which are presenting very promising data at ASH 2013. 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 and/or upfront 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.
1. Kantar Health, CancerMPact® Patient Metrics United States, accessed June 4, 2013.
2. Goede et al., Abstract 7004, ASCO 2013.
3. Goede et al., Abstract 6, ASH 2013
4. Hillmen et al., Abstract 528, ASH 2013
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Greg Wolfe, PhD, Senior Consultant, Clinical and Scientific Assessment, Kantar Health