Treatment for Bone Metastases may Increase Survival

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Treatment for Bone Metastases may Increase Survival in Lung Cancer Patients

http://blog.lungevity.org/2011/07/18/zg ... otti-wclc/

July 18th, 2011 - by Dr. Jack West

Late last year, the new agent XGEVA (denosumab), an agent that helps inhibit destruction of bone, was approved by the FDA for patients with skeletal metastases from solid tumors, in the wake of a randomized phase III trial that demonstrated a significant reduction in the rate of development of skeletal-related events (SREs)(including fractures induced by the metastasis, need for narcotic pain medication, or need for palliative radiation to a bone lesion) compared with the pre-existing standard of Zometa (zoledronic acid) for bone metastases. However, there was no difference in overall survival in the trial as a whole, which included patients with multiple myeloma or solid tumors other than breast cancer and prostate cancer (which were each studied in separate trials). A few months later, the report from the phase III trial was published, and I actually wrote the editorial that accompanied this piece, in which I argued that while XGEVA reduced SREs, the fact that there was no improvement in survival and considerably higher cost made XGEVA a very reasonable and even compelling option but not necessarily a clear winner as a declared standard of care when the cost vs. benefit of the agent over Zometa is taken into consideration. I also raised the point that if overall survival (OS) were to be improved in a subset of patients, the argument favoring XGEVA would be more compelling, as was noted in a very limited way for patients with NSCLC in the randomized trial:

It is therefore notable that, in a post hoc analysis of OS in the Henry et al( 11) trial, the HR for NSCLC was statistically superior with denosumab for patients with advanced NSCLC.

Among the many interesting presentations from the World Conference on Lung Cancer in Amsterdam was one by Dr. Giorgio Scagliotti that provides far more detail on the post hoc (retrospective) analysis of patients with lung cancer from this trial, which I would argue make me far more inclined to recommend XGEVA for patients with bone metastases from lung cancer, even if the results weren’t completely conclusive in a pure sense.

The entire overall trial enrolled 1776 patients with a range of cancer types, of which 40% had NSCLC and 9% had SCLC: this large subset of 811 patients with lung cancer served as the basis for this presentation. Looking at the entire group with lung cancer, there was a statistically significant 20% improvement in OS that translated to a 1.2 month prolongation in median OS, as illustrated in the figure (click the blog link to see the graph).

In fact, this benefit appeared to be of the same magnitude in patients with NSCLC or SCLC, as shown (click the blog link to see the graph).

Finally, within the large subset of patients with NSCLC (702 of the 811 with lung cancer), the benefit appeared very comparable in patients with adenocarcinoma vs. squamous cell NSCLC, with a bit higher magnitude of a survival benefit in patients with squamous NSCLC (click the blog link to see the graph).

In fact, the difference in median survival (in the 1-2 month range for these subsets) appears to underestimate the true benefit, since the curves become more separated out over time.

So what should we make of these data? When you step back and try to decide what to make of the resutls, it’s appropriate to not get too hung up on the statistical significance of these results in either direction. This was a post hoc subset analysis, which means that the results can’t be taken as the gospel: the trial wasn’t really designed to answer this question, and you could characterize the positive results as just a “fishing expedition” that happened to show these results that were then highlighted. On the other hand, this is a very large group of patients, and my interpretation is that the survival benefit is likely real even if not 100% proven in a prospective trial, and that it appears to be present for both NSCLC and SCLC, and in both of the main NSCLC subtypes. Notably, the mechanism for this apparent survival benefit isn’t clear, but there are studies looking into this question in earnest now.

In the larger trial and a few others (one just focusing on patients with bone metastases from prostate cancer, and another just in patients bone metastases in the setting of breast cancer), XGEVA has a similar and really not worse tolerability, a more convenient means of administration (under the skin rather than an IV infusion), doesn’t require frequent monitoring of kidney function the way Zometa does, and does significantly reduce the rate of skeletal complications in patients with bone metastases.

Taken together, my overall impression is that there was already a strong if not definitive case to be made for using XGEVA over Zometa in patients with bone metastases from solid tumors, including lung cancer, but cost and question of value were relevant disadvantages that could fairly fit into the equation. However, if we believe that the survival benefit is real and clinically significant (and I do, on both counts, despite the formal caveats of a retrospective analysis of patient subsets), this is enough to convince me that XGEVA is a clearly stronger alternative, and frankly could be considered a relative bargain for providing a survival benefit of up to a couple of months for a small fraction of the cost of many other agents that we use in this setting (Avastin comes immediately to mind, though there are others that don’t make a great case for value). Even though I had expressed some caution about XGEVA in my editorial based on the available data from that analysis, I’m now convinced that the value proposition of it just went way up for the lung cancer community.