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Nicholas Vogelzang, MD: Unmet Needs in Oncology
October 24, 2016
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Klara Czobor:  Our first question Dr. Vogelzang is what malignancy do you primarily treat in your practice?

Dr. Vogelzang: Being a general oncologist in private practice, I get to treat many different malignancies. I primarily treat prostate, kidney, and bladder cancer. I also treat patients with testicular cancer and sarcoma, as well as smaller numbers of patients with non-small cell lung, colorectal, and pancreatic malignancies.

Klara Czobor: Could you please outline what you believe to be the treatment gaps for some of these malignancies?

Dr. Vogelzang: Yes, let’s start with prostate cancer. The most pressing clinical need right now in my practice is what should be done after patients fail the taxanes. The taxane we initially use is docetaxel, and then when patients relapse, we use cabazitaxel.

Just recently, I had a patient who relapsed on cabazitaxel but is currently healthy. Guidelines state that we should send him to hospice or give him mitoxantrone, which has never been shown to be effective as a third or fourth line treatment. I always try to use a platinum-based agent following taxane failure, but exactly what to use after taxane failure is a huge unmet need. I don’t have any standard of care therapy to give my patients following taxane failure, and as I’ve just mentioned, these patients are quite healthy.

Klara Czobor: So do you send these patients to hospice or do you place them in a clinical trial, or do you try different sequences of therapies?

Dr. Vogelzang: Well, note that these patients have already received a large number of different therapies. They all receive hormone therapy, sipuleucel-T, abiraterone, enzalutamide, radium 223, docetaxel, and cabazitaxel, and they’re all relatively healthy. So they’ve already gone through the standard treatments. This results in a huge unmet medical need, namely what to do after cabazitaxel. That’s 25,000 people per year who don’t have an effective, approved treatment available to them.

Stephen Strudwick: Do you envision there being any therapies or classes of therapies on the horizon that may satisfy this unmet need?

Dr. Vogelzang: Not yet. There are ongoing clinical trials. Most notable are the PARP inhibitors, which seem highly active in patients with germline and somatic DNA repair deficiency. These may be the same patients who respond to platinum-based therapy. As far as the other agents are concerned I’m not too optimistic about the results. I do give platinum agents to many cabazitaxel refractory patients, or I’ll try whatever therapy possible to keep the disease under control. However, I do have to be mindful of possible issues with insurance reimbursement.

Stephen Strudwick: So regarding some of the other malignancies you see in your practice, what are the challenges associated with treating these malignancies?

Dr. Vogelzang: There are a number of effective regimens available now for pancreatic cancer including gemcitabine, Abraxane, FOLFIRINOX, and liposomal irinotecan, all of which can be used sequentially. But following use of these therapies, all that’s available to patients are clinical trials. Unfortunately, many of these patients do not qualify for these trials, as they may, for example, have renal dysfunction or neuropathy. So enrolling patients in clinical trials can be challenging, especially if they have already received 3 lines of chemotherapy. That’s a big unmet need.

There are a number of exciting and novel therapeutic options for patients with kidney cancer, including lenvatinib, cabozantinib, and nivolumab. In fact, the large number of available therapies has actually enabled me to use some options again in later lines of therapy. Thus the need for more therapies for patients with renal cell carcinoma is not as pressing as it is for some other malignances.

For bladder cancer, once an upfront regimen has been used, either as a neoadjuvant or for treating metastatic disease, the next option is the newly FDA approved drug atezolizumab (Tecentriq). It now appears that the other immune check point agents (pembrolizumab, nivolumab, durvalumab, and avelumab) are also active so we should see more FDA approvals in 2017. Other future options, FGFR3 inhibitors are being developed by Janssen and Incyte, will hopefully be available soon. However, FGFR mutations or overexpression are only found in about 10-12% of patients. So finding new therapies to treat patients with bladder cancer is also an unmet medical need. I currently initially treat patients with MVAC or a GC (gemcitabine-cisplatin), then atezolizumab, and then I’ll use a taxane and ramucirumab. Ramucirumab added to docetaxel is also a promising second or third line option.

Klara Czobor: What therapeutic developments in oncology are you looking forward to seeing in the near future?

Dr. Vogelzang: Well, it’s a bit premature, but I’m hoping that Prostvac, a new immune therapy from BMS, will prove to be efficacious in prostate cancer, especially given its novel mechanism of action. Otherwise, there are no other emerging therapies for prostate cancer that appear to me to be “game-changing”. There are a number of agents in development for prostate cancer that have similar mechanisms of action to existing, approved therapies. Once approved, their labels may reflect slight differences compared with existing therapies.

Note that Radium 223 effectively treats prostate cancer but is currently limited to 6 doses. Being able to re-treat patients with Radium 223 would be an exciting development. Studies are underway to look at higher doses of Radium and or longer duration of therapy. The agent may also be more effective if used when the cancer is still in the hormone sensitive phase.

Regarding treatment advances for patients with renal cell cancer, my guess is that combined therapies will become the standard of care in the future. The use of monotherapies such as sunitinib or pazopanib may decrease in favor of combined therapies such as an immune agent combined with another agent such as bevacizumab, ipilimumab or axitinib. Overall survival in renal cell cancer may be further increased when using a combined therapeutic approach.

Klara Czobor: Are there any other malignances for which you foresee challenges in the near future?

Dr. Vogelzang: Well, patients with non-small cell lung cancer who have received EGFR therapies are in need of second generation and third generation agents. Pfizer does have a new agent that appears effective in ALK-mutated lung cancer, but that’s a rare indication.

A major challenge associated with treating non-small cell lung cancer is how to appropriately treat patients who have a poor performance status. There are some clinical trials available for these patients, but in general, currently available therapies are not effective. We hope that the immune check point inhibitors will be safe and effective when used as first line therapy in such patients

I’m glad to say that patients with sarcoma now have a number of therapeutic options including trabectedin and eribulin after first line doxorubicin. Just this month, the FDA approved olaratumab, an antibody against platelet-derived growth factor, in combination with doxorubicin. The combination achieved a median survival of 26.5 months compared to 14.7 months for doxorubicin alone. These advances are very good news for sarcoma patients who generally are in the 40-50 age range.

Stephen Strudwick: Which malignancy do you feel has seen the most advancements in treatment over the last couple of years?

Dr. Vogelzang: Definitely kidney cancer, followed by prostate cancer, and then bladder cancer.

Unfortunately, drug resistance is emerging, and will continue to emerge as novel therapies for these malignances become established. Acquired immune checkpoint inhibitor resistance is being observed in both kidney and bladder cancers. Specifically, nivolumab resistance in kidney cancer and atezolizumab resistance in bladder cancer are becoming major problems. Note that acquired immune checkpoint inhibitor resistance is also being observed patients with melanoma who have received ipilimumab and nivolumab.

There are a number of ongoing trials of therapies that may “inhibit” checkpoint inhibition resistance. These therapies include epigenetic modulating agents, which may change the genetic structure of tumors allowing them to be recognized by the immune system. While these agents are still in the early stages of development, they are promising.

Also note that immune checkpoint therapies do not appear to be effective in some major malignancies such as colon and prostate cancer. This “overall resistance” to immune checkpoint therapies is a major issue, and a number of pharmaceutical companies are trying to ascertain how to increase the effectiveness of these therapies in these cancers.

So I think in general, addressing overall and acquired resistance to immunotherapies is going to be an important focus of clinical trials in the future.

Stephen Strudwick: So are there any other malignancies that we haven’t discussed, which you believe are about to see some important advances?

Dr. Vogelzang: Well, I think important advances are being made in the treatment of patients with brain tumors. I just saw an interesting article discussing the treatment of pediatric brain tumors with nivolumab, and there’s definitely room for the development of further efficacious therapies.

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1 comment

  1. This is very interesting. Thank you!