The introduction of draft regulations implementing the Affordable Care Act has begun. On November 20, 2012, HHS released its Proposed Rule, “Standards Related to Essential Health Benefits, Actuarial Value and Accreditation”.
The Proposed Rule bears watching and comment for a number of reasons. First and foremost, the Rule does not provide the “Protected Classes” designation that the Medicare Part D Drug Benefit allocated to 6 “therapeutic” classes; one of which was antineoplastics. In the establishment of the Part D benefit, essentially all FDA-approved antineoplastic agents were deemed as “protected” and thus covered. Such protection was deemed important to assure that serious conditions like cancers have available appropriate options to assure patient access to needed therapeutics. Under the newly proposed rule for the Essential Health Benefits (EHB) Packages for Qualified Health Plans, including Plans that will participate in the Health Exchanges, the inclusive nature of the “Protected Class” has been omitted. This disconcerting circumstance was indeed presaged by a lonely footnote at the bottom of the last half page of the HHS December, 2011 EHB informational bulletin that closed with: “we do not intend to adopt the protected class of drug policy in Part D.”
The benchmark for drug/biologic inclusion then becomes the greater of one drug in each category or class or the same number of drugs in each category and class of the EHB Benchmark plan. The focus on benchmark plan designs is on the largest small employer plan in the state. As the size of the plan decreases, the sophistication of benefit design and understanding of cancer therapeutics can be expected to decrease as well. The Proposed Rule then holds out the Guidelines of the United States Pharmacopeia (USP) as an organizational tool to help plans determine classes and categories of drugs that must be considered. One issue with the USP’s fine work is that updating may not occur for more than two years or so. It is noteworthy that in 2012, the FDA has approved over a dozen new drugs and biologics as cancer therapeutics.
The bottom line on all this is that as the science of cancer advances our understanding of the multiple genetic causes for cancers through RNA mediated expression of proteins our ability to develop targeted therapies is enhanced. However, the policy-based benefit rules (e.g., EHBs) offered threaten to diminish the availability of and access to the innovative mechanisms of action needed to make treatment more effective, less toxic and more efficient.
by Bill McGivney, PhD
National Health Policy Expert
McGivney Global Advisors
Pomalidomide is a next-generation immunomodulatory agent in development for relapsed/refractory multiple myeloma, designed to follow in the footsteps of its siblings, Revlimid (lenalidomide, Celgene) and Thalomid (thalidomide, Celgene). The first evidence that pomalidomide could be a true successor to Revlimid came from the Phase II MM-002 trial, which randomized 221 patients to pomalidomide plus low-dose dexamethasone (LoDEX) versus pomalidomide alone. Patients enrolled in that trial were heavily pre-treated with a median of five prior therapies, including Velcade (bortezomib, Millennium/Johnson & Johnson) and Revlimid. Results from this study were first presented at ASH 2011 (Richardson, Abstract 634) and were updated at ASCO 2012 (Vij, Abstract 8016). A partial response (PR) or better was observed in 30% of patients treated with pomalidomide plus LoDex compared with 9% for patients treated with pomalidomide alone, and responses of minor response (MR) or better were 45% compared to 25%. The median progression-free survival (PFS) of pomalidomide plus LoDex was associated 3.8 months versus 2.5 months for patients treated with pomalidomide monotherapy (HR 0.73, p=0.037), and the overall survival (OS) was 14.4 months versus 13.6 months (HR 0.85, p=0.449). The regimen was well-tolerated with a discontinuation rate due to adverse events of 6% in the pomalidomide plus LoDex arm versus 12% in the pomalidomide-alone arm. The most common Grade 3/4 toxicities in the pomalidomide plus LoDex arm versus pomalidomide alone were neutropenia (38% and 47%, respectively), anemia (21%, 22%), pneumonia (19%, 14%), thrombocytopenia (19%, 22%), and fatigue (10%, 10%). Based on these encouraging data, Celgene has filed for accelerated approval in the United States and for conditional approval in Europe. The U.S. Food and Drug Administration (FDA) has accepted this application for standard review, with a PDUFA date of February 10, 2013. These data also created a lot of buzz in the myeloma community – the recent approval of Kyprolis (carfilzomib, Onyx) has started to close a gap in the treatment armamentarium, but a hole still exists that pomalidomide could help fill.
To confirm the activity seen in MM-002, Celgene initiated the Phase III NIMBUS study (MM-003; NCT01311687), which randomized 455 patients with relapsed/refractory multiple myeloma 2:1 to treatment with pomalidomide plus LoDEX versus high-dose dexamethasone (HiDEX). Patients must have received at least two prior lines of therapy, which had to have included prior Revlimid and prior Velcade. A first look at the data from NIMBUS came in the late-breaking abstract session on the last day of the 2012 ASH conference (Dimopoulos, Abstract LBA6).
The use of pomalidomide plus LoDEX significantly improved PFS compared to HiDEX (3.6 months versus 1.8 months, HR 0.45, p<0.001) with very clear separation of the Kaplan-Meyer curves. The response rates were also significantly improved in the combination arm (24% versus 3%, p<0.001). Importantly, OS was significantly improved in the combination arm (median not reached versus 7.8 months, HR 0.53, p<0.001), a result that is even more impressive when we consider that 29% of patients on the HiDEX arm received pomalidomide upon progression, and that these patients were heavily pre-treated, with a median of five prior therapies. Additionally, the level of benefit was also maintained in patients refractory to both Revlimid and Velcade: PFS (3.2 months versus 1.7 months, HR 0.48, p < 0.001) and OS (median not reached versus 7.4 months, HR 0.56, p < 0.001). These results are only loosely tempered by an increase in Grade 3/4 neutropenia (42% versus 15%) and febrile neutropenia (7% versus 0%). All other reported Grade 3/4 toxicities (thrombocytopenia, infections, hemorrhage, glucose intolerance, neuropathy and venous thromboembolism) were similar between the two arms. The minimal increase in toxicity is reflected in the low discontinuation rates due to adverse events (7% versus 6%).
The data were undeniably impressive, but pomalidomide will enter an increasingly crowded market space. Kyprolis, a next-generation proteasome inhibitor, was given an accelerated approval in the U.S. based on results from a Phase II trial. Onyx has initiated three Phase III trials: ASPIRE (NCT01080391; RevDex with or without Kyprolis in relapsed myeloma), FOCUS (NCT01302392; Kyprolis versus best supportive care in heavily pre-treated myeloma patients) and ENDEAVOR (NCT01568866; Kyprolis plus dexamethasone versus Velcade plus dexamethasone in relapsed patients). Further behind in development are the pan-deacetylase inhibitor panobinostat (Novartis), the PI3K/AKT inhibitor perifosine (Æterna Zentaris) and the anti-CS1 monoclonal antibody elotuzumab (Bristol-Myers Squibb/AbbVie). Elotuzumab is being examined in combination with Revlimid plus dexamethasone in both newly diagnosed (ELOQUENT-1; NCT01335399) and relapsed patients (ELOQUENT-2; NCT01239797).
In spite of the increased competition, pomalidomide will be eagerly included into the drug armamentarium for myeloma patients. Physicians are excited about these new agents, as represented by the large number of Phase I or II trials presented at ASH 2012 examining new drug combinations, including one Phase I/II study that showed impressive efficacy (56% MR or better, 70% six-month PFS) with the combination of both Kyprolis and pomalidomide with LoDEX in heavily pre-treated patients (Shah, Abstract 74). After a five-year dry-spell, the introduction of Kyprolis this year and the data for pomalidomide at ASH 2012 portend to a new era in multiple myeloma therapy.
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Arnold DuBell, PhD, Associate Consultant, Kantar Health
The combination of CHOP plus Rituxan (rituximab, Genentech/Roche; R-CHOP) has been the traditional standard of care in the United States and Europe for follicular lymphoma (FL) and mantle cell lymphoma (MCL). That regimen is associated with a range of adverse effects, including cardiac, hematologic and neurologic toxicity, as well as infectious complications. Many physicians feel that CHOP has a role in treating more aggressive diseases such as diffuse large B-cell lymphoma but debate whether such an aggressive regimen is warranted for treatment of patients with indolent lymphomas. Very encouraging data for the two-drug combination of Treanda (bendamustine, Teva Pharmaceuticals) plus Rituxan was first reported at ASH 2009, suggesting that it may be a more effective and less toxic regimen than the standard R-CHOP.
Treanda is approved for use as a monotherapy in relapsed and refractory indolent non-Hodgkin’s lymphoma (iNHL). This combination has been studied in front-line FL in two Phase III trials: the German Study Group Indolent Lymphomas (StiL) NHL 1 study (first reported at ASH 2009) and the U.S. BRIGHT study. An ASCO 2012 update (median follow-up 45 months) of StiL (Rummel, Abstract 3) showed a doubling of the median progression-free survival (PFS) in the R-Treanda arm (69.5 months versus 31.2 months for the R-CHOP group, p<0.0001; HR=0.58). Overall survival did not differ between the two groups, partly because nearly half of the R-CHOP patients whose disease continued to progress were then permitted to cross over to the experimental arm. Both drug combinations had similar overall response rates (92.7% for R-Treanda and 91.3% for R-CHOP), but the R-Treanda combination had significantly more complete responses (39.8% vs. 30.0%, p=0.021) than the R-CHOP combination. In addition, the R-Treanda regimen reported lower rates of alopecia (15% vs. 62%), Grade 3/4 neutropenia (29% vs. 69%), leucopenia (37% vs. 73%), peripheral neuropathy (18% vs. 73%), stomatitis (16% vs. 47%), and infections (31% vs. 41%) and led to less growth factor support overall (4% vs. 20%). Skin rash (42% vs. 23%) and Grade 3/4 lymphocytopenia (74% versus 43%) were the only toxicities that were increased in the R-Treanda arm. In sum, the StiL study showed similar response rates, improved PFS and less toxicity versus R-CHOP and was hailed with much excitement at ASCO. The initial presentation of results from STiL also supported a Category 1 recommendation for its use in newly diagnosed follicular NHL by the National Comprehensive Cancer Network and led to off-label utilization of this regimen in first-line therapy in nearly one-fifth of U.S. patients (Kantar Health, CancerMPact Treatment Architecture, 2012).
The one downside of the StiL trial was that it only enrolled patients from Germany. Thus, Cephalon/Teva initiated the BRIGHT study in March 2009 to confirm the results in U.S. patients and to support regulatory approval by the FDA. The results of this much anticipated follow-on study, comparing efficacy and safety of R-Treanda with the standard treatment regimens of R-CHOP or R-CVP as first-line treatment for indolent FL or MCL, were presented Tuesday morning at ASH (Flinn, Abstract 902). The primary objective of BRIGHT was to demonstrate non-inferiority of complete response (CR) rate of R-Treanda versus standard treatment. Secondary measures included overall response rate (ORR), PFS, and overall survival. While BRIGHT did prove non-inferiority, the results were disappointing compared with the StiL study. The data cutoff for this presentation was June 27, 2012.
Of 447 randomized patients, 436 received treatment (R-Treanda n=221; R-CHOP/R-CVP n=215 (R-CHOP n=99; R-CVP n=116)) and were evaluable for safety. Of these, 419 patients (R-Treanda n=213; R-CHOP/R-CVP n=206 (R-CHOP 97; R-CVP n=109)) were evaluable for efficacy. The arms were well balanced. The CR rate was numerically higher (31%) for R-Treanda than R-CHOP/R-CVP (25%) and statistically non-inferior (p=0.0225); interestingly, R-Treanda was statistically superior (Rate ratio= 1.95; p=0.018) in the subpopulation of MCL patients. The ORR was 94% for R-Treanda and 84% for R-CHOP/R-CVP (90%/83%). Disappointingly, PFS and OS data are immature and were not presented. The speaker, Dr. Flinn, did present the immature PFS data when pressed by the audience. The 30-month curves were overlapping and crossing, a trend that does not bode well for final results.
The adverse event profile in BRIGHT favored Treanda, but the benefit was surprisingly less than was observed in StiL. Neuropathy (all grades: 6% R-Treanda vs. 38% R-CHOP/48% R-CVP), neutropenia (Grade 3/4: 45% vs. 86%/56%) and alopecia (all grades: 4% vs. 41%/21%) were higher in the R-CHOP/R-CVP arms. Nausea (all grades: 63% R-Treanda vs. 58% R-CHOP/39% R-CVP), vomiting (all grades: 27% vs. 13%/13%), lymphopenia (Grade 3/4: 62% vs. 33%/28%), opportunistic infections (all grades: 11% vs. 7%/9%), rash (all grades: 15% vs. 7%/9%), and respiratory disorders (Grade 3/4: 7% vs. 2%/2%) were higher in the R-Treanda arm. Growth factor support was unusually high (compared with the StiL study), with 40% of patients in the R-Treanda and R-CVP arms and 61% of patients in the R-CHOP arm receiving growth factor support. Dose delays were more common for R-Treanda-treated patients (35% vs. 19%), and dose reductions were less common (22% vs. 29%), resulting in a similar dose intensity in all arms. Fatal adverse events occurred in six R-Treanda patients (pneumonia, respiratory failure and sepsis; acute respiratory failure; cardiac arrest; pneumonia; chronic obstructive pulmonary disease; lung cancer) and one R-CHOP/R-CVP patient (sepsis). This concerning result was questioned by the audience and the answer that “deaths were equal across all arms” seemed to side-step this important issue.
Many investigators rushed to the microphone to question Dr. Flinn about the discrepancy in adverse events reported in StiL and BRIGHT. Most concerning are the high rates of infection, nausea and vomiting not previously seen with Treanda. Dr. Flinn did offer some explanations. For example, the definition of infection was broad, including shingles and oral herpes, which might have increased these rates. He had no explanation for the increased nausea and vomiting, saying only that anti-emetic use was equivalent in all arms. But the audience was not satisfied and was left stirred up and buzzing. A similar sentiment followed a separate presentation given by Dr. John Burke on Sunday afternoon (Abstract 155), which showed improved quality of life (QoL) in the R-Treanda arm, but physicians in the audience seemed skeptical, criticizing the lack of quantification provided.
Until more follow-up (and mature PFS and OS) data is provided we will have to remain unsatisfied. For now, in patients with advanced indolent NHL and MCL, R-Treanda produces a CR rate that is non-inferior to that of R-CHOP/R-CVP. Additionally, the adverse event profile of R-Treanda was distinct from that of R-CHOP/R-CVP. While the lower incidence of neuropathy, neutropenia and alopecia are certainly benefits for R-Treanda that both physicians and patients will appreciate, they are countered by the higher rates of other toxicities equally troublesome. The one bright spot is the significantly higher CR rate (51% vs. 24%) in the subgroup of patients with MCL.
So what will happen to this combination going forward? Initially, Cephalon planned to submit a regulatory application for the first-line setting in the U.S. in the first-half of 2011, according to company guidance in late 2010 (Cephalon Q3 earnings call, October 28, 2010). However, it appears that Teva’s acquisition of Cephalon has pushed back the timeline. In February 2012, Teva filed Treanda for approval in the front-line indication and was waiting for FDA response and a Prescription Drug User Fee Act (PDUFA) date (Teva conference presentation, February 27, 2012). The FDA’s answer came on October 23, 2012, asking for more data. The NCCN seems similarly nonplussed, having demoted first-line R-Treanda for FL from Category 1 to Category 2A in its latest guidelines update for NHL (v3.2012). With the results of the StiL study demonstrating clear efficacy and the BRIGHT trial showing such different results with a potential lack of PFS benefit, Treanda approval in the front-line setting is now questionable.
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Mara Jeffress, PhD, Associate Consultant, Kantar Health
Acute myeloid leukemia (AML) is a disease of high unmet need with a generally poor prognosis. This is especially true in the elderly population, with only approximately 45% of these patients receiving aggressive therapy with curative intent (Kantar Health, CancerMPact Treatment Architecture, 2012). Dacogen (decitabine, Eisai /Astex) was recently approved in Europe for use in elderly AML patients (but was rejected by the FDA in the same indication), and Phase III trials of both sapacitabine (Cyclacel) and Vidaza (azacytidine, Celgene) are ongoing in newly diagnosed elderly AML patients. Presentations of positive Phase II data in elderly AML patients at ASH 2012 suggest that two new targeted agents – quizartinib (AC220, Ambit Biosciences/Astellas) and volasertib (BI6727, Boehringer Ingelheim) – may be efficacious in this population and are poised to enter Phase III development within the next year.
Volasertib in an inhibitor of Polo-like kinase 1 (Plk1), which is involved in spindle assembly during mitosis. Preliminary results from the randomized Phase II portion of a Phase I/II study were presented at ASH 2012 (Maertens, Abstract 411). Eighty-six newly diagnosed AML patients ineligible for intensive therapy were randomized to treatment with either low-dose cytarabine (LoDAC) alone or LoDAC plus volasertib. Significantly more patients in the volasertib plus LoDAC arm achieved an objective response (p<0.0523, CR: 19.0%, CRi: 12.0%) compared with the control arm (CR: 6.7%, CRi: 6.7%). Also, the addition of volasertib to LoDAC significantly extended event-free survival (5.6 months versus 2.3 months, HR: 0.56, p<0.0237), and there was a statistical trend toward an increase in overall survival (8.0 months versus 5.2 months, HR: 0.66, p=0.0996). However, this efficacy was accompanied by an increase in adverse events, with patients in the volasertib plus LoDAC arm experiencing a higher incidence of Grade 3+ gastrointestinal adverse events (21% versus 7%), infections (Grade 3: 48% versus 23%), metabolism-related adverse events (Grade 3: 15% versus 7%) and respiratory adverse events (Grade 3: 23% versus 13%). Based on the promising Phase II results, the speaker announced that Boehringer Ingelheim plans to initiate a Phase III trial of volasertib in the first quarter of 2013. The POLO-AML-2 trial will randomize 660 previously untreated AML patients aged 65 and older who are ineligible for high-intensity therapy to be treated with either LoDAC alone or LoDAC plus volasertib.
Fms-like tyrosine kinase 3 (FLT3) is commonly overexpressed in AML, and approximately 30-35% of AML patients have FLT3 internal tandem duplications (FLT3-ITD), which confer a poor prognosis compared with FLT3 wild-type patients (Gale, Blood, 2008, 11(5): 2776-2784). Midostaurin (PKC-412, Novartis) is currently the only FLT3 inhibitor in Phase III development, but its pivotal RATIFY trial is focused on younger patients, evaluating the addition of midostaurin to standard 7 + 3 daunorubicin and cytarabine induction in newly diagnosed AML patients aged 60 years or younger. Quizartinib is a selective FLT3 inhibitor with a low plasma IC50 of 18 nM (compared to ~1000 nM for midostaurin). Final results were presented from a single-arm Phase II study of quizartinib in 333 AML patients who were FLT3-ITD-positive and FLT3-ITD-negative (Cortes, Abstract 48). The study was divided into two cohorts. The first cohort included second-line patients at least 60 years of age, and data from this cohort are discussed here. The second cohort included third-line patients at least 18 years of age, and data from this cohort will be presented late Monday afternoon at ASH 2012. In the 90 FLT3-ITD-positive elderly patients treated with quizartinib, 3% achieved a complete remission (CR) + CRp, and 50% achieved a CRi. In the 42 FLT3-ITD-negative elderly patients treated with quizartinib, 5% achieve a CR + CRp, and 31% achieved a CRi. The ability to achieved a CR is something that wasn’t observed with midostaurin in its Phase IIB study, suggesting that quizartinib’s higher selectivity may translate into greater clinical activity. Overall survival with quizartinib was similar regardless of FLT3-ITD status, with a median survival of 25.3 weeks for FLT3-ITD-positive patients and 19.0 weeks for FLT3-ITD-negative patients. As expected from previous investigation of quizartinib, the most common Grade 3/4 adverse events were hematological (anemia: 33% for FLT3+ and 20% for FLT3-, febrile neutropenia: 33% for FLT3+ and 48% for FLT3-thrombocytopenia: 29% for FLT3+ and 19% for FLT3-), asthenia (12% for FLT3+ and 5% for FLT3-), and QT prolongation (10% for FLT3+ and 12% for FLT3-). The speaker announced that Phase III randomized trials are planned for the end of 2013, but details were not provided.
Compared with Dacogen, which was recently approved in Europe for newly diagnosed elderly patients, both quizartinib and volasertib (plus LoDAC) produce higher overall response rates. Volasertib plus LoDAC also appears to result in a survival benefit similar to Dacogen. In the case of quizartinib, however, it is currently unclear whether the extremely high response rate will translate into a meaningful survival benefit in a randomized setting. Considering the fact that Dacogen was rejected by the FDA primarily because the survival benefit was perceived to lack clinical meaningfulness, it will be important for each of these new agents to show a clear statistical increase in overall survival in their Phase III studies to gain approval in the United States. In addition, each new agent has its own unique toxicity profile. Quizartinib has consistently resulted in QT prolongation in addition to causing hematologic toxicities similar to Dacogen. In contrast, volasertib primarily results in increased gastrointestinal and respiratory adverse events as well as infection (including febrile neutropenia). However, considering the poor prognosis and lack of options for elderly patients newly diagnosed with AML, further development of new therapeutic options is a welcome development indeed!
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Cory Blaiss, PhD, Analyst, Kantar Health