May 02, 2017
By George D. Demetri, MD, FACP, FASCO
Dana-Farber Cancer Institute and Harvard Medical School
On October 19, 2016, olaratumab, the first monoclonal antibody therapeutic for the treatment of patients with metastatic or surgically incurable soft tissue sarcomas (STS), received accelerated approval from the U.S. Food and Drug Administration (FDA) for use in combination with doxorubicin. This represented the first new therapy approved by the FDA for the initial treatment of STS since the approval of doxorubicin more than 40 years ago.
The FDA, knowing the pressing unmet need of patients with life-threatening STS, reviewed olaratumab with orphan drug and priority review status, as well as fast track and breakthrough therapy designation. This also led to an analogous approval, known as a conditional marketing authorization, from the European Commission (EC) on November 11, 2016. These accelerated/conditional approvals were granted with the requirement that the manufacturer, Eli Lilly and Company, conduct a randomized controlled (phase III) trial to verify and further describe the clinical benefit of olaratumab given with doxorubicin in patients with STS. Importantly, that phase III trial was already nearly fully accrued by fall 2016, although the results are evolving and remain unreported.
The approvals were based on a single randomized clinical trial involving 133 patients with metastatic STS who were randomly assigned to receive the combination of olaratumab plus doxorubicin versus single-agent doxorubicin. That trial showed no statistically significant increase in either rates of progression-free survival (PFS) or objective responses. However, a striking and statistically significant increase in overall survival (OS) was demonstrated with the addition of olaratumab to doxorubicin compared to doxorubicin alone (26.5 vs. 14.7 months, respectively; HR 0.46; p = 0.0003).1 This is a far greater OS benefit than might be expected given the lack of impact on PFS.
Given these potential internal inconsistencies in the trial that supported regulatory approval, should physicians use olaratumab as a new standard of care for patients with metastatic STS today, or wait until the phase III trial results are available? In this issue’s Current Controversies in Oncology column, I offer support for the current use of olaratumab and the regulatory accelerated/conditional approvals, and my colleague Dr. Jaap Verweij offers support for waiting for the definitive results.
The Case for the Current Use of Olaratumab
Medical decisions are often fraught with imperfect information. In the case of accelerated approvals of “breakthrough therapy”–designated agents, the foundation for approval should be sufficiently strong in an unquestionably serious illness without other effective alternatives, so that the decision-making is more easily justifiable even without certainty.
In this clinical case, there is no question that metastatic STS is a very serious and potentially life-threatening set of cancers. The heterogeneity of STS is widely appreciated: not all subtypes are equally aggressive, and there is no biomarker to predict whether any type of conventional chemotherapy will benefit a given patient with STS. Nonetheless, in the subsets of metastatic STS for which an expert physician would consider doxorubicin therapy, there is no doubt about the gravity of the disease.
Should the FDA and the EC have approved olaratumab for use today, or should they have waited for the definitive phase III trial? In my opinion, the actions of the FDA and EC show a strong sensitivity to the plight of patients and families facing rare life-threatening diseases. The single randomized trial demonstrated a very impressive beneficial impact, with prolonged OS in the patients who received the combination of olaratumab plus doxorubicin. Although it is highly unexpected that any OS benefit of this magnitude would not be accompanied by an even larger impact on PFS, “the data are the data.” The agencies ruled in favor of patients today by using the available information.
If the regulatory agencies had not approved olaratumab, current patients might be faced with a loss of a year or more of life, since the phase III trial will likely not mature for another year or longer. Given that the median OS of patients with metastatic STS receiving first-line chemotherapy remains in the range of 12 to 30 months in many trials, a loss of nearly an extra 12 months of median lifespan is highly clinically impactful and could represent a near-doubling of survival. Why should patients have to die waiting for the phase III trial? That is the strong message from the regulatory agencies, and it is completely aligned with the wishes of patients, families, and health care professionals who want to offer the best current options to patients. This is a particularly good example, since the addition of olaratumab seemed to add remarkably little to no additional toxicities to the chemotherapy alone. There will, no doubt, be a financial toxicity with the addition of olaratumab, but as physicians caring for patients with rare life-threatening diseases, we can rest assured that these uncommon cases in severe need should not overly stress any high-resource nation’s health care cost burden. Therefore, by this logic, patients with rare STS may reasonably be allowed earlier access to expensive agents with such large impact in early, unconfirmed trials, since it would take much longer to accrue definitive large trials, and current patients should not be forced to miss out on potential benefits while larger trials are in progress.
As physicians and patients who do want the best options, however, it is also critical that we view this situation for what it is: simply the early access to an agent which has early data supporting impact. What if the definitive phase III data, when finally available, do not support any statistically significant OS benefit from giving olaratumab with doxorubicin compared to doxorubicin alone?
In that case, we should maintain the rigor of our analyses and seek confounding effects (both in the underpowered phase II randomized trial, as well as in the definitive phase III trial). Perhaps the control group did somewhat worse than might be expected in the phase II trial, while the experimental group did somewhat better, leading to the positive impact on the composite outcome metric of OS, which is based upon what happens during the trial as well as being confounded by any and all post-study interventions?
If the phase III data eventually prove positive and confirm the phase II benefit, patients treated today will be thankful that they were able to access this life-prolonging therapy. However, if the phase III data eventually show no benefit, at least patients treated today will not have lost anything from their health status, as there appears to be no increase in toxicities (other than cost) from adding olaratumab to doxorubicin. If the phase III trial data prove negative, we would expect the approvals of olaratumab to be annulled rapidly.
We all know that statistics can be confounded by the play of chance, especially in small numbers of heterogeneous patients with diseases as disparate as STS without any molecular selection biomarkers. It is also relevant to note that no biomarker was found to predict benefit in the randomized phase II trial testing this highly specific targeted agent developed to act through antibody-mediated blockade of the platelet-derived growth factor (PDGF) receptor alpha (PDGFRα).
For clinical practice today, the accelerated availability to this agent offers clinicians a promising (though not as yet definitive) and rational new option for patients facing these serious, life-threatening sarcomas. As a community, we should thank the regulatory agencies for allowing broad distribution of olaratumab so that patients today can benefit while the data evolve to guide practice based on the most definitive and comprehensive evidence possible. Today, we have a single multicenter, prospective randomized phase II trial: that is enough to drive practice while awaiting the final word from the fully accrued phase III study.
One final point: it is a testament to the collaborative spirit of the international sarcoma clinical research community that the large phase III randomized trial of olaratumab in STS was fully accrued with a target population of nearly 500 study participants in about 1 year from study initiation (NCT02451943). This timing also allowed physicians to support the phase III testing without having to address ethical questions of equipoise, as the regulatory approvals in the United States and Europe were granted when the phase III trial had essentially been fully accrued.
In summary, the availability of this agent certainly sets a new, though conditional, set of standards for patients and physicians who are considering doxorubicin-based therapy for STS. It is a positive addition to our therapeutic armamentarium, at least for the moment—and hopefully, once benefit is confirmed, forever!
The Case for Awaiting Definitive Phase III Results
By Jaap Verweij, MD
Erasmus University Medical Center
More than 40 years after the first reports on activity of doxorubicin in STS, the armamentarium for drug treatment of this rare group of diseases, albeit expanded in those 4 decades, is still fairly limited. With the exception of the advent of imatinib for the treatment of the sarcoma subtype gastrointestinal stromal tumors (GIST), major advances have not occurred, and doxorubicin is still considered as a gold standard for most other STS subtypes.
The outcome of the well-performed and thoroughly analyzed randomized phase II study on doxorubicin +/- olaratumab reported by Tap,1 and outlined by Dr. Demetri in this issue, is therefore fascinating—but at the same time, deeply puzzling.
Olaratumab is a fully human IgG1 monoclonal antibody selectively targeted against, and binding to, the human PDGFRα. Thereby it blocks PDGF ligand binding and specifically inhibits PDGFRα activation and downstream signaling. Overexpression or aberrant activation of PDGFRα has been reported in several tumor types, both on cancer cells and in tumor stroma. Targeting PDGFR signaling may therefore affect tumor growth directly, as well as indirectly via effects on the tumor stroma. PDGFR inhibition has also been reported to decrease the interstitial pressure in the tumor, resulting in an improved delivery of co-administered cytotoxic agents.2,3 Olaratumab, either alone4 or combined with doxorubicin,5 exhibited tumor growth inhibition in human STS cancer xenografts. These data stimulated clinical studies on the interaction of olaratumab with chemotherapy.
In view of the fact that the topic of investigation was the addition of a novel drug to a standard agent, the randomized design applied by Tap et al. indeed was the only appropriate one. However, randomized phase II designs, by definition, should still be considered as screening tools, and not as designs that can provide definitive proof of efficacy. For cytotoxics, regardless of diseases involved, the positive predictive value of a phase II study, as far as OS is concerned, has been limited.6 In the 5 decades of its existence, the EORTC Soft Tissue and Bone Sarcoma Group performed many phase II and III studies on current standard cytotoxic drugs such as doxorubicin and ifosfamide in the first-line treatment of metastatic disease. And almost without exception, the phase II studies always yielded better results than the subsequent phase III studies.7 This does not mean that the drugs studied were inactive, but the phase II study simply largely overestimated the true treatment effect size. While experience with targeted agents is somewhat better,8 we should never lose sight of the limitations of trial design, and thus the outcome of the study reported by Tap et al. should be assessed as a positive signal, rather than definitive evidence.
Importantly, the study protocol required that PDGFRα expression was assessed by immunohistochemistry at a central laboratory before randomization. After the study was completed, the used assay was found to recognize both PDGFRα and PDGFRβ, so a new PDGFRα-specific assay was developed and used for all post-hoc efficacy analyses. Of concern, in those post-hoc analyses Tap et al. found that in the majority (66%) of the patients in their study, there was no expression of the drug target in the tumor tissue (and immediate environment).
An additional cause for caution comes from the fact that another randomized phase II trial pursuing the same concept of interaction in non–small cell lung cancer (NSCLC), in a combination of paclitaxel plus carboplatin, failed to show any additional benefit,9 which challenges the validity of the hypothesis. Studies combining olaratumab with mitoxantrone in prostate cancer, and with liposomal doxorubicin in ovarian cancer, have completed accrual but results have not yet been reported.
So, while at face value the results of the clinical study of Tap et al. seem to confirm preclinical observations, there is no supportive evidence for the concept from other clinical trials, and most importantly, they leave us with the problem that it is difficult to explain how a drug can work in absence of its target. If other, unknown mechanisms of interaction between olaratumab and cytotoxic drugs exist, explaining the outcome of the study, these will first need to be elucidated.
PDGFR inhibition has been pursued for quite some years, also in STS. Many of the VEGFR inhibitors also effectively block PDGFR. While these drugs did express single-agent activity in various tumor types, they were not very active in STS, with two exceptions. All such multitargeted kinase inhibitors that also blocked PDGFR were effectively blocking KIT as well and, likely because of the latter, were found to be very active in the KIT-mutated sarcoma subtype GIST. In other subtypes, activity was at best modest, albeit that pazopanib, one of these agents, showed statistically significant prolongation of PFS and received market authorization in most non-GIST STS subtypes based upon the outcome of a placebo-controlled randomized phase III study.10
Combinations of these multitargeting PDGFR inhibitors with cytotoxic drugs yielded considerable toxicity and, likely because of this, have never shown effects of the magnitude currently suggested for olaratumab. Supportive evidence for the observation from this perspective is therefore also lacking.
In contrast to those multitargeted agents, olaratumab, being a monoclonal antibody with a single target, up to now has not shown any impressive single-agent activity, and was found to be inactive in GIST.11
Another puzzling observation in the study is the divergence of the survival curves after treatment completion. A similar observation of a bigger magnitude of improvement in OS than in PFS was made in the recent phase III study comparing eribulin to dacarbazine in previously treated STS.12 The fact that we now have two studies in STS showing such discrepancy is unusual. How can one explain these survival curves in absence of, or as an only modest effect of, the treatment on the anatomic size of the tumor and the time to first progression? It has been suggested in both cases that the drugs (olaratumab, as well as eribulin) sensitize to the effect of subsequent therapy.
Tap et al. performed very thorough post-hoc sensitivity analyses to explore the effect of subsequent antitumor therapy, and suggest that the inhibitory effect of olaratumab on PDGFRα signaling might persist. Again, this is somewhat difficult to understand, if in the majority of the patients the drug’s target was not even present.
The study also leaves us with other questions, mostly related to small numbers of patients on study.
There are over 70 different histologic STS subtypes, with very heterogeneous disease aggressiveness and treatment sensitivity. Whether the imbalance in numbers of liposarcomas and “other” sarcomas between the two study arms hides a possible explanation of observed effect requires additional experience. We should also realize that the number of deaths affecting the OS on study numerically only differed by six cases, which is a small number on which to base a change of practice.
In view of the high unmet medical need in patients with STS, the findings of Tap and colleagues are absolutely interesting, but they require confirmation in a larger study. It is good to know that the involved company immediately succeeded the phase II study by a double-blind phase III study (ANNOUNCE, NCT02451943) with doxorubicin plus olaratumab or placebo. The results of this study are eagerly awaited, alongside a better understanding of the mode of action of olaratumab. In addition, we will need to await affirming data on a reliable biomarker related to PDGFRα for optimum patient selection.
In fall 2016, olaratumab received conditional marketing approval both in the United States and in Europe. This presents the practicing physician with a two-sided ethical dilemma. If evidence-based medicine is to prevail, the marketing authorization based on a phase II study may be considered preliminary. Should the phase III study be unable to confirm the results of the phase II study, and olaratumab be considered inactive, providing the drug now to patients outside of a trial setting would mean a debatable increase of financial burden to society. Should the phase III results, however, confirm the phase II study and thereby provide true evidence of effect, it would mean that withholding the drug now could be seen as withholding from patients a chance of benefitting from an active treatment.
Early marketing approval does not always solve our problems.
- Tap WD, Jones RL, Van Tine BA, et al. Lancet. 2016;388:488-97.
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- Tonra J, Deevi D, Carrick F, et al. Enhanced antitumour activity of anti-platelet derived growth factor receptor alpha antibody, IMC-3G3, in combination with doxorubicin against a human soft-tissue sarcoma xenograft model (A67). Presented at: AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics International Conference; November 2005: Philadelphia, PA.
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