Translating an Improved Understanding of Disease Biology Into New Targets and Combinations for the Treatment of Advanced Skin Cancers

Course Director

Antoni Ribas, MD, PhD

Antoni Ribas, MD, PhD
Jonsson Comprehensive Cancer Center
University of California Los Angeles
Los Angeles, California

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Part 2 of a 2-part series

Dr. Ribas provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


The management of advanced skin cancers, including melanoma and basal cell carcinoma, is a challenging problem. However, a better understanding of the mechanisms and molecular pathways underlying the development of these tumors has led to the identification of a number of new drug targets. This, in turn, has resulted in the development of important therapeutic approaches, and many clinical trials are underway that will provide further insight into the efficacy, safety, and optimal use of these treatments and therapeutic combinations. It is important for clinicians to remain current on these advances and understand how to optimally integrate the new therapies into practice.


This activity is supported by an educational grant from Genentech.
Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Antoni Ribas, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for Amgen Inc.; Genentech, Inc.; GlaxoSmithKline; Merck & Co., Inc.; and Novartis Corporation.
Other Financial or Material Support from Kite Pharma, Inc. in the form of stock ownership.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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What are the current research directions and key clinical trials with targeted therapies in melanoma and non-melanoma skin cancers that oncologists should be aware of?

Dr. Ribas: Evidence, both preclinical and clinical for the combination of a BRAF inhibitor and a MEK inhibitor demonstrate that there is a benefit for doing the combined therapy.1-4 The reason is because when we give a BRAF and a MEK inhibitor, we're hitting melanoma twice where it really counts, which is on the pathway that leads to the oncogenic driver signal—the mitogen-activated protein [MAP] kinase pathway. We're preventing that melanoma cell from being able to escape with many of the mechanisms that lead to escape from single-agent BRAF inhibitor.5 So that leads to better initial responses, and that has been seen with the early studies with dabrafenib and trametinib,6 and also with the combination of vemurafenib and cobimetinib, and then it also leads to more durable responses. The very important features of these combinations are that, not only are they more efficacious, but they are also less toxic. And that's because adding a MEK inhibitor to a BRAF inhibitor avoids a feature of single-agent BRAF inhibitors, which is called paradoxical activation of the MAP kinase pathway. And that leads to decreased toxicities—in particular, decrease of the secondary squamous cell carcinomas that are seen with single-agent BRAF inhibitors; also decrease in most of the skin toxicities that are induced by skin proliferation; and also decrease in the joint pains which are a common feature of BRAF inhibitors.3,7 So, I think it's a winner combination, and I'm pretty sure that that will become our new standard of care.

The final proof of this will be available once the randomized clinical trials with dabrafenib-trametinib versus either dabrafenib alone or vemurafenib alone,8,9 or the clinical trial of vemurafenib and cobimetinib compared to vemurafenib alone10 will be reported, which we hope will be within the next year.

But I'm sure that we're not going to stop there, because we're starting to understand what happens when melanoma becomes resistant to BRAF and MEK inhibitors. And we're seeing that several signals from the outside can lead to a state where some melanoma cells harbor the secondary processes that lead to higher resistance. And blocking receptor tyrosine kinases like c-Met may lead to better initial responses and less ability of melanoma [cells] to persist and become truly resistant. And also, we're [now] understanding some of the processes of resistance that go through the activation of an alternative pathway, the PI3/Akt pathway, and how a BRAF inhibitor and an Akt inhibitor could lead to secondary benefits. And there's a clinical trial open at SWOG that is going to be testing such a combination.11

Narrator: Based upon an understanding of the underlying molecular pathogenesis, targeted therapies are being developed for other non-melanoma skin malignancies as well. For example, the hedgehog signaling pathway can cause basal cell proliferation and tumor growth.12 In adults, this pathway is normally inhibited by the patched homolog 1 (PTCH1). Signaling in this pathway is initiated by the cell surface receptor smoothened homolog (SMO). Mutations of PTCH1 may prevent inhibition of SMO activation of the hedgehog pathway, or mutations of SMO may result in activation of the pathway.13-15

Vismodegib is an oral small molecule inhibitor of SMO that blocks the activation of the hedgehog pathway and is approved for the treatment of basal cell carcinoma recurrence after surgery and locally advanced or metastatic disease.16-18 Other targeted agents are undergoing evaluation for basal cell carcinoma, including BMS-833923, IPI-196, LDE225, PF-04449913, LEQ506, and TAK-441.

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What are the current research directions and key clinical trials with immunotherapies in melanoma that oncologists should be aware of?

Dr. Ribas: There's been a lot of interest to apply immunotherapy to the treatment of melanoma. The human immune system has a lot of checks and balances to prevent activation of the immune system against cells, and those checks and balances are limiting the ability of the immune system to attack melanoma. The first evidence of this came from blocking CTLA-4, first in mouse models, where they demonstrated that releasing this early break to the immune system activation, which is limiting the signals that lead to the activation of a T cell, could result in antitumor activity in a mouse.19 That was taken into the clinic with the clinical testing of ipilimumab and another CTLA-4–blocking antibody, tremelimumab, that demonstrated that a small percentage of patients with melanoma could have durable responses to these therapies. Ipilimumab was the first agent that demonstrated overall survival benefit in melanoma.20,21

Narrator: Tremelimumab, another monoclonal antibody directed against CTLA-4, showed activity in early-phase clinical studies in previously treated patients; however, a phase 3 trial of tremelimumab versus chemotherapy in previously untreated patients with melanoma showed a prolongation in response duration among those treated with tremelimumab, but the difference in overall survival was not statistically significant.22

Dr. Ribas: Now, we know that there [are] other breaks, and the next one that has become clinically validated is a break that's on the effector mechanism of the T cells. When a T cell gets into the tumor and tries to kill the cancer, the cancer can protect itself by expressing a protein called PD-L1, which is the ligand for a receptor called PD-1 that's on the T cell.23,24 The new antibodies that block PD-1 or PD-L1 take away this PD-1/PD-L1–negative interaction.

Narrator: These antibodies include nivolumab and MK-3475 (also known as lambrolizumab), which are directed against PD-1, and BMS-936559 and MPDL3280A, which are directed against the PD-1 ligand.

Dr. Ribas: The cancer can no longer hide from T cells, and that's leading to responses that tend to be durable, because the immune system has the ability to recognize and then remember what it has attacked before.

There are several immunomodulating antibodies that are being developed to other negative regulators, like TIM3 or LAG3. There are also immune-activating antibodies that try to turn on the positive interactions. But then there's a possibility of doing combinations of these agents. The clinical testing of this has already started, and there was a report in the New England Journal of Medicine by Wolchok and colleagues earlier this year, where they put together the CTLA-4–blocking antibody ipilimumab and the PD-1 antibody nivolumab.25 And they had a response rate that was between 30% and 40% in patients with metastatic melanoma, which by all practical means seems to be beyond what either agent would have done by itself. That was at the cost of having increased toxicities, where around 50% of the patients had grade 3 to 4 toxicities. Most of them seemed to be manageable, being biochemical toxicities of increased transaminases or lipase, but it tells us that, as we are taking away these immune system breaks, we can get better responses, but we also have to balance the potential of toxicities.

Where I think the field is going is in selecting patients based on the initial characteristics of the tumor—is the PD-1/PD-L1 inhibitory signal limiting an immune response that otherwise would be happening in that patient? Then we could give single-agent PD-1 or PD-L1 antibodies, and there [are] a lot of programs that are trying to select patients based on this biomarker. The data with MK-3475, or lambrolizumab, as [a] single agent is very encouraging in the phase 1 trial.26 The response rate overall was 38%, and at the highest dose of the antibody, a group of patients had a response rate of 52%, which is something that is pushing the limits of what we thought immunotherapy could achieve in this disease. And then in patients who do not have those selectable markers, we could probably be thinking about combinations that could revert that tumor into being more immune-sensitive, and then have these agents be active.

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What are the current research directions and key clinical trials with combined immunotherapy with targeted therapy in melanoma that oncologists should be aware of?

Dr. Ribas: We discussed that there [are] these advances in the treatment of melanoma that are based on two fronts, one understanding the biology of the cancer and blocking BRAF, and understanding the immunobiology of this cancer and releasing breaks that limit immune responses to the cancer. The benefits of these two modes of therapy are very different. BRAF-inhibitor–based therapy gives high initial response rates that tend to not be durable in the majority of patients, so patients develop acquired resistance—as opposed to immunotherapies like ipilimumab or high-dose interleukin-2, which give very low response rates, but those tend to be durable and can last years.

So it's very logical to think, why don't we put them both together, especially knowing that BRAF inhibitors should not negatively impact the lymphocyte, and lead to [a] high rate of durable responses, which is our ultimate goal. We performed a phase 1 clinical trial combining the BRAF inhibitor vemurafenib with the CTLA-4–blocking antibody ipilimumab, and we had to close the study in the second cohort of patients. And it was reported as a letter in the New England Journal of Medicine, disclosing that this combination became toxic with the increase in liver-function testing, in particular transaminases, in six out of the first ten patients.27 There was one patient with elevation of bilirubin, leading to the closing of the study.

But that does not negate the concept; we just need to work a little bit harder to be able to test it. There may be scheduled changes that could be done. It's not clear that we need to have the full doses of an immunotherapeutic when it's given with a BRAF inhibitor, because a BRAF inhibitor can paradoxically activate lymphocytes and lead to a state of over-immune activation. And then there's the potential of using the new PD-1 and PD-L1 antibodies, together with a BRAF inhibitor, either single-agent or with a MEK inhibitor, that would decrease the paradoxical MAP kinase activation, and maybe decrease the toxicities. But then we'll be worried if a MEK inhibitor has a detrimental effect on lymphocytes.

So there's plenty to be tested in the clinic; I think eventually we can find combinations that lead to a high frequency of durable responses.

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  8. A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma. Accessed October 25, 2013.
  9. Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma (COMBI-v). Accessed October 25, 2013.
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This activity is supported by an educational grant from Genentech.
Additional support provided by Penn State College of Medicine and Answers in CME.

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Q&A: Current Status and New Directions in the Treatment of Advanced Skin Cancers

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