The emerging treatment landscape for patients with high-risk multiple myeloma is burgeoning with new classes of drugs, novel agents, and fresh combination strategies that offer many promising and exciting options for future therapeutic approaches, according to experts who participated in a recent 

, the panel of clinical and research experts discussed strategies for defining and treating multiple myeloma, and described anticipated changes in the treatment paradigm during a Peer Exchange session entitled “Treatment of Multiple Myeloma.”

The optimal treatment of multiple myeloma incorporates the administration of three medications, rather than two, in most transplant-eligible patients, noted 

However, clinical trials, including large international studies (FIRST, UPFRONT, and MOVE), have demonstrated efficacy with two-medication regimens, such as lenalidomide and dexamethasone and bortezomib-based regimens, noted 

. On this basis, Jagannath stated that it is difficult to only recommend the use of a three-medication regimen.

In his practice, Jagannath administers bortezomib, lenalidomide, and dexamethasone, explaining that, “My principle is that you’re exposing the patient to one proteasome inhibitor, one immunomodulatory, one steroid. You want to give all classes of drug because multiple myeloma has multiple clones, and so you want to be able cover most of the clone especially in the newly diagnosed first time treatment.”

Proteasome inhibitors as a class are going to be an integral part of myeloma therapy for decades to come, said 

“A big challenge at the moment is that patients must travel to the clinic to receive an infusion or subcutaneous injection,” said Kumar. “The ability to give something orally would certainly change the paradigm in the disease, now that we can develop very effective oral route combinations, especially since the proteasome/immunomodulatory combinations are probably one of the most effective regimens.”

Ixazomib is the first oral proteasome inhibitor in clinical trials and was granted orphan drug designation in multiple myeloma in the United States and Europe in 2011. The drug has been studied in the relapse setting as a single agent and has been shown to be active in patients who had previously received bortezomib, said Kumar, a leading investigator in ixazomib. In one study, the combination of ixazomib with lenalidomide and dexamethasone demonstrated a 90% response rate, including a 60% very good partial response rate, among newly diagnosed patients.

It was well tolerated, with skin rash and gastrointestinal side effects.

In the international, double-blind, placebo-controlled, phase III, TOURMALINE-MM1 trial, 722 adult patients with relapsed and/or refractory multiple myeloma were randomized to receive ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone.

Though no specific data have been disclosed, the interim analysis, reported in February 2015, found that the primary endpoint of improvement in progression-free survival (PFS) was met.

Elotuzumab is a monoclonal antibody that targets the SLAMF7 receptor, which is present on the surface of almost all plasma cells. It is the first monoclonal antibody to show success in clinical trials in multiple myeloma. As a single agent in refractory multiple myeloma, elotuzumab induced stabilization of disease. However, when combined with lenalidomide and low-dose dexamethasone, there was an 80% response rate,

 with a durability and survival benefit that “was really quite striking,” said 

He said that further clinical trial results demonstrated a median PFS of 33 months for the combination of elotuzumab plus lenalidomide and low-dose dexamethasone.

 The most common toxicity was an infusion-related reaction similar to that seen with other anticancer monoclonal antibodies, said Lonial.

Looking forward, Lonial noted, there are two large randomized phase III trials that have completed accrual. One of them is a relapsed trial of elotuzumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone.

 The other trial is studying the same three-drug combination in transplant-ineligible patients with newly diagnosed disease.

Berenson noted that elotuzumab’s major drawback is the long infusion timeframe. He explained that a trial is being conducted to test the efficacy of a more rapid infusion. With a reduced infusion period, coupled with its tolerability, he argued that elotuzumab “may supplant some of these other drugs, which have a lot of side effects.”

Jagannath commented about the remarkable durability of response, even in patients who had adverse cytogenetics. “Using antibodies, we may be able to somehow overcome some of the adverse cytogenetic risk factors which are not quite amenable to the chemotherapeutic operation,” he said. Jagannath and Berenson noted that this agent could be used in the front line, after first relapse, and possibly as a maintenance therapy.

The ASPIRE trial compared carfilzomib, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in relapsed multiple myeloma, said Lonial. The median PFS was 26.3 with carfilzomib versus 17.6 months without (HR = 0.69; 95% CI, 0.57-0.83; 

 Jagannath noted that these results clearly demonstrated that the triple therapy regimen is superior to doublet therapy in a relapse setting. In the control arm of the ASPIRE trial, the long remissions seen with lenalidomide and dexamethasone were unprecedented, suggested Berenson. Another outstanding result of ASPIRE was the comparability of the side effect profile between the two study arms, noted Kumar.

In the FOCUS trial, which was conducted predominantly in Europe, patients were randomized to receive either single-agent carfilzomib or cyclophosphamide and prednisone.

 The two arms were similar in PFS and overall survival outcomes, reported Lonial. Each of these agents is associated with unique adverse events, panelists noted.

Pomalidomide is third in the family of immunomodulatory drugs (IMiDs) approved for the treatment of patients with multiple myeloma. It is currently administered to patients who have relapsed after receiving another IMiD and a proteasome inhibitor. Pomalidomide can be utilized in older patients who may have relapsed on treatment with lenalidomide plus dexamethasone, according to Kumar.

Combination strategies are intriguing. Data have shown that nearly 80% of lenalidomide-refractory patients respond to the combination of pomalidomide, bortezomib, and dexamethasone, Kumar indicated. Additionally, the combination of pomalidomide with doxorubicin and dexamethasone in lenalidomide-refractory patients has demonstrated promise, Berenson added.

Histone deacetylase (HDAC) inhibition represents another promising approach for patients with multiple myeloma. The FDA approved the first HDAC inhibitor, panobinostat, in combination with bortezomib and dexamethasone in late February, based on a prespecified subgroup analysis from the phase III PANORAMA-1 trial.

 In this 193-patient analysis, the median PFS with panobinostat was 10.6 months versus 5.8 months with placebo (HR = 0.52). Additionally, the tumor shrinkage rate with panobinostat was 59% versus 41% with bortezomib and dexamethasone alone.

Panobinostat was approved with a Boxed Warning and a Risk Evaluation and Mitigation Strategy regarding severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiogram changes.

“It’s hard to know how to use a new medication which offers a modest improvement in outcomes but at the cost of significant toxicity,” 

Although side effects can be a concern, Lonial commented that the HDAC drug class is an active and effective class when combined with proteasome inhibitors or IMiDs.

Anti-CD38 monoclonal antibodies such as daratumumab and SAR650984 have emerged as potential treatments for patients with multiple myeloma.

Data have demonstrated promise for these therapies both as single-agents and in combination with lenalidomide. Moreover, these treatments appear to be well tolerated, with infusion reaction as the primary adverse event, said Zonder.

In May 2013, single-agent daratumumab received a breakthrough therapy designation from the FDA as a treatment for patients with multiple myeloma following two lines of therapy. In combination with lenalidomide and dexamethasone, daratumumab demonstrated an overall response rate (ORR) of 75% among 20 patients. In an expansion cohort of patients who received daratumumab at the maximum-tolerated dose of 16 mg/kg, the ORR was 92.3%.

In a phase Ib trial, SAR650984 in combination with lenalidomide and dexamethasone demonstrated an ORR of 58%, with a clinical benefit rate of 65%, including a 6% stringent complete response rate. In patients receiving the 10-mg/kg dose, the ORR was 63%.

Clinical trials continue to assess novel treatment approaches for patients with multiple myeloma, including PD-1 inhibitors, peptide vaccines, and kinase inhibitors. With the growing number of agents, the next hurdle to overcome will be costs, the panelists agreed.

			Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). 

			Takeda announces that the first interim analysis of the phase 3 study of oral ixazomib in patients with relapsed or refractory multiple myeloma met the primary endpoint of improvement in progression-free survival [press release]. Cambridge, MA, and Osaka, Japan: Takeda Pharmaceutical Company Limited; February 10, 2015.

			Richardson PG, Jagannath S, Moreau P, et al. Final results for the 1703 phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01239797.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01335399.

			Stewart AK, Rajkumar SV, Dimopoulos MA ,et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma [published online December 6, 2014]. 

			Ludwig H, Masszi T, Pertucci MT, et al. Carfilzomib vs low-dose corticosteroids and optional cyclophosphamide in patients with relapsed and refractory multiple myeloma: a phase 3 study (FOCUS). ESMO 2014 Congress. Abstract LBA28.

			Richardson PG, Hungria VTM, Yoon SS, et al. Panorama 1: A randomized, double-blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma. 

			Plesner T, Arkenau HT, Lochorst HM, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. 

			Martin TG, Baz R, Benson DM et al. A Phase Ib dose escalation trial of SAR650984 (anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. 

Articles

The emerging treatment landscape for patients with high-risk multiple myeloma is burgeoning with new classes of drugs, novel agents, and fresh combination strategies that offer many promising and exciting options for future therapeutic approaches.

New Paradigm Emerging in Multiple Myeloma Therapy

There is great enthusiasm about the role of immune checkpoint inhibitors in cancer treatment. The recent approval of nivolumab in the non—small cell lung cancer (NSCLC) setting marks a unique shift in the treatment landscape of this malignancy, one that harnesses the patient’s own immune system to target the tumors.

The challenge in using these agents, according to experts who participated in a recent 

 Peer Exchange program, is pinpointing ways of identifying which patients will reap the greatest benefit.

, the panel of clinical and research experts discussed the burgeoning and evolving field of immunotherapy and personalized medicine during a Peer Exchange session entitled “Aiming for Precision Medicine in NSCLC.”

Immunobiologists have successfully identified the underlying mechanisms related to tumor induced immune suppression on the infiltrating lymphocytes and immune cells in the tumor microenvironment. The understanding of these mechanisms has led to several therapeutic insights, including the programmed death receptor-1 (PD-1).

PD-1 is a type 1 transmembrane protein expressed on immune cells, and tumors can express the PD-1 ligands, PD-L1 and PD-L2. In general, tumor cells express PD-L1, which binds to PD-1, causing T cells not to attack the tumor. PD-1/PD-L1 inhibitors block this interaction, allowing for an immune response. Thus, the development of mechanisms to combat either PD-1 or PD-L1 intuitively makes sense.

Along with nivolumab, which was approved for NSCLC in March, a number of PD-1/PD-L1 checkpoint inhibitors are in clinical trials. These antibodies include pembrolizumab which, like nivolumab, targets PD-1, and MPDL3280A and MEDI4736, which are aimed at PD-L1.

These agents work by blocking the interaction between PD-1 and PD-L1. The data for these agents produce a consistent response rate ranging from 15% to 25%, Socinski noted. One of the remarkable things about the response, he added, is the durability of many of these responses.

, reviewed the findings from the phase II CheckMate-063 and the phase III CheckMate-017 trials, which led to the approval of singleagent nivolumab in heavily pretreated patients with advanced squamous cell NSCLC. In the CheckMate-063 trial, the objective response rate with nivolumab, at an 11-month follow-up, was 15%. The estimated 1-year survival rate was 41% and the median overall survival (OS) was 8.2 months.

Additionally, CheckMate-017 demonstrated that nivolumab extended OS compared with docetaxel in patients with pretreated squamous cell NSCLC 

 “I think most of us are eagerly awaiting to see the full presentation of this data because it does have the potential to be a practice-changing trial,” said Stinchcombe.

		Table. Survival Statistics in Pivotal Nivolumab NSCLC Trial

		NSCLC indicates non—small cell lung cancer.

While a subgroup of patients are reaping benefits from immunotherapy, one issue that oncologists must be cognizant of is pseudoprogression.

, discussed the phenomenon of pseudoprogression, during which 10% to 20% of tumors will grow before they start to shrink. They discussed strategies for assessing the difference between pseudoprogression and actual progression, including scans.

Herbst also described how different patient and tumor characteristics, including smoking status, histologies, and mutations, might exhibit different responses to immunotherapy.

In contrast to the lack of success with many other current therapies, studies are finding activity with immunotherapy in patients with squamous lung cancer, who are smokers, and in tumors that harbor 

As oncologists learn more about the effectiveness of immunotherapy, another goal is to gain a better understanding of these agents’ associated toxicities, which are very different from standard cytotoxic chemotherapies or the tyrosine kinase inhibitor(TKI) class of drugs. 

, described the more common side effects, such as colitis, fatigue, and pneumonitis, and explained that while diarrhea is a common toxicity of many treatments, it is more serious with the immunotherapies, as it is often coupled with colitis. She stressed that oncologists must also become “very cognizant that [patients] may actually be more likely to develop an autoimmunity.”

Treatment with PD-1 inhibitors results in a tremendous response in a minority of patients, noted Stinchcombe. Research is still needed to find a biomarker that is predictive for response in order to guarantee that only patients who will respond actually receive treatment.

In April, investigators reported that pembrolizumab demonstrated an overall response rate of 45.2% among a cohort of patients with high PD-L1-expressing NSCLC in the KEYNOTE-001 trial.

 The choice of biomarker, however, is not straightforward.

“Each company that’s developing a PD-1 or PD-L1 drug has also developed their own test for how we select these patients,” said Wakelee. “They’re based on PD-L1 expression, but just as each of the therapeutic drugs is a different antibody, the antibodies to look for PD-L1 are different, as well as the threshold and which cells we are looking at.” Wakelee described the complexity of PD-L1 expression and, thus, the variation of thresholds for positivity and test interpretations. In addition, patient selection for trials of these agents may affect rates of response and, given the trials’ goals of demonstrating high response rates, many studies may not be inclusive of all patients who could benefit from these types of agents.

Tsao added that PD-L1 is a very dynamic marker—it fluctuates during the course of the disease.

She also said that there is a wealth of data coming out about strategies to induce PD-L1 expression.

Herbst mentioned that gamma interferon is the single best inducer of PD-L1. He added that, “In the postbiopsy, you’re going to see upregulation of PD-L1 in a patient who is responding with more T cells, so when you measure is going to make a big difference.”

Until more is learned, Tsao stated, it remains problematic to use PD-L1 as a biomarker. Herbst suggested that if PD-L1 is not the best marker, there might be another T-regulatory cell that can be measured. He explained that due to the toxicities of these checkpoint inhibitors, there has to be a strategy for weeding out patients who will not benefit from these agents.

In an effort to individualize treatment, genetic testing is being implemented not solely at the time of diagnosis. Herbst stated that obtaining tissue samples from individuals with lung cancer at initial diagnosis and relapse helps guide care. Molecular testing can identify mutations in 

 and fusions in ALK and ROS1, subsequently determining which therapies may be effective. He noted that currently approximately 20% of patients have so-called actionable mutations, and that researchers are looking at ways to personalize care for the other 80%.

Tsao discussed the ALCHEMIST lung cancer trial, which she described as “…basically a surgical trial where patients get surgical resection and then, based on their profiling, they get [targeted therapy].

 mutant, they’ll get an EGFR TKI as adjuvant therapy.”

 She listed other similar precision medicine studies including the NCI-MATCH trial and the Lung-MAP trial.

Third-Generation Tyrosine Kinase Inhibitors

First- and second-generation EGFR TKIs target both mutant and wild-type receptors, accounting for the typical EGFR inhibitor toxicities of rash and diarrhea. Third-generation EGFR inhibitors are designed to be more specific for mutant 

, said Socinski, and thus are associated with less skin and gastrointestinal toxicity.

The third-generation TKIs were developed with the goal of targeting the T790M mutation, the major secondary mutation for resistance. This mutation occurs in about 50% to 60% of patients with known 

 mutations after exposure to first- and second-generation EGFR inhibitors, stated Socinski.

Two third-generation agents currently in development are rociletinib and AZD9291. In 

-positive tumors, response rates are over 50% with these investigational agents. Socinski noted that patients with 

-negative disease also receive some benefit, and thus these two agents should not be ruled out as a treatment in that population. Rociletinib may cause hyperglycemia that is typically manageable, and both agents may cause minor cardiac abnormalities.

Socinski discussed the possibility of using these third-generation agents in earlier treatment settings, and noted that with growing options, the most effective sequencing of treatments will also need to be determined. Wakelee and Herbst added that combining ALK and EGFR-targeted therapies with immunotherapy might be another approach in the future.

			Ramalingam SS, Mazieres J, Planchard D, et al. Phase II study of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer. Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. Abstract Number: LB2.

			Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2015.

			Garon EB, Rizvi N, Hui R, et al. Efficacy of pembrolizumab (pembro; MK-3475) and validation of PD-L1 expression as a biomarker in patients (pts) with non-small cell lung cancer (NSCLC): findings from KEYNOTE-001. Presented at: 2015 AACR Annual Meeting; April 18-22, 2015; Philadelphia, PA. Abstract 9109.

			The ALCHEMIST lung cancer trials. National Cancer Institute website. http://www.cancer.gov/researchandfunding/areas/clinical-trials/ alchemist. Published August 18, 2014. Accessed April 24, 2015.

			NCI molecular analysis for therapy choice program (MATCH) & pediatric MATCH. National Cancer Institute website. http://www.cancer. gov/researchandfunding/areas/clinical-trials/match. Updated March 2, 2015. Accessed April 24, 2015.

			Lung-MAP. http://www.lung-map.org. Accessed April 24, 2015.

The recent approval of nivolumab in the nonâ€“small cell lung cancer setting marks a unique shift in the treatment landscape of this malignancy, one that harnesses the patient's own immune system to target the tumors. However, there are challenges in using these agents.

Taking Lung Cancer Care into the Precision Medicine Era

Treatment options are expanding in the setting of metastatic melanoma. In January, the National Comprehensive Cancer Network (NCCN) revised its melanoma treatment guidelines to include pembrolizumab and nivolumab, along with ipilimumab, among the preferred systemic options for patients with advanced or metastatic disease.

 These immunotherapy advances are among the emerging treatment approaches that make it an exciting time for patients with melanoma and their physicians, according to experts who participated in a recent 

, the panel of clinical and research experts discussed the evolving treatment of metastatic melanoma during a Peer Exchange session entitled “Updates on the Treatment of Malignant Melanoma.”

An increased understanding of tumor pathology and immunology has led to seven new melanoma drug approvals since 2011, including the recent approvals of the PD-1 inhibitors nivolumab and pembrolizumab. In addition, several completed and ongoing trials show promise that these immunotherapies will improve survival for patients with melanoma. The integration of immunotherapy is still evolving, and the panel discussed several key issues related to its current and future use.

Although much progress has been made with immunotherapy, there are still no definite predictors for response to agents that inhibit PD-1 or its ligand PD-L1. 

, described a retrospective study of patients on pembrolizumab.

 The researchers “quantified to baseline tumor size in every patient and found out that that was the number one independent prognostic factor, both for survival as well as for response.”

Questions remain whether PD-1 or PD-L1 expression should be used as a predictive marker for nivolumab and pembrolizumab.

, explained that even though “there are increasing data coming out to suggest that PD-L1 expression is associated with the higher response rate...the corollary is that even though the response may be lower in the PD-L1-negative [tumors], there are still some patients who will respond.”

With several immunotherapies available for the treatment of malignant melanoma, oncologists are challenged with assessing treatment response. 

 explained that there can be a “lot of angst when you have to decide, is someone having true progression or is someone having what we know as pseudo-progression, which is essentially an inflammatory response, an immunologic response to the therapy around the tumors where things look worse but the patient is actually responding.” It is not uncommon for patients to have new lesions develop and other lesions get larger before responding to therapy, 

 explained. For instance, in the phase III OPTiM study

 looking at talimogene laherparepvec (TVEC), an intralesionally administered oncolytic vaccine, almost half of patients who ultimately achieved a durable response had growth of their initial melanoma beforehand, said Andtbacka, who helped lead the study.

Other situations that challenge response assessment with immunotherapy include late responders and responders who have persistent lesions. With persistent lesions, a PET scan can verify the patient’s response and isolated persistent lesions can even be treated with surgery or radiotherapy.

Pavlick explained that when assessing how a particular patient is faring on therapy, the patient’s condition is the most important factor, with imaging results and laboratory values being secondary. For example, she said that if a patient appears to be stable or improving but the scan looks worse, she typically tracks the patient for another 6 to 8 weeks to assess disease progression. Joseph added that if the patient was taking a PD-1 inhibitor, he would repeat the scan in 12 weeks, unless there is clinical deterioration.

Hamid added that he would continue therapy in a patient who has stable disease on immunotherapy because these patients have overall survival similar to that of patients who achieve a classic complete remission. Achieving stable disease appears to be meaningful, especially with immunotherapy. This will be important information for oncologists treating cancers other than melanoma. Andtbacka explained that if patients with prolonged stable disease want to discontinue therapy, he follows them with CT or PET scans every 3 months. It is not uncommon, he remarked, to go back and operate and find that there is only fibrosis there and no active tumor. Importantly, Kaufman added, there doesn’t appear to be cross-resistance among immunotherapies; thus, a patient who doesn’t respond to one immunotherapy may respond to another.

The optimal duration of therapy with nivolumab and pembrolizumab remains an unanswered question that is an important goal for randomized trials. According to Joseph, patients in clinical trials have stayed on these agents indefinitely. However, many patients who have achieved complete remission seek to discontinue therapy at some point. Pavlick stressed that the overall effect of constantly stimulating the immune system must be considered.

Joseph noted that he has stopped PD-1 inhibitor therapy successfully, but that late relapses have been reported anecdotally. Joseph added that the risk of discontinuing treatment seems to be low because patients can be retreated with the PD-1 inhibitor at recurrence. Kaufman confirmed that some patients will respond to immunotherapy again when retreated. This has been seen with ipilimumab and interleukin-2 (IL-2). However, until more is known, his preference is to try a different therapy in a patient whose disease progresses after PD-1 inhibitor therapy.

Pavlick observed that although the toxicities with PD-1 inhibitors are not benign, they appear to be more easily managed than the toxicities with other immunotherapies she is accustomed to administering.

“PD-1 is probably the easiest drug I’ve ever administered as an oncologist,” remarked Joseph.

While rash, thyroid-related problems, and fatigue are common side effects, they are not dose-limiting. Pneumonitis is more of a concern for patients with lung cancer who receive PD-1 inhibitor therapy; however, oncologists still need to be highly suspicious of pneumonitis when a patient on a PD-1 inhibitor presents with respiratory symptoms, shortness of breath, cough, or difficulty breathing.

There is a scientific rationale for combining immunotherapies with one another and with other types of therapy for the treatment of advanced melanoma, with the ultimate goal of improving efficacy while maintaining tolerability. While the combination of the BRAF inhibitor dabrafenib with ipilimumab proved far too toxic, the clinical trial results for nivolumab with ipilimumab were very impressive. In fact, preclinical studies in mice have shown the additive potential for triple immunotherapy with CTLA-4, PD-1, and PD-L1 blockade, said Kaufman. He added that it remains unclear as yet what the toxicity profile would be for that combination. However, with some of the less toxic agents, TVEC and granulocyte-macrophage colony-stimulating factor (GM-CSF), it might be possible to think about three- and four-drug combinations.

The most mature data of combined immunotherapies in melanoma are from a study looking at ipilimumab with nivolumab.

 However, other immunologic agents are now being combined; for example, TVEC with ipilimumab or pembrolizumab, and ipilimumab with GM-CSF.

The trial of ipilimumab and GM-CSF9 actually showed a decrease in some of the toxicities over monotherapy, particularly gastrointestinal toxicities, said Kaufman.

Whether it is two or three agents being combined, it will be important to understand how to combine them to achieve greater responses with the least amount of toxicity for patients. “If we can increase response rates,” said Hamid, “maybe we can increase the long-term durability of responses and long-term survival advantage.” Pavlick commented that “you’re getting more efficacy when you combine them, but you’re also getting more toxicity, and I think that’s my biggest concern.” She said that with combined ipilimumab and nivolumab, a large percentage of patients will develop profound, rapid-onset diarrhea, similar to the way it presents with ipilimumab, and it needs to be managed early.

Radiation therapy is taking on an increased role based on evidence of an abscopal effect in combination with immunotherapy. An abscopal effect is a phenomenon in the treatment of metastatic cancer where localized treatment of a tumor causes not only shrinkage of the treated tumor but also shrinkage of distant tumors. According to Joseph, it is reassuring that the addition of radiation therapy can improve tumor response without adding further toxicity. Joseph described a case that exemplifies the additive effect of combining ipilimumab and radiation therapy in which a patient with a large lung metastasis had a much better response with the combination than what would be expected with either treatment alone. Concurrent stereotactic radiotherapy and ipilimumab are used in patients with brain metastases as well, explained Andtbacka. It is ideal to start immunotherapy as early as possible to try to achieve the abscopal effect. Hamid commented that the combination has resulted in significant responses in patients with melanoma who also have brain metastases.

Oncologists who treat patients with melanoma are collaborating with other physicians more often as therapeutic options and their associated toxicities continue to expand. The involvement of surgeons, interventional radiologists, pathologists, and others is necessary from diagnosis through treatment.

In addition, recognizing and managing the varied dermatologic, gastrointestinal, and endocrine toxicities may require additional specialties. Patients require and deserve a multidisciplinary approach based on the growing complexity involved in treating melanoma, noted Andtbacka.

			NCCN Clinical Practice Guidelines Melanoma Version 2.2015. Published January 1, 2015. Accessed March 24, 2015.

			Joseph RW, Elassaiss-Schaap J, Wolchok JD, et al. Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. 

			Kefford R, Ribas A, Hamid O, et al. Clinical efficacy and correlation with tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475. 

			Andtbacka RHI, Collichio FA, Amatruda T, et al. OPTiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. 

			Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT01740297. Accessed March 25, 2015.

			Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma. 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02263508.Accessed March 25, 2015.

			Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. 

Immunotherapy advances are among the emerging treatment approaches that make it an exciting time for patients with melanoma and their physicians.

Sara Thier, PhD, MPH

Articles

New Paradigm Emerging in Multiple Myeloma Therapy

Taking Lung Cancer Care into the Precision Medicine Era

Experts Explore Immunotherapy Frontier in Melanoma