Antoni Ribas, MD, PhD; Jeffrey S. Weber, MD, PhD


June 12, 2014

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Ongoing Breakthroughs in Immunotherapy

Antoni Ribas, MD, PhD: Hello. I am Antoni Ribas, Professor of Medicine at the University of California in Los Angeles. I want to welcome you to this edition of Medscape Oncology Insights on melanoma. Today we will be sharing with you the highlights from the melanoma presentations at the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

I am joined by Dr. Jeffrey Weber, Director of the Donald A. Adam Comprehensive Melanoma Research Center. Dr. Weber is a senior member of the H. Lee Moffitt Cancer Center in Tampa, Florida. Hello, Jeff.

It's been another spectacular ASCO meeting, with a lot of advances in melanoma. We are going to touch on several highlights, and I'd like to start with the PD-1 and PD-L1 antibodies. How do you see the field moving forward?

Jeffrey S. Weber, MD, PhD: Among the abstracts that were truly impressive and noteworthy, 6 were about immuno-oncology and 3 were about targeted therapies. That tells us where the field is going. Remember, in 2013, Science[1] magazine said that immuno-oncology was the breakthrough of the year. I would have to agree with them.

PD-1 Agent 'Pretty Darn Impressive'

The melanoma oral sessions included 4 very impressive abstracts[2,3,4,5] on PD-1 or PD-L1 antibodies. I was the discussant for the session. It opened with the first new PD-1 antibody that we have heard of, and data from a relatively small study[2] of about 100 patients, which had a fairly good 1-year survival rate of 64%. However, it only had about a 5%-6% response rate. That was pidilizumab (CT-011). In a competitive landscape, even though the 1-year survival data looked impressive and the overall survival curve looked good -- 10 years ago that might have cut it in the melanoma field for further development -- I would be hard-pressed to have enthusiasm for it. This was a very well-done study and a beautiful presentation by Mike Atkins, but I am hard-pressed to want to take pidilizumab further, given the current landscape.

Dr. Ribas: We have raised the bar so high within a short period of time that we are not excited about something that has activity.

Dr. Weber: In both the nivolumab and pembrolizumab abstracts[3,4] (your own abstract on pembrolizumab with 411 patients), we are looking at an average of about a 40% response rate across a number of different cohorts. Yours are updated data from last year, when we heard about 135 patients in 3 cohorts. Now we have 411 patients -- a very impressive phase 2 experience with pembrolizumab (MK-3475).We are looking at close to a 40% response rate, and a lesser response rate (28%) in those who failed ipilimumab. This is consistent with my experience in PD-1 trials, in which the response rate in those who failed was 25%-26%. It is similar, but in those who were ipilimumab-naive, most of whom were previously untreated, we are getting close to a 40% response rate, with 1-year survivals in the range of 67%-69% and an 18-month survival of 62%. Do the extrapolation; we are talking about at least a 24-month median survival, and that's pretty darn impressive data from pembrolizumab. We have high expectations that the drug will receive approval from the US Food and Drug Administration (FDA) before the end of this year.

There was an update by Steve Hodi[3] on the data that were presented last year by Mario Sznol.[5] This was a 107-patient phase 1/2 trial of nivolumab, which is another PD-1 antibody. We had a publication in 2012 from Suzanne Topalian[6] in the New England Journal of Medicine, an update at ASCO last year,[5] a report in the Journal of Clinical Oncology,[7] and now yet another update. This time, survival is in the realm of 17.5 months, across a 100-fold cohort in terms of dose. Many patients were previously treated with 2-4 regimens, so, to be honest, pretty beat-up patients were compared with the pembrolizumab patients, but the response rate was still 32%.

They did not report data on ipilimumab-refractory patients. I presented those data at the poster session.[8] There was a 33% response rate in the ipilimumab-naive group; I showed a 26% response rate in the ipilimumab-refractory group. The median survival is excellent, but it's still less than 24 months, albeit in a group of patients of whom many were treated at suboptimal nivolumab doses and who had already been through multiple regimens. Nonetheless, the updated data were impressive, showing very good survival. Clearly, any drug with more than a 30% response rate in patients who have been through a median of 3 previous regimens in melanoma is looking very good. That drug, we assume, is going to come up for registration sometime this year.

Combo Yields 2-Year Survival of 75%

The highlight was the last abstract that was presented by Mario Sznol.[9] This was an update of the concurrent ipilimumab/nivolumab study. Now we are getting into another dimension, although admittedly another dimension of survival, response, and side effects. The response rate is about 45% in an updated expanded cohort of those with concurrent nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg (the standard dose). This regimen could be continued for as long as 96 weeks. The response rate was in the mid-40% range, but of greater importance, the 2-year survival was in the high-70% range. That is very impressive. It is perhaps the best 2-year survival that I have ever seen, an important landmark in melanoma. Most responders in the concurrent expansion cohort (16 or 17 patients) were still in remission at the time of reporting. Although the overall follow-up in the most recent cohort is short, this trial has been going on for at least 3 years, so there is some good follow-up for all of the concurrent patients. The data look very impressive in terms of efficacy.

That must be balanced against a 62% rate of grade 3/4 immune-related adverse events (IRAEs), many of which were easily reversible. In fact, only about half of them required an interruption of treatment. These days, when you get asymptomatic elevations of liver function tests, amylase levels, or lipase levels, the FDA will let you continue once you stop and let the patient recover and the adverse event is grade 1 or less. This is a significant rate of side effects. Whenever the rate of side effects at grade 3/4 exceeds the response rate, you have to sit up and take notice. Nonetheless, a 70%-plus survival rate at 2 years is outstanding in melanoma.

We then heard an ipilimumab abstract from Lex Eggermont[10] on the first large, randomized adjuvant ipilimumab trial ever presented. This was the EORTC trial in which patients with stage IIIA, IIIB, or IIIC disease were randomly allocated to ipilimumab at 10 mg/kg for a 12-week induction, followed by up to 3 years of treatment every 12 weeks vs placebo. The endpoint was progression-free survival (PFS), and there was a definite difference: about 26 months vs 17 months. The median PFS increased, and the hazard ratio met its preexisting endpoint of 0.75. The rate of grade 3/4 IRAEs was 40% or higher. Many patients had to stop treatment. Most of these IRAEs occurred within the first 12 weeks. There were a modest number of deaths: 6 deaths in 425 patients who received ipilimumab. Nonetheless, it was a successful trial.

The dose of 10 mg/kg is not standard in the United States or Europe. It raises issues of whether this will be taken forward by the sponsor for registration, particularly with such a high rate of grade 3/4 IRAEs. You have to think carefully about whether this is balanced by the benefits. This is going to raise plenty of questions.

Is Toxicity an Issue?

Dr. Ribas: I am sure that we are going to be discussing these trials a great deal. Is the rate of toxicity higher than what is seen in the metastatic setting?

Dr. Weber: It was very similar to the metastatic setting. The investigators in the EORTC were much less experienced in managing ipilimumab, especially at the high doses used. In the group of patients who were treated on that trial, we saw a fair number of significant IRAEs, primarily hypophysitis. It seemed that the rate of hypophysitis was slightly higher, but in fact, when that was explored by the pharmaceutical company, that was not the case. It is more an issue of perception than reality.

In the big picture, the rate of deaths was low. The therapy was well tolerated. Most of the patients were stage IIIB and IIIC resected patients, and those are very high-risk patients. There was a clear benefit relative to the potential side effects.

Dr. Ribas: The data will not be available for a long time (2-3 years), but we will have the E1609, which is an ECOG trial with SWOG participation; the results of this group; and results of a concurrent high-dose interferon group, which is the standard of care in the United States. It will be interesting to see results in the 3-mg/kg group.

Dr. Weber: The issue with this trial is that placebo would not be the standard of care in the United States. It's very difficult to compare 10 mg/kg of ipilimumab with a standard when the standard is different in Europe and in the United States. That will complicate things, and we will be debating and discussing this for years to come.

Best Median Survival for a Targeted Therapy

Dr. Ribas: We also heard abstracts on targeted therapies. We have advances both in NRAS and BRAF mutants, and these were combination therapies. What was your take on those?

Dr. Weber: I was very impressed by Jeff Sosman's presentation[11] of the CDK-4 inhibitor combined with the MEK inhibitor 162, and the fact that significant numbers of partial responses were seen. There was a 33% response rate, admittedly with small numbers, but it's still early. This was a phase 1 study with only 22 patients in 2 or 3 cohorts at the lower doses. Nonetheless, the NRAS-mutated population -- which are BRAF wild-type because the 2 mutations are mutually exclusive -- was a relatively hopeless cohort in terms of targeted therapy, and now it looks preliminarily like there will be a useful and efficacious targeted therapy for at least the 15% of melanoma patients who are NRAS-mutated BRAF wild-type. The data look good so far. Many of the partial responses were unconfirmed, but it's early, and I look forward to a favorable toxicity profile and a very good response rate when the phase 2 expansion is held. It was a very meritorious presentation. It could be a real game-changer for the BRAF wild-type population, which in terms of targeted therapy is completely underserved.

We heard from Keith Flaherty,[12] who gave us an update on the BRF-113220 trial. That was the 409-patient, phase 1/2 trial in which the important data were published in 2012 by Keith in the New England Journal of Medicine.[13] I presented these data at ASCO last year.[14] This was a randomized study with 162 patients, of whom 54 received dabrafenib alone (the BRAF inhibitor), 54 received dabrafenib with a lower dose of the MEK inhibitor trametinib, and 54 received dabrafenib and what we hoped was the optimal dose of the MEK inhibitor. The updated data showed a clear superior response rate: 76% vs the mid-50% range for either of the other arms.

The survival data were presented here for the first time. There was a 25-month median survival with a significant tail on the curve. Our institution was the biggest accruer to that trial. About 20% of our patients at years 3-4 are still on treatment and doing well, with many complete responses over time. It is a very impressive treatment. It makes you wonder: Maybe a BRAF-mutated patient who starts on this combination should not receive immunotherapy first. I would like to know what happened to the patients who failed the combination and then went on to immunotherapy. A debate is raging in our field about whether we should give immunotherapy or targeted therapy first, but I can't argue with a 25-month median survival -- the best in any phase 2 trial of a significant size that I have ever seen.

Awaiting the Full Story on COMBI-D

Those are very encouraging data. The last presentation in that session on Sunday morning was from Georgina Long,[15] who presented the very preliminary data from the first scheduled data cut of the COMBI-D trial of dabrafenib plus trametinib vs dabrafenib alone, with dabrafenib at 150 mg twice daily and trametinib at what we think is the optimal dose (2 mg daily). There was a clear benefit in terms of PFS, with a P value that was statistically significant at 0.028. However, the medians differed only by about 2 weeks (9.2 and 8.8 months). The dabrafenib group did better, and the combination group did slightly worse than in the phase 2 study.

I agree with Georgina that it is too early to decide whether the PFS is going to be 2 weeks or 3 months. It was pointed out that there were many censored patients early on who clinically progressed and never underwent a second scan. You would think that those would be patients who would be scored as progressors, but they were not. They didn't enter into this. You did a nice job on focusing on the PFS curve and making us realize that this the first data cut and there will not be another data cut until next year. That will tell the real story. Admittedly, there was crossover in this study because these drugs are now available. It will be difficult to interpret the survival curves beyond the crossover, but it looks very good for now. Up to the crossover, the hazard ratio for the combination vs dabrafenib is 0.63, which represents a 37% lower chance of dying. I am very optimistic about using the combination, and I typically use it in all of my off-protocol BRAF-mutated patients as opposed to using single agents.

Is Melanoma Treatment Going Viral?

Dr. Ribas: We would like to touch on one last presentation, in a different population. It was a randomized trial[16] of an injectable oncolytic virus called T-VEC compared with granulocyte-macrophage colony-stimulating factor (GM-CSF). We saw data[17] last year on the primary endpoint, global responsiveness, which was positive by study design. This year we saw the overall survival data. What is your take on that?

Dr. Weber: The preliminary overall survival at the first data cut was a P value of .07. The responses were 16% vs 2%. Obviously you don't expect any responses with GM-CSF, so 2% would be essentially zero. A 16% response rate overall in a patient with injectable local-regional disease plus systemic disease is pretty modest. Although the data are real and there is evidence of benefit, we now know that the overall survival has improved to 0.051. That is close to being able to show to the satisfaction of the oncologic community that there are benefits to giving this injectable therapy.

Injectable therapies are making a comeback. When we were fellows many eons ago, we were injecting bacillus Calmette-Guérin, interferon, and IL-2 into local-regional melanoma metastases. That is ancient history. Now there are some interesting drugs, and T-VEC is one of them. I see this as a niche drug that would be best used to prime the immune system and follow up with a drug such as pembrolizumab, nivolumab, ipilimumab, or a combination of those. After priming the immune system, you then boost it with the checkpoint protein inhibitors. That's where I see intralesional therapy going.

Dr. Ribas: We have a lot to work on. You are pointing out things that will be expecting in the near future -- these combinations with immunotherapies, targeted therapies, and injectables. When we put them all together, as we are starting to do, it's an exciting time.

Jeff, thank you very much for the outstanding summary. And thank you all for joining us for Medscape Oncology Insights. This is Antoni Ribas, reporting from the ASCO meeting 2014.


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