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XGEVA (Denosumab) for Lung Cancer: Survival Benefit Suggested by Retrospective Subset Analysis of Key Trial

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Late last year, I reviewed the approval of the agent XGEVA (denosumab) for patients with skeletal metastases from solid tumors after a randomized phase III trial demonstrated a significant reduction in the rate of development of skeletal-related events compared with the pre-existing standard of Zometa (zoledronic acid) for bone metastases. Importantly, 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 publication of the phase III trial came out, and I actually wrote the accompanying editorial, in which I argued that while the results showing improvement in the endpoint of skeletal-related events, no improvement in survival, marginally better side effect profile, but considerably higher cost made XGEVA a very compelling option but not necessarily an iron-clad unchallanged standard of care when the cost vs. benefit of the agent over Zometa is taken into consideration.

Though I suggested that the results were provocative but not overwhelming from the bird’s eye view, I 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 al11 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. Dr. Weiss provided a summary of the presentation in his great review of that day, but here I’ll provide a little more information (primarily just the “picture’s worth a thousand words” synopsis).

The 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 below:

os-denosumab-vs-zoledronic-acid

(click on image to enlarge)

In fact, this benefit appeared to be of the same magnitude in patients with NSCLC or SCLC, as shown below:

os-nsclc-denos-vs-zoled os-sclc
Finally, as noted by Dr. Weiss, within the group of patients with NSCLC (702 of the 811 with lung cancer), the benefit seemed comparable in patients with adenocarcinoma vs. squamous cell NSCLC, with a bit higher magnitude of a survival benefit in patients with squamous NSCLC:

os-nsclc-by-histologic-type

As Dr. Weiss suggested in his preliminary discussion of this report, 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? 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. As Dr. Weiss noted, the mechanism for this apparent survival benefit isn’t clear, but there are studies looking into this question in earnest now.

Along with the improvement in SREs and this reported improvement of survival in patients with lung cancer, XGEVA has a similar and really not worse tolerability, a more convenient means of administration (under the skin rather than an IV infusion), and it doesn’t require frequent monitoring of kidney function the way Zometa does.

Taken together, my overall take 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. In fact, as a therapeutic agent beyond its role as a supportive care agent, XGEVA could frankly be considered a relative bargain in 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 (Hello, Avastin!). 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.

Thoughts?


11 Responses to XGEVA (Denosumab) for Lung Cancer: Survival Benefit Suggested by Retrospective Subset Analysis of Key Trial

  • ssflxl says:

    Dr. West

    Do you give Xgeva after someone has bone mets or do you give it to anyone with metastatic lung cancer (may not involve bone)hoping to prevent bone mets. Is it used for prevention of bone mets?

    thanks

    ssflxl

  • Dr West says:

    No, it’s not studied at all and not indicated for people without a history of bone metastases. I also wouldn’t presume in any way that the survival benefit described above would be generalizable to lung cancer patients who don’t have established bone metastases.

    -Dr. West

  • DianaJ says:

    I had severe adverse reaction to Xgeva five hours after the injection on April 14, 2011. I had chest and back pain as well as severe vomiting; ended up in the ER for IV pain med and Zofran.
    Since then I have not had Xgeva again and my oncologist wants me to switch to Zometa. I just finished 4 cycles of carbo/taxol and earlier had successful radiation for bone met in pelvic bone. I will be looking at starting Zometa and Lucanix trial. Since Zometa and Lucanix are both considered immuno type of treatments; is there any problem with getting both treatments concurrently?

  • Dr West says:

    I don’t think of Zometa as being particularly immune-mediated. Regardless, I don’t believe there is any reason to suspect any significant interaction or contraindication to pursuing these two approaches concurrently.

    -Dr. West

  • DianaJ says:

    Thanks Dr. West for your timely response. I really wanted to try Xgeva again….but my adverse reaction was frightening and my body was shaking as if in shock.

  • Laya D. says:

    YAYYYYYYYY (given that my Mom had her 3rd infusion of XGEVA last week)!!!!!

    Laya

  • Apra says:

    This is the first time i’m hearing of XGEVA. This site is really priceless. My husband was having Zonetrib? or Zometa for bone mets. Is this the agent causing so much side effects? He has it infused along with Carbo/Paclitaxol
    Apra

  • Dr West says:

    Acute side effects are less common with XGEVA (although they tend to get milder for Zometa with more treatments after the first few), & kidney problems are less frequent with XGEVA (though can happen uncommonly for both); the feared but fortunately relatively rare side effect of osteonecrosis of the jaw (ONJ) is seen comparably (around 1% of patients) with both, while low blood calcium levels are seen more commonly with XGEVA, though that risk is much lower if people take supplemental calcium and vitamin D as recommended.

    -Dr. West

  • Apra says:

    My husband was prescribed Shellcal 500 but no vitamin D was prescribed. Should I ask the doctor? I find that the doctors here do not like proactive patients. So I am in a bind. I’m afraid to suggest Xgeva too for the next chemo. I wonder if Cisplatin and Zometa can go together since both cause kidney problems. This time he has had no problems with Carbo/Taxol and 4mg Zoledronic acid. (third round).
    Though he is complaining about a nagging pain in the back which I hope is just pain radiated from the healing scars of herpetic zoster lesions, I don’t dare think they might be related to bone mets.
    Apra

  • Dr West says:

    Vitamin D should be available over the counter, so taking at least 400 units/day and perhaps 1000 units is likely to be an easy option to pursue even if you don’t get a prescription from the doctor.

    It’s fair to wonder whether a potentially kidney-damaging agent like cisplatin combined with a drug like Zometa may lead to a higher incidence of kidney problems, but to my knowledge that hasn’t actually been directly evaluated.

    -Dr. West

  • roosty says:

    These studies have indicated that Xgeva does indeed have a benefit in OS vs. Zometa.

    http://www.medpagetoday.com/clinical-context/LungCancer/36021

    Regards,
    Shane

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