The Life Sciences Report: You have been a principal investigator in several different clinical trials exploring skin cancers and their metastatic manifestations. Because of your position at a major teaching institution, do you see mostly advanced-stage or late-stage patients? Are you ever able to see early-stage or treatment-naïve patients?
Sanjiv Agarwala: Being in an academic/teaching institution, it can go either way. Because of my specific interest and expertise in melanoma, and having maintained good working relationships with community oncologists and other physicians in the area, I tend to have patients referred at all stages. Of course, many of them are advanced stage because those patients need me more. But I do get patients with early-stage melanoma, at least for an opinion.
Here at St. Luke's Cancer Center, when a patient is referred to us, we keep him or her in our database and on our clinic schedule so that we are able to pick up any kind of recurrence or metastases early and intervene in a timely manner, either with treatment or with enrollment in a clinical trial.
TLSR: Were you trained as a hematologist/oncologist?
SA: Yes. Some melanoma specialists come from a dermatology or surgery background, but I was trained in hematology/oncology and, before that, in internal medicine. I'm technically triple-boarded. But as I have developed my career, I have focused on melanoma and the immune system, and that's pretty much all I do now.
TLSR: Would you briefly compare melanoma versus squamous cell carcinoma versus basal cell carcinoma? What sets melanoma apart? Is it a propensity to metastasize to very tragic areas, such as the brain and liver?
SA: Absolutely. Skin cancer as a whole is extremely common. More than several million patients per year develop skin cancer in the U.S. But melanoma is the least common of all the skin cancers, and is diagnosed in approximately 90,000 (90K) Americans per year. What sets it apart, aside from being the least common, is that it is also, unfortunately, the most dangerous. However, the good news is that if melanomas are picked up early, most of them can be cured—and thank goodness most of them are picked up early.
"Provectus Biopharmaceuticals Inc.'s PV-10 produced not only a local shrinkage of tumor, but also significant responses in noninjected lesions."
There are a couple of issues that make melanoma so dangerous. One is that many melanomas don't look like what you might expect a melanoma to look like, and so they're hard to identify. The second issue is that melanoma does have a propensity to metastasize. But it's a tricky cancer that metastasizes even when it's small, which is somewhat unique. When you think you've picked it up early, and you dig deeper, clear the margins, do the sentinel lymph node mapping and so on, you might find that even a small tumor has already metastasized. These factors make melanoma unique.
Another thing is that when melanoma metastasizes to different parts of the body, it tends to metastasize to more dangerous areas—the more tragic areas, as you put it—like the brain and liver. Any organ can be involved, however, and in fact, the most common site of melanoma metastasis is the lung, as well as other subcutaneous tissues, where patients tend to have a better prognosis and survival rate than those with metastases to the liver or the brain.
TLSR: Squamous cell carcinoma occurs much more frequently, and it also metastasizes, doesn't it?
SA: Yes. But squamous cell metastasizes much less frequently than melanoma. Basal cell carcinomas very rarely metastasize. Still, both these cancers can metastasize and become a clinical problem, and should therefore not be ignored.
TLSR: All tumors, solid as well as those of hematologic origin, learn to circumvent chemotherapeutic agents and even antibodies. Tumor cells evade and even learn how to pump out therapeutic drugs. At a later stage of disease, do you see melanoma as more resistant to chemotherapy than, let's say, squamous cell carcinoma?
SA: Yes, indeed. Melanoma is actually one of the most resistant tumors to any kind of chemotherapy—not only compared to squamous cell of the skin, but to any cancer, including lung cancer, head-and-neck cancer and breast cancer. This extreme resistance to chemotherapy is why classic chemotherapy drugs are rarely used in melanoma, and almost never as a frontline option. Melanoma has the ability to evade the immune system, but it also arouses the interest of the immune system more than some other cancers. That is why we have used immunotherapy as a treatment modality for melanoma with some success.
TLSR: Is this the reason that interferon, an immunotherapy, has been such a popular therapeutic agent in melanoma?
SA: Yes. In fact, until recently, there were basically three drugs that were U.S. Food and Drug Administration (FDA)-approved for melanoma. One is interferon, an immunotherapy that is used in adjuvant therapy, which is prevention of relapse or recurrence. Another drug used in the metastatic setting is interleukin-2 (IL-2), which is given in high doses that can produce significant toxicity. It's a bit hard to use in most patients. There is also a chemotherapy drug called dacarbazine, which was approved in an era when treatment regimes were different. It's been around for 30 years and has never actually shown a survival advantage in melanoma; I honestly don't think it would be approved by the FDA today.
"In the future we will be diagnosing all cancers mostly on genotype."
A lot of progress is being made in melanoma therapies right now, mostly in immune and targeted therapies. As I said, the immune system is very important in melanoma, which is exactly why interferon has been used quite extensively in the adjuvant setting for a while, and will continue to be used for some time to come.
TLSR: When the pathologist sees a melanoma lesion under the microscope and looks at its histopathology, the diagnosis of melanoma is not hard to make. Are we getting to the point where our diagnoses are becoming even more differentiated? Are we starting to see melanomas diagnosed by their genotype—by their epigenotype or mutations—as we see in breast cancer and some other areas?
SA: Those kinds of mutations are not so much used for diagnostic purposes. The melanoma is still diagnosed by its histopathology and the use of special stains performed by the pathologist. But the next step, which is now routine, is to test the melanoma genotype, specifically looking for certain mutations that have value both in prognosis and therapy. You used the breast cancer paradigm; certainly that is what's happening.
I think that, ultimately, what we call melanoma will prove to be not one disease, but that we will diagnose different types of melanoma in a molecular sense. We know that melanomas that arise from the skin are different from those that arise from the mucosa. These melanomas, in fact, have different mutations, and the affected patients have different prognoses, as well as different responsiveness to drugs. We're just beginning to scratch that surface. But in the future we will be diagnosing all cancers mostly on genotype.
TLSR: What targets look interesting to you today on the molecular level?
SA: The BRAF mutation is certainly the most important, and the most widely used. More than one drug has been approved for treatment of patients who have the BRAF mutation, and those drugs can be quite effective. The BRAF mutation is present in approximately 40–50% of patients with melanoma, and that makes it very interesting. We saw the approval of a first-in-class BRAF inhibitor, vemurafenib (Zelboraf; Genentech/ Roche Holding AG [RHHBY:OTCQX]) back in August 2011.
"A lot of progress being made in melanoma therapies right now, mostly in immune and targeted therapies."
Genentech is also developing a MEK/BRAF combination inhibitor, which is not yet approved but is in clinical trial. We're waiting for the results. Genentech, to my knowledge, is the frontrunner in the targeted therapy area, and is now studying its antibody, MPDL3280A, targeting PD-L1 (programmed cell death-ligand 1), which is upregulated on tumor surfaces. The idea behind the anti-PD-L1 and anti-PD-1 (programmed cell death-1) antibodies is to unmask the tumor cells, thereby taking the brakes off the immune system, in part by rejuvenating T cells. These drugs make the immune system much more powerful, and are changing immunotherapy for us. We've always thought of immunotherapeutic agents as having very low response rates and being very slow-acting. Now we think immunotherapy can actually have high response rates and can work quicker.
TLSR: Are there other targets you think could be interesting?
SA: There is a c-KIT mutation, which is more common in mucosal melanomas. Another mutation, called NRAS, is common in cutaneous or skin melanomas. NRAS, interestingly, does not occur if you have a BRAF mutation, so if you don't have a BRAF, you should look for the NRAS. Clinical trials are in progress now targeting NRAS mutation-positive melanomas.
We're just beginning to explore this arena. There are going to be other mutations out there, and we are just beginning to learn which drugs might target those mutations. The BRAF mutation is ready for prime time. The others are being developed.
TLSR: I note that you've been doing a study testing interferon alfa versus peginterferon alfa-2b (Sylatron; Merck & Co. Inc. [MRK:NYSE]). Could you comment on that?
SA: Most of my research has been done in high-dose interferon, and I have been involved with these trials through the Eastern Cooperative Oncology Group (ECOG), where I've been a coinvestigator and a coauthor of many papers. The pegylated interferon, or peginterferon, regimen work was done in Europe. Based upon a large European trial, peginterferon is now available in the U.S., and I'm using it with some of my patients right now.
The only study on pegylated interferon that I'm involved with currently is a quality-of-life study. It's our theory and our observation that patients who receive pegylated interferon have a better quality of life, but no one's actually proven that, so we are comparing pegylated interferon to high-dose interferon. It's not a randomized trial.
TLSR: When you talk about quality of life, is this about terminal-stage disease?
SA: No—in fact, quite the opposite. Just to clarify, interferons are used in early-stage disease, such as stage IIB, IIC or III disease. We are talking about patients who are potentially cured from the surgical standpoint, but because of a high recurrence rate could be affected again in the future. Interferon is used in an effort to lower the risk of recurrence.
"What sets melanoma apart, aside from being the least common skin cancer, is that it is also, unfortunately, the most dangerous."
However, these drugs are not perfect, and we can't guarantee they will work. Frankly, a patient may not need the drug, but we just don't know. Therefore, when you have someone who's potentially cured, quality of life becomes a very important issue. While the drugs do reduce the risk of recurrence and, in some cases, improve survival, the patient has to deal with the toxicity. The study focus is on maintaining a high quality of life during this treatment, and not on end-stage patients.
TLSR: This is an investigator-sponsored, observational study?
SA: It's a 100-patient trial pilot study. It was a concept I put forth from our cancer center; we have funding from Merck & Co., which makes interferon and is very interested in these data. Merck has given us an unrestricted grant to do this research.
TLSR: I note that the final data collection for this trial is supposed to be complete in December 2014.
SA: The trial will be open longer than that, I'm sure. We hope to get 100 patients in the study by December, but we may not. The trial will remain open until we get 100 patients. We'll analyze the data and then, hopefully, we'll learn something interesting, publish it, and potentially move into a larger trial.
TLSR: Three years ago there was a tremendous amount of excitement surrounding the approval of ipilimumab (Yervoy; Bristol-Myers Squibb Co. [BMY:NYSE]) for melanoma. Are you using this antibody?
SA: I am. Ipilimumab is approved and indicated for advanced melanomas that are metastatic but not surgically curable—for stage IV patients, and unresectable stage IIIs.
There was tremendous excitement about the approval of this agent because it was the first-ever drug to be approved in advanced melanoma based upon a survival advantage in a randomized clinical trial. There have been others since then, but this was a breakthrough. Ipilimumab has a role, but not as an adjuvant therapy—not just yet. Trials with ipilimumab are ongoing in the adjuvant setting.
TLSR: Is the theory here that if ipilimumab works, and shows a survival advantage in stage IV, it could be helpful in earlier-stage disease?
SA: Exactly right.
TLSR: What's the future of melanoma therapies, Sanjiv? Is it going to come down to training a patient's system to deal with the disease?
SA: I think the future of melanoma therapies is going to be twofold. First, as we learn more about these various molecular pathways and targets, we're going to find drugs that will specifically hit those targets and will potentially be very effective. We already see this with the BRAF mutation. The other path is with immunotherapies. We are developing and learning much more about the immune system and how we might stimulate it to be more powerful.
"The future will feature both immunotherapies and targeted therapies, and then we'll work on how to put them together."
The great advantage of immunotherapy is that it doesn't require or depend on a specific mutation, at least that we know of. We can give the therapy to all patients with advanced melanoma who qualify. For the mutational drugs, the patient has to be mutation-positive for the therapy to work. Immunotherapies also tend to be more durable in their outcome and response, though that could change as we develop new agents on the targeted side.
I think the future will feature both these therapies, and then we'll work on how to put them together. Do we use them at the same time or in sequence? Which goes first, which goes second? We are going to spend many years doing the science and the research.
TLSR: You've discussed some large pharmas and their efforts. Amgen Inc. (AMGN:NASDAQ), a large biotech, is also doing some work in your area. Could you briefly talk about what it's doing in melanoma?
SA: Amgen has a very interesting agent, talimogene laherparepvec (T-Vec). It is an interesting agent because it's an intralesional (direct tumor injection) therapy that produces a localized systemic immune response primarily using a viral vector to manufacture granulocyte macrophage colony-stimulating factors (GM-CSFs). Amgen completed a randomized clinical trial of T-Vec versus subcutaneous GM-CSF with a durable rate of response endpoint. The trial was positive and the data were presented at the American Society of Clinical Oncology (ASCO) meeting last year. I am sure we'll see an update this year at ASCO, which will take place in Chicago at the end of May and beginning of June.
T-Vec has efficacy. I think the only issue with this particular drug is that the trial was done in an era when we didn't have ipilimumab, or some of the other newer drugs for melanoma. The landscape has changed, and it will be interesting to see where T-Vec will fit in. I'm not sure of Amgen's plans in terms of submitting it for regulatory approval—I assume it will. Once it's approved—if it's approved—how will clinicians use it? Will they use it in combination? To me, an intralesional therapy is much more interesting in combination with ipilimumab and other immunotherapy agents.
TLSR: Speaking of intralesional therapies, you have been a principal investigator in clinical trials studying Provectus Biopharmaceuticals Inc.'s (PVCT:OTCQB) drug PV-10 (10% rose bengal disodium). Tell me about that.
SA: PV-10 is an interesting agent. I have done work with it in a Phase 2 trial. We've presented and published abstracts on the data.
PV-10 is also an intralesional therapy. What is so interesting is that PV-10 produced not only a local shrinkage of tumor, but we also saw a significant number of patients with significant responses in noninjected lesions. We call that a bystander effect. The agent must have a distant effect, which we believe is working through the immune system. Our colleagues at the H. Lee Moffitt Cancer Center & Research Institute are coming up with nice data that explains how the immune system might be affected and improved with PV-10. Once again, though, PV-10 is an intralesional therapy, so it needs to be researched in patients with locoregional (restricted to a local area) disease. When you get a distant bystander effect, it's a bonus—it's great to see.
TLSR: In your comments about Amgen's T-Vec, you said it would be much more interesting used in combination with another agent. What about PV-10 in combination?
SA: A drug such as PV-10 would be extremely interesting to combine with other immunotherapies, particularly because it's very safe. In fact, the median age in the trial we did with PV-10 was more than 70 years. The treatment had very little systemic toxicity—in fact, almost no systemic toxicity. Almost all the toxicity was local, in terms of some pain and inflammation. I can give it to a much older and more medically compromised patient population. But then, wouldn't it be nice to combine with another immunotherapy and see if we can get a synergistic effect? That's what I hope we will do with PV-10.
TLSR: With regard to the bystander effect, I'm wondering about how longer-term studies with PV-10 could turn out with respect to preventing recurrence of disease and metastasis. The problem with that, as I see it, is that you must have a tumor present in which you will inject the drug to achieve that immunological, or bystander, effect. The clinician must administer the drug before the tumor mass is excised. Is that indeed the case?
SA: Yes—a tumor needs to be in place. These patients have generally had multiple surgical treatments but the disease has recurred, and a tumor is present because of that. You need to inject a tumor to stimulate and set up the necrosis—the desired chemoablative effect—in the tumor, and potentially trigger the immune response as well. Currently, we are using PV-10 in clinical trials in disease that is not surgically resectable.
"Melanoma has the ability to evade the immune system, but it also arouses the interest of the immune system more than some other cancers."
But, you do bring up an interesting concept. If you have a patient with a lesion that you can resect surgically—one that you can actually remove—perhaps you could give a single injection—or more than one—of PV-10 prior to resection in an effort to stimulate the immune system. You would remove the tumor after that. This is, however, a research question. I would love to see that trial happen, but it has not yet been done.
TLSR: I know we're talking relatively small numbers, but have the responses to PV-10 therapy looked durable so far?
SA: What we're seeing is that both the injected lesions and the bystander effect tend to be durable. Obviously, we are looking at a Phase 2 database, so we would need to confirm that in a larger trial, potentially in a Phase 3 trial. But with the 80-patient data we have in Phase 2, the responses look durable.
TLSR: I'm noting that Provectus has an expanded access (compassionate use) protocol going on with PV-10. A lot of companies, especially small companies, might not want to dirty up their new drug application or final label by including late- or end-stage patients. I think this shows a lot of confidence in the program.
SA: I agree. We have an expanded access program available for patients who might benefit from this therapy. Obviously, I would only use that protocol for patients who have tried and exhausted most other options, because this is still an investigational drug.
TLSR: Have there been any interesting responses that you've seen in these expanded access patients?
SA: There have been. What we've seen in the expanded access program pretty much reproduces what we've seen in the Phase 2 trial. It's a smaller number of patients—I think we've had nine patients at my center so far. I don't know the data from the other centers as yet. But what we've seen with our expanded-access patients gives us confidence that our data from the Phase 2 study are robust.
TLSR: Sanjiv, it's natural, in most cases, for the first physician seeing a melanoma patient to want to treat that patient, whether that's the dermatologist or the oncologist. Because they may specialize in this area, it's not obligatory for the first clinician to refer the patient to a center like St. Luke's, is it?
SA: That's true to some extent. I think dermatologists are often the ones who diagnose the melanoma based on a skin lesion, and they sometimes refer and sometimes don't. I find that as oncologists build relationships, dermatologists tend to refer more patients. Often, these patients need fairly good management. Also, by having access to a center with expertise in melanoma, dermatologists may feel quite comfortable in getting a blessing, if you will—or an opinion—because they never know when the patient might need us. The patient might as well get to know us early.
TLSR: It seems to me that as long as community physicians know you're not their enemy or that you're not going to make them look bad, they may be more willing to refer at an earlier stage.
SA: That's exactly what we try to foster. I make it very clear that if a physician sends someone to me for a second opinion, and if whatever I'm going to offer that patient is exactly the same as what the referring physician can offer, I encourage the patient to go back. There's no point in having a patient travel a long distance to see me.
Because melanoma is relatively rare, many oncologists would prefer to have the patient treated by me here at St. Luke's because of some of the intricacies of the new therapies, especially in more advanced disease cases. But I always give patients that option. Also, you're right that we never want to make referring physicians look bad. We also don't want them to feel like if they send patients to us, they will never hear about the cases again. We provide good feedback and keep referring clinicians in the loop. We don't steal their patients, so to speak.
TLSR: It has been a pleasure talking to you about melanoma. Thank you.
SA: It's my pleasure. We can look forward to very interesting data from all the agents we have talked about at the upcoming ASCO meeting.
Dr. Sanjiv Agarwala is chief of medical oncology and hematology at St. Luke's Cancer Center in Bethlehem, PA, and professor of medicine at Temple University School of Medicine in Philadelphia. He is nationally and internationally recognized as an expert in the research and treatment of melanoma and cutaneous malignancies. He graduated from the University of Bombay, and did residencies and fellowships at the University of Bombay in India, Dunedin University in New Zealand and University of Pittsburgh. Dr. Agarwala has special interest and expertise in immunotherapy for cancer. He has been principal investigator for several clinical trials involving immunotherapy and targeted therapy for melanoma and other malignancies. He has written more than 100 publications and book chapters on melanoma and other research areas. He is board-certified in oncology, hematology and internal medicine, and is an active member of several professional and scientific societies, including the American Association for Cancer Research, the American Society of Clinical Oncology, the European Society of Medical Oncology and the Society for Melanoma Research.
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