Hope after standard melanoma immunotherapies fail

Omid Hamid, MD, discusses promising agents and combinations that offer hope to patients with melanoma for whom standard checkpoint agents and/or targeted therapies are not an option.

 http://www.onclive.com/web-exclusives/novel-checkpoints-offer-hope-after-standard-melanoma-immunotherapies-fail  

Determining the next step for a patient with melanoma who has failed or is not a candidate for existing targeted therapies or immunotherapies can be a challenge.  However, there is hope, says Omid Hamid, MD, chief of Translational Research and Immunotherapy, and director of Melanoma Therapeutics at The Angeles Clinic.

“There are times when you throw your hands in the air and say, ‘I’ve run out of options,’” he says. “But, all you need to do is look in another direction, open another cabinet, and realize that there are a ton of new options for our patients. These are nontraditional agents that maybe would not come to mind, but can be very effective in first-line, second-line, or any line.”

Currently, several new checkpoint inhibitors and costimulatory molecules are being explored. These include those that target glucocorticoid-induced tumor necrosis factor receptor (GITR)—which is expressed on CD4- and CD8-positive T cells—in addition to T-regulatory cells, NK cells, and dendritic cells.  GITR binds to its ligand on antigen presenting cells (APCs) and endothelial cells to promote T-cell activation. A number of GITR agonists are in clinical trials, including TRX518, developed by the biotech startup GITR Inc.  OX40, also known as CD134, is another option for patients with melanoma, says Hamid.  This targets the tumor necrosis factor (TNF) receptor, which is primarily found on the surface of activated cytotoxic and regulatory T cells. MedImmune is developing 3 different OX40-targeting agonists: MEDI6383, MEDI0562, and MEDI6469.  Combination regimens also offer an additional option for patients, says Hamid. Often, agents that do not have much activity alone in a patient may work well with something else.

In an interview with OncLive, Hamid discusses promising agents and combinations that offer hope to patients with melanoma for whom standard checkpoint agents and/or targeted therapies are not an option. 

OncLive: What new agents are available that are showing great potential?

Hamid: There are newer checkpoint agents such as GITR, OX40, and 4-1BB. These new checkpoint inhibitors are showing response after failure with traditional checkpoints. Adaptive T-cell therapeutics, which used to be considered “boutique drugs,”—meaning they were difficult for physicians to find—are now transitioning into normal centers like ours, thanks to collaborations. Antibody-drug conjugates have a role in melanoma, as well. These are phase II options, and some of them will be in phase III soon. 

What should a community oncologist know about these newer agents?

They need to have an understanding of the approved drugs and combinations, the toxicities of these agents, and how to mitigate those toxicities so patients can get back on therapy and get the proper dose intensity. These agents are going to go through clinical trials and will be in their clinics soon.  Community oncologists need to refer patients to enroll in clinical trials. There are a lot of pressing questions that we can answer through clinical trials. What breeds resistance? What are the biomarkers that predict response? How do we treat toxicities, and where do go from here?  There are newer toxicities out there, and physicians need to keep up with the literature in order to understand these and how to treat them. 

Is there potential for these newer agents to be used in combination with existing ones?

Absolutely. Some of these new drugs will be great companion agents. As a single agent, we may see a low response rate; however, in combination, we may see improved response rates because the agents are synergistic.  In the course of 2 or 3 years, we have gone from single-agent trials, to combination trials, to triplet trials.  The future is going to be adding more tolerable regimens, and discussing whether we should be stopping treatment earlier if we get early responses. All of these are going to move forward on a PD-1 backbone, BRAF backbone, or a CTLA-4/PD-1 combination backbone. There is no doubt that, by this time next year, we are going to be talking about triplet trials.

Are there particular combinations being investigated that you are excited about?

I presented data at the 2015 Society for Melanoma Research Congress on the triplet combination of a BRAF inhibitor, a MEK inhibitor, and an anti–PD-L1 agent that showed significant response, good tolerably, and a good duration of response. That is what is up and coming. It is currently being looked at in 3 major trials.  I hope we can get past the idea that, “we need to select from one agent or another” and find a combination regimen that has a higher efficacy, initially.

Here's a link to some of that data:  Combos looking good...

And a more recent discussion:  Weber and Agarwala discuss combination therapies for melanoma 

Wishing you all my best - c

Determining the next step for a patient with melanoma who has failed or is not a candidate for existing targeted therapies or immunotherapies can be a challenge.

However, there is hope, says Omid Hamid, MD, chief of Translational Research and Immunotherapy, and director of Melanoma Therapeutics at The Angeles Clinic.

“There are times when you throw your hands in the air and say, ‘I’ve run out of options,’” he says. “But, all you need to do is look in another direction, open another cabinet, and realize that there are a ton of new options for our patients. These are nontraditional agents that maybe would not come to mind, but can be very effective in first-line, second-line, or any line.”

Currently, several new checkpoint inhibitors and costimulatory molecules are being explored. These include those that target glucocorticoid-induced tumor necrosis factor receptor (GITR)—which is expressed on CD4- and CD8-positive T cells—in addition to T-regulatory cells, NK cells, and dendritic cells.

GITR binds to its ligand on antigen presenting cells (APCs) and endothelial cells to promote T-cell activation. A number of GITR agonists are in clinical trials, including TRX518, developed by the biotech startup GITR Inc.

OX40, also known as CD134, is another option for patients with melanoma, says Hamid.

This targets the tumor necrosis factor (TNF) receptor, which is primarily found on the surface of activated cytotoxic and regulatory T cells. MedImmune is developing 3 different OX40-targeting agonists: MEDI6383, MEDI0562, and MEDI6469.

Combination regimens also offer an additional option for patients, says Hamid. Often, agents that do not have much activity alone in a patient may work well with something else.

In an interview with OncLive, Hamid discusses promising agents and combinations that offer hope to patients with melanoma for whom standard checkpoint agents and/or targeted therapies are not an option.

OncLive: What new agents are available that are showing great potential?

Hamid: There are newer checkpoint agents such as GITR, OX40, and 4-1BB. These new checkpoint inhibitors are showing response after failure with traditional checkpoints. Adaptive T-cell therapeutics, which used to be considered “boutique drugs,”—meaning they were difficult for physicians to find—are now transitioning into normal centers like ours, thanks to collaborations. Antibody-drug conjugates have a role in melanoma, as well. These are phase II options, and some of them will be in phase III soon.

What should a community oncologist know about these newer agents?

They need to have an understanding of the approved drugs and combinations, the toxicities of these agents, and how to mitigate those toxicities so patients can get back on therapy and get the proper dose intensity. These agents are going to go through clinical trials and will be in their clinics soon.

Community oncologists need to refer patients to enroll in clinical trials. There are a lot of pressing questions that we can answer through clinical trials. What breeds resistance? What are the biomarkers that predict response? How do we treat toxicities, and where do go from here?

There are newer toxicities out there, and physicians need to keep up with the literature in order to understand these and how to treat them.

Is there potential for these newer agents to be used in combination with existing ones?

Absolutely. Some of these new drugs will be great companion agents. As a single agent, we may see a low response rate; however, in combination, we may see improved response rates because the agents are synergistic.

In the course of 2 or 3 years, we have gone from single-agent trials, to combination trials, to triplet trials.

The future is going to be adding more tolerable regimens, and discussing whether we should be stopping treatment earlier if we get early responses. All of these are going to move forward on a PD-1 backbone, BRAF backbone, or a CTLA-4/PD-1 combination backbone. There is no doubt that, by this time next year, we are going to be talking about triplet trials.

Are there particular combinations being investigated that you are excited about?

I presented data at the 2015 Society for Melanoma Research Congress on the triplet combination of a BRAF inhibitor, a MEK inhibitor, and an anti–PD-L1 agent that showed significant response, good tolerably, and a good duration of response. That is what is up and coming. It is currently being looked at in 3 major trials.

I hope we can get past the idea that, “we need to select from one agent or another” and find a combination regimen that has a higher efficacy, initially.
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