Feature

PD-1 blockade provides ‘dramatic advance’ for the treatment of advanced melanoma

Suzanne L. Topalian

Immunotherapy agents — including ipilimumab, nivolumab and pembrolizumab — have changed the landscape of the treatment of advanced melanoma, resulting in 3-year survival rates of up to 58%.

In 2008, a large retrospective analysis by Korn and colleagues showed that for patients with advanced unresectable melanoma, the 3-year OS was approximately 5%,” Suzanne L. Topalian, MD, professor of surgery and oncology at Johns Hopkins Medicine, director of the melanoma program at the Kimmel Cancer Center, and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, told HemOnc Today.

“This is compared with the current state of affairs, where we see approximately a 50% 3-year OS rate with the more modern immunotherapy regimens, either anti-PD-1 by itself or combined with ipilimumab,” she added. “So that’s a 10-fold increase in the expected OS at 3 years for patients with advanced metastatic melanoma. That really is a dramatic advance.”

The FDA approved ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-CTLA-4 agent, for the treatment of unresectable locally advanced or metastatic melanoma in 2011. In 2014, the FDA approved nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck), both PD-1 blockers.

More studies are underway to assess PD-1 blockade in the adjuvant and neoadjuvant settings, as well as for other skin cancers.

Topalian discussed the use of immunotherapy for the treatment of melanoma and other skin cancers at the Wistar Institute Noreen O’Neill Melanoma Research Symposium in June.

HemOnc Today spoke with Topalian about the current state of anti-PD-1 drugs in melanoma, research challenges and future directions of study.

 

Question: What is the current state of PD-1 blockade in melanoma/skin cancers?

Answer: The current options for patients who have advanced melanoma include ipilimumab, which was approved in 2011, and two anti-PD-1 drugs that were approved in 2014: nivolumab and pembrolizumab. The immunotherapy combination of ipilimumab and nivolumab also is approved. More recently, FDA approved nivolumab in the adjuvant setting for patients with stage 3 disease that spread to the regional lymph nodes or very limited stage 4 disease that spread to distant organs that can be removed surgically. These patients receive anti-PD-1 after surgery with the intention of preventing relapse.

At this year’s AACR Annual Meeting, we heard a report of pembrolizumab conferring survival benefits in the adjuvant setting. The expectation is that a second anti-PD-1 drug, pembrolizumab, may also receive FDA approval for this indication.

Researchers also are exploring whether we could treat patients at an even earlier stage before they have surgery for their melanoma. These would be patients whose melanoma can be removed with an intent to cure them, but because of certain characteristics of the tumors or the patients, we know that there is a high risk for recurrence. These groups of patients might receive an anti-PD-1 agent before they go to surgery with the intent to prevent postsurgical relapse. This neoadjuvant approach is still in the clinical trial stage and is a work in progress.

 

Q: How has PD-1 blockade impacted melanoma outcomes?

A: Anti-PD-1 has now provided us with the foundation for treating melanoma. We know that if this drug is the first treatment patients receive for advanced melanoma, they have a high likelihood of response. Even in the later-line settings, after patients have received one or more systemic therapies, they still have a reasonable chance of responding to anti-PD-1, even if they did not respond to prior therapies. Anti-PD-1 drugs now are foundational for melanoma therapeutics. We are attempting to build on that success by combining anti-PD-1 with other kinds of therapies for treating melanoma and to develop better biomarkers to identify the patients who are most likely to respond to anti-PD-1 drugs.

 

Q: What challenges remain in this research area?

A: Even if we’re helping approximately 40% to 50% of patients with advanced melanoma, there’s the other 50% who we are not able to help at this time with anti PD-1. That is the challenge we now face — how to approach those patients. A lot of work is going on now to determine the factors that are driving response or resistance to therapy.

In melanoma, there is a very strong story with kinase inhibitors. About 50% of patients with melanoma have tumors that share the common mutation BRAF V600E. Tumor cells that have this mutation are constituently activated. There are several drugs now that are approved by the FDA or currently in testing that block that pathway. There is research going on now in melanoma, combining kinase inhibitors with immunotherapies. Both of these treatment approaches are effective, but they work by entirely different mechanisms.

Q: What role might tumor mutational burden play in predicting responses to anti-PD-1?

A: There is a lot of information in the literature — not only for melanoma but for other types of cancers — suggesting that tumors with a high mutational burden are more likely to respond to anti-PD-1 drugs. The idea behind this is that mutated genes lead to the production of abnormal proteins, which have never been seen before by the immune system. They can be very strong immunostimulants because they are viewed as being foreign in the same way that bacteria or viruses are foreign to the immune system. The thinking is that the more mutations, the more the immune system has a chance of recognizing and reacting against the tumor. However, this is not a hard and fast rule. There are certainly many examples in the literature of tumors with a low mutational burden that respond to anti-PD-1 and, looking at it in the reverse way, there are tumors with a very high mutational burden that don’t respond to anti-PD-1. It’s not a perfect predictor, but it’s a reasonable guide to help us understand how anti-PD-1 is working and to identify patients or types of cancers that are more likely to respond to anti-PD-1.

 

Q: What about other biomarkers?

A: Before we started investigating tumor mutational burden, the earliest biomarker we looked at in the context of anti-PD-1 therapy was PD-L1 immunohistochemistry. This is an assay that is done on pretreatment tumor biopsies to look for expression of PD-L1 protein, which is the major ligand for PD-1. The idea behind this test is that it may not be important to block PD-1 in tumors that do not express PD-L1. In other words, that checkpoint pathway may not be important in that particular tumor.

In 2012, in The New England Journal of Medicine, we published the first evidence suggesting that PD-L1 expression with immunohistochemistry in pretreatment tumors increased the likelihood of response to anti-PD-1 therapy. That was later borne out in certain cancer types — although not in all — where the FDA has now approved several different PD-L1 immunohistochemistry tests to guide anti-PD-1/PD-L1 therapies in patients with lung cancer, melanoma, cervical cancer and bladder cancer.

 

Q: You mentioned that the tests are generally done pretreatment. Is there any benefit to assessing PD-L1 expression during treatment or after stopping treatment?

A: That is being done in a research capacity right now. The question is whether we can combine anti-PD-1 with other kinds of therapy and, if the other therapy is administered first, would it provoke an immune response against the tumor which might be reflected in heightened PD-L1 expression? PD-L1 is often expressed by tumor cells under immune attack, so in that sense it can be a marker of immune response in the tumor — the immune cells secrete cytokines that then provoke PD-L1 expression.

In tumors that don’t express PD-L1 at the beginning, the question is whether we can give some kind of therapy — such as radiation therapy, certain kinds of chemotherapies, epigenetic therapy or a kinase inhibitor — that would provoke inflammation in the tumor. Then, if a tumor biopsy done during treatment showed the tumor had started to express PD-L1, will that be a useful marker to suggest starting an anti-PD-1 at that point? These studies are ongoing on an experimental basis to see what we can do clinically that would modulate PD-L1 expression to reflect a stronger immune response in the tumor.

 

Q: Aside from melanoma, what other skin cancers are benefitting from PD-1 blockade?

A: When we’re talking about PD-1 blockade, we’re talking about blocking the pathway that also includes PD-L1. We know that for several different cancer types now, blocking either side of that pathway can cause regression of advanced cancers. There’s a rare form of skin cancer, Merkel cell carcinoma, for which the anti-PD-L1 drug avelumab (Bavencio, EMD Serono/Pfizer) has been effective in the setting of advanced unresectable disease. Nivolumab and pembrolizumab have been shown to have an impact against advanced Merkel cell carcinoma, either in the first-line or later-line treatment settings. It’s anticipated that these drugs will also be approved by the FDA for treating Merkel cell carcinoma.

We also presented data at this year’s ASCO Annual Meeting about neoadjuvant anti-PD-1 therapy for Merkel cell carcinoma, showing a high proportion of pathologic responses in the resected tumors after only 4 weeks of nivolumab therapy, which is very encouraging information.

The other main types of skin cancers — basal cell carcinoma and squamous cell carcinoma — don’t have any approved PD-1-blocking agents, but they are being studied in clinical trials and there is very encouraging information for both types of tumors that they may be quite responsive to anti-PD-1 drugs. I imagine that once it’s established that these PD-1 drugs are effective in basal cell and cutaneous squamous cell cancers in the metastatic setting, that treatment will also be tested in the earlier setting for those cancers.

 

Q: What research is ongoing in difficult-to-treat populations ?

A: One population that we’re very interested in are solid organ transplant recipients chronically receiving immunosuppressive drugs. We know that skin cancers are much more common among patients who have a solid organ transplant. These patients are on lifelong immunosuppressants to protect the transplanted organ. When they develop skin cancers, it can be very difficult to treat because there’s a balance between trying to reduce the immunosuppressive drugs, so the immune system will be better able to fight off the cancer, but then the patient may lose the transplanted organ. There is research ongoing in this area now and clinical trials are being started to specifically address this patient population.

Another difficult-to-treat population are patients who are HIV positive. Historically, such patients have been excluded from immunotherapy trials because it was assumed their immune system would not be capable of mounting the same kind of response against cancer as a HIV-negative person. But, now that we know that anti-PD-1 drugs are generally safe, there is more incentive to see if these drugs can be used in the HIV-positive population with cancer. There are clinical trials ongoing now to specifically look at these patients, not only for skin cancers but for various other kinds of cancers, so we’ll see what develops in that area.

Q: How does PD-1 blockade compare to targeted agents, like the recently approved BRAF/MEK combination of encorafenib (Braftovi, Array BioPharma ) and binimetinib (Mektovi , Array BioPharma)?

A: PD-1 blockade does not depend on any specific mutation in the tumor. That’s in contrast to the targeted BRAF/MEK agents, for which the tumor must have a certain BRAF mutation for those drugs to have a chance of working. So, the BRAF/MEK drugs would exclude about 50% of patients with melanoma who don’t have that mutation.

Another point of difference is the side effects. As you might imagine, the major side effects of PD-1 blockade are immune-related side effects — in some cases, they resemble autoimmune disorders — whereas the side effects of BRAF/MEK inhibitors are similar to the side effects we’ve seen with other kinds of kinase inhibitors, including rash and fever.

Further, BRAF inhibitors, when they work, can do so very rapidly, sometimes within several days. For patients with very large burdens of melanoma or very rapidly advancing disease, we may want to use those drugs first because the immunotherapy drugs don’t attack the tumor cells directly. They work indirectly through the immune system, which means they can take a bit longer to have an antitumor effect.

Finally, in terms of the durability of the benefit from the drugs, most of the studies show that durability of response with the immunotherapy drugs is superior to the kinase inhibitors. Both classes of drugs are very effective in certain patients with melanoma, but they work by different mechanisms.

 

Q: What are your short-term and long-term expectations for treatment with anti-PD-1 drugs?

A: For the short term, we now have an arsenal of drugs available to use among patients with melanoma, for those who have undergone surgical resection and those who cannot undergo surgical resection and have more advanced disease. That is a real change in the landscape of melanoma therapeutics compared with 10 years ago.

Looking into the future, there’s still a lot to be done, including expanding this kind of therapy to other kinds of skin cancers and to difficult-to-treat populations. We aim to achieve a much better understanding of response and resistance to anti-PD-1 so that we can effectively design combination regimens with other drugs or other kinds of therapies, like radiation or chemotherapy, to have more effectiveness than monotherapy with anti-PD-1. – by Cassie Homer

 

For more information:

Suzanne L. Topalian, MD, can be reached at 1550 Orleans St., CRB2, Room 508, Baltimore, MD; email: stopali1@jhmi.edu.

Disclosure: Topalian reports research grants from Bristol-Myers Squibb, and that her spouse is a consultant for MedImmune, Merck and Pfizer.

Suzanne L. Topalian

Immunotherapy agents — including ipilimumab, nivolumab and pembrolizumab — have changed the landscape of the treatment of advanced melanoma, resulting in 3-year survival rates of up to 58%.

In 2008, a large retrospective analysis by Korn and colleagues showed that for patients with advanced unresectable melanoma, the 3-year OS was approximately 5%,” Suzanne L. Topalian, MD, professor of surgery and oncology at Johns Hopkins Medicine, director of the melanoma program at the Kimmel Cancer Center, and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, told HemOnc Today.

“This is compared with the current state of affairs, where we see approximately a 50% 3-year OS rate with the more modern immunotherapy regimens, either anti-PD-1 by itself or combined with ipilimumab,” she added. “So that’s a 10-fold increase in the expected OS at 3 years for patients with advanced metastatic melanoma. That really is a dramatic advance.”

The FDA approved ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-CTLA-4 agent, for the treatment of unresectable locally advanced or metastatic melanoma in 2011. In 2014, the FDA approved nivolumab (Opdivo, Bristol-Myers Squibb) and pembrolizumab (Keytruda, Merck), both PD-1 blockers.

More studies are underway to assess PD-1 blockade in the adjuvant and neoadjuvant settings, as well as for other skin cancers.

Topalian discussed the use of immunotherapy for the treatment of melanoma and other skin cancers at the Wistar Institute Noreen O’Neill Melanoma Research Symposium in June.

HemOnc Today spoke with Topalian about the current state of anti-PD-1 drugs in melanoma, research challenges and future directions of study.

 

Question: What is the current state of PD-1 blockade in melanoma/skin cancers?

Answer: The current options for patients who have advanced melanoma include ipilimumab, which was approved in 2011, and two anti-PD-1 drugs that were approved in 2014: nivolumab and pembrolizumab. The immunotherapy combination of ipilimumab and nivolumab also is approved. More recently, FDA approved nivolumab in the adjuvant setting for patients with stage 3 disease that spread to the regional lymph nodes or very limited stage 4 disease that spread to distant organs that can be removed surgically. These patients receive anti-PD-1 after surgery with the intention of preventing relapse.

At this year’s AACR Annual Meeting, we heard a report of pembrolizumab conferring survival benefits in the adjuvant setting. The expectation is that a second anti-PD-1 drug, pembrolizumab, may also receive FDA approval for this indication.

Researchers also are exploring whether we could treat patients at an even earlier stage before they have surgery for their melanoma. These would be patients whose melanoma can be removed with an intent to cure them, but because of certain characteristics of the tumors or the patients, we know that there is a high risk for recurrence. These groups of patients might receive an anti-PD-1 agent before they go to surgery with the intent to prevent postsurgical relapse. This neoadjuvant approach is still in the clinical trial stage and is a work in progress.

 

Q: How has PD-1 blockade impacted melanoma outcomes?

A: Anti-PD-1 has now provided us with the foundation for treating melanoma. We know that if this drug is the first treatment patients receive for advanced melanoma, they have a high likelihood of response. Even in the later-line settings, after patients have received one or more systemic therapies, they still have a reasonable chance of responding to anti-PD-1, even if they did not respond to prior therapies. Anti-PD-1 drugs now are foundational for melanoma therapeutics. We are attempting to build on that success by combining anti-PD-1 with other kinds of therapies for treating melanoma and to develop better biomarkers to identify the patients who are most likely to respond to anti-PD-1 drugs.

 

Q: What challenges remain in this research area?

A: Even if we’re helping approximately 40% to 50% of patients with advanced melanoma, there’s the other 50% who we are not able to help at this time with anti PD-1. That is the challenge we now face — how to approach those patients. A lot of work is going on now to determine the factors that are driving response or resistance to therapy.

In melanoma, there is a very strong story with kinase inhibitors. About 50% of patients with melanoma have tumors that share the common mutation BRAF V600E. Tumor cells that have this mutation are constituently activated. There are several drugs now that are approved by the FDA or currently in testing that block that pathway. There is research going on now in melanoma, combining kinase inhibitors with immunotherapies. Both of these treatment approaches are effective, but they work by entirely different mechanisms.

 

PAGE BREAK

Q: What role might tumor mutational burden play in predicting responses to anti-PD-1?

A: There is a lot of information in the literature — not only for melanoma but for other types of cancers — suggesting that tumors with a high mutational burden are more likely to respond to anti-PD-1 drugs. The idea behind this is that mutated genes lead to the production of abnormal proteins, which have never been seen before by the immune system. They can be very strong immunostimulants because they are viewed as being foreign in the same way that bacteria or viruses are foreign to the immune system. The thinking is that the more mutations, the more the immune system has a chance of recognizing and reacting against the tumor. However, this is not a hard and fast rule. There are certainly many examples in the literature of tumors with a low mutational burden that respond to anti-PD-1 and, looking at it in the reverse way, there are tumors with a very high mutational burden that don’t respond to anti-PD-1. It’s not a perfect predictor, but it’s a reasonable guide to help us understand how anti-PD-1 is working and to identify patients or types of cancers that are more likely to respond to anti-PD-1.

 

Q: What about other biomarkers?

A: Before we started investigating tumor mutational burden, the earliest biomarker we looked at in the context of anti-PD-1 therapy was PD-L1 immunohistochemistry. This is an assay that is done on pretreatment tumor biopsies to look for expression of PD-L1 protein, which is the major ligand for PD-1. The idea behind this test is that it may not be important to block PD-1 in tumors that do not express PD-L1. In other words, that checkpoint pathway may not be important in that particular tumor.

In 2012, in The New England Journal of Medicine, we published the first evidence suggesting that PD-L1 expression with immunohistochemistry in pretreatment tumors increased the likelihood of response to anti-PD-1 therapy. That was later borne out in certain cancer types — although not in all — where the FDA has now approved several different PD-L1 immunohistochemistry tests to guide anti-PD-1/PD-L1 therapies in patients with lung cancer, melanoma, cervical cancer and bladder cancer.

 

Q: You mentioned that the tests are generally done pretreatment. Is there any benefit to assessing PD-L1 expression during treatment or after stopping treatment?

A: That is being done in a research capacity right now. The question is whether we can combine anti-PD-1 with other kinds of therapy and, if the other therapy is administered first, would it provoke an immune response against the tumor which might be reflected in heightened PD-L1 expression? PD-L1 is often expressed by tumor cells under immune attack, so in that sense it can be a marker of immune response in the tumor — the immune cells secrete cytokines that then provoke PD-L1 expression.

In tumors that don’t express PD-L1 at the beginning, the question is whether we can give some kind of therapy — such as radiation therapy, certain kinds of chemotherapies, epigenetic therapy or a kinase inhibitor — that would provoke inflammation in the tumor. Then, if a tumor biopsy done during treatment showed the tumor had started to express PD-L1, will that be a useful marker to suggest starting an anti-PD-1 at that point? These studies are ongoing on an experimental basis to see what we can do clinically that would modulate PD-L1 expression to reflect a stronger immune response in the tumor.

 

Q: Aside from melanoma, what other skin cancers are benefitting from PD-1 blockade?

A: When we’re talking about PD-1 blockade, we’re talking about blocking the pathway that also includes PD-L1. We know that for several different cancer types now, blocking either side of that pathway can cause regression of advanced cancers. There’s a rare form of skin cancer, Merkel cell carcinoma, for which the anti-PD-L1 drug avelumab (Bavencio, EMD Serono/Pfizer) has been effective in the setting of advanced unresectable disease. Nivolumab and pembrolizumab have been shown to have an impact against advanced Merkel cell carcinoma, either in the first-line or later-line treatment settings. It’s anticipated that these drugs will also be approved by the FDA for treating Merkel cell carcinoma.

We also presented data at this year’s ASCO Annual Meeting about neoadjuvant anti-PD-1 therapy for Merkel cell carcinoma, showing a high proportion of pathologic responses in the resected tumors after only 4 weeks of nivolumab therapy, which is very encouraging information.

The other main types of skin cancers — basal cell carcinoma and squamous cell carcinoma — don’t have any approved PD-1-blocking agents, but they are being studied in clinical trials and there is very encouraging information for both types of tumors that they may be quite responsive to anti-PD-1 drugs. I imagine that once it’s established that these PD-1 drugs are effective in basal cell and cutaneous squamous cell cancers in the metastatic setting, that treatment will also be tested in the earlier setting for those cancers.

 

Q: What research is ongoing in difficult-to-treat populations ?

A: One population that we’re very interested in are solid organ transplant recipients chronically receiving immunosuppressive drugs. We know that skin cancers are much more common among patients who have a solid organ transplant. These patients are on lifelong immunosuppressants to protect the transplanted organ. When they develop skin cancers, it can be very difficult to treat because there’s a balance between trying to reduce the immunosuppressive drugs, so the immune system will be better able to fight off the cancer, but then the patient may lose the transplanted organ. There is research ongoing in this area now and clinical trials are being started to specifically address this patient population.

Another difficult-to-treat population are patients who are HIV positive. Historically, such patients have been excluded from immunotherapy trials because it was assumed their immune system would not be capable of mounting the same kind of response against cancer as a HIV-negative person. But, now that we know that anti-PD-1 drugs are generally safe, there is more incentive to see if these drugs can be used in the HIV-positive population with cancer. There are clinical trials ongoing now to specifically look at these patients, not only for skin cancers but for various other kinds of cancers, so we’ll see what develops in that area.

PAGE BREAK
 

Q: How does PD-1 blockade compare to targeted agents, like the recently approved BRAF/MEK combination of encorafenib (Braftovi, Array BioPharma ) and binimetinib (Mektovi , Array BioPharma)?

A: PD-1 blockade does not depend on any specific mutation in the tumor. That’s in contrast to the targeted BRAF/MEK agents, for which the tumor must have a certain BRAF mutation for those drugs to have a chance of working. So, the BRAF/MEK drugs would exclude about 50% of patients with melanoma who don’t have that mutation.

Another point of difference is the side effects. As you might imagine, the major side effects of PD-1 blockade are immune-related side effects — in some cases, they resemble autoimmune disorders — whereas the side effects of BRAF/MEK inhibitors are similar to the side effects we’ve seen with other kinds of kinase inhibitors, including rash and fever.

Further, BRAF inhibitors, when they work, can do so very rapidly, sometimes within several days. For patients with very large burdens of melanoma or very rapidly advancing disease, we may want to use those drugs first because the immunotherapy drugs don’t attack the tumor cells directly. They work indirectly through the immune system, which means they can take a bit longer to have an antitumor effect.

Finally, in terms of the durability of the benefit from the drugs, most of the studies show that durability of response with the immunotherapy drugs is superior to the kinase inhibitors. Both classes of drugs are very effective in certain patients with melanoma, but they work by different mechanisms.

 

Q: What are your short-term and long-term expectations for treatment with anti-PD-1 drugs?

A: For the short term, we now have an arsenal of drugs available to use among patients with melanoma, for those who have undergone surgical resection and those who cannot undergo surgical resection and have more advanced disease. That is a real change in the landscape of melanoma therapeutics compared with 10 years ago.

Looking into the future, there’s still a lot to be done, including expanding this kind of therapy to other kinds of skin cancers and to difficult-to-treat populations. We aim to achieve a much better understanding of response and resistance to anti-PD-1 so that we can effectively design combination regimens with other drugs or other kinds of therapies, like radiation or chemotherapy, to have more effectiveness than monotherapy with anti-PD-1. – by Cassie Homer

 

For more information:

Suzanne L. Topalian, MD, can be reached at 1550 Orleans St., CRB2, Room 508, Baltimore, MD; email: stopali1@jhmi.edu.

Disclosure: Topalian reports research grants from Bristol-Myers Squibb, and that her spouse is a consultant for MedImmune, Merck and Pfizer.

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