Anna Azvolinsky, PhD

A new generation of agents that target androgen synthesis and androgen receptor (AR) signaling have provided proof of concept and robust data to support the hypothesis that the androgen pathway remains an important factor throughout the treatment of patients with castration-resistant prostate cancer (CRPC), according to Robert Dreicer, MD, MS.

Although CRPC formerly was considered a &ldquo;hormone refractory&rdquo; disease, there are now 2 recently approved antiandrogen therapies and approximately 10 novel agents in development, according to Dreicer in a presentation March 2014 at the

7th Annual Interdisciplinary Prostate Cancer Congress

Yet there are many unanswered questions about how best to integrate antiandrogen therapies into the treatment paradigm for CRPC, particularly in light of other new agents that the FDA has approved during the past 3 years. &ldquo;Drug development is outpacing our ability to understand the sequential and combination utility of these therapies,&rdquo; said Dreicer, who is chair of the department of solid tumor oncology at the Taussig Cancer Institute and a professor of medicine at the Cleveland Clinic Lerner College of Medicine in Ohio.

In 2011, the FDA approved the first novel antiandrogen agent, orally available abiraterone acetate (Zytiga), in combination with prednisone for patients with metastatic CRPC based on the COU-AA-301 phase III clinical trial.

The trial showed a survival advantage compared with placebo for patients treated with the abiraterone regimen who had progressed following chemotherapy, providing proof that the androgen pathway remains relevant throughout the course of prostate cancer and that patients need to be maintained at castratelevels of testosterone after progression following primary androgen- deprivation therapy, noted Dreicer. A second phase III trial in the prechemotherapy setting demonstrated that men treated with abiraterone achieved a significant increase in radiographic progression-free survival (rPFS), but the study did not show a statistically significant survival advantage.

Abiraterone works by inhibiting the lyase CYP17, an enzyme important in the pathway of both testicular and extragonadal androgen synthesis.

In 2012, the FDA approved enzalutamide (Xtandi) for the treatment of men with metastatic CRPC who have previously received docetaxel. Enzalutamide, which is supplied in capsules, has a mechanism of action distinct from that of abiraterone; enzalutamide prevents AR interaction and blocks downstream pathway activity. The phase III AFFIRM trial showed that enzalutamide prolonged survival in men with CRPC in the postchemotherapy setting compared with placebo.

In the subsequent PREVAIL trial in patients with CRPC who had not received prechemotherapy, men treated with enzalutamide had an improved rPFS and a 29% reduction in the risk of death compared with participants in the placebo arm.

Novel androgen-targeting agents currently under investigation include lyase inhibitors and AR inhibitors. Because these agents have mechanisms of action similar to those of either of the two agents already in use in clinical practice, it may be difficult to show improvement in efficacy, Dreicer noted.

&ldquo;The development of these agents has presented us with some interesting dilemmas,&rdquo; said Dreicer. &ldquo;The reality is that going head to head in a setting where there are very similar drugs already may not be a strategy for drug approval going forward.&rdquo;

For example, a second-generation CYP17 inhibitor, orteronel (TAK 700), did not show a survival advantage compared with placebo in an interim analysis of the ELM-PC5 phase III study,

although the drug did show a benefit in rPFS in patients who had previously been treated with chemotherapy. However, a geographic analysis showed that in parts of the world that do not currently have access to either abiraterone or enzalutamide, there was a survival advantage. Other lyase inhibitors in development include CFG920, VT-464, and EN3356.

Likewise, there are new antiandrogens in development. ARN-509, an AR antagonist, is bypassing both the pre- and postchemotherapy settings and is currently being tested in an earlier patient population-patients categorized as high-risk M0, prior to the spread of disease to lymph nodesin an effort to prevent progression to metastatic disease.

Other antiandrogens being explored include ODM-201, AZD-3514, and EZN-4176.

Another agent, galeterone (TOK-001), is considered both a lyase inhibitor and an antiandrogen. Galeterone has 3 distinct mechanisms of actions, according to the NCI Drug Dictionary: (1) as an AR antagonist; (2) as a CYP17 inhibitor; and (3) as an agent that decreases overall AR levels.

With the emergence of new active therapies, many clinical questions have emerged. Dreicer told the audience that he uses the &ldquo;one-third&rdquo; rule: one-third of patients will be inherently unresponsive to these newer agents, one-third will have short-lived responses of several months, and another third will have long-term responses. The issue for the field is to identify each of these patient subsets, which is currently not possible. As patients are moved from one treatment regimen to another, cross-resistance also may become an issue since the molecular pathways of resistance for these compounds are multiple and may be overlapping.

Other questions not yet addressed in the field are the optimal timing to start these agents and when to stop therapy. &ldquo;You could argue that maintaining testosterone close to zero is a good thing but the cost of abiraterone may be too high for many patients,&rdquo; Dreicer acknowledged.

The role of combination therapy in the CRPC setting also remains an open question. One study addressing the potential benefit of combining lyase inhibition with AR inhibition is an Alliance for Clinical Trials in Oncology phase III trial that will randomize patients 1:1 to either enzalutamide or enzalutamide with abiraterone plus prednisone.

Other issues include whether or not agents that decrease skeletal events are necessary in addition to enzalutamide or abiraterone (because both of these agents alone have been shown to decrease skeletal events in metastatic CRPC patients) and whether or not moving these agents to premetastatic and adjuvant settings can potentially cure patients.

Prostate cancer research will need to address these questions quickly because the increasingly complex treatment paradigm is putting pressure on the development of new drugs, as are the economics of treating patients with the newer, relatively more costly agents, concluded Dreicer.

de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer.

Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy [published online December 10, 2012].

Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy [published online August 15, 2012].

Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide in men with chemotherapy- na&iuml;ve metastatic prostate cancer (mCRPC): results of phase III PREVAIL study.

Dreicer R, Jones R, Oudard S, et al. Results from a phase 3, randomized, doubleblind, multicenter, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy (ELM-PC5 trial.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01946204.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01949337.

Articles

A new generation of agents that target androgen synthesis and AR signaling have provided proof of concept and robust data to support the hypothesis that the androgen pathway remains an important factor throughout the treatment of CRPC.

Androgen-Targeting Therapies Increasing in CRPC

In the last decade, there have been tremendous improvements in the treatment of HER2-positive breast cancer with new HER2-targeted agents improving survival in both the adjuvant and metastatic settings. At the Miami Breast Cancer Conference, we spoke about this progress and the current focus of research in the HER2-positive breast cancer setting with breast cancer expert, Sunil Verma, MD, MSEd, FRCPC, an associate professor at the University of Toronto and chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Canada.

What is the current state of HER2-targeted therapy in metastatic disease?

In metastatic disease, over the past decade, we have seen a nearly doubling of the overall survival (OS) for patients with metastatic HER2-positive breast cancer since the pivotal publication of Slamon et al, in 2001, which showed an improvement from a 20-month to 25-month survival with integration of trastuzumab, and now we are seeing an improvement in OS with the addition of pertuzumab with docetaxel in the CLEOPATRA study, which is beyond 45 months. This survival improvement has been fueled through integration of new agents, such as pertuzumab, and also through the continuation of HER2-positive therapy with trastuzumab and lapatinib. The other key achievement is the development of T-DM1. This is the first time in solid tumors that an antibody-drug conjugate has been shown to be associated with an improvement in OS with superior toxicity profile. And so having both an improved OS with less toxicity is a remarkable achievement for our patients with HER2-positive disease.

What about for HER2-positive therapies in the adjuvant setting?

Targeted Oncology spoke about progress in the treatment of HER2-positive breast cancer with breast cancer expert, Sunil Verma, MD, MSEd, FRCPC.

Q & A With Dr. Sunil Verma: Targeted Treatments for HER2-Positive Breast Cancer

The first combination therapy for advanced melanoma received approval from the Food and Drug Administration (FDA) January 2014. The oral, targeted combination of a MEK inhibitor, trametinib (Mekinist) and a BRAF inhibitor, dabrafenib (Tafinlar) was approved for patients with metastatic melanoma whose tumors harbor a

mutation. Both drugs were approved for the same indication as single agents in 2013.

Combinations of next-generation targeted agents for advanced melanoma are also currently in phase III trials. A phase III, randomized 3-arm open-label study of MEK162 plus LGX818 and LGX818 monotherapy compared with vemurafenib in patients with unresectable or metastatic

mutant melanoma is currently enrolling patients.

As a way to attempt to overcome resistance that tumors develop to targeted agents and to boost the responses to immunotherapy agents, researchers are not only testing novel combinations of targeted agents, but also testing these targeted treatments in combination with immunotherapies. &ldquo;Combinations of therapies are really where the field is currently putting much of the effort,&rdquo; said Jeffrey A. Sosman, MD, professor of medicine at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

Jedd D. Wolchok, MD, PhD, Explains Immune Checkpoint Blockade

Wolchok is the chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center.

The first combination of a targeted agent with an immunotherapy tested in the clinic was the phase I trial of concurrent treatment with vemurafenib plus ipilimumab in patients with

-mutated melanoma at the approved, full doses of each agent. Unfortunately, this combination resulted in grade 2 and 3 liver toxicity in the form of elevations of aminotransferase (ALT) in 7 of the 10 patients enrolled on the trial.

Two of the patients also had grade 2 or 3 elevations in bilirubin along with ALT elevations. Although these cases of hepatotoxicity were not symptomatic and resolved after drug discontinuation, the study researchers closed the trial.

Both agents on their own were known to cause liver enzyme elevations. What is not clear from these results is whether these toxicities are specific to the combination of vemurafenib and ipilimumab or whether this could be a class effect of BRAF inhibitors or checkpoint blockade inhibitors.

Still, preclinical studies suggest that adding a BRAF inhibitor to an immunotherapy regimen could increase antigen presentation and potentially boost the efficacy of the patient&rsquo;s immune cells.

According to Patrick Hwu, MD, immunologist and chair of the department of melanoma medical oncology at the MD Anderson Cancer Center, research from his laboratory also suggests that BRAF inhibitors inhibit VEGF which generally keeps T cells from infiltrating tumors. Inhibiting the BRAF pathway may allow more T cells to infiltrate the tumor.

Other trials combining a targeted with an immunotherapy agent are ongoing. Triple combinations are also beginning to be explored: two clinical trials combining dabrafenib, trametinib, and ipilimumab in patients with

-mutated melanoma as well as the double combination of trametinib plus ipilimumab for BRAF wild-type patients are currently being tested.

The newer immunotherapy antibodies, anti-PD1 and anti-PD-L1, which are in late-stage clinical trials, are also beginning to be tested in combination with targeted, oral agents. One example is the combination of the anti-PD-L1 antibody, MEDI4736, with dabrafenib and trametinib.

&ldquo;Combining anti-PD1 and anti-PD-L1 agents with targeted therapies may be a way around the toxicity seen in the initial [ipilimumab plus vemurafenib] trial,&rdquo; said Margaret K. Callahan, MD, PhD medical oncologist and immunotherapy specialist at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City. Other approaches being designed and entering the clinic are sequential rather than concomitant combinations, such as the phase II trial testing the efficacy and safety of vemurafenib, given for an initial 6 weeks, followed by ipilimumab for 4 doses every 3 weeks.

Researchers, including Callahan and Hwu are looking to

models to test the efficacy of potential of combination therapies. &ldquo;There are so many possibilities of combinations, which is a wonderful issue and challenge,&rdquo; said Hwu. &ldquo;But we can&rsquo;t afford to run too many trials in the era of diminishing research resources. We have to be smarter and isolate those combinations that are most likely to work.&rdquo;

According to Callahan, so far the data are useful, but do not provide a substantial blueprint for designing rational clinical trials. &ldquo;We are in situation where the field has been moving so fast that the pre-clinical data is scrambling to catch up,&rdquo; said Callahan who believes that the next few years will see an uptick in valuable preclinical and clinical data that will allow clinicians to make better therapy decisions.

One challenge in planning combination therapy trials is that thus far, mouse models have not been useful in predicting potential toxicities in humans. For example, neither colitis nor uveitis was documented in mice given anti-CTLA4 antibodies such as ipilimumab.

Combinations of immunotherapy antibodies with other oral, kinase inhibitors are also in the works. Unlike the boost in immune cell activity following exposure to a BRAF inhibitor, MEK inhibitors have been shown to interrupt T-cell activation, at least

But according to Callahan, analyses of patients&rsquo; tumor samples do not suggest this inhibitory effect. &ldquo;We still have a lot to understand on how targeted agents effect immune responses. There are some data points but no substantial coherent storyyet&rdquo; said Callahan.

Another approach is the combination of antibodies against immune checkpoint pathways. Combining ipilimumab with nivolumab, an anti-PD1 antibody, resulted in a 40% objective response in a phase I clinical trial of 53 patients.

At the maximum tolerated dose, 53% of patients had an objective response with tumor reductions of 80% or greater. High-grade adverse events were relatively high, occurring in 53% of patients, but similar to the types of toxicities experienced by patients receiving ipilimumab alone. The most common types of adverse events were increases in liver enzymes. Nivolumab is not yet approved by the FDA. It is currently being tested as a monotherapy in phase III clinical trials for melanoma and other tumor types. &ldquo;This phase I combination study generated an exciting signal that is now being followed up in a phase III clinical trial,&rdquo; said Callahan. A phase III trial is now ongoing, comparing ipilimumab or nivolumab with the combination of the two antibodies. This 3-arm study is especially well-designed, set up to answer the big question of whether the benefit of the combination is substantial or incremental and outweighs the toxicity, according to Callahan. &ldquo;This trial has the potential to redefine what is first-line therapy for melanoma,&rdquo; Callahan said.

Even newer antibodies against other immune checkpoint proteins are already in pre-clinical and early stage clinical trials. These include receptor targets such as LAG3 and TIM-3. &ldquo;Our immune system can be very dangerous to us which is why there are many molecules that can inhibit the immune system and alleviating those brakes will be beneficial in cancer,&rdquo; said Hwu.

Thus far, laboratory studies show that these immune inhibitory pathways are unique and nonredundant with the CTLA-4 and PD-1 pathways, suggesting that combining agents against two different pathways could be synergistic in stimulating the immune system against tumors. A phase I trial testing an anti-LAG3 antibody either as a monotherapy or in combination with nivolumab in patients with solid tumors is already underway.

For these newer antibodies, there is preclinical mouse model data of antitumor effects, but how well this will translate into human trials and which tumors are most likely to respond are outstanding questions. Before embarking on novel combinations with these newer antibodies, however, results of phase I monotherapy trials with these agents to demonstrate they safe in the clinic are first needed.

Another immunotherapy combination early stage trial that is currently being planned is the combination of the anti-PD1 antibody, MK-3475, with an oncolytic vaccine, talimogene laherparepvec (T-Vec). MK-3475 is currently under review by the FDA for approval as a monotherapy in patients with metastatic melanoma. T-Vec is a re-engineered herpes simplex virus, injected locally into tumors, that then divides inside the tumor cells, causing them to lyse and releasing GM-CSF, an immune cell growth factor. It&rsquo;s not clear whether T-Vec can exert a distal effect on internal, metastasized tumors, but Sosman noted that injection of the vaccine into skin lesions can shrink both those tumors that are injected and adjacent lesions. &ldquo;This combination is promising, particularly because both MK-3475 and T-Vec have generally mild side effects,&rdquo; said Sosman.

Hwu agrees. T-Vec allows the release of many immunogenic antigens from the lysed tumor cells that can activate the immune system against the cancer. &ldquo;Adding T-Vec to an anti PD-1, anti-PD-L1 or anti-CTLA4 antibody makes a lot of sense in theory,&rdquo; said Hwu.

&ldquo;I am hopeful that these combinations, both immunotherapy with another immunotherapy and immunotherapies with targeted agents will result in better responses and longer lives for patients with melanoma,&rdquo; said Hwu. &ldquo;Additionally, this research will enable approaches to move forward in other tumor types.&rdquo;

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01909453.

Liu C, Peng W, Xu C, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice.

Ribas A, Hodi, FS, Callahan, M et al. Hepatotoxicity with combination of vemurafenib and ipilimumab.

Boni A, Cogdill AP, Dang P, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01767454.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01940809.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT02027961.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01673854.

Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma.

NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier NCT01968109.

The first combination therapy for advanced melanoma received approval from the Food and Drug Administration (FDA) January 2014.

New Crop of Combination Strategies Growing for Melanoma

Melanoma experts and researchers have gained ground in the development of novel and effective immunotherapies as well as targeted agents for those patients with metastatic melanoma who harbor specific tumor mutations. The immunotherapy ipilimumab (Yervoy), a cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibody, was approved by the US Food and Drug Administration (FDA) in 2011. Since then, 2 BRAF inhibitors, vemurafenib (Zelboraf) and dabrafenib (Tafinlar), and the MEK inhibitor trametinib (Mekinist), have all been approved as monotherapies for patients whose tumors harbor a

In January 2014, the combination of dabrafenib and trametinib received accelerated approval based on a randomized phase II clinical trial. Several large phase III randomized trials to test the combination of a BRAF inhibitor plus a MEK inhibitor versus a BRAF inhibitor alone in larger patient cohorts have completed accrual and are now ongoing.

Michael A. Postow, MD, on Sequencing Strategies in Melanoma

Postow is an attending physician in the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center.

Another class of immunotherapy agents, anti-programmed cell death 1 (anti-PD-1), and anti-PD-ligand 1 (anti-PD-L1) antibodies, have shown promising efficacy rates in patients with advanced melanoma and are being tested in large phase III clinical trials.

These agents target PD-1, an immune checkpoint protein, and its ligand, PD-L1, which are part of a pathway distinct from CTLA4, but which also function to negatively regulate the immune response. These agents have shown promising efficacy rates in patients with advanced melanoma.

The new treatment options are unprecedented in advanced melanoma. Just 10 years ago, patients with this aggressive cancer had the option of either minimally effective chemotherapy or a high-toxicity immunotherapy treatment called high-dose IL-2, which works for only a small minority of patients.

With this new surge of therapy options, including new immunotherapy and targeted agents still in early clinical trials, clinicians who specialize in melanoma are determining how to best sequence these agents and to understand how to tailor treatment to a patient&rsquo;s specific course of disease. &ldquo;There is no solid evidence on how best to sequence therapy or which therapy to give first to a patient with metastatic melanoma,&rdquo; said Patrick Hwu, MD, immunologist and chair of the department of melanoma medical oncology at the MD Anderson Cancer Center in Houston, Texas. Hwu favors the use of an immunotherapy as a first-line therapy for a patient with metastatic  stage IIIC or stage IV &mdash; disease.

&ldquo;What a patient wants is to be able to be here in 10 years&rsquo; time or even longer. I call it the 10-year club. Right now, only an immunotherapy has the potential to prolong survival that long,&rdquo; said Hwu. &ldquo;Hopefully, combinations of targeted therapies will evolve to also have long-term benefits of 10 years or more, but for now, immunotherapy is it.&rdquo;

Hwu&rsquo;s preference is to enroll the patient on an anti-PD-1 or anti-PD-L1 clinical trial because these immunotherapies are relatively less toxic compared with other types of immunotherapies, allowing even those patients who are older and who have comorbidities to tolerate the regimen. &ldquo;I believe that the vast majority of patients with metastatic melanoma should be treated with an anti-PD-1 once these antibodies are approved,&rdquo; Hwu said.

If a patient does not respond, Hwu will try ipilimumab or high-dose IL-2, both FDA-approved regimens. Hwu has helped to pioneer the technique of a type of adoptive T-cell therapy that harvests a tumor sample and  expanding the patient&rsquo;s own population of tumor infiltrating lymphocytes (TILs) in vitro &mdash; subsequently injecting these back into the patient to home in and attack the tumor. Hwu also favors this approach, although the technique is only available at specialized immunotherapy centers such as the MD Anderson Cancer Center and the National Cancer Institute.

One critical question with immunotherapy options is how long a patient should remain on therapy. Jeffrey A. Sosman, MD, professor of medicine at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, will have a patient stay on an immunotherapy regimen  either an anti-PD-1, anti-PD-L1, or anti-CTLA4 antibody &mdash; as long as possible to provide the best chance to see late responses. In some cases, however, patients with aggressive disease demonstrate a rapid decline in performance status, indicating that the immunotherapy is not working.

&ldquo;These patients generally do very poorly with immunotherapy, and there is no reason to continue therapy with the immunotherapy regimen,&rdquo; said Sosman. But for those patients who may have a mixed response with some growing and some shrinking tumors, it is worth continuing the regimen for longer periods, according to Sosman.

&ldquo;I will try to give up to 24 weeks of treatment and use clinical judgment and tumor assessments to decide whether the patient is likely to respond,&rdquo; Sosman said. There is no formula for how best to gauge whether a patient who may have stable disease could benefit from staying on an immunotherapy regimen longer.

&ldquo;It can be difficult to find evidence in favor of continuing with an immunotherapy for 24 or more weeks, but when I see a patient who appears to be clinically much better, it&rsquo;s likely they are responding,&rdquo; said Sosman.

How long to keep a patient who is responding on an immunotherapy also remains a question. Ipilimumab is approved for use in 4 doses given every 3 weeks. But the newer anti-PD-1 and anti-PD-L1 antibodies have so far been given indefinitely in clinical trials.

&ldquo;If a patient has a complete response, it is reasonable to stop the drug,&rdquo; said Adil I. Daud, MD, professor of medicine at the Helen Diller Family Comprehensive Cancer Center in San Francisco, California.

&ldquo;But right now, we are mostly keeping patients on these antibodies, particularly if they have stable disease or a partial or mixed response,&rdquo; Daud said.

Not all patients are eligible for front-line immunotherapy, however. Patients who have large masses of fast-growing tumors and have poor performance status are not as likely to respond to immunotherapy, according to Hwu. For patients with aggressively growing tumors whose melanoma is

-mutation positive, the BRAF-plus-MEK inhibitor combination is likely the best option.

These targeted agents typically result in a rapid response and often patients can get symptomatic relief within weeks. &ldquo;If you don&rsquo;t see a benefit within 4 to 6 weeks, then the patient is not likely to respond,&rdquo; said Sosman.

Some preclinical data suggest that intermittent scheduling of BRAF inhibitors, and a possibly BRAF-plus-MEK combination, can markedly delay resistance to therapy, allowing tumors to respond for longer periods of time.

Melanoma tumors can become dependent or addicted to the presence of a BRAF inhibitor, Sosman explained. A trial by SWOG, a National Cancer Institute-supported cooperative group that supports cancer clinical trials, will be soon testing this hypothesis.

For the approximately 20% of patients whose melanoma harbors an NRAS mutation, targeted agents and combinations of targeted agents are being explored, including MEK 162, cyclin-dependent kinase 4/6 (CDK4/6), and phosphatidylinositol-3-kinase (PI3K) inhibitors. Whether timing of response will be similar for this patient population remains to be seen.

Still, other clinicians favor treating patients with advanced melanoma who are

-mutation positive with a BRAF inhibitor first, followed by immunotherapy. &ldquo;It is reasonable to start with immunotherapy, especially for those patients who have less tumor mass, since patients are not cured with BRAF-inhibitor treatment. Both options are valid, as there are no clinical trial data showing one approach is better than another  it is really dealer&rsquo;s choice,&rdquo; Daud stated.

The rationale for a using a targeted agent regimen first is to decrease the tumor mass, which may result in a better response to subsequent immunotherapy. The concept that

-mutated tumors become more aggressive after the development of resistance to a BRAF inhibitor has generally not been supported by either anecdotal evidence or by smaller clinical trials, according to Daud.

In his practice, Daud said that he has a low threshold for switching a patient from a BRAF inhibitor or the BRAF-plus-MEK inhibitor combination to immunotherapy.

&ldquo;We have so many choices for therapies these days,&rdquo; he said, adding that he. believes that patients should be exposed to both the BRAF-plus-MEK inhibitor combination as well as either a PD-1 or PD-L1 antibody, if the patient has

-mutated disease, you may be doing a disservice to the patient by not giving him or her exposure and choices of both of these drug types. One of these treatments may be drastically effective, and you don&rsquo;t want to delay using this treatment until the patient has a poor prognosis,&rdquo; Daud stated.

Retrospective data both from clinical trial experiences as well as from the real-world setting are beginning to be analyzed. One such recent, relatively small study from Italy of 93 patients with

-mutated melanoma suggests that the 48 patients who received ipilimumab first, followed by either vemurafenib or dabrafenib, had a longer median overall survival, compared with those 45 patients who received a BRAF inhibitor first.

Median overall survival from first treatment was 9.9 months for patients treated with vemurafenib after ipilimumab and 14.5 months for those treated with dabrafenib after ipilimumab. For patients treated with a BRAF inhibitor first, median overall survival from the end of BRAF inhibitor therapy for those who did not complete the full ipilimumab regimen was 1.2 months compared with 12.7 months for those who did complete their ipilimumab therapy.

Another recent retrospective study also showed that, while controlling for prognostic factors, patients who receive ipilimumab first, followed by a BRAF inhibitor, had longer survival compared with those who were treated with a BRAF inhibitor first (19.6 months and 13.4 months, respectively).

Still, these results are from small and retrospective patient cohorts. Prospective trials are needed to understand whether sequencing immunotherapy prior to a BRAF inhibitor really results in better outcomes or whether only certain types of patients benefit from this type of sequencing.

Whether a sequencing approach of a targeted, oral agent, followed by an immunotherapy will work well will be explored in planned clinical trials, according to both Hwu and Sosman.

Kudchadkar RR, Gonzalez R, Lewis K. New targeted therapies in melanoma.

Das Thakur M, Salangsang F, Landman AS, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.

Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian Cohort of the Ipilimumab Expanded Access Program [published online ahead of print January 31. 2014].

Ackerman A, Klein O, McDermott D, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors [published online ahead of print February 27, 2014].

Ascierto PA, Margolin K. Ipilimumab before BRAF inhibitor treatment may be more beneficial than vice versa for the majority of patients with advanced melanoma [published online ahead of print February 27, 2014].

Melanoma experts and researchers have gained ground in the development of novel and effective immunotherapies as well as targeted agents for those patients with metastatic melanoma who harbor specific tumor mutations.

Anna Azvolinsky, PhD | Authors

Articles

Androgen-Targeting Therapies Increasing in CRPC

Q & A With Dr. Sunil Verma: Targeted Treatments for HER2-Positive Breast Cancer

New Crop of Combination Strategies Growing for Melanoma

Approaches to Sequencing in Melanoma: Three Melanoma Specialists Weigh In