SAN FRANCISCO - For decades, melanoma specialists had few treatments to offer their patients. Recent drug approvals and an expanding list of experimental agents and combinations, though, have improved that scenario. With those choices, however, come questions about how to optimize individual patient care. To help oncologists address the issue, two melanoma experts here at the Oncology Congress described their criteria for selecting first-line therapy for patients with advanced melanoma.

Although the meeting program billed the presentations by Mario Sznol, MD, Professor and Vice-Chief of Medical Oncology and Co-Director of the Melanoma Program at Yale School of Medicine, and Jeffrey Sosman, MD, Professor of Medicine and Director of the Melanoma and Tumor Immunotherapy Program at Vanderbilt-Ingram Cancer Center, as a debate over first-line immunotherapy versus first-line targeted therapy, the speakers agreed on more information than not.

Ipilimumab: A Powerful Tortoise

Both Dr. Sznol and Dr. Sosman emphasized that the drugs' characteristics and pharmacodynamics go a long way toward determining which patients should receive which drug.

Ipilimumab works by taking the brakes off the patient's immune system, allowing it to attack and control the tumor. Clinical trial results indicate that some patients will have robust responses to the drug, and that the responses may continue long after treatment is completed.

"Clearly five to 10 percent of patients will develop very durable remissions with ipilimumab," Dr. Sznol said. "Not all of these patients have complete remissions. Some of the patients that I think are long-term responders had mixed responses, with maybe 80 to 90 percent of their tumors regressing, a single lesion progressing, which is taken out surgically, and they continue benefiting for a long time."

The downside to ipilimumab and other immunotherapies is that responses take time, and time is something many advanced melanoma patients unfortunately don't have. Therefore patients who have aggressive disease or a large tumor burden are not likely to benefit from ipilimumab treatment. That said, subgroup analyses in the clinical trials suggest that some patients with high-risk disease by classic characteristics can respond to the drug.

"Just having high LDH or M1c disease is not a reason for not treating a patient with ipilimumab," Dr. Sznol said. "I think you have to determine how fast a patient's disease is progressing and how much tumor burden he has when you make that decision."

Vemurafenib: A Fast-Moving Hare

In contrast to ipilimumab-and most cancer treatments-vemurafenib and other BRAF inhibitors work at lightning speed. However, only those patients whose tumors carry a BRAF mutation should receive a BRAF inhibitor. "It is very important that patients who do not have BRAF mutation should not get vemurafenib," Dr. Sosman said. "There is data that it could accelerate their disease."

In addition to speed, BRAF inhibitors induce responses in approximately 80% of patients. The downside to these agents is that resistance develops relatively quickly in many responders, with a median progression-free survival of six to seven months.

But that is just the median, Dr. Sosman emphasized. "There are patients who relapse at six to seven weeks, but there is also a tail that is much more impressive than we initially appreciated."

The randomized Phase III trial with vemurafenib will not yield overall survival data due to crossover, but overall survival data are available from a single-arm Phase II trial. Of the 132 patients enrolled, 61% had M1c disease, about half had high LDH, and more than half had two or more prior therapies. Yet the median overall survival is 15.9 months, said Dr. Sosman, who noted that the trial data have not yet been published, much to his consternation. "That is probably the longest overall survival I've seen in a large multicenter phase II trial," he said.

Moreover, when his team looks at the 48 patients who participated in the Phase I vemurafenib trial and who received the Phase II dose or close to it, there were some long-term responders. With a follow-up of two to three years, seven patients remain on therapy and four have no signs of progression.

Dr. Sosman cautioned that although these numbers are small, they do suggest that some patients can have sustained response to the drug. Median overall survival in these patients was 14.5 months, with landmark analyses showing a 54% one-year survival rate and a 33% two-year survival rate.

Another misconception about BRAF inhibitors that Dr. Sosman sought to dispel is the idea that all patients who get these agents relapse with aggressive disease. "Many of these patients relapse at a single site, get resected, and can go back on their BRAF inhibitor," he said. "There is a group of patients who relapse very rapidly with uncontrolled disease, but the best indicator is that those are the patients who come in like that."

Matching Patients & Drugs

For patients who have rapidly progressing disease, the only real choice is vemurafenib, both experts agreed. It is unlikely that these patients can wait the amount of time required for ipilimumab treatment and responses.

"There is no doubt, we would all agree, that vemurafenib is the only therapy we have ever had for symptomatic patients with high LDH who need rapid improvement in their performance status," Dr. Sosman said. Prior to vemurafenib, he said, he would have recommended hospice for many of these individuals.

Remarkably, though the patients who seem to derive the most benefit from vemurafenib are the same ones who are most likely to benefit from ipilimumab-the ones with slower growing disease and less tumor bulk. For such patients, Dr. Sosman said he can't make a passionate argument that they should all get vemurafenib. "But if your goal is to put patients into remission for as long as possible-which is something that as oncologists we all try to do with good quality-then vemurafenib is much more likely to do that [based on response rates].

"But certainly these are the patients also where you may see long-term responses with ipilimumab and IL2."

Dr. Sznol raised the issue of sequencing when he considered these patients. He noted that giving vemurafenib first may make it difficult to give ipilimumab later because a patient who relapses on vemurafenib may not have the time to respond to immunotherapy.

By contrast, if one starts with ipilimumab, vemurafenib may still be effective at progression because it works so quickly.

"In a perfect world, we would lead with a BRAF inhibitor and then a month or two later, when T cells have infiltrated the tumor, we would add ipilimumab," Dr. Sznol said. "But we are in an artificial situation right now because we don't have the answers to the [necessary] trials of the two agents together" to know how best to combine or sequence them.

Dr. Sosman noted that some of the patients who participated in the Phase II vemurafenib trial received ipilimumab after progression, and that a few responses to the immunotherapy had been reported. "I can say BRAF inhibitors do not impair immune responses, and in fact, there is some evidence from Jedd [Wolchok, MD, PhD] that it may enhance immune responses."

Dr. Sznol said the issues he weighs when deciding between the therapies are the rapid versus slow responses, patient tumor burden (low burden better suited for immunotherapy), patient history of autoimmune disease, which would exclude them from ipilimumab therapy due to excess toxicities, a low lymphocyte count may predict lower response to ipilimumab, and acute versus long-term toxicity (Immunotherapy is associated with more acute toxicity but better long-term quality of life, with the chance to be off maintenance therapy). He noted that both drugs can control brain metastases in some patients, and thus the presence of CNS disease is not a point of selection.

Clinical Trials Still Necessary

For patients who either don't respond to the single agents or aren't eligible to receive them, there are numerous ongoing clinical trials. For example, Dr. Sznol says that early results with an antibody against PD-1, which is another T cell regulatory protein, have shown considerably higher response rates than seen with ipilimumab and many of the complete responses are durable.

In the targeted therapy arena, there are combinations of BRAF inhibitors with MEK inhibitors. Phase I data showed a marked reduction in squamous cell cancers, relatively to single-agent BRAF inhibitor therapy, but the efficacy trials for the combination are ongoing.

But at the end of the session, both Dr. Sznol and Dr. Sosman said that what is really needed now are combination and sequencing trials with vemurafenib and ipilimumab. Dr. Sosman noted that even patients who have a complete durable response to vemurafenib will likely relapse at some point, and that there are already five or six known mechanisms of resistance to the agent.

If, on the other hand, one can combine the agents, researchers might get the high response rates of vemurafenib and the durability of response seen with ipilimumab. So far, though, that trial has not opened for enrollment.

NEW YORK CITY-There is very compelling biology to indicate a role for vascular endothelial growth factor (VEGF) in normal ovarian function, as well as the growth and development of advanced-stage ovarian cancer, providing a rationale for targeting VEGF with agents such as bevacizumab.

"It's a given that VEGF is a biologically relevant target and that bevacizumab is an effective therapeutic agent with acceptable toxicity," said Michael A. Bookman, MD, Chief for Hematology/Oncology and Professor of Medicine at the University of Arizona Cancer Center, speaking here at the Chemotherapy Foundation Symposium. "It's just a question of who should be treated, and when, and with what compounds and combinations.

"What's missing from recent bevacizumab trials is that we haven't nailed down the optimal dose, timing, duration, and sequence of bevacizumab administration, and we still don't have predictive biomarkers to guide treatment interventions for bevacizumab."

Dr. Bookman noted that data from several recent trials with bevacizumab in ovarian cancer suggest that prolongation of progression-free survival appears greater in the front-line management of patients with large-volume disease, as well as in the setting of recurrent disease.

He said it appears that bevacizumab can be used for high-risk patients as maintenance post-chemotherapy or at the time of recurrence, either as a single agent or in combination with chemotherapy, although some people might certainly challenge these points.

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Best in Advanced, Recurrent Disease

Dr. Bookman said bevacizumab seems to be largely targeting the host or environment rather than directly targeting the tumor itself, as the tumor makes VEGF which triggers an angiogenic response from the host. "The implication is that bevacizumab will probably work better in patients who have ascites or large volume disease which have been associated with a high VEGF state. Treating someone [with bevacizumab] after optimal cytoreductive surgery and chemotherapy with only microscopic residual disease may not provide much benefit, because there's not much tumor-related VEGF in the body."

That's a hypothesis that could be tested, he said, but the data are showing consistently that larger volume disease, recurrent disease, and patients with ascites seem to have more immediate benefit from bevacizumab than people treated after chemotherapy and surgery in the front-line setting.

He said that ascites is the most well-recognized hallmark of VEGF production-"you can almost guarantee that is related to VEGF production in ovarian cancer, and if you treat with an anti-VEGF it will respond, perhaps not 100%, but the ability to control ascites is impressive."

In Recurrent Disease

Another speaker, William P. McGuire, MD, Director of the Weinberg Cancer Center and Professor of Medicine and Oncology at Georgetown University, agreed with Dr. Bookman on the use of bevacizumab in recurrent disease rather than in primary treatment of advanced ovarian cancer.

He said in the OCEANS trial with platinum-sensitive recurrent disease, the hazard ratios for progression-free and overall survival were significantly better (PFS HR 0.45) than in either trial of primary therapy, GOG218 (PFS HR 0.717) or ICON7 (PFS HR 0.81).

"This suggests that bevacizumab has a greater role in recurrent disease," he said.

The reason might be seen in early trials of neoadjuvant taxane therapy for ovarian cancer which showed that treatment actually increases microvessel density, as measured by CD31 and CD105.

Pro-angiogenic factors from bone marrow may also be involved during recovery from previous chemotherapy, Dr. McGuire said. That would make antiangiogenic therapies have a proportionally greater effect following prior cytotoxic therapy.

Smaller Trials Needed

Dr. Bookman said the most important question researchers should ask, with bevacizumab or any new agent, is how to use an investigational drug at the point in time and optimal clinical-biologic setting when it can provide the most benefit, "and not just run them in a large Phase III front-line trial designed to achieve FDA approval."

"I'm being critical, but I have shared these thoughts with industry," he said. "We need to do more small, intelligent, randomized, exploratory studies to figure out what's important.

"Eventually you have to do the large Phase III randomized trials to establish a new standard of care, and to achieve FDA registration, but at least you would be conducting these trials in the right population at the right time. Current Phase III trials involve millions of dollars and substantial clinical resources. Many of these large trials are negative, in part, due to unrealistic and untested expectations."

Dr. Bookman said it's necessary, with industry collaboration, to develop comparative and combinatorial data for targeting angiogenesis and associated pathways using selective randomized Phase II trials.

"The pharmaceutical industry and academic laboratories have shifted their priorities, and are not creating new cytotoxic chemotherapy drugs, but are, instead, concentrating on newer molecular targeted agents. So now we are [in a way] putting chemotherapy aside, and have to switch paradigms and focus on molecular targeted approaches, growth factors, antiangiogenesis, and intracellular signal transduction cascade."

This is challenging, he said, because it involves a network, and when one element is perturbed it causes feedback responses, corrective responses, or escape responses in other pathways. This calls for a new paradigm in testing, Dr. Bookman said.

"Taking one drug, testing it in the old fashioned way and saying it is good or not may not be the preferred strategy," he said, in an interview. "It may be more appropriate to test drugs in combination so you knock out multiple arms of the same pathway or related pathways."

He said companies may be slow to engage in research to evaluate and compare these agents, and may not feel comfortable sharing intellectual property, until they have at least one primary FDA approved indication for their drug.

"Once FDA approval is obtained, it is easier to do combination and comparative studies, but while it is still an investigational drug and not approved, it is very hard unless you have a neutral broker in the middle like the National Cancer Institute or something similar."

He said he would like to see more early studies with small numbers of patients, to determine whether a bevacizumab-type drug is better than a tyrosine-kinase inhibitor or not, or whether to use them in combination, or use with an mTOR inhibitor (for example).

"We could have answered those questions many years ago if we had done those small trials, but it's been hard to get the pharmaceutical industry to collaborate and sponsor these trials.

"What we need are more intelligent, smaller studies, such as randomized Phase II trials, to tell us what the Phase III trials should be," he said. "We are jumping from small studies with new agents directly into Phase III trials that are costing $100 million."

Our current clinical trials infrastructure is complex, with substantial administrative and regulatory overhead. In that context, larger studies are actually easier to conduct, he said. As a result, we are compelled to launch several large trials, but they are studying one drug at a time, primarily to seek a pathway toward regulatory approval, rather than looking at the science and biology and figuring out how to do the very best for our patients. In addition, running large Phase III trials obligates our centers to focus clinical resources and enroll patients into these studies, making it harder to address the scientific and clinical questions we have."

WILLIAM P. MCGUIRE, MD, ended his presentation by asking whether society can afford bevacizumab as it is used now, noting that the literature in general shows that new therapies costing less than $100,000 per life year saved are considered economically rational-for example, when paclitaxel was added to platinum in the GOG 111 study in the mid-1990s, the incremental cost effectiveness ratio was about $30,000, but comparing maintenance paclitaxel in the GOG178 study with maintenance bevacizumab in GOG218, those were $13,000 and $327,000, respectively-"certainly not a great buy."

Can We Afford Bevacizumab?

Dr. McGuire ended his presentation asking whether society can afford bevacizumab as it is used now. He said the literature in general shows that new therapies costing less than $100,000 per life year saved are considered economically rational. For example, he said, when paclitaxel was added to platinum in the GOG 111 study in the mid-1990s, the incremental cost effectiveness ration (ICER) was about $30,000 (though obviously less now that paclitaxel is generic).

But comparing maintenance paclitaxel in the GOG178 study with maintenance bevacizumab in GOG218, the ICERs were $13,000 and $327,000 respectively-"certainly not a great buy," he said.

And a study comparing the three arms of GOG218 revealed ICERs of $480,000 for concurrent paclitaxel-carboplatin-bevacizumab, and $401,000 for paclitaxel-carboplatin-bevacizumab followed by maintenance bevacizumab (Lesnock: Gynecol Oncol 2011 Sep;122[3]:473-478), making consolidation paclitaxel far more cost-effective than bevacizumab following upfront treatment of advanced epithelial ovarian cancer.

"No one has done an analysis from the OCEANS trial yet, but clearly with a better hazard ratio for bevacizumab in that study it will certainly be a better buy than in GOG218," he said.

NEW YORK CITY-Phase III trials have shown that the anti-VEGF agent bevacizumab has an important role in treating advanced ovarian cancer. But VEGF is not the only driver of angiogenesis, and targeting VEGF is not the only way to inhibit angiogenesis in this disease.

Antiangiogenic agents with different mechanisms of action include the multi-targeted tyrosine kinase inhibitors that target VEGFR, angiopoietin antagonists, PARP inhibitors, and molecules that target the folate receptor.

"We've been hypnotized a bit that [angiogenesis] is about VEGF, because there are other drivers," said Bradley Monk, MD, Professor in the Division of Gynecologic Oncology at Creighton University School of Medicine at St. Joseph's Hospital and Medical Center in Phoenix. Dr. Monk discussed new agents in ovarian cancer in a presentation here at the Chemotherapy Foundation Symposium.

Dr. Monk said he has a degree of optimism about treating ovarian cancer, but that is countered by the large number of pathways involved in ovarian cancer and the limited number of drugs approved for it by the Food and Drug Administration.

"Ovarian cancer is one of the deadliest solid tumors, yet there is no FDA-approved targeted agent, and no new drugs at all have been approved by the FDA for ovarian cancer in more than five years," he said.

Folate an Important Target

Folate is a promising target in ovarian cancer, but not through the mechanism by which folate is taken into the cell. The target is the folate receptor, which Dr. Monk said is an emergency pathway that is overexpressed in ovarian cancer. This molecule can be targeted with a humanized antibody that induces antibody-dependent cytotoxicity and complement cytotoxicity.

The antifolate farletuzumab (MORab-003) has shown antitumor activity and favorable toxicity in Phase I and II trials in first relapse of platinum-sensitive ovarian cancer, Dr. Monk said.

"This is an exciting approach, because [in a Phase II trial) there was a 90% normalization in CA-125 and a 70% response rate."

Folate-linked drugs can be attached to a wide variety of compounds, Dr. Monk said, including chemotherapy, immunotherapy, gene therapy imaging agents,- liposomes, nano-particles, and proteins.

And because folate is small compared with antibody, folate-linked drugs can achieve superior tumor penetration, he said.

EC-145, a conjugate that selectively binds to cells that overexpress the folate receptor, is in an ongoing Phase II randomized trial combined with pegylated liposomal doxorubicin. Dr. Monk said this combination yielded better disease control in second- or third-line treatment than does pegylated liposomal doxorubicin alone.

Because there are no predominant driving mutations of any importance in ovarian cancer, Dr. Monk said researchers are also targeting the microenvironment. But he said this is not the same type of pathway-driven cancer one would think of in other diseases such as lung cancer.

In this realm, aflibercept, a VEGF-trap agent, is an anti-angiogenic agent that has the advantage of hitting multiple targets. Its lack of target specificity leads to unexpected toxicity, but also promising efficacy, he said. Interestingly, reductions in tumor blood flow have been seen on dynamic MRI within 48 hours of aflibercept administration.

The Tie2 tyrosine kinase receptor is another novel target, Dr. Monk said, targeted by AMG-386, a recombinant peptibody against the angiopoietin antagonist peptide-Fc fusion protein.-386 potently and selectively inhibits angiopoietin-1 and angiopoietin-2, which bind Tie2.

Dr. Monk noted that a Phase II trial showed that dose matters with AMG-386. In that placebo-controlled trial of AMG-386 plus paclitaxel in platinum-resistant patients, all patients in the AMG-386 10 mg arm had a CA-125 reduction, but not all those in the 3 mg arm did.

"This anti-angiogenesis approach has a toxicity profile distinct from that of VEGF-axis agents such as bevacizumab and aflibercept," Dr. Monk said. The unique toxicity is edema, and patients have also experienced peripheral neuropathy related to paclitaxel. But there is not the bowel perforation or hypertension seen with anti-VEGF therapy, he said.

Two large randomized Phase III trials with AMG-386 plus paclitaxel (TRINOVA-1) and with pegylated liposomal doxorubicin (TRINOVA-2) are ongoing, and a front-line trial (TRINOVA-3) is planned.

He noted that another class of activated targeted agents in recurrent ovarian cancer inhibits the enzyme poly-ADP ribose polymerase (PARP). PARP inhibitors are particularly active in tumors with BRCA1 or BRCA2 dysfunction, he said, and cause multiple double-strand DNA breaks that cannot be efficiently repaired, leading to apoptosis.

Normal cells are spared since they have intact homologous DNA repair (normal BRCA function), he said.

"Because ovarian cancer is genetically unstable, I believe cytotoxics are still important." The most important cytotoxic agent in ovarian cancer to date is NKTR-102, a topoisomerase-I inhibitor-polymer conjugate with reduced peak concentrations and a continuous concentration profile.

Inhibiting MET

Another speaker at the meeting discussed the activity of cabozantinib (XL-184), an oral inhibitor of MET and VEGFR2.

Ronald J. Buckanovich, MD, PhD, Assistant Professor of Internal Medicine and Obstetrics and Gynecology at the University of Michigan Comprehensive Cancer Center, said MET overexpression has been observed in advanced ovarian cancer, and agents that inhibit MET show activity in preclinical models.

"Simultaneous targeting of the MET and VEGF signaling pathways with cabozantinib may therefore be a promising treatment strategy," he said.

In a randomized Phase II discontinuation trial of cabozantinib in advanced ovarian cancer, the overall disease control rate was 53% by Week 12. Response rates were 18% in platinum-refractory patients, 22% in platinum-resistant patients, and 29% in platinum-sensitive patients.

"After 36 weeks of follow-up, the median duration of response has not been reached," he said.