Prashant Kapoor, MD

S. Vincent Rajkumar, MD

LOCATION! LOCATION! LOCATION! That’s what home buyers are frequently cautioned about before purchasing a property. For trialists, and more importantly, practicing oncologists, a study’s design, akin to a property’s location, must be taken into account prior to buying into the results and changing clinical practice. 

On both accounts ENDEAVOR, an open-label, randomized phase III clinical trial in patients with relapsed or refractory multiple myeloma that compares two structurally different proteasome inhibitors—carfilzomib (Kyprolis; at 56 mg/m² dose) and bortezomib (Velcade; administered either subcutaneously or intravenously) in combination with low-dose dexamethasone, falls somewhat short. The study was declared a positive trial in 2016, after the first interim analysis showed a superior overall response rate (77% vs 63%) and a near doubling of progression-free survival (median = 18.7 vs 9.4 months, hazard ratio [HR] = 0.53, P < .0001) for the carfilzomib/dexamethasone arm.¹ The results of the second planned interim analysis, after the protocol amendment to abbreviate the study timeline, were first announced through a late-breaking abstract at the International Myeloma Workshop, New Delhi, India, in March 2017 and published in August 2017.² The findings offered the ultimate prize: translation of better overall response rate and progression-free survival, the surrogate endpoints, into a virtually insurmountable and statistically significant 7.6-month advantage in median overall survival, a secondary endpoint, for the carfilzomib/dexamethasone arm (47.6 vs 40 months, HR = 0.79, one-sided
P = .01). 

Overall response rate √! Progression-free survival √! Overall survival √! If establishing the supremacy of carfilzomib/dexamethasone was the goal of ENDEAVOR, the experimental arm performed spectacularly by almost any measure and was the clear winner against an ostensibly active “control arm” (bortezomib/dexamethasone). But as we scratch the surface, the patina of equipoise in the trial diminishes considerably.

Devil Is in the Design 

AS DISCUSSED in the June 10, 2016, issue of The ASCO Post, this study offers a textbook case on how interpretation of modern cancer trials is dramatically affected by the initial study design.³ Do the updated results demonstrating an overall survival advantage for carfilzomib/dexamethasone alter our view of the trial and its interpretation? Unfortunately, although the article is well written and is a model for how a cancer clinical trial ought to be reported, the updated survival results cannot overcome fundamental design issues. The trial shows that in a world in which carfilzomib is not commercially available, those who have access to the drug through a trial live longer (improvement in median overall survival, 7.6 months) than those who do not. 

To use carfilzomib ahead of bortezomib, we need evidence to support that sequence matters, and the ENDEAVOR trial design does not allow us to make this determination.

— Prashant Kapoor, MD, and S. Vincent Rajkumar, MD

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What the trial does not show is whether the patients live longer if they receive carfilzomib first (ahead of bortezomib) or if they receive bortezomib first and are then switched to carfilzomib at disease progression. Only 8% of the patients in the bortezomib/dexamethasone arm ever received carfilzomib. In other words, the trial conclusively proves the value of carfilzomib, and if this were the first registration trial, it would have been the basis of initial regulatory approval of carfilzomib for the treatment of myeloma. But the clinical practice question facing us today is not whether we should use carfilzomib but rather which proteasome inhibitor should we use first. The trial as designed does not answer that, and no amount of additional analysis of the trial will provide the answer. 

Does Sequence Matter? 

WHY IS THIS important? Myeloma is a chronic cancer where patients go through multiple regimens in sequence over many years. Which regimen is used first affects one’s quality of life, adverse-event profile, and importantly, cost of care and convenience. In these aspects, carfilzomib is at a disadvantage. It is more cumbersome to administer, requiring twice weekly intravenous infusions, has a higher risk of grade 3 to 4 adverse events, and is far more expensive, especially at the doses that produced these impressive results. To use carfilzomib ahead of bortezomib, we need evidence to support that sequence matters, and the ENDEAVOR trial design does not allow us to make this determination. 

Our plea to investigators is to refrain from proclaiming every new regimen as ‘a new standard of care.’

— Prashant Kapoor, MD, and S. Vincent Rajkumar, MD

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Further, despite data that the use of carfilzomib is effective in patients whose disease was refractory to bortezomib,⁴ crossover of patients on the bortezomib/dexamethasone arm to carfilzomib was not permitted. This design deprived the control population of an effective agent, whereas patients in the experimental arm had full access to bortezomib before and after protocol therapy. To what extent a plainly weak control arm was made incontrovertibly weaker by additional biases remains an open question. Our goal here is not to find fault; we recognize that due to differing and unpredictable regulatory standards, one is forced to design trials in ways that may seem unreasonable in hindsight. We are using this trial more as an example to illustrate the complexity of clinical trial interpretation. 

Systematic Bias 

FOR A LARGE proportion of the subjects who had been previously exposed to bortezomib (n = 502), the trial was essentially a comparison of trying a chemically different proteasome inhibitor (carfilzomib) vs retreatment with the same one they had previously received. This subset included 8% of previously exposed patients whose disease was refractory to bortezomib prior to being re-treated with this agent. The updated analysis offers the reassurance that carfilzomib has efficacy (although somewhat lower) in patients with prior exposure to bortezomib as in those who are bortezomib-naive. 

Another source of bias was the suboptimal schedule of bortezomib administration. Here again, the updated results show the vast majority of patients received bortezomib subcutaneously (the preferred route), lessening another source of bias that would have potentially made the control arm weaker. Still, it is impossible to completely eliminate biases retrospectively. Thus, we cannot ignore the fact that the trial compared twice-weekly bortezomib (known to be associated with a higher risk of neuropathy) with carfilzomib administered at a souped-up dose of 56 mg/m². 

Teasing Out the Nuances 

BOTH BORTEZOMIB and carfilzomib are indispensable in the modern treatment of myeloma. Therefore, although as discussed previously, the ENDEAVOR trial cannot be used to justify the use of carfilzomib ahead of bortezomib, we can learn a lot from this trial that will be invaluable for clinical practice. First, both drugs appear to be equally well tolerated. This may not be readily apparent, since the number of deaths on treatment and serious adverse events appear higher on the carfilzomib/dexamethasone arm. However, the investigators, to their credit, report an analysis of adverse events adjusted for person-years of exposure, which is critical in studies where the median treatment exposure is markedly different between the two arms. Reassuringly, this analysis showed no difference in the rate of serious adverse events between carfilzomib/dexamethasone and bortezomib/dexamethasone. 

Second, Table 3 in the article, outlining the toxicity associated with the regimens, is a gem. This is how we would like adverse events reported. From this table, it is apparent that it is important to keep in mind the small but definite risk of hypertension, dyspnea, and cardiac failure associated with carfilzomib. On the other hand, the risk of neuropathy is definitely lower with this drug compared with bortezomib. 

Finally, a comparison of overall survival results from other randomized trials in the relapsed setting (outlined well in the discussion section of the article) shows it is extremely difficult to achieve this magnitude of survival benefit, even with trials that lacked an active control equivalent. This reveals the value of carfilzomib as an added option for the treatment of myeloma. 

Take-Home Points 

HOW DO THE ENDEAVOR RESULTS change our current practice? With a definitive improvement in overall survival, ENDEAVOR ensconces the safety and efficacy of carfilzomib and provides evidence supporting the use of the drug at higher doses if and when clinically indicated (perhaps for patients with aggressive relapse and for patients who do not respond to carfilzomib at lower doses). The trial also shows that in patients previously treated with bortezomib, carfilzomib remains an important option and must be considered. 

Based on these results one cannot conclude that carfilzomib should be used ahead of bortezomib for reasons previously stated. In this regard, data from the CLARION trial (a phase III study of carfilzomib/melphalan/prednisone vs bortezomib/melphalan/ prednisone) are sobering and show no survival benefit with the front-line use of carfilzomib compared with bortezomib. We need to await the results of the ENDURANCE trial comparing bortezomib/lenalidomide (Revlimid)/dexamethasone vs carfilzomib/ lenalidomide/dexamethasone. 

The superiority of carfilzomib/dexamethasone in a swiftly advancing field does not make it a new standard of care. The regimen is outdated. Six randomized trials have already established triplets as the preferred option for most patients with myeloma at the time of relapse.5 In fact, a number of carfilzomib-based triplets are already used in clinical practice in the United States. Even the dosing of carfilzomib clinicians could routinely use (27 mg/m², 36 mg/m², 56 mg/m², or 70 mg/m²) has become more complex. Thus, our plea to investigators is to refrain from proclaiming every new regimen as “a new standard of care.” Rather we need to endeavor to conduct and complete clinical trials that provide specific insight on optimal sequencing for clinical practice—a task that requires totally different trial designs than needed for regulatory drug approval.⁶ It is Design! Design! Design! ■

DISCLOSURE: Dr. Kapoor is a principal investigator on studies for which the Mayo Clinic receives research funding from Amgen, Takeda, and Sanofi. Dr. Rajkumar reported no conflicts of interest. 

Dr. Kapoor is Assistant Professor of Medicine and Oncology, and Dr. Rajkumar is Professor of Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota.

REFERENCES 

1. Dimopoulos MA, Moreau P, Palumbo A, et al: Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): A randomised, phase 3, open-label, multicentre study. Lancet Oncol 17:27-38, 2016. 

2. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al: Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): An interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol 18:1327-1337, 2017. 

3. The ENDEAVOR trial: A case study in the interpretation of modern cancer trials. The ASCO Post, June 10, 2016. Available at http://www.ascopost.com/issues/june-10-2016/the-endeavor-trial-a-case-study-in-the-interpretation-of-modern-cancer-trials/. Accessed October 23, 2017. 

4. Siegel DS, Martin T, Wang M, et al: A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 120:2817-2825, 2012. 

5. Rajkumar SV, Kyle RA: Progress in myeloma—A monoclonal breakthrough. N Engl J Med 375:1390-1392, 2016. 

6. Moreau P, Rajkumar SV: Multiple myeloma—Translation of trial results into reality. Lancet 388:111-113, 2016.