The Treatment of Relapsed Metastatic Melanoma Using a Novel Immunotherapy Combination:

An Interview with Mario Sznol, MD

Lisa Raedler, PhD, RPh

Interview with the Innovators

During the 2014 annual meeting of the American Society of Clinical Oncology (ASCO), Mario Sznol, MD, presented Abstract LBA9003—Survival, Response Duration, and Activity by BRAF Mutation Status of Nivolumab and Ipilimumab Concurrent Therapy in Advanced Melanoma—on behalf of his colleagues and fellow investigators. The presentation summarized objectives, methods, and long-term findings from a phase 1 study of concurrent and sequenced nivolumab and ipilimumab (Yervoy) in heavily pretreated patients with metastatic melanoma.¹

Ipilimumab was the first immune checkpoint inhibitor approved for use in the treatment of inoperable stage IV metastatic melanoma. Introduced in 2011, this anti–CTLA-4 (cytotoxic T-lymphocyte antigen-4) monoclonal antibody has become a standard option for patients with either BRAF-mutated or BRAF-wild type (unmutated) metastatic melanoma.²

Nivolumab targets the programmed death–1 (PD-1) or CD279 cell surface membrane receptor on cancer cells. When PD-1 binds to its ligands, PD-1 ligand 1 (PD-L1) and PD-1 ligand 2 (PD-L2), lymphocyte activation is downregulated, essentially masking the cancer cell from the host’s immune system. By inhibiting the interaction between PD-1 and its ligands, therapies like nivolumab promote antigen-specific immune (T-cell) responses, such that cancer cells are more easily recognized and eliminated by the immune system.³

Nivolumab is currently in clinical development for multiple solid and hematologic tumors, including metastatic melanoma, advanced non–small cell lung cancer (NSCLC), metastatic renal cell cancer, colon cancer, head and neck cancer, glioblastoma, relapsed diffuse large B-cell lymphoma, and follicular lymphoma.⁴

Data regarding the combination of ipilimumab and nivolumab in metastatic melanoma generated significant attention during the 2013 ASCO meeting, when phase 1 survival statistics were characterized as “spectacular.”5 Longer-term results from this study, as presented by Dr Sznol in 2014, continue to be notable. He reported that the combination of ipilimumab and nivolumab produced an “unprecedented” median overall survival (OS) of 40 months for patients with metastatic melanoma, which is “nearly double” that of median OS figures that have been reported for either agent administered alone. The 1-year and 2-year OS rates across all cohorts were 85% and 79%, respectively. In the cohort of patients receiving nivolumab (1 mg/kg) and ipilimumab (3 mg/kg), which is the approach being tested in an ongoing, randomized trial, 1-year and 2-year OS rates were 94% and 88%, respectively.

In the phase 1 trial, 94 patients with inoperable stage III or IV melanoma who had received up to 3 previous systemic therapies received concurrent treatment with ipilimumab and nivolumab in various dose schemes. Approximately half (55%) of patients who enrolled in this phase 1 trial had very advanced melanoma (stage M1c), and 60% had received no previous systemic treatments.

Among the 53 patients, 42% demonstrated objective responses to ipilimumab and nivolumab concurrent therapy, with complete responses observed in 17%. Tumor shrinkage was described as rapid and extensive. Responses were also durable, with 18 of 22 responses (82%) ongoing at the time of analysis. Clinical responses were seen regardless of BRAF mutation status or PD-L1 status, and across all dose cohorts.

In this combination trial, rates of adverse events (AEs), including immune-related AEs, were higher than previously observed for ipilimumab and nivolumab when used as single agents. However, they were characterized as manageable and reversible in almost all patients. Severe (grade 3/4) AEs were observed in 62% of patients receiving concurrent ipilimumab and nivolumab, the most common of which were elevated lipase levels (15%), elevated liver enzymes (14%), and gastrointestinal side effects (14%).

Dr Sznol and colleagues continue to follow patients in 8 dosing cohorts of this phase 1 study of concurrent and sequential ipilimumab and nivolumab. Additionally, a 3-arm phase 3 trial is comparing the combination of ipilimumab and nivolumab with nivolumab monotherapy and ipilimumab monotherapy, and a phase 2 randomized study is comparing combination therapy to ipilimumab monotherapy in metastatic melanoma.

These new agents were the topic of an interview with melanoma expert and lead investigator in the nivolumab clinical development program, Mario Sznol, MD, from Yale University. Dr Sznol is a medical oncologist affiliated with Yale; he is Professor of Medicine (medical oncology); Clinical Research Program Leader of the Melanoma Program and Yale Cancer Center; and Co-Director of the Yale Specialized Programs of Research Excellence (SPORE) in Skin Cancer.

Q: The subject of immuno-oncology continues to generate significant attention at ASCO, and among investors and the media. Can you provide a brief overview of its evolution?

Dr Sznol: For years, we tried a variety of different approaches to activate the immune system against melanoma and other tumor types, primarily cytokines, like IL [interleukin]-2. Then vaccines were tried. This was an attempt to either immunize patients by doing something to the tumor inside the body or by isolating tumor antigens, removing them, and then giving them back in a more immunogenic fashion. This did not work terribly well.

Sometime in the mid-1990s, immune checkpoint inhibitors were discovered. People learned that, to activate the immune system, ligand receptor interactions occur between antigen-presenting cells and T cells. When T cells get into the tumor microenvironment, there are also ligand receptors that can inhibit their function. Instead of trying to activate the immune system by stimulating with cytokines or vaccines, the thought was that perhaps patients already had an immune response against their cancer that was being inhibited by these checkpoints. If you just block these checkpoints, those T cells could work more effectively.

The first new drug was ipilimumab, which got just a little attention because it had activity in melanoma. Clearly, it improved survival and gave a small subset of patients amazingly durable remissions. Some patients remain disease free for 10 years. This is what we saw with IL-2.

Q: Is it fair to think that ipilimumab and other newer immunotherapies are less toxic than cytokines?

Dr Sznol: They are different, but I would not say that one is more or less toxic than the other. In a subset of patients, ipilimumab can cause substantial toxicity. We see autoimmune reactions, which are inflammatory events against normal tissue: diarrhea, colitis, hepatitis, endocrinopathy, skin toxicities. Any organ in the body can be affected. We have seen cytopenias, arthralgias, leptomeningitis, and, very rarely, a Guillain-Barre syndrome­type reaction. These can be scary toxicities, but we have learned how to manage them. In the vast majority of patients, we reverse the toxicity.

Q: Do you see a correlation between the severity of toxicity with ipilimumab and depth of response?

Dr Sznol: There are some reports that side effects and efficacy correlate, but other studies with larger samples show only a weak association. The answer is that we really do not know. I personally think that there probably is some association between these phenomena.

Q: More checkpoint inhibitors have moved into clinical testing. How is the PD-1 blockade different from blocking CTLA-4 with ipilimumab?

Dr Sznol: PD-1 blockers have changed the way we view immunotherapy because they have demonstrated activity outside of melanoma and kidney cancer, in tumors like bladder cancer and head and neck cancer…. Because of its very low toxicity, use of single-agent anti–PD-1 would be reasonable for “borderline” [melanoma] patients. If they do not respond, we can consider adding an anti–CTLA-4, ideally on a protocol. PD-1 antibodies can be safely combined with ipilimumab in most patients, although there is an increased incidence of toxicity.

Q: PD-1 and PD-L1 inhibitors are in development for the treatment of a variety of tumor types. Among the PD-1 inhibitors, nivolumab is furthest along, with others moving quickly to catch up. Are these therapies different? Are they distinctive?

Dr Sznol: We know that blocking PD-1 and PD-L1 is different based on the biology. PD-1 has 2 ligands, PD-L1 and PD-L2, whereas PD-L1 binds to PD-1 and CD80. This distinction might translate to different biological effects. However, so far, these agents have looked pretty similar [in the clinic]. Perhaps PD-1 blockade gives a little more pneumonitis, but it is such a low incidence and manageable, I do not know that this is a differentiator. At the moment, maybe PD-1 and PD-L1 inhibitors are not completely interchangeable, but they are very close…. I should note that all antibodies are not equal; they might hit the same target, but they have different affinities. Not all antibodies are “good” antibodies.

Q: Data were presented regarding the combination of carboplatin and a taxane with ipilimumab in metastatic melanoma.6 What is your impression of attempts to combine chemotherapy and immuno-oncology agents?

Dr Sznol: These combinations are much less interesting to me. Over time, immunotherapy combinations will predominate over immunotherapy-chemotherapy combinations. Immunotherapy-chemotherapy combinations do not make a lot of biologic or scientific sense. A lot of oncologists are wedded to giving chemotherapy. These agents have some activity, so the thinking is that we have to try immunotherapy plus chemotherapy. But, in tumors like melanoma, we can see bulky disease go away just with immunotherapy. It can happen very quickly. Whether chemotherapy combinations, on balance, will help or hurt remains unclear to me. From my perspective, I would not give these combinations, but this is why we do clinical trials.

Q: Also reported here at ASCO was a study combining ipilimumab with dabrafenib and trametinib in metastatic BRAF-mutated melanoma.7 This triple-drug combination was deemed too toxic in light of 2 episodes of gastrointestinal perforation. The dabrafenib-ipilimumab combination tested in the same trial, however, was considered safe, and study of this doublet continues. What is your impression of these observations?

Dr Sznol: You have to be careful with small trials. You can see a bad side effect twice and then not see it for the next 30 patients. When you get unlucky like that, you can come to the wrong conclusion that the combination is too toxic. Granted, it is scary to go beyond 2 perforations. But I am not convinced that we are seeing a true interaction of these drugs. That being said, I am still more interested in combinations of ipilimumab and PD-1 antibodies. I am not sure that you need combinations with targeted agents at all. A lot of us are beginning to think that the activity is from combining immunotherapies together. Targeted agents and chemotherapy may be important in a small subset of patients, but these are not drivers. Immunotherapy is the driver, and these others serve an adjuvant role. It is hard for me to believe that sunitinib and a PD-1 blockade is going to be a lot better than a PD-1 blockade plus CTLA-4 in renal cell cancer, for example.

Q: What are the next steps in immunotherapy development?

Dr Sznol: To date, we have seen all of this activity with just 2 checkpoint inhibitors. There are many other targets in the immune system: other ways to inhibit checkpoints, ways to stimulate immune responses while concurrently blocking inhibitory mechanisms. These approaches might give us a lot more activity in these other tumor types.

We are also starting to understand which tumors might respond to just checkpoint inhibitors, versus tumors in which you might require costimulation along with checkpoint inhibition. Still other cancers may need something to expand the T-cell response and drive it into the tumor, or even create the T-cell response because it may not be there. This is where the other major advance, cell therapy, comes in. This is the work that the University of Pennsylvania is doing with genetically modified T cells directed against CD19, as well as research related to tumor infiltrating cells (TILs). All of these approaches can enhance the activity of checkpoint inhibitors. When you put all of these together, we have not even scratched the surface of the potential for these therapies in malignancy.

Q: Let’s move to the future and presume that several PD-1 inhibitors are approved for use in various tumors: one in melanoma, one in bladder cancer, and one in NSCLC. General oncologists in community practices see patients with each of these tumor types. What aspects of these agents are most important for them to understand?

Dr Sznol: Oncologists should keep in mind that none of these great agents cure cancer. If a patient can travel and go on a clinical trial, they should enroll. Otherwise, oncologists will have to select the antibody for the tumor type for which it has been approved. If you have a patient with bladder cancer come in, and you know that they responded to a specific single-agent antibody, the best approach is to put them on a trial using that antibody in combination [at relapse]. We are looking to cure these diseases. Even with the activity seen now, not everyone benefits from [single-agent] treatment.

Q: There is no clear biomarker for immunotherapy response in melanoma. How does an oncologist decide between a BRAF inhibitor and an immunotherapy agent targeting either CTLA-4 or PD-1 for a newly diagnosed metastatic melanoma patient whose tumor expresses the BRAF mutation?

Dr Sznol: Immunotherapies are agnostic to the BRAF mutation, of course. But we do not have comparative data, and there is no biomarker. There are, however, clinical features that help us. If someone comes in with rapidly progressing melanoma and poor performance status, we would probably offer them a targeted therapy —a BRAF inhibitor—first. We might then add in or substitute immunotherapy as they are improving or when they achieve maximum response.

In the absence of a clinical trial, and if the patient is not progressing rapidly, you have a choice. I would give the immunotherapy first to try for a durable remission. If you see early on that the patient is not responding, you can always come in with a targeted therapy. I do not think that the 3- to 4-month delay in receiving the BRAF inhibitor would make a difference in outcomes.

We could also go to an anti–PD-1 in that patient; it has similar response rates in patients who had previous ipilimumab compared with those who did not receive ipilimumab. In our institution, we do not recommend a targeted agent until we have given several lines of immunotherapy. If the patient is on ipilimumab, we usually wait until week 18 or 20 to make a change. We get their first scans at week 12, and if they look stable or better, they stay on. If not, we move them on to another immunotherapy or targeted agent at week 12.

Q: This is clearly a burgeoning field. What is your advice for young oncologists and researchers who wish to study immunotherapies?

Dr Sznol: There are many targets and lots of opportunities to look at other checkpoints, costimulatory agents, and combinations of these. The options are almost infinite. We have only 2 checkpoint inhibitors in the clinic at this point. There are many novel molecules and cell therapies: some target a cytokine to a tumor antigen, or link a costimulatory agent to a tumor antigen, or CD3 to a tumor antigen. If it were me, at this time, I would focus on combinations of checkpoint inhibitors and costimulatory agents. I think these are very important.

In terms of translational research, we do not know much about the biology of individual tumor types. With TILs, we need to understand whether they are antigen­-specific, what costimulatory molecules are expressed, what checkpoints are expressed, and the inhibitory influences that occur within the microenvironment. Then we need to know how to intervene. What combination of agents activates T cells in the microenvironment in the in vitro setting? There are tons of things to do if you were a young investigator; it is a wide open field. It is truly an exciting time to treat melanoma and other tumor types.

Q: Certainly, much attention is focused on immuno-oncology on the part of the media and the investment community.

Dr Sznol: Yes. Another good measure of the potential for this field is the interest of pharma in developing these agents. To my knowledge, almost every big pharmaceutical firm and lots of small biotechnology companies are investing in immuno-oncology. And several firms are working together to do combination trials, which is a very positive sign. This [lack of partnership] had been one of the biggest hurdles in moving the field forward, so it is great to see. Of course, we still think that things could move faster.

Disclosure Statement
Dr. Sznol is a paid consultant for Bristol-Myers Squibb.

References
1. 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). J Clin Oncol. 2014;32:5s(suppl). Abstract LBA9003.
2. Yervoy (ipilimumab) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2013.
3. 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;366:2443.
4. Bristol-Myers Squibb website. Nivolumab Clinical Research Studies. www.clinical cancerstudy.com/about_the_studies.aspx. Accessed June 6, 2014.
5. Bath C. ‘Spectacular’ Results with Immunotherapies in Melanoma Galvanize the Oncology Community. ASCO Post. July 10, 2013. www.ascopost.com/issues/july-10,-2013/spectacular-results-with-immunotherapies-in-melanoma-galvanize-the-­oncology-community.aspx. Accessed June 26, 2014.
6. Jamal R, Belanger K, Friedman JE, et al. A randomized phase II study of ipilimu­mab (IPI) with carboplatin and paclitaxel (CP) in patients with unresectable stage III or IV metastatic melanoma (MM). J Clin Oncol. 2014;32:5s(suppl). Abstract 9066.
7. Puzanov I, Callahan MK, Linette GP, et al. Phase 1 study of the BRAF inhibitor dabrafenib (D) with or without the MEK inhibitor trametinib (T) in combination with ipilimumab (IPI) for V600E/K mutation-positive unresectable or metastatic melanoma (MM). J Clin Oncol. 2014;32:5s(suppl). Abstract 2511.

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