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Interview August 01, 2013



Immunotherapy in Melanoma




In this interview, Dr. Michael Postow, Assistant Attending Physician with the Melanoma–Sarcoma Oncology Service at Memorial Sloan-Kettering Cancer Center, and Dr. Tony Nimeh, Research Physician at Brigham and Women’s Hospital, discuss advances in immunotherapy for melanoma.

Dr. Postow is enthusiastic about the promising early data on the effects of blocking the programmed death-1 (PD-1) receptor using nivolumab and lambrolizumab, antibodies with specific activity against PD-1. However, he cautions that therapy using immunomodulators needs to be administered with care because of immune-mediated side effects and the occasional need for immunosuppressants. Large phase III studies will be necessary to determine the full potential benefits of these PD-1 immunomodulatory drugs. The ultimate hope is to win FDA approval for the drugs, making them accessible to the many patients in need.

Dr. Nimeh: Dr. Postow, would you discuss the recent data on nivolumab that were presented at ASCO?

Dr. Postow: Nivolumab is one of several very promising new antibodies that target the PD-1 receptor. Previous data on nivolumab had been published in 2012 in The New England Journal of Medicine1 This year at ASCO, long-term data from those studies were presented, and we learned more about PD-L1 as a potential biomarker for PD-1 therapy with nivolumab.

Dr. Mario Sznol presented long-term data on PD-1 treatment with nivolumab in the Melanoma/Skin Cancers Oral Abstract session.2 The drug toxicity profile was extremely favorable, even over time and with continued dosing. The lack of accumulation of additional toxicities over time is obviously very important with any ongoing, continuous therapy.

The median overall survival also appeared quite favorable, when compared with prior historical data in advanced melanoma. The median overall survival was 16.8 months across all of the different doses that were evaluated. Of course, cross-trial comparisons need to be interpreted with caution, particularly in a phase I trial such as this one; but, these results are certainly promising and, based on the results, several larger-scale, randomized, phase III studies are being conducted to test the drug’s benefits in a larger population.

Potential biomarkers for Nivolumab

Dr. Nimeh: Are there any immunotherapy biomarkers that might help identify the best candidates for nivolumab?

Dr. Postow: At this point, there are no specific biomarkers that have been studied thoroughly enough, and provided data that are convincing enough, to influence the selection of a patient for PD-1 antibody therapy. PD-L1, however, is being examined as a potential biomarker for nivolumab in ongoing large phase III trials.

To put this in context, we need to keep in mind certain principles in immunotherapy. Most anticancer therapies target the tumor itself. With biomarkers, we attempt to detect genetic changes in the tumor, or changes within oncogenic signaling pathways, to help us direct therapies at the tumors. In contrast, all of these immunomodulating antibodies (such as PD-1) act on, and target, the patient’s normal immune cells rather than the tumor itself. Because of that difference, it has been very difficult to identify a biomarker that would influence patient selection. In concept, every patient could potentially benefit from immunotherapy if it was used appropriately and in the right sequence or combination.

There is a lot of discussion about PD-L1 as a potential biomarker for nivolumab and perhaps other PD-L agents. In biomarker studies of PD-L1, patients are considered positive if they have at least 5% membranous staining on the tumor surface by immunohistochemical analysis. These patients preliminarily appear to have a greater likelihood of tumor shrinkage. However, some patients have an excellent response even though their tumors do not have PD-L1 expression. Therefore, patients who do not express PD-L1 should still be considered for treatment with agents such as nivolumab.

Nearly 50% of patients with melanoma have a BRAF mutation. Patients with BRAF mutations are expected to do just as well with nivolumab and other immunotherapies as patients without BRAF mutations. There are no convincing data to suggest that the response to immunotherapy depends on the particular mutation found in the tumor, especially with BRAF. Often, small-molecule targeted therapies, such as vemurafenib, dabrafenib, and trametinib, are approved by the FDA and used for patients with BRAF mutations. Combinations of these targeted agents are also being tested to see if they are better than single agents themselves. 

The specific sequences or combinations of therapies that are most beneficial are still being evaluated in clinical trials.  For a patient who has a mutation such as BRAF, we do not yet know, based on available data, whether it is preferable to start treatment with immunotherapy or with targeted therapy. It has been our practice, for an asymptomatic patient (who does not need an immediate response), to start with immunotherapy. This gives the patient an opportunity for long-term durable benefit. However, for the patient who has symptomatic disease or a large tumor burden, we prefer to begin with targeted therapy, as we feel this gives him or her the best chance for immediate tumor shrinkage (which seems to occur more readily with the targeted agents).

Dr. Nimeh: Blockade of the PD-1 and PD-L1 pathway may be effective against tumors in which PD-L1 is expressed at the cell surface, reflecting a baseline, “preactivated” state of the immune system. Is there anything we can do to up-regulate PD-L1 in cells that are not in such a preactivated state?

Dr. Postow: That’s an excellent question and one that is the focus of several ongoing investigations. It is not yet completely clear which specific treatment modalities would up-regulate PD-L1 because we have not yet done enough prospective trials, with pre- and post-treatment biopsies, to assess PD-L1 changes associated with a specific intervening therapy.

PD-L1 is believed to be up-regulated in the setting of chronic inflammation. This may be a mechanism by which the tumor cells create their own resistance to otherwise effective antitumor immunity. When tumor-infiltrating lymphocytes interact with the tumor, it has been shown (through interferon-gamma secretion) that PD-L1 can be expressed. Thus, perhaps the tumor has found a way to protect itself from these immunologic onslaughts of tumor-infiltrating lymphocytes. Perhaps we need to find ways to increase this immune-cell infiltration within the tumor to cause a PD-L1 up-regulation leading to an increased susceptibility to the beneficial effects of PD-1 therapy.

Bear in mind that we have not yet determined the appropriate sequence or combination to up-regulate PD-L1 clinically, after which we could use the PD-1 antibody to enact a response. It is a critical point that even patients whose tumors are PD-L1 negative can still respond to PD-1 blockade.

Side effects of immunotherapy

Dr. Nimeh: What are the side effects of immunotherapy to be aware of, and how do you manage them?

Dr. Postow: Immunotherapy enhances the body’s immune system, and our hope is that this results in improved antitumor immunity against the malignancy. Unfortunately, this activation of the immune system can also result in reactivity against tissues not involved in the malignancy, creating important side effects. And since patients often require immunosuppression for the treatment of immune-related side effects, the potential for the development of opportunistic infections is important to keep in mind.

Inflammatory pneumonitis is particularly relevant for antibodies that block the PD-1 axis. A few patients, unfortunately, died from complications of pneumonitis in one of the phase I trials. However, with increasing recognition and prompt treatment using immunosuppressants, we believe that this potential side effect can be effectively managed. The number of patients who experience pneumonitis is very low, particularly those in whom it occurs to any significant degree.

Renal insufficiency is another side effect—elevated creatinine levels have been associated with the PD-1 agents. Colitis and diarrhea seem to be more of a problem with CTLA-4 blockade than with PD-1 blocking agents.

The main point to remember, though, is that all of these agents can cause immune-related adverse events, which are generally easily managed with prompt recognition and the initiation of steroids or other immunosuppressants. Long-term sequelae are generally extremely mild, if they occur at all.

No maximum tolerated dose has been established in dose-escalation studies with PD-1 agents. These drugs are very well tolerated because the mechanism for adverse effects is different from that which occurs in chemotherapy or targeted therapy.   

Measuring response to immunotherapy

Dr. Nimeh: How is response to immunotherapy measured, and how is “success” defined?

Dr. Postow: Ultimately, we will assess the response to immunotherapy differently from the methods we have been using up to this point. Right now, however, response to immunotherapy is assessed using traditional radiographic response criteria, such as those applied to other investigational agents. Basically, these are the modified World Health Organization response criteria or the RECIST criteria.

Traditional response endpoints, apparent on CT scans or PET scans, can often be misleading and potentially underestimate the long-term survival benefits accrued with immunotherapies. The reason is that the patterns of response that occur with immunotherapy are different from those observed with traditional chemotherapy. For example, with immunotherapy, new lesions may appear in the presence of an otherwise decreasing tumor burden, and there may even be an apparent worsening of overall tumor burden, prior to ultimate shrinkage of the tumor burden and a response.

The immune-related response criteria have been investigated for patients treated with ipilimumab (an anti−CTLA-4 blocking antibody now approved by the FDA), and it was proposed that a novel set of response criteria should be applied to that drug. In fact, the novel immune-related response criteria appeared to better approximate the long-term survival benefits of the drug as compared with traditional radiographic response endpoints. The newly proposed response criteria still need to undergo prospective evaluation. Nevertheless, immunotherapies, particularly the PD-1 agents, demonstrate high response rates even with traditional radiographic response criteria, such as RECIST.

We are still struggling to establish the best surrogates to apply in early-phase trials and to ascertain how well these surrogates correlate with overall survival. Overall survival, therefore, remains the most important endpoint in clinical trials evaluating the immunologic agents. Interestingly, a greater number of patients have achieved long-term survival after treatment with ipilimumab than were considered to have responded by traditional radiographic response criteria.

Treatment regimens in immunotherapy

Dr. Nimeh: With new treatment approaches emerging, what is the potential for combining immunotherapies—for example, ipilimumab and granulocyte-macrophage colony-stimulating factor (GM-CSF)—or adding targeted therapy?

Dr. Postow: Many new agents appear to be promising as monotherapies. It is very exciting to think about the possibility of additive (or potentially synergistic) benefits if we combine more than one in appropriate and rational ways.

At ASCO this year, Dr. Stephen Hodi presented data which showed that patients who received ipilimumab 10 mg/kg in combination with GM-CSF had improved overall survival as compared with patients who received ipilimumab 10 mg/kg alone.3 The results were consistent with those from preclinical evaluations in mice. This combination treatment demonstrates the potential promise of combining these immunologic agents.

We reported in The New England Journal of Medicine,4 and also presented at ASCO this year,5 that, in a phase I trial involving a small number of patients, the combination of nivolumab with ipilimumab resulted in a very impressive response rate.

Whether or not these responses to combination nivolumab and ipilimumab (which have been durable) translate into long-term overall survival benefit is the subject of an ongoing phase III study. At this juncture, we do not yet know whether it is better to combine nivolumab and ipilimumab initially or to sequence them, one followed by the other. Patients can respond to nivolumab even if they have not responded to ipilimumab and vice-versa. We are hopeful that the large-scale phase III trials will answer these questions regarding the relative merits of combination therapy vs monotherapy. Combinations of targeted therapy and immunotherapy are also very exciting to investigate. Several prior evaluations6,7 have suggested that treatments such as BRAF inhibitors can result in immunologic effects that may be additive or synergistic when combined with immunotherapy.

We conducted a phase I trial in which we combined vemurafenib with ipilimumab.8 Unfortunately, the trial was discontinued because the rate of hepatotoxicity was too high. One of the many lessons we learned from that trial was the importance of carefully evaluating combinations of targeted therapy with immunotherapy in early-phase clinical trials, in which dosing and scheduling are very carefully monitored. It is possible that sequencing these agents, or using specific combinations, will be more tolerable and possibly beneficial.

One ongoing study is evaluating the use of dabrafenib and ipilimumab, with or without the MEK inhibitor trametinib.9 We are hopeful that this study will provide some additional information on the possibility of combining targeted agents with immunotherapy for patients with advanced melanoma. At this point, we would not recommend combining immunotherapy and targeted therapy outside of the context of a clinical trial. We encourage the enrollment of patients in such trials.

  • References
    1. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.

    2. Sznol M, Kluger HM, Hodi FS, et al. Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538). Paper presented at: American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, Illinois. J Clin Oncol. 2013(suppl; abstr CRA9006).

    3. Hodi SF, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of Gm-CSf (GM) and ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013(suppl; abstr CRA9007).

    4. Wolchok JD, Kluger HM, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-133.

    5. Wolchok JD, Kluger HM, Callahan MK, et al. Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). Paper presented at: American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, Illinois. J Clin Oncol. 2013(suppl; abstr 9012).

    6. Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225-1231.

    7. Comin-Anduix B, Chodon T, Sazegar H, et al. The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations. Clin Cancer Res. 2010;16(24):6040-6048.

    8. Ribas A, Hodi SF, Callahan C, et al. Hepatotoxicity with Combination of Vemurafenib and Ipilimumab [correspondence].N Engl J Med 2013;368(14):1365-1366.

    9. Phase I study of the BRAF inhibitor dabrafenib +/− MEK inhibitor trametinib in combination with ipilimumab for V600E/K mutation positive metastatic or unresectable melanoma. NCT01767454. Accessed July 14, 2013.



Copyright © 2013 Elsevier. All rights reserved.


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brooke's picture
Replies 5
Last reply 8/8/2013 - 4:11pm
Replies by: POW, brooke, Becky

After all the wonderful responses and advice I received from everyone in my initial post, it seems that finding a melanoma specialist is key!

My husband is insured by Kaiser Permanente (an HMO in Colorado) and I know it can be very difficult to be accepted outside of their facilities.

I was wondering if anyone has had luck getting referred to the University of Colorado melanoma center or any other melanoma specialists with Kaiser insurance?



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presleerae's picture
Replies 11
Last reply 8/7/2013 - 1:33am

HI everyone.  I am new to this site and don't know if I'm in the right place.  My husband has just been diagnosed with a malignant melanoma.  I have the pathology report and would like to share it with you all to see if anyone can help me understand it better.  Is this where I post the details of the report?  I feel ignorant about it and I'm really scared and am having alot of anxiety problems because of it.  He is the love of my life and I will stand by him all the way.  Just needing answers. 

We go to a dermatologist on August 15 and to an oncologist on August 19.  


Please let me know where to post this report.  Thank you so much in advance, and I apologize if I'm in the wrong place.


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Hi everyone - new here! :)   I have a question about "dissolving stitches" <-- only putting quotations around them because they aren't seemingly dissolving.  The stitches on my upper, left back - you can physically feel them through the skin.  You can feel them running from one side to another and it's been almost 4 months.  Surgery date was April 12th and they are defintely still there.  Now, the incision under my left arm is fine; I don't feel any stitches there.  

The only thing different is that obviously the skin on your back is tighter....maybe that is the problem?  It doesn't hurt at all, I'm not having any issues (other than of course the random sharp pains that you feel from the sites - but I wouldn't call that an "issue" per se).  

Has anyone else run into this with "dissolving" stitches?  How long did they typically take to dissolve?  



"Everything happens for a reason"


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NYKaren's picture
Replies 7
Last reply 8/12/2013 - 10:12am

Hi everyone,
I had MRI last week & saw neurosurgeon yesterday. He said all looks good. Tumors are dying and no new ones. Phew! I am tapering completely off steroids by end of week. I had a scare about 2 weeks ago, inflamed brain mets, more steroids & day in hospital to make sure all was ok. I had lost most of my ability to speak for a few hours & landed in the urgent care of NY Hospital. I couldn't remember much, but I did manage to tell the doc what my doc's name is: Kondziolka. How's that for a mouthful?

I have another set of CT scans in 2 week on the 20th, then finally will have blood work/and will sign informed consent on the 21st ( and be randomized) for Merck PD1 phase II trial. Boy I wish it could still be the phase I study, but at least if its chemo, it doesn't have to stay that way. Now, since I did have the scans and know it (was) brain mets, and positive lymph nodes, and spots in lungs and possibly liver, i have the dabrafinib in my back pocket too. The mail order pharm says it's on it's way. It sounds like people are being approved for mono-therapy.

I guess that's it for now.

Don't Stop Believing

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gabsound's picture
Replies 13
Last reply 8/8/2013 - 3:20am

June 12, 2013 my beautiful, loving, and courageous wife Julie passed away.
 On Wednesday June 5th we discovered in the hospital emergency room she had suffered hemorrhaging from the brain mets discovered only weeks before. After spending several days in the ICU she came home under hospice care. She passed away in our home surrounded by loving family.

I haven't read all of her entries to this site, but I'm certain Julie offered many intelligent and loving words to the people with melanoma. That's who she was. A genuinely caring person. 
Every so often she would come to me crying her eyes out to tell me that someone on the melanoma site had posted losing a loved one to this disease. I could feel her pain. She felt the loss deeply.  

Julie received comfort from the kind and thoughtful comments from fellow melanoma patients and caregivers. Thank you all for your advice and encouragement these last couple of years.
Julie and I were married for 30 years. I am so proud and blessed to have known and loved this amazing woman.


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Replies by: Anonymous, JerryfromFauq, POW, Janner
Gene test identifies non-metastatic melanoma patients at high risk of recurrence.    Article Date: 06 Aug 2013 - 2:00 PDT

I'm me, not a statistic. Praying to not be one for years yet.

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VSlim's picture
Replies 9
Last reply 8/7/2013 - 5:42pm

Hi all, This is my first posting on the site. My husband was diagnosed two years ago (unknown origin, it showed up in the lymph nodes in his neck). He has been treated at Sloan Kettering with surgery, radiation, and most recently ipilimumab but the disease is still spreading. His doctor at Sloan is recommending their clinical trial of Bristol Myers' anti PD-1 (nivolumab) but it's randomized v. chemo. I've been searching for a nonrandomized trial of the Merck anti PD-1 in our area (New York) but so far no success. The site has twice given me hope--only to find that the trials are no longer enrolling. If anyone knows of a trial in our area, I'd very much appreciate knowing about it.

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I'm me, not a statistic. Praying to not be one for years yet.

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They normally rrefused IL-2 to people with brain metastes.

July 31, 2013 — In a retrospective study, Saint Louis University researchers have found that patients with melanoma brain metastases can be treated with large doses of interleukin-2 (HD IL-2), a therapy that triggers the body's own immune system to destroy the cancer cells.

I'm me, not a statistic. Praying to not be one for years yet.

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I have come to realize my only post on here was about my mothers death. Knowing she was an avid writer on this board, I now hope to continue this tradition.  After my mom passed, I was astonised by how much support I recieved on here. Now, after nearly two years, I'm breaking the silence and vow to be supportive as my mother was when she was on here. 

As far as melanoma awareness goes, I have spoken to the Delaware house of represenatives about melanoma, I am working with Delaware health and social services to push more awareness in my state, and I did my senior research project on melanoma, which I am happy to say i got a 100% on. I will continue my research in college and my advocacy as well. I am studying biology for pre-medicine, maybe not oncology per say, but I would like to save lives. 

I will be attending Eastern University in St. Davids Pennsylvania, where I am a member of the leadsership fellows program, a scholarship through the school. I hope to use my leadership platform to start a skin cancer group or something of the sort around my sophomore year. 


My prayers go out to all the patients, family members, and anyone else affected by this disease. I know prayers kept my mother alive better than any medicine could, and it can work for you too.

If anyone would like to email me regarding awareness, grieving, coping, or any research, you can contact me at as I regularly check this email. 


Blessings to all and stay strong, 

Lilith Elmore

Freshman at Eastern University, Biology major

Now faith is being sure of what we hope for and certain of what we do not see. Hebrews 11:1

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94z28joe's picture
Replies 3
Last reply 8/5/2013 - 6:40pm
Replies by: aldakota22, 94z28joe, POW

went to the doctor to follow up after surgery to remove local reoccurance and was told I'm off the ippi vs interferon trial. I thought I would be able to stay on but, was told it wasnt working so I am being taken off the trial. :( They have me scheduled for scans on thursday to see where we go from here.

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DeniseK's picture
Replies 6
Last reply 8/8/2013 - 4:19pm

Hello Everyone,

Well this Melanoma is full of surprises.  I went in for my Gamma Knife this last Thursday thinking they were going to zap 5 of my 7 brain mets.  SURPRISE I had 18!!  He said he used double contrast so he could see every little tiny met I had so some of them were less than 1mm but I spent ALL day at the center with that Dang Frame bolted to my head, which by the way was the worst part.  So now I wait for 30 days and I should be brain stable, then another 30 days and I should hopefully be stable to go into a trial.  I'm getting my 3rd infusion of Ipi on August 15th with the last dose on Sept 5th.  This Thursday I will be switching from Z to Dabrafenib, really surprised my insurance covered it. 

The pain in my arm has subsided, just mild tumor pain which I hope is the t-cells attacking but havent noticed much if any decease in the size of the tumor.  It appears to be stable which I will take!

I'm hoping by 1st of October to be in trial for Anti PD 1 if my brain cooperates. 

I'm not having any severe side effects from combining Z with Ipi yet.  I'm taking a Reishi Mushroom supplement which helps protect your liver so I think that's helping.

Just wanted to update everyone on my treatment and share my surprises.

All my best to all,


Cancer Cannot cripple love, silence courage, destroy friendship, shatter hope or conquer the spirit.

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