Immunotherapy Combination Nivolumab Plus Ipilimumab Receives FDA Approval for Metastatic Melanoma

By Christina Pernambuco-Holsten,

Thursday, October 1, 2015

A doctor wearing a white lab coat writes on a white board with a marker.

The US Food and Drug Administration approved a combination immunotherapy treatment for people with metastatic melanoma. This means patients will now have access to the drug outside of clinical trials. MSK’s Jedd Wolchok created and tested the combination and lead the approval process.

  • The FDA has approved combination ipilimumab-nivolumab therapy for people with advanced melanoma.
  • This means patients now have access to the treatment.
  • It’s the first combination immunotherapy treatment approved by the FDA.
  • The combination shows remarkable results and extends patients’ lives.

Today, the US Food and Drug Administration (FDA) approved the immunotherapy combination nivolumab (Opdivo®) plus ipilimumab (Yervoy®) for use in patients with metastatic melanoma. This is the first-ever combination immunotherapy to receive approval by the FDA. To learn more, we spoke with Memorial Sloan Kettering medical oncologist and cancer immunologist Jedd Wolchok, the physician-scientist leading this work.

Where did the idea to combine nivolumab and ipilimumab come from?

 The idea to combine these two immunotherapies emerged after we had strong scientific evidence that each one was effective by itself. We had worked with ipilimumab for several years, but it appeared to benefit only 20 percent of patients. Nivolumab had shown early signs of good activity for newly diagnosed patients, and a similar medicine (pembrolizumab) had activity in disease that was refractory — which means it wasn’t responding to treatment —  or relapsed after initial treatment with ipilimumab. Then there were lab experiments that showed the two strategies worked well together. So in 2010, before either drug had FDA approval on its own, we embarked on the phase I trial testing the combination of the two. Ultimately the results showed a 53 percent response rate — quite a bit higher than we expected. For some patients, it was very dramatic. We would get scans back showing that virtually all of the disease had gone away.

After the first 15 to 20 people, we began working with our colleagues at Bristol-Myers Squibb to design phase II and then phase III trials. The results of the phase II trial were presented in April during a meeting of the American Association for Cancer Research and published in the New England Journal of Medicine by my colleague Michael Postow, who was a fellow in our group back when we did the phase I trial. This past June, I presented the phase III results at the American Society of Clinical Oncology annual meeting.

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So it took five years from start to finish. That’s fast!

Yes, to me that’s the most exciting thing. We’ve gone from presenting the initial data to rolling this treatment out for standard use in quite a reasonably short period of time.

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What do you attribute this rapid pace to?

A few things. First, we saw an unmistakable signal when using the combination in patients. And these patients had a high unmet need — they didn’t have many other treatment options. Then there was exceptional coordination between the FDA, the academic investigators, and our industry colleagues. This example actually shows that drug development doesn’t necessarily require enormous studies with many years of follow-up. It’s possible to move at a much faster pace when everyone is collaborating effectively.

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Can you describe the moment you knew this combination was going to be a success?

By my desk, I have an email pinned up from one of our pathologists dated July 7, 2010. It has the pathology results from one of the very first patients to receive the regimen. This patient had a very large lump on his side, and every time he came in it got smaller and smaller. But after four doses, it wasn’t completely going away, and we wondered if the disease was resistant to treatment.

One of our surgeons, Mary Sue Brady, removed the lump, and I was so very eager to know what was going on that I waited outside the operating room while it was being removed. “What did it look like?” I asked her colleague when she came out. “Oh, just metastatic melanoma,” she said, and I was so disappointed.

Then, a week later, I got an email with the pathology report.

Completely necrotic tumor surrounded by immune cells — the histologic picture of treatment success.

In other words, the tumor was dead. I smiled, I printed it out, and it’s been hanging on my cork board ever since. And that was our second patient to receive the combination.

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As someone who has dedicated his career to improving treatment for people with advanced melanoma, what does this mean for you?

When I joined the MSK faculty in 2000, the median survival for patients with advanced melanoma was seven months with the best treatment available at that time. Now we are routinely hearing about two- and three-year survival. In the last study we did, we were seeing patients with 14 months of progression-free survival — which means they lived with their disease but it didn’t grow or spread — and that’s just an estimate. It gives you a flavor for how rapidly the expectations for life have changed, and it happened all within the first part of just one person’s career.

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How has MSK’s focus on collaboration and translational research made this advance possible?

MSK has had a tradition of excellence in treating melanoma and in developing novel therapies. Immunotherapy has actually been a focus at MSK since the late 1890s, and we have been a part of all the major immunotherapy advances throughout the history of cancer treatment.

For this particular regimen, we were among the very first to use this novel combination, we designed the pivotal studies that have supported approval, and we’ve done some of the most important research to understand who benefits and why. We haven’t answered all the questions yet, but we look forward to pursuing the answers and understanding how we use this regimen to help even more patients, for example those with lung cancer and other cancer types.

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Does this treatment apply too choroid melanoma as well?

We forwarded your message to Dr. Wolchok, and he said this therapy is currently being tested on some patients with choroid melanoma, but it's too early to report any data on the effectiveness. Thank you for your comment.

My wife is having Gastro intestinal caner-adenocarcinocmo metastatic cecum- nodes in different part of stomach and liver. Can you suggest the treatment thorugh immunotherapy and its success and cost.

Is there anything about this new treatment that can be used to prevent a recurrence of melanoma that was removed....I.e. A recurrence down the road that expresses itself in a different area of the body? Thank you...Linda Beach

Dear Linda, thanks so much for your question. The treatment is used for disease that has already recurred. Our doctors recommend that people who've been treated for melanoma have regular check-ups to monitor for recurrence and the development of other skin cancers.

You might also be interested to learn about our new 3-D total body photography program:….

Thanks for your question!

My dad is stage 4 melanoma. Has already taken Yervoy a few years ago, BRAF inhibitors, and also Keytruda. He is now showing signs of Keytruda resistance. Is he eligible for this drug combo?

Thank you for reaching out. We recommend that your father speak with his healthcare team about whether he this combination therapy would be appropriate for him. As the combination has now been FDA-approved, it might be a treatment option.

I asked if there is or is being developed a targeted therapy for sickle cell anemia?

Not at Memorial Sloan Kettering. You might want to consult those sources to learn what other research centers are doing.

My brother (lives in Denver) had a melanoma removed from his calf in 2013 with a follow up xray each April. About a month ago he felt a lump in his groin. He went to the doctor and they did: Chest xray, ct chest/abd/pelv, us abdomen, mri brain and tested his liver. The cancer returned to the chest, abodmen and in the groin is a tumor. His brain and liver are clean. They are now testing him for a gene to get him into a trial and we are also trying to get him to Dr. Rene Gonzalez in Denver. Are we doing everything we can?

Dear Janet, we are sorry to hear about your brother's diagnosis. Only a physician who has examined your brother and reviewed his medical records can comment on whether all appropriate options are being explored. If he would like to make an appointment with one of our specialists for a second opinion, please ask him to call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

Dear Dr. Wolchok, Our daughter, Jennifer, has courageously fought neuroendocrine cancer for 13 years, via uncounted major surgeries, including a Whipple, two liver transplants, liver and pancreas resections, hip and femur replacements.
She has not had immunologic-based chemotherapy. She's experiencing multiple tumors around her body...fortunately, not yet in her lungs. No treatment options remain.
We can't help but wonder what the dangers might be for her to be treated with the combination protocol?
Godbless your pioneering work.

Dear Stephen, we are very sorry to hear about your daughter. She has been through so much. Unfortunately, our doctors can't offer specific medical advice on our blog, but if you are interested in consulting with one of our specialists to discuss whether there are treatment options (including clinical trials) that may not yet have been explored, please call our Physician Referral Service. They can answer your questions and can be reached at 800-525-2225. Thank you for reaching out to us.

Might this type of therapy be applicable to leukemia?

Dear Sally,
While this particular combination of immunotherapy drugs is not being tested in leukemia, several other immunotherapy approaches are. These include CAR T therapy, other checkpoint inhibitors, and stem cell transplants. Memorial Sloan Kettering has open clinical trials in all of these areas. If you would like to learn more, please visit

Thank you for your comment.

Dear Drs, I have stage 4 mucosal melanoma. I've had my rectum and anus removed. I'm only 55 and have children and myself that are horrified. I want and need to live. I've had 6 doses of keytruda with mixed responses. I want to come there to see your melanoma specialists as I'm not sure what's going to happen. What about the combination of the two drugs or T cell therapy. I want the drastic treatment so I have a chance to live. I have 3 rumors in my pelvic area, there not going away, please researchers and melanoma experts at you me, don't let me lose my children to this disease. You have more options than anyone there. Accept me and me live thru this, please, Sincerely, LindaRichardson

Is there an online source where patients share their experience with the nivolumab or nivolumab plus treatment?

Doug, you might want to check out MSK's online community, Connections. Patients there can share experiences about a range of cancer treatments and get advice from other patients and caregivers. It is open to all cancer patients, not just those being treated at MSK. To learn more, you can go to…. Thank you for your comment.

I am stage 3a melanoma. No complete lymph node dissection and only one positive for melanoma after my sentinel lymph node biopsy. Would I be able to get this combination therapy?

Stacy, thank you for reaching out. We recommend that you speak with your healthcare team about whether this combination therapy would be appropriate for you. If you are interested in consulting with one of our specialists, please call our Physician Referral Service. They can answer your questions and can be reached at 800-525-2225.

My sister has neuroendocrine cancer and does not have the somatostatin receptor usually targeted in treatment. We found out today the chemo she has had for the past few months did not work and she has two tumors on her adrenal gland. Is anyone testing this combination (Nivolumab and Ipilimumab) therapy for neuroendocrine cancer?

Dear Valerie, we are sorry to hear about your sister's diagnosis. You did not indicate whether she has gastrointestinal neuroendocrine cancer or pulmonary neuroendocrine cancer, so we have included links to both disease guides on our site for you to get more information about treatment options.

Pulmonary Neuroendocrine Tumors:

Gastrointestinal Neuroendocrine Tumors:

And here's more information about Adrenal Gland Tumors:

If she would like to make an appointment with one of our specialists to discuss her treatment options, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

Dear Drs.
My brother is 43 years old.
Amonth and a half ago He was started to hobble on his left foot he got several medical tests and MRI the diagnosis melanoma with metastatic stage 4 to the brain.
he started for 5 times radio therapy FSR
to his brain every time a half hour radiation
also he got thrombosis on his left foot treated by Clexane injection twice a day
on the 11/10/16 my brother strat immunotherapy treatment by Opdivo for every 2 weeks
I would like to know how can my brother gets the treatment of the combinziia of Opdivo and YervoY ??
Please your kind help asap.
We are from Israel and my brother is treated in Sheba Medical Center
Thanks in advance !

Dear Maor, we are sorry to hear about your brother's diagnosis. If you would like to arrange for one of our specialists to conduct a medical records review by mail or an in-person appointment to discuss possible treatment recommendations, please contact our International Center at To learn more about our services for patients who live outside of the United States, please visit Thank you for reaching out to us.

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