Melanoma in Focus: Update on Novel Therapy, Emerging Agents, and Optimizing Patient Care Presentation 1

Transcription

1 Presentation 1 The following is a transcript from a web-based CME -certified multimedia activity. Interactivity applies only when viewing the activity online. This activity is supported by educational grants from Genentech, Merck & Co., Inc. and Prometheus Laboratories Inc. Dr. Weber: Hello. This is Dr. Jeffrey Weber. I'm from the H. Lee Moffitt Cancer Center in Tampa, Florida. Welcome to this educational activity in which we review some of the recent evidence on the efficacy of immunotherapies and targeted agents in melanoma. After completing the activity, access the post-test and evaluation form by clicking on the red Credit button. I encourage you to download the slides and any other activity features that may interest you. evaluation for CME credit: 1

2 Presentation 1 Immunotherapy in Melanoma: Present and Future PD-1: programmed death 1. Dr. Weber: A timeline of the development of immunotherapy in melanoma at a glance would show you that one of the first immunotherapies ever approved by the FDA for melanoma was in 1996, when high-dose alpha interferon was approved as adjuvant therapy for high-risk resected melanoma. Several years later came the first immunotherapy that was approved for metastatic disease, interleukin-2. It was a fairly long interval until 2011 when the next immunotherapy was approved which was really a sea change in the way we treat patients with melanoma which was ipilimumab, the first checkpoint protein inhibitor for metastatic second-line and first-line melanoma. A number of new checkpoint inhibitors were in development at that point, and the first one was just approved. That's pembrolizumab, which is a PD-1 blocking antibody. And sometime, we hope, by the end of 2014, we'll have a second PD-1 antibody approved in melanoma, which is nivolumab. evaluation for CME credit: 2

3 Presentation 1 CR: complete response; HD: high-dose; ORR: overall response rate; OS: overall survival; PR: partial response. 1. Atkins MB et al. J Clin Oncol. 1999;17: Daniels G et al American Society of Clinical Oncology Annual Meeting (ASCO 2014). Abstract Kaufman HL et al. Nat Rev Clin Oncol. 2013;10: Dr. Weber: In evaluating the role of IL-2 in melanoma, there's no question that you can see a significant response rate in patients with metastatic disease, with an overall response rate noted to be about 16% across many studies, but with a durable complete remission rate of about 6% with advanced melanoma. The approval of high-dose interleukin-2 was early proof that immunotherapy actually offered some durable benefit in melanoma, but the toxicity of this treatment is a serious concern, with most patients requiring intensive monitoring sometimes ICU care and [it is] just a very labor-intensive treatment to be administering to patients, who generally are under the age of 65 [years] and have to have good cardiac status and an excellent performance status. evaluation for CME credit: 3

4 Presentation 1 There has been a recent compendium of data from a national registry of patients getting high-dose interleukin-2, with a median survival of 20 months, which is quite impressive. Although, to be honest, in most cases, this is not used as a front-line therapy outside a very few elite academic centers, because it can be challenging to administer, and it's really only something that should be done, in general, at specialty centers. Nonetheless, in looking at the survival curves, if someone achieves a complete response, shown at the left-hand corner of this slide, most of those patients are probably going to be cured, because they have survival out to 10 years without recurrence. evaluation for CME credit: 4

5 Presentation 1 MHC: major histocompatibility complex; PD-L1: PD-1 ligand; TCR: T-cell receptor. 1. Ribas A. N Engl J Med. 2012;366: Dr. Weber: Moving beyond interleukin-2 to what we call the checkpoint protein inhibitors, it became apparent in the last decade that there were two events that allowed the immune system to attempt to recognize cancer. And one of them was the priming phase, which takes place in the lymph nodes on the left, which shows that there's T cell with its T-cell receptor presenting itself to a peptide MHC complex on a dendritic cell, which is really the antigen being recognized; with a second interaction called the second signal, where CD28 on the T cell recognizes B7 on the antigen-presenting dendritic cell. If you increase CTLA4, which is really the brake, it'll interrupt the CD28-B7 interaction and suppress the T cell from actually recognizing the antigen. But as you can imagine, if you look at that little red Y-shaped antibody, if it blocks the CTLA4, it allows the second signal to proceed unfettered and allows the immune system to work well. evaluation for CME credit: 5

6 Presentation 1 A somewhat similar system occurs in the periphery, and that periphery could be in a normal tissue, it could be in a tumor. So now we're not in the lymph node anymore; we're at a cancer cell and that T cell has to recognize the cancer cell, but it requires multiple interactions. One of the interactions is actually a brake on the immune system, and that's when PD- L1 on the cancer cell binds PD-1, a receptor on the T cell. And when that happens, it will suppress immunity. Once again, if you look at the little red-shaped antibodies, if you blocked either the PD-1 or the PD-L1, as you can imagine, you would cut the brake, and again allow the immune system to proceed in an unfettered manner not just in the peripheral lymph nodes, but now in a key location within the tumor. evaluation for CME credit: 6

7 Presentation 1 AE: adverse event. 1. Hodi FS et al. N Engl J Med. 2010;363: Robert C et al. N Engl J Med. 2011;364: Weber JS et al. Cancer. 2013;119: Weber JS et al. J Clin Oncol. 2012;30: Fecher LA et al. Oncologist. 2013;18: Dr. Weber: One of the first drugs developed to try to interrupt that process was called ipilimumab, which is a drug that blocks the CTLA4-B7 interaction. It was actually the first checkpoint protein inhibitor to be approved based on the fact that multiple phase 3 trials showed that it improved survival in patients with both previously treated and untreated advanced metastatic melanoma, and [patients taking] it had about a 10% to 15% response rate. evaluation for CME credit: 7

8 Presentation 1 Using ipilimumab uncovered the so-called immune-related adverse events, which are toxicities that develop during the 12 weeks of induction treatment, when the drug's given every 3 weeks four times. [The] toxicities [are] almost always reversible when managed with proper treatment guidelines, using vigilant monitoring and the use of steroids and other immunosuppressives. But nonetheless, in about 10% to 15% of patients, these immune-related adverse events could be significant and dose-limiting. And on the right, it shows the kinetics, where skin effects develop early on, after a dose or two. Then come the GI events, which we take very seriously, with colitis as a major manifestation. And then late in the game, toward the end of the four doses of induction ipilimumab, come endocrine events, with hypophysitis and then hepatic inflammation or hepatitis. evaluation for CME credit: 8

9 Presentation 2 Novel Immune Checkpoint Inhibitors in Melanoma Ig: immunoglobulin. 1. Hamid O et al. N Engl J Med. 2013;369: Robert C et al. Lancet. 2014;384: Dr. Weber: Ipilimumab is now an approved drug in routine practice, but over the last couple of years, two new PD-1 inhibitors new checkpoint inhibitors have been developed. And the first one that's made it through the FDA regulatory circuit is pembrolizumab. And the early findings from this trial, which utilized a humanized monoclonal IgG antibody that blocked the PD-1 receptor on T cells to interrupt the negative signaling (or interrupt the brake), showed that you had a very impressive response rate when you use this antibody at either 10 mg/kg every 2 or 3 weeks, or even at 2 mg/kg every 3 weeks. evaluation for CME credit: 9

10 Presentation 2 In an early study of 135 patients published last year, 52% confirmed response rate [was observed] in patients who got 10 mg every 2 weeks, although it was accompanied by a modest level of adverse events up to 24%, consisting of fatigue, rash, [and] diarrhea. But most of the events were pretty low-grade. And in general, it was felt that this antibody was very well tolerated, with responses in the 30% to 40% range, even at 2 mg every 3 weeks. evaluation for CME credit: 10

11 Presentation 2 IPI: ipilimumab. 1. Ribas A et al American Society of Clinical Oncology Annual Meeting (ASCO 2014). Abstract LBA9000. Dr. Weber: So that initial trial was then expanded, and it was a complicated phase 1/2 trial where patients who were ipilimumab-naïve got three different regimens: 10 mg every 2 weeks, every 3 weeks, or 2 mg every 3 weeks. And then ultimately, there was a randomized group of patients who got either 10 mg every 2 or 10 mg every 3 [weeks]. And then at the end, a group of patients who were ipilimumab-refractory got either 10 mg every 3 weeks or 2 mg every 3 weeks. evaluation for CME credit: 11

12 Presentation 2 PFS: progression-free survival; RECIST: Response Evaluation Criteria In Solid Tumors. 1. Ribas A et al. ASCO Abstract LBA National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Melanoma. V Available at Dr. Weber: And in the initial study, which encompassed 411 patients, there was 34% overall response rate by central review, a higher rate in the ipi[limumab]-naïve patients, and a lower rate, 28%, in the ipi[limumab]-refractory patients. But these were durable responses, with a 69% survival rate at 1 year, 62% at 18 months, and a median progression-free survival of 5.5 months, which are very impressive data. And at the time these data were presented at ASCO [2014], 88% of the responses were ongoing. evaluation for CME credit: 12

13 Presentation 2 1. Kefford R et al. ASCO Abstract Dr. Weber: The investigators also assessed whether PD-L1 staining on the tumor, which was allegedly a predictive marker meaning, if it was present, you'd respond to a PD-1 antibody, if it's absent you wouldn't. But they found you could still respond: You had a 13% response rate if you're PD-L1 negative, but a 49% rate if you're [PD-L1 ]positive. So the staining of the tumor for this PD-L1, the substance whose interaction with PD-1 you're blocking with the antibody, was not a predictive marker, since you could still respond if you're negative. But it clearly shows there's an association between PD-L1 staining and outcome in patients treated with this antibody. evaluation for CME credit: 13

14 Presentation 2 1. Kefford R et al. ASCO Abstract Dr. Weber: Interestingly, if you look at the progression-free survival for the PD-L1 positive patients in this slide, it shows on the left-hand panel you do better in terms of PFS if you're positive for the staining for L1 than if you're negative. Yet, when you look at survival, the whole thing tends to fall apart. Look at the right-hand panel: It shows that the P value for the difference in survival by PD-L1 staining versus negative is 0.3, which means there's really no significant difference. evaluation for CME credit: 14

15 Presentation 2 1. Ribas A et al. ASCO Abstract LBA9000. Dr. Weber: This is a safe drug, but if you look here at the grade 3/4 toxicities, <12% spread through fatigue, itching, rash, diarrhea, arthralgia, [and] nausea. So the toxicities that are severe with this drug are well spread among many different categories, not concentrated in any one category. And again, the conclusion is, this was a very welltolerated drug. evaluation for CME credit: 15

16 Presentation 2 DoR: duration of response. 1. Hodi FS et al. ASCO Abstract Dr. Weber: The other PD-1 antibody is called nivolumab, and this one is a fully human monoclonal antibody, also IgG4. And again, this is a treatment that induces durable responses. It was tested in a phase 1 study with doses 0.1 all the way up to 10 mg/kg [in] 107 patients. An update was presented at this past ASCO [2014], showing that 64% of the responses lasted beyond 24 weeks. Duration of response was superb, at 22.9 months. And the 2-year survival was 48%. The 3-year survival was 41%, which is excellent compared to any other therapy we know. And at the dose chosen to take forward to phase 3 studies, the median survival in the initial phase 1 study was 20.3 months, with a median PFS at 9.7 months. The grade 3/4 drug-related adverse events were <10%, and mostly consisting of skin [toxicities], GI [events], and endocrinopathy. evaluation for CME credit: 16

17 Presentation 2 Nivo: nivolumab. 1. Kluger H et al. European Society for Medical Oncology 2014 Congress (ESMO 2014). Abstract 1085O. Dr. Weber: Nivolumab has been combined with ipilimumab, and some impressive data were presented both at this year's ASCO [2014] and recently at the ESMO [2014] meeting, showing that when you combine ipilimumab with nivolumab, you can get a very high response rate [that is] approaching 50%, with very long duration of response. And this is a swim plot shown here looking at multiple different cohorts that, in the top five groups, are all concurrent, given together, and in the lower two groups given sequentially. And it shows that what is labeled cohort 8, which is the dose of ipi[limumab] and nivo[lumab] taken forward to phase 3 studies, virtually all patients treated so far have ongoing responses although fairly high toxicity. evaluation for CME credit: 17

18 Presentation 2 1. Kluger H et al. ESMO Abstract Dr. Weber: And then looking at survivals, here we show the ipilimumab-nivolumab combination with the survival curve, and it's a little complex. But, we're looking at a 2- year survival of between 79% and 88%, which is phenomenal. I remind you, virtually all other therapies for melanoma have median survivals of about 2 years, so that's very impressive. evaluation for CME credit: 18

19 Presentation 2 HRQOL: health-related quality of life Dr. Weber: At ESMO [2014], recent data were reported on nivolumab tested in a phase 3 study in patients who had previously been treated with ipilimumab, most of whom had failed [treatment]. Patients were treated until they progressed or had unacceptable toxicity. And some of the nivolumab patients were treated beyond progression if the investigators felt they were deriving benefit and tolerating the drug. The initial endpoint of this study was response, which we would of course get very quickly after only a modest number of patients finished 24 weeks of treatment. And ultimately survival is the other primary endpoint, which will take more events to occur. evaluation for CME credit: 19

20 Presentation 2 NR: not reached. 1. Weber J et al. ESMO Abstract LBA3. Dr. Weber: But in that trial, 36 of 38 responders in this trial continue in remission, and the response rate for the nivolumab group by RECIST 1.1 central assessment was 32%, with four CRs, versus only 11% for investigator-choice chemotherapy, with no complete responses. And again, 95% of the nivolumab responses were ongoing, and the median duration of response has not been reached. If you look at the time to response, [it was] much more favorable for nivolumab, with 2.1 versus 3.5 months for chemotherapy. And while the median duration of response is only 3.5 months for chemotherapy, it's going to be way beyond that. It's not been reached yet for the nivolumab. evaluation for CME credit: 20

21 Presentation 2 1. Weber J et al. ESMO Abstract LBA3. Dr. Weber: In looking at the toxicity of that study, again, similar to pembrolizumab, a spread of very low levels of grade 3 treatment-related toxicity, only about 1% of each or less for skin, GI, endocrine, hepatic, pulmonary, infusion reactions or kidney [toxicities]. So again, all of these grade 3/4 treatment-related events resolved completely, and corticosteroids were easily used in the majority of these patients to achieve resolution. Altogether, 5% or fewer of patients in this trial with nivolumab had grade 3/4 immunerelated adverse events. evaluation for CME credit: 21

22 Presentation 3 BRAF Inhibitors and Other Targeted Agents in Melanoma 1. Heidorn SJ et al. Cell. 2010;140: Poulikakos PI et al. Nature. 2010; 464: Hatzivassiliou G et al. Nature. 2010;464: Dr. Weber: A little less than half of all patients with metastatic melanoma have mutations in the BRAF gene, which is an essential signaling component of the so-called MAP kinase pathway. There is a molecular test for the BRAF mutation, and the vast majority of mutations, as shown on the upper right side, are at the V600 amino acid, and there are now multiple FDA-approved tests to find that out, as testing is now a routine part of the treatment of any patient with stage 3 and 4 melanoma. evaluation for CME credit: 22

23 Presentation 3 Dr. Weber: There's been an awful lot of excitement about the BRAF target and the ability to inhibit it with drugs. And it's known that a little less than half of all patients with metastatic melanoma have mutations in the so-called BRAF gene. In 2011 the first BRAF inhibitor, vemurafenib, was approved for metastatic disease that's V600-positive, and the standard of care had generally been until recently to use single-agent vemurafenib or dabrafenib. But early this year, the FDA approved the combination of dabrafenib and trametinib one is a BRAF inhibitor, dabrafenib, and the other is a MEK inhibitor, trametinib. So dual pathway inhibition is now approved, and is probably more effective than single inhibition. evaluation for CME credit: 23

24 Presentation 3 Chapman PB et al American Society of Clinical Oncology Annual Meeting (ASCO 2014). Abstract 8502^. Dr. Weber: Now, we've had some updates on the use of these single drugs. Vemurafenib, of course, was the first one approved, and at the ASCO [2014] meeting this past year, we had an update on the original phase 3 trial of vemurafenib versus chemotherapy. And it suggests that at the end of the day, looking at the longer-term survival, you had an excellent response rate of 57%, with almost 6% complete responders. And the median survival here is between 16 and 20 months, which is very impressive. evaluation for CME credit: 24

25 Presentation 3 DTIC: dacarbazine. 1. Hauschild A et al. European Society for Medical Oncology 2014 Congress (ESMO 2014). Abstract Dr. Weber: And looking at the dabrafenib phase 3 trial that got dabrafenib approved last year which, again, was compared to chemotherapy we had an update at the ESMO [2014] meeting where dabrafenib showed a 20-month median survival, which is an outstanding median survival [and] clearly superior to the dacarbazine arm. In that trial, you could cross over from dacarbazine to dabrafenib, so the 15-month survival for dacarbazine reflects a third of the patients actually crossing over to get what is obviously a superior drug. If you look at 2-year survival, [it is] 45% for dabrafenib which, again, is pretty good, with that median survival of 20 months. Because it's a crossover, the hazard ratio favors dabrafenib, but it's probably never going to be statistically significant, because a crossover will always invalidate a survival analysis. So if you censor it at the time of the crossover, clearly, there's an obvious superiority for dabrafenib versus chemotherapy. evaluation for CME credit: 25

26 Presentation 3 Dr. Weber: So given the data that we've had on the combination of BRAF and the MEK inhibitors, the big question today is, is single-agent BRAF inhibition still viable in practice treating patients in front-line BRAF-mutated melanoma? So we've had three studies that have been done in combination, which I think now put to rest the idea that we should be using single-agent BRAF inhibitors. evaluation for CME credit: 26

27 Presentation 4 New Evidence on the Role of Targeted Therapy in Melanoma 1. Long GV et al American Society of Clinical Oncology Annual Meeting (ASCO 2014). Abstract Dr. Weber: The COMBI-d study was a test of dabrafenib plus trametinib versus dabrafenib alone. So this was an attempt to show that combination with a MEK inhibitor was better than that particular BRAF inhibitor, dabrafenib. And this was a randomized phase 3 trial where the median progression-free survival was 9.3 months for the combo versus 8.8 for just the dabrafenib, which is a good drug. But again, the P value is <.5. The hazard ratio across the PFS curve was 0.75, with a relatively short follow-up of 9 months. But if you look at the curve, it's pretty obvious the combination has a better progression-free survival than dabrafenib alone. So these data to me suggest very strongly I would always use dabrafenib plus trametinib ahead of dabrafenib alone. evaluation for CME credit: 27

28 Presentation 4 D + T: dabrafenib + trametinib; vem: vemurafenib. 1. Robert C et al. European Society for Medical Oncology 2014 Congress (ESMO 2014). Abstract LBA4. Dr. Weber: And then, if you look at the recent data just shown at ESMO [2014] reporting on COMBI-v, which is dabrafenib plus trametinib versus the standard vemurafenib, the single-agent BRAF inhibitor, if you look at the overall survival curve shown here, it's pretty obvious that you have a superiority in survival for the combination versus the standard vemurafenib alone even though the follow-up is short and you have lots of hash marks beyond 3 to 4 months. The two-sided P value is.005, which is quite impressive, and the hazard ratio is 69%, indicating a 31% decrease in the risk of dying over time. And if you look at the median for vemurafenib, it's 17 months. But if you look at the median for dabrafenib-trametinib, it hasn't been reached. And again, look at the blue curve: It's above the 50% mark at the time of this analysis. evaluation for CME credit: 28

29 Presentation 4 My prediction is you're going to see way beyond 20 months median survival at the end of the day in this study of vemurafenib versus the combination of dabrafenib and trametinib. And I think it's pretty clear that the combination is going to be superior. evaluation for CME credit: 29

30 Presentation 4 COBIM: cobimetinib; NE: not estimatable; PBO: placebo. 1. McArthur G et al. ESMO Abstract LBA5. 2. Larkin J et al. N Engl J Med. 2014; Epub ahead of print September 29. Dr. Weber: There's been another combination study, and this was called COBRIM, which was vemurafenib plus cobimetinib, which is another MEK inhibitor, compared to vemurafenib alone. And this was another randomized phase 3 study. Here the endpoint was progression-free survival. And again, if you look at the combination versus single-agent vemurafenib, [there was] obvious superiority for the combination at 9.9 months median progression-free survival versus only 6.2 months, which is consistent with past history and past practice with vemurafenib. But look at that hazard ratio: It's an outstanding 0.51, meaning you have a 49% decreased chance of relapsing if you use the combination, with a P value of And this is almost 500 patients. We're looking forward to survival data, which are immature, but at the presentation, it was made clear that the initial survival data showed that the survival was superior to the combination compared to single-agent vemurafenib. evaluation for CME credit: 30

31 Presentation 4 DFS: disease-free survival; DMFS: distant metastasis-free survival; FFR: freedom from relapse Dr. Weber: Finally, we await the results of adjuvant studies of these drugs. For example, there is an adjuvant ongoing study called the BRIM8 trial of vemurafenib versus placebo in patients at high risk for recurrence of melanoma, but who have been rendered free of disease and have stage 3 resected disease. And again, it's a placebo-controlled blinded study of 1 year of vemurafenib given orally versus the placebo for that period of time. And investigator-assessed relapse-free survival is the endpoint, as well as overall and distant metastasis-free survival. That's an ongoing study; it has not completed its accrual. Simultaneously, there's another trial called the COMBI-AD study of patients who were randomly allocated to receive dabrafenib plus trametinib versus placebo, somewhat similar in design to the BRIM8 study. COMBI-AD just finished its accrual, and we'll be hopefully hearing about the results of these studies in the next year or two. evaluation for CME credit: 31

32 Presentation 4 1. Gibney GT et al. ASCO Abstract Puzanov I et al. ASCO Abstract Dr. Weber: In conclusion, there's no question that immunotherapy is now a major component of patient care in metastatic melanoma. We initially had IL-2, then we had CTLA4 blockade with ipilimumab in 2011, and now in the new era, we have multiple PD- 1 blocking agents. One of them just got approved, pembrolizumab. Nivolumab we hope will get approved before the end of They're both excellent drugs. For pembrolizumab, a 24% response rate in patients who have progressed after receiving prior ipilimumab, or a BRAF inhibitor, if they're BRAF-mutated. And the most recent data presented at ESMO [2014] show a 32% response rate in the same population in a phase 3 study of nivolumab compared with chemotherapy. In the future, hopefully we'll see multiple new checkpoint agents. We'll see drugs like IDO inhibitors, which are drugs that decrease immunosuppression. We're going to see the use of oncolytic viruses, like T-VEC, and all of these have promising activity in combination with ipilimumab. And we'll see whether they also look very good with pembrolizumab and nivolumab. evaluation for CME credit: 32

33 Presentation 4 Dr. Weber: We know that targeted therapy continues to evolve. We now know, based on the data we've just heard at ESMO [2014] and at ASCO [2014], that the combination [of] BRAF plus MEK inhibitors are more active and are better front-line options than singleagent BRAF inhibitors, and frankly should absolutely replace the use of single-agent BRAF inhibitors in common practice. And the current options are vemurafenib, dabrafenib, both BRAF inhibitors, and now trametinib, which is a MEK inhibitor, and hopefully coming up we'll have the MEK inhibitor cobimetinib being approved. And there are a number of promising other combinations and inhibitors of CDK4 that look like they might be effective with both MEK, BRAF, and the combination of BRAF plus MEK inhibition. So, finally, I'd say there's an awfully bright future for both immunotherapy and targeted therapy of melanoma, and we look forward to new data coming along each year. Thank you very much. evaluation for CME credit: 33

34 Presentation 4 Narrator: This activity has been jointly provided by Purdue University College of Pharmacy and PVI, PeerView Institute for Medical Education. evaluation for CME credit: 34