The OBR Blog

December 14, 2015 - 09:12 am Posted in Featured comments0 Comments

by Arnold DuBell; co-authored by Stephanie Hawthorne

In the past, patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer were treated with single-agent hormonal agents – either tamoxifen if the patient is premenopausal or an aromatase inhibitor (AI) if she is postmenopausal. This old paradigm was shattered in 2012 with the publication of the Phase III BOLERO-2 results, which showed the benefit of adding the mTOR inhibitor Afinitor® (everolimus, Novartis) to exemestane in patients whose disease was refractory to either letrozole or anastrozole.1 This result was followed in 2014 with the presentation of final analysis of the Phase II PALOMA-1/TRIO-18 data, which showed a strong progression-free survival (PFS) benefit of adding the CDK4/6 inhibitor Ibrance® (palbociclib, Pfizer) to letrozole as a first-line treatment option.2 Based on these data, Afinitor was approved by the U.S. Food and Drug Administration (FDA) in 2012, and Ibrance was granted accelerated approval in 2015.

Other agents are in development in this treatment setting, making the HR+ metastatic breast cancer clinical space very competitive: other CDK4/6 inhibitors in late-stage development include ribociclib (Novartis) and abemaciclib (Eli Lilly); Syndax is currently running a trial for the HDAC inhibitor entinostat; and Roche and Novartis are developing their PI3K inhibitors (Roche’s taselisib and Novartis’s alpelisib and buparlisib) in this space as well.  This last agent was the subject of a presentation at the last oral general session at the 2015 San Antonio Breast Cancer Symposium, as Dr. Jose Baselga from Memorial Sloan Kettering presented the results of the BELLE-2 trial.3

BELLE-2 randomized 1,147 postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer who progressed on or after aromatase inhibitor therapy to 500 mg/day Faslodex®(fulvestrant, AstraZeneca) plus placebo or buparlisib 100 mg/day. Dr. Baselga noted that the treatment arms were not completely balanced, as the placebo arm included slightly more chemotherapy-pretreated patients (24.5% versus 31.0%). This trial had three primary endpoints: PFS in the full patient population, PFS in the main population (which excluded patients with unknown PI3K activation status) and PFS in patients whose tumors had “activated” PI3K. This last group included only those patients with PIK3CAmutations and/or PTEN loss. This screening was based on archival tumor tissues. Additionally, a prospective yet exploratory endpoint was PFS in those patients who had PIK3CA mutations from blood circulating tumor cell DNA (ctDNA) as assessed by BEAMing technology.4

BELLE-2 met some but not all its co-primary endpoints. In the full patient population, buparlisib modestly but significantly improved median PFS by 1.9 months (6.9 months versus 5.0 months, HR 0.78, one-sided p<0.001). A similar benefit for buparlisib was seen in the “main” population (HR 0.80, one-sided p=0.003; median values not provided). However, in the PI3K-activated group of patients, buparlisib only showed a trend of a PFS benefit (6.8 months versus 4.0 months, HR 0.76, one-sided p=0.014).* Buparlisib non-significantly improved response rates in both the full population (11.8% versus 7.7%) as well as in patients with PI3K-activated tumors (10.6% versus 8.2%). Overall survival (OS) data were not presented.

The exploratory endpoint analysis was the most interesting. In the 200 patients with ctDNA PIK3CAmutations, the addition of buparlisib significantly improved PFS by 3.8 months (7.0 months versus 3.2 months, HR 0.56, one sided p<0.001). The presence of these mutations appeared to be predictive for benefit, as there was no added benefit of buparlisib in the 387 patients with PIK3CA WT ctDNA (6.8 months versus 6.8 months, HR 1.05, one-sided p=0.642). This predictive nature for ctDNA PIK3CAmutations was extended to response rate as well (Mutant: 18.4% versus 3.5%; WT: 11.6% versus 10.6%).

One of the possible explanations for buparlisib’s modest benefit in the full population was an increased treatment discontinuation rate due to adverse events (13.2% versus 1.8%), resulting in a reduction in the median duration of treatment (4.2 months versus 5.0 months). Grade 3-4 adverse events of note increased in the buparlisib arm included elevated ALT (25.5% versus 1.1%), elevated AST (18.0% versus 2.8%), hyperglycemia (15.4% versus 0.2%), rash (7.9% versus 0%) and depression (4.4% versus 0.4%).

Although the trial did achieve some of its primary endpoints, the modest nature of the improvements in two of these endpoints as well as inability to meet a third co-primary endpoint throws some doubt into the future prospects for buparlisib. This is in light of the strong benefit seen with Ibrance. Both the Phase II first-line PALOMA-1 trial (HR 0.488)2 and the Phase III 2L+ PALOMA-3 trial (HR 0.422)5 may have set a high bar for expectations regarding the degree of benefit required for novel targeted therapeutics in combination with hormone therapy in this setting. Moreover – and as noted above – there is such a large competitive set of agents for this setting that further leads one to question what will happen next for buparlisib. Also, Novartis has another ongoing late-stage trial for buparlisib: the BELLE-3 trial (NCT01633060) is randomizing patients to Faslodex with or without buparlisib. BELLE-3 differs in that enrolled patients will have had to have progressed on an mTOR inhibitor (likely Afinitor) in addition to a prior aromatase inhibitor. These data are expected next year.

Although exciting, the exploratory data based on PIK3CA mutations in ctDNA need to be confirmed in further prospective studies. One notable question that needs to be addressed in future studies is why the cohort of patients with PI3K-activated tumors as assessed through archived tissue samples failed to meet its endpoint. During the question period following the presentation, Dr. Baselga suggested that this result was not simply due to the presence of patients with PTEN loss in the PI3K-activated tumor group; he seemed to believe the use of BEAMing technology on the ctDNA samples was a more sensitive measure for the presence of a predictive biomarker. If Novartis chooses to pursue this approach, it will be moving to reinforce an idea heard repeatedly at this year’s conference. The individualized nature for breast cancer is more than just the three different groupings currently used to decide treatment approach (HR+, HER2+, triple-negative) but will be further segmented so that individual patients will receive the best treatment.

* It should be noted that due to the use of three co-primary endpoints, the one-sided α was split using a gate-keeping approach to keep the overall type-1 error at α=0.025.  Therefore, the p-value required for meeting the endpoint in the PI3K activated group was 0.01.


  1. Baselga J, NEJM, 366: 520, 2012
  2. Finn RS, Lancet Oncology, 16:25, 2014
  3. Baselga, Proc of the San Antonio Breast Cancer Symposium, Abstract S6-01, 2015
  4. Higgins M, Clin Cancer Res, 18:3462, 2012.
  5. Turner, NEJM, 373: 209, 2015.

December 08, 2015 - 01:12 pm Posted in Featured comments0 Comments

by Stephanie Hawthorne; co-authored by Len Kusdra

Treatment of chronic lymphocytic leukemia (CLL) has enjoyed somewhat of a renaissance in the past couple of years. Until recently, therapy for both front-line and relapsed disease usually consisted of a Rituxan® (rituximab, Genentech)-based regimen often in combination with chemotherapy agents such as fludarabine or Treanda® (bendamustine, Teva). While CLL is a rather indolent disease and is usually sensitive to chemotherapy, curative outcomes are rare and the disease is associated with multiple relapses and multiple lines of treatment; about 70% of patients will go on to receive second-line therapy, and about 50% will receive third-line therapy.1 The lack of clinical development of more effective agents that can induce a more durable response has remained a high unmet need. This has changed recently with the approvals of novel agents such as Gazyva® (obinutuzumab, Roche/Genentech), Imbruvica®(ibrutinib, Pharmacyclics/Janssen) and Zydelig® (idelalisib, Gilead), which have begun to shift the landscape of front-line and relapsed disease, offering physicians more options to treat CLL. The various cytogenetic subpopulations exhibit differing responses for therapy and present a challenge on how to best treat them. One such population in CLL has been those patients carrying a del17p mutation, which has been shown to be associated with poor response to chemotherapy.

Venetoclax (ABT-199/GDC-0199, AbbVie, in collaboration with Genentech) is a small molecule inhibitor of Bcl-2, a protein that promotes cell survival; its overexpression is characteristic of CLL, thus representing a tantalizing target. Venetoclax monotherapy showed impressive activity in its dose-finding Phase I trial, demonstrating objective response rates (ORR) in over 70% of patients with CLL.2 This encouraged AbbVie to push venetoclax into late-stage clinical development with the initiation of two pivotal trials: a Phase II trial (NCTO1889186) evaluating venetoclax monotherapy in relapsed patients with del17p mutation and the Phase III MURANO trial (NCT02005471) evaluating venetoclax plus Rituxan versus Rituxan plus Treanda in a broader relapsed patient population.

Results from the Phase II trial were presented at a plenary session on Monday at the 57th American Society of Hematology (ASH) Annual Meeting, and the data continue to support the robust activity of venetoclax.3 Patients (n=107) were initially treated with venetoclax on a weekly dose ramp-up schedule (20, 50, 100, 200 and 400 mg) followed by a continual dose of 400 mg until disease progression or discontinuation for other reasons; this ramp-up dosing schedule along with risk-based prophylaxis was implemented to reduce the incidence of tumor lysis syndrome (TLS), a serious adverse event that was observed in early trials with venetoclax. The primary endpoint was ORR as determined by an independent review committee (IRC) as well as by investigator review. Secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. As determined by IRC, the ORR was 79.4% (95% CI: 70.5%–86.6%), the complete remission with incomplete marrow recovery (CR/CRi) rate was 7.5%, and the nodular partial remission (nPR) rate was 2.8%. Of note, 52% of patients had no CLL in the bone marrow and 40% were minimal-residual disease (MRD)-negative in the peripheral blood, suggesting deep responses with venetoclax treatment. Median time to normalization of absolute lymphocyte count was 22 days, and only four out of 87 patients evaluated did not have normalization of absolute lymphocyte counts. In measuring tumor lesion diameter, 92% of patients (89/96) had a 50% of greater reduction in their largest nodal lesion diameter from baseline measurements. There were also very encouraging signals in durability of response. Estimates showed that responses continued at one year in 84.7% of patients who exhibited any kind of response, in 100% of patients exhibiting a CRi/nPR, and in 94.4% of patients who achieved MRD-negativity. The 12-month estimate of PFS was 72.0% (95% CI: 61.8-79.8) and 12-month estimated OS was 86.7% (95% CI: 78.6-91.9). The most common Grade 3-4 adverse events were neutropenia (17% Grade 3, 23% Grade 4), anemia (18%), thrombocytopenia (15%) and infection (20%, most common being upper respiratory tract). Laboratory signs for TLS occurred during the ramp-up period in five patients with no clinical consequence and were managed through dose interruption and electrolyte management.

Based on these promising data in relapsed/refractory del17p CLL, AbbVie has submitted an application for regulatory approval with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).4 Given the efficacy results and coupled with the breakthrough status awarded to venetoclax in May 2015 for this same treatment setting, approval of venetoclax seems likely to occur in the near future. In this context, the MURANO trial will serve as the confirmatory study, as well as expanding utilization options for venetoclax to include combination regimens. Excitement for this agent will be high, particularly in light of its strong efficacy in a patient population that is particularly difficult to treat (second-line, del17p). The remission rate is impressive on its own, but more important is the durability of the responses, since del17p patients have historically lost their responses to chemotherapy quickly.  The PFS rate observed in this study with venetoclax (in patients treated with a median of two prior lines of therapy) appears superior to the PFS historically reported for del17p CLL patients in the first-line setting.

Venetoclax will have to compete with both Zydelig and Imbruvica. Imbruvica is approved for relapsed/refractory CLL (and has U.S. approval specifically in del17p patients without a line of therapy designation), and Zydelig was approved in combination with Rituxan in the relapsed setting (although its European label specifies use in first-line del17p patients and the National Comprehensive Cancer Network (NCCN) also recommends its use in relapsed del17p patients5). Imbruvica and Zydelig are heavily entrenched in the CLL market,1 and new data and indications are expanding their use rapidly (including impressive results from Study 115 for Zydelig in combination with Treanda and Rituxan in relapsed CLL that were presented immediately prior to the venetoclax results6). Venetoclax may have difficulty penetrating the treatment paradigm, although its clinical data suggests it may be superior to these two agents in the del17p subset. The pivotal RESONATE trial for Imbruvica enrolled 127 patients with del17p, and in that subset Imbruvica produced a 48% ORR and six-month PFS was 83%.7 In the pivotal Study 116, Zydelig plus Rituxan produced an 80% ORR in the subset of 20 del17p patients enrolled in the trial, with a six-month PFS of more than 80% and 12-month PFS of over 60%.8 In comparison, venetoclax seems superior to Imbruvica (nearly double ORR) and possibly comparable to Zydelig (although the sample size in which Zydelig was studied was very small to draw sweeping conclusions). These comparisons will work in venetoclax’s favor and could make it the go-to drug in del17p patients. A significant concern for venetoclax may be the incidence of TLS. While the new dosing scheme utilized to minimize the risk is encouraging, the prolonged “step-up” dosing protocol and the necessary patient monitoring and potential hospitalization in high-risk groups could prove difficult to implement into regular clinical practice upon launch. Certainly the high response rates are difficult to ignore, but if the administration is viewed as cumbersome, physicians may be hesitant to adopt venetoclax into their treatment algorithm, particularly in certain patient populations such as the elderly, who are at an increased risk of TLS and are associated with comorbidities.

Despite these concerns, one must keep things in perspective: In a disease that once suffered from a lack of significant clinical advancement, the current battle among multiple highly active and novel therapies is certainly better than a stalemate of none.


  1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed December 8th, 2015.
  2. Roberts AW, Davids MS, Pagel JM et. al. “Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.” NEJM, Dec 6, [Epub ahead of print], 2015.
  3. Stilgenbauer S, Eichhorst BF, Schetelig, J, et al. Venetoclax (ABT-199/GDC-0199) Monotherapy Induces Deep Remissions, Including Complete Remission and Undetectable MRD, in Ultra-High Risk Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion: Results of the Pivotal International Phase 2 Study. Abstract LBA6, American Society of Hematology Annual Meeting, December 2015.
  4. Abbvie, Press Release, December 6, 2015
  5. National Comprehensive Cancer Network (NCCN) guidelines, accessed December 8, 2015.
  6. Zelenetz AD, Robak T, Coiffier B, et al. “Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: Results of a Phase 3 randomized, double blind placebo-controlled study.” Abstract LBA5, American Society of Hematology Annual meeting, December 2015
  7. Byrd JC, Brown JR, O’Brien S, et al. “Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia.” N Engl J Med 2014;371:213-23.
  8. Sharman JP, Coutre SE, Furman RR, et al. “Efficacy of idelalisib in CLL subpopulations harboring del(17p) and other adverse prognostic factors: Results from a phase 3, randomized, double-blind, placebo-controlled trial.”  J Clin Oncol 32:5s, 2014 (suppl; abstr 7011^)

December 07, 2015 - 02:12 pm Posted in Featured comments0 Comments

by Stephanie Hawthorne; co-authored by Elizabeth Clarke

The field of immunotherapy in oncology has exploded in the last few years, particularly in the case of immune checkpoint inhibitors, which block the immune system’s “brakes” by inhibiting either CTLA-4, PD-L1, PD-L2 or PD-1 (although inhibitors of other immune checkpoint molecules are also in early stages of development). Since the original FDA approval of Yervoy® (ipilimumab, BMS/Ono Pharmaceuticals), development of this field has accelerated rapidly. Currently, two PD-1 inhibitors are marketed ‒ Opdivo®(nivolumab, BMS/Ono Pharmaceuticals) in melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) and Keytruda® (pembrolizumab, Merck & Co.) in melanoma and NSCLC ‒ and there is considerable Phase III development of these and several PD-L1 inhibitors in other solid tumor and hematologic indications, making the market for these highly efficacious agents increasingly crowded.

At the 57th American Society of Hematology (ASH) Annual Meeting in Orlando this week, Merck reported the results from both a single-arm Phase I and a single-arm Phase II trial, evaluating the efficacy and safety of two different combinations of Keytruda in relapsed/refractory multiple myeloma. There is a strong rationale for targeting the PD-L1/PD-1 axis in multiple myeloma, as PD-L1 expression is naturally high across all stages of the disease, and T-cell expression of the molecule is increased in relapsed/refractory patients.1

First, an open-label, Phase I, multicenter, non-randomized, dose-escalation trial (NCT02036502, KEYNOTE-023) evaluated the safety, tolerability and efficacy of Keytruda plus Revlimid® (lenalidomide, Celgene) and low-dose dexamethasone (RevDex) in the relapsed/refractory setting (median of four prior lines of treatment). With a median follow-up of 296 days, the objective response rate (ORR) was 76% (nine of the 17 patients achieved a partial response and four of the 17 achieved a very good partial response). In addition, a whopping 94% of patients experienced reduction in M protein or free light chains (which are biomarkers of active disease) with a median of 50% reduction in levels. The median duration of response was 9.6 months and the median time to first response was rapid, at 1.2 months. The combination was well-tolerated, with only three patients experiencing a dose-limiting toxicity (DLT): neutropenia (Grade 3/4), infectious pneumonia (Grade 3) and tumor lysis syndrome (Grade 3) with hyperuricemia (Grade 4). Based upon these data, the maximum tolerated dose/maximum administered dose (MTD/MAD) was established as Keytruda 200 mg fixed dose in combination with standard dose RevDex (Revlimid 25 mg and low-dose dexamethasone 40 mg). What is so remarkable about the “promising preliminary activity” observed with Keytruda in this study, as aptly stated by the discussant Dr. Jesus San Miguel, is that many of the patients included in the trial were refractory to Revlimid.2 Indeed, the preliminary results of KEYNOTE-023 demonstrate that PD-1 blockade with Keytruda in combination with RevDex is associated with promising disease-targeted activity and a tolerable safety profile in heavily pretreated relapsed/refractory multiple myeloma patients.

In addition to the Phase I results, interim data were reported from an ongoing single-arm, Phase II trial (NCT02289222, conducted at the University of Maryland and partially sponsored by Merck) evaluating the efficacy and safety of Keytruda in combination with Pomalyst® (pomalidomide, Celgene) and dexamethasone in relapsed/refractory patients. In the study, relapsed/refractory multiple myeloma patients (median of three prior lines of treatment) received 28-day cycles of Keytruda (200 mg IV every two weeks) plus Pomalyst (4 mg daily x 21 days) and dexamethasone (40 mg weekly). Hematologic toxicities (Grade 3 or higher) were neutropenia (29%), lymphopenia (17%) and thrombocytopenia (8%). The most common non-hematologic adverse events included (Grade ≤2; ≥3): fatigue (n=12; 1), constipation (n=10; 0), dyspnea (n=9; 2), itching (n=6; 0), muscle spasms (n=6; 0) and hyperglycemia (n=5; 0). Objective responses were observed in 16 of 27 (60%) evaluable patients, including stringent complete response (n=1), very good partial response (n=4) and partial response (n=11); additionally, eight patients had stable disease. The time to best response (as in KEYNOTE-023) was rapid, with a median value of 2.0 months. Data on survival and progression-free survival (PFS) is very preliminary (only 7.4 months’ follow-up), but looking at the Kaplan-Meier curves suggests the six-month overall survival exceeds 80% and six-month PFS exceeds 60%.3 Overall, the data demonstrate that Keytruda in combination with Pomalyst and dexamethasone has favorable therapeutic activity and an acceptable safety profile in heavily pretreated multiple myeloma and thus may represent an efficacious combination regimen for this indication (similar to the results seen above with Keytruda + RevDex).

Presumably based on early readout of these data, Merck initiated two Phase III trials of Keytruda in multiple myeloma in October 2015. At the time, the data prompting those trial initiations was unknown, so the readout of these two studies at ASH sheds light on the rationale for their initiation. KEYNOTE-183 (NCT02576977) will randomize patients to treatment with Pomalyst/dexamethasone with or without Keytruda as third-line or later treatment (prior therapy with an immunomodulatory and proteasome inhibitor is required). KEYNOTE-185 (NCT02579863) will randomize newly diagnosed patients to treatment with Revlimid/dexamethasone with or without Keytruda. In addition to Keytruda, the checkpoint inhibitors Opdivo (with or without lirilumab; NCT01592370), atezolizumab (with or without Revlimid; NCT02431208), and durvalumab (with or without Pomalyst; NCT02616640) are being evaluated in this space (Phase I trials), putting Keytruda well ahead of the competition in this indication. However, the market in relapsed/refractory multiple myeloma is already quite crowded. In November 2015 alone, this space has seen three new approvals ‒ the anti-CD38 antibody Darzalex™ (daratumumab, Genmab), the next-generation proteasome inhibitor Ninlaro® (ixazomib, Millennium/Takeda) and the SLAMF7-directed antibody Empliciti™ (elotuzumab, BMS/AbbVie) ‒ in addition to the numerous other agents that have been previously approved for this disease (Kyprolis® (carfilzomib, Amgen), Farydak® (panobinostat, Novartis), Pomalyst, Revlimid, and Velcade® (bortezomib, Takeda)).

Is there room in the relapsed/refractory space for immune checkpoint inhibitors? The early-stage Keytruda trials described here evaluate the agent in the context of established backbone therapies (e.g., RevDex), which should bolster the efficacy of the therapy and more easily incorporate it into the treatment paradigm. By initiating two Phase III trials at nearly identical times, Merck is positioning Keytruda well for incorporation into practice. Ultimately, given what we know about the efficacy of checkpoint inhibitors in other tumor types, the KEYNOTE-185 trial in first-line may be where Keytruda ultimately fits into practice; however, that trial will likely take longer to read out, which positions the KEYNOTE-183 trial as the first opportunity for Keytruda to enter the myeloma market in the relapsed/refractory setting. This is the first Phase III trial seeking to add a novel targeted agent onto a Pomalyst/dexamethasone backbone regimen, so this strategy is diving into unknown waters but comes with the advantage of distinguishing Keytruda from the other targeted agents seeking development in combination with doublet regimens. If Keytruda ends up being as successful in multiple myeloma as it is in a host of other tumor types, it could present a fair challenge to these already-existing therapies.


  1. Paiva, B, et al.  PD-L1/PD-1 presence in the tumor microenvironment and activity of PD-1 blockade in multiple myeloma. Leukemia. 2015 Oct;29(10):2110-3.
  2. Miguel, JS et al., ASH 2015 (Abstract 505).
  3. Plesner T et al., ASH 2015 (Abstract 506).

December 07, 2015 - 02:12 pm Posted in Featured comments0 Comments

by Stephanie Hawthorne; co-authored by Len Kusdra

Cytarabine-based intensive chemotherapy remains standard of care for patients with acute myeloid leukemia (AML); however, about 70% of patients will relapse within five years of initial therapy, thus highlighting the need for development of more efficacious regimens.1 While therapy has traditionally consisted of a “one-size-fits-all” concept, it is better appreciated that AML is a rather heterogeneous disease comprising various subtypes with complex genetic and chromosomal changes. Some of these genetic aberrations have been identified in AML, but it is unclear whether these changes represent viable therapeutic targets. Perhaps the only one that has been the focus of clinical development has been FLT3, a tyrosine kinase that plays a role in hematopoiesis; mutations in this gene are believed to play a role in the development of AML. Two major classes of mutations have been identified: point mutations in the tyrosine kinase domain (FLT3-TKD) or the presence of internal tandem repeats (FLT3-ITD). Of the two classes, FLT3-ITD is the more common aberration, occurring in about 30% of AML patients, and has been associated with poor prognosis and shorter overall survival.2 Despite the promise of FLT3-ITD as a target, its history has been turbulent, as evidenced by the failure of lestaurtinib (Cephalon), a FLT3-targeted agent that failed in its pivotal trial and called into question the rationale of inhibiting FLT3-ITD and threatening further clinical development on this target.

Novartis hopes to change that with its development of midostaurin, an oral multitargeted kinase inhibitor with activity against FLT3. In early-stage trials, midostaurin showed promising activity both as monotherapy and in combination with induction therapy in patients with FLT3 mutated AML compared with FLT3 wildtype AML. Encouraged by these data, Novartis initiated the RATIFY trial in collaboration with Cancer and Leukemia Group B (CALGB-10603; NCT00651261), a Phase III double-blind study evaluating midostaurin versus placebo, both in combination with standard first-line systemic therapy, in AML patients younger than 60. Only patients with FLT3 mutations were enrolled and stratified according to whether they had had a high FLT3 allelic fraction (≥0.7) or a low FLT3 allelic fraction (<0.7); a third cohort consisted of patients with mutations in the kinase domain (FLT-3 TKD). As part of induction therapy, patients received the 7+3 regimen (daunorubicin 60 mg/m2 IV d1-3 and cytarabine 200mg/m2 d1-7 IV) plus midostaurin (50mg oral daily) or placebo. Patients who achieved a complete remission after one or two cycles of induction went on to receive consolidation (four cycles of cytarabine (3g/m2 on days 1, 3, 5) plus midostaurin (50mg oral, daily) or placebo), followed by 12 months of maintenance with midostaurin or placebo at the same dose used during induction and consolidation.  There was no prespecified mandate on the use or not of stem cell transplantation, but the details presented at the 57th American Society of Hematology (ASH) Annual Meeting suggest that midostaurin (or placebo) was not continued for patients who received a stem cell transplantation (less than 50% of patients who received consolidation went on to receive maintenance). The primary endpoint of the trial was overall survival (OS), and secondary endpoints included event-free survival (EFS). While analysis of the results was set to occur at 509 deaths, the slow rate of events led the investigators to amend the protocol to allow for primary analysis at 357 events. With the shadow of lestaurtinib’s failure in its own clinical trial and the challenge in recruitment in RATIFY, many asked: Would midostaurin live up to its potential?

At the ASH annual meeting held in Orlando, that question was answered, with midostaurin demonstrating significant activity in FLT3+ AML patients.3 In total, 717 patients were enrolled, with 360 enrolled in the midostaurin arm and 357 receiving placebo. Evaluation of toxicity revealed no significant safety signals in the midostaurin arm. The most common Grade 3+ adverse events in the placebo versus midostaurin arms were febrile neutropenia (82% versus 81%), infection (38% versus 40%), diarrhea (16% versus 15%), and rash/desquamation (13% versus 8%). The rate of Grade 5 events was also similar between both arms (5.3% in the placebo arm and 5% in the midostaurin arm).

Addition of midostaurin to initial therapy led to a statistically significant improvement in OS and EFS. Patients receiving midostaurin had an OS of 74.7 months (95% CI: 31.5 months-not reached) versus 25.6 months in the placebo group (95% CI: 18.5-42.9 months) (HR=0.77, p=0.007). The four-year survival rate in the midostaurin arm was 51.4% and 44.2% in the placebo group. The benefit in OS was seen across all three subgroups, although it was strongest in patients carrying the FLT3-TKD mutation (HR=0.65, p=0.05), compared with patients with FLT3-ITD high (HR=0.8, p=0.09) and FLT3-ITD low (HR=0.8, p=0.08). The complete response (CR) rates at day 60 were similar between patients receiving midostaurin (59%) and placebo (53%) (p=0.15). Censoring of OS data at the time of transplant (57% of patients received a transplant at some time during their treatment) maintained the OS benefit achieved in patients in the midostaurin arm compared with placebo (four-year OS 63.8% versus 55.7%; HR=0.75, p=0.04). EFS also was significantly improved in patients receiving midostaurin versus placebo (8.0 months versus 3.0 months; HR=0.79, p=0.0.0025), and once again the greater level of benefit was achieved in FLT3-TKD patients (HR 0.75, p=0.02) compared with FLT3-ITD high (HR 0.77, p=0.04) or FLT3-ITD low patients (HR 0.85, p=0.10). Among all patients achieving a CR during induction or consolidation, the EFS benefit achieved with midostaurin was still significant (11.3 months versus 6.1 months, HR 0.73, p=0.0002).

Novartis has guided that it plans to submit regulatory applications in 2016,4 and results from the RATIFY trial should support approval. If approved, what will physicians’ reception to midostaurin be? The dearth of novel agents in this disease will certainly favor its utilization. While Mylotarg® (gemtuzumab ozogamicin, Pfizer) also is being studied in newly diagnosed patients, its troubled history may hinder its utilization, which would help midostaurin be the first novel agent to be approved in for newly diagnosed patients.  However, midostaurin faces challenges of its own. RATIFY was initiated almost eight years ago, and since then the standard of care in AML has changed with respect to utilization of stem-cell transplantation increasing as part of initial therapy. This poses problems for the interpretation of the OS data from RATIFY and whether the survival data presented here will translate into long-term benefits for both transplanted and non-transplanted patients. However, that analysis would extend the trial even longer. Indeed, the investigators noted that in 2014 and 2015 the rates of events plateaued down to six events and three events, respectively, thus providing rationale for the trial amendment to shorten the time for primary analysis. Even so, physicians may hesitate to adopt midostaurin without clear longer-term results. Adding to this hesitation is the decision as to which patient population to administer midostaurin. Elderly patients are less likely to receive an intensive chemotherapeutic regimen such as 7+3, and indeed patients older than 60 years were excluded from eligibility in RATIFY.  The limitation of enrollment to ages 18-60 narrows the eligible population to only one-quarter of newly diagnosed AML patients, and layering on the 30% incidence rate of FLT3+ disease (assuming incidence does not vary by age) leaves less than 10% of AML patients eligible for treatment with midostaurin. Another challenge is midostaurin’s mechanism of action as a FLT3 inhibitor.

Other FLT3-targeted agents ‒ quizartinib (Daiichi-Sankyo Inc.; previously Ambit Biosciences), crenolanib (Arog Pharmaceuticals) and ASP-2215 (Astellas) ‒ are being evaluated in the relapsed setting, and encouraging data has been reported for sorafenib in this setting (when used in combination with azacitidine), which has led to its recommended use in relapsed FLT3+ patients  by the National Comprehensive Cancer Network (NCCN).  Midostaurin will be unchallenged initially in newly diagnosed FLT3+ patients, but should any of these competitors move into first-line testing they could pose a direct threat to midostaurin. For now, midostaurin represents a move forward in the right direction in a disease that has historically suffered from a lack of significant innovation.


  1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed December 6, 2015.
  2. Frohling S, Schelnk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372-4380.
  3. Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Plenary session, Abstract 6, American Society of Hematology Meeting, December, 2015
  4. Novartis, press release, December 6, 2015

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