Anti-PD-1 therapies show significant benefit in desmoplastic melanoma

Zeynep Eroglu

Single-agent therapy with anti-PD-1 inhibitors induced response rates of 70% within a cohort of patients with metastatic desmoplastic melanoma.

Zeynep Eroglu, MD, medical oncologist in the department of cutaneous oncology at Moffitt Cancer Center and assistant professor at University of South Florida, and colleagues retrospectively analyzed 60 patients with advanced desmoplastic melanoma who underwent treatment with PD-1 or PD-L1 therapy.

Forty-two patients achieved significant tumor response, with nearly half of responders showing a complete response and the rest showing a partial response. Nearly three-quarters of patients remained alive at 2 years.

HemOnc Today spoke with Eroglu about the study results, the potential benefit anti-PD-1 and anti-PD-L1 therapies may offer this patient population, and whether it will be possible for patients with desmoplastic melanoma to avoid surgery.

 

Question: Why did you choose to study PD-1/PD-L1 therapies in desmoplastic melanoma?

Answer: It is a rare subtype of melanoma, diagnosed by pathologists, and makes up less than 4% of melanoma cases. Typically, for patients with early-stage disease, the most common treatment is surgical resection. However, given the typical location of desmoplastic melanomas in the head and neck — often as solid masses adherent to surrounding tissue — patients may require large, disfiguring surgeries. Although the tumors have a high mutation burden, there are no actionable driver mutations that can be targeted with drugs. Further, there was concern that the pathology of desmoplastic melanoma — with this dense connective tissue surrounding the tumor cells — may limit immune infiltration into the tumor and make them less responsive to anti-PD-1 therapies. However, there was anecdotal experience that patients with metastatic desmoplastic melanoma treated with anti-PD-1 therapies seemed to do a lot better than expected. We wondered whether this was an incidental finding from a few patients, or whether these patients actually responded better to these drugs than other patients with metastatic melanoma.

 

Q: What initial challenges did you face?

A: Because this is such a rare subtype, we knew it would be challenging to find enough patients from one cancer center to come to any meaningful conclusions, so we collaborated with other cancer centers in the United States and Australia. More than 1,000 cases were reviewed and, ultimately, we found 60 patients with advanced desmoplastic melanoma who received treatment with anti-PD-1 or PD-L1 therapies. We then examined these cases with regard to patient characteristics, tumor response rates and survival, and we analyzed tumor samples from these patients if they were available.

 

 

Q: What did you find?

A: We were pleasantly surprised to see that what we thought may have been an anecdotal observation turned out to be accurate. Seventy percent of the 60 patients treated with anti-PD-1/PD-L1 therapies had an objective tumor response. Typically, with anti-PD-1 antibodies alone in metastatic melanoma, we see a 30% to 40% response rate. With the desmoplastic subtype, we found the response was quite higher. Forty-two patients achieved a response. Twenty-three had a partial response and 19 had a complete response. Two-year PFS was 63% and 2-year OS was 74%.

 

Q: Because the study population was small, is it possible to generalize these results?

A: That is a valid point. This is a retrospective data set, and the results definitely should be validated with a prospective trial. There is an ongoing phase 2 clinical trial run through SWOG, led by principal investigator Kari Kendra, MD, PhD, from The Ohio State University. The S1512 study has two cohorts. One cohort, in which patients with metastatic desmoplastic melanoma are receiving the anti-PD-1 agent pembrolizumab (Keytruda, Merck), essentially is the same population as our retrospective cohort. The hope is that, in a prospective clinical trial, the same high response rates and prolonged survival will be observed. However, it is important to note that the SWOG trial has a neoadjuvant cohort for patients with early-stage/primary desmoplastic melanoma, and those patients are receiving three cycles of pembrolizumab prior to surgery. Anti-PD-1 therapies are not commercially available for patients with early-stage melanoma yet. The hypothesis is that patients with primary desmoplastic melanoma treated with anti-PD-1 therapy upfront would require a much smaller surgical resection.

 

Q: What implications might these findings have for clinical practice?

A: Anti-PD-1 drugs are commercially available for patients with metastatic melanoma, but often combinations of two immunotherapy drugs — such as nivolumab (Opdivo, Bristol-Myers Squibb) with ipilimumab (Yervoy, Bristol-Myers Squibb) — are used to try to improve response and PFS rates beyond those seen with single-agent anti-PD-1 therapy. However, these combinations can lead to significantly higher likelihood of severe side effects than anti-PD-1 drugs alone. Our data suggest that upfront single-agent anti-PD-1 therapy may well be sufficient to treat patients with advanced desmoplastic melanoma, and this may potentially spare them the increased toxicities observed with combination immunotherapy regimens. The promising survival data also may help clinicians as they discuss treatment expectations and prognosis with this subgroup of patients. For patients with primary/early-stage desmoplastic melanoma, we will have to see whether it is possible for them to have much less extensive surgeries if they receive a few cycles of anti-PD-1 therapy first.

 

Q: Is the goal to eliminate surgery , or will that not be possible?

A: That is a great question. For patients with early-stage desmoplastic melanoma, perhaps it may be possible for many of them avoid surgery if a great pathologic response to neoadjuvant pembrolizumab is observed. However, without having prospective trial data, it is premature to say at this point, so we will have to wait for results of the SWOG study.

 

Q: When might prospective data emerge to answer this question?

A: The SWOG trial has been open to accrual since last year. Within the next couple of years, as the trial nears completing accrual, hopefully the data will come out for both the metastatic and early-stage desmoplastic melanoma cohorts. To obtain the results sooner, we would encourage any site that is part of a cooperative group like SWOG to enroll patients on to that study. – by Rob Volansky

 

Reference:

Eroglu Z, et al. Nature. 2018;doi:10.1038/nature25187.

 

For more information:

Zeynep Eroglu, MD, can be reached Moffitt McKinley Outpatient Center, 10920 McKinley Drive, Tampa, FL 33612; email: zeynep.eroglu@moffitt.org.

 

Disclosure: Eroglu reports no relevant financial disclosures.

Zeynep Eroglu

Single-agent therapy with anti-PD-1 inhibitors induced response rates of 70% within a cohort of patients with metastatic desmoplastic melanoma.

Zeynep Eroglu, MD, medical oncologist in the department of cutaneous oncology at Moffitt Cancer Center and assistant professor at University of South Florida, and colleagues retrospectively analyzed 60 patients with advanced desmoplastic melanoma who underwent treatment with PD-1 or PD-L1 therapy.

Forty-two patients achieved significant tumor response, with nearly half of responders showing a complete response and the rest showing a partial response. Nearly three-quarters of patients remained alive at 2 years.

HemOnc Today spoke with Eroglu about the study results, the potential benefit anti-PD-1 and anti-PD-L1 therapies may offer this patient population, and whether it will be possible for patients with desmoplastic melanoma to avoid surgery.

 

Question: Why did you choose to study PD-1/PD-L1 therapies in desmoplastic melanoma?

Answer: It is a rare subtype of melanoma, diagnosed by pathologists, and makes up less than 4% of melanoma cases. Typically, for patients with early-stage disease, the most common treatment is surgical resection. However, given the typical location of desmoplastic melanomas in the head and neck — often as solid masses adherent to surrounding tissue — patients may require large, disfiguring surgeries. Although the tumors have a high mutation burden, there are no actionable driver mutations that can be targeted with drugs. Further, there was concern that the pathology of desmoplastic melanoma — with this dense connective tissue surrounding the tumor cells — may limit immune infiltration into the tumor and make them less responsive to anti-PD-1 therapies. However, there was anecdotal experience that patients with metastatic desmoplastic melanoma treated with anti-PD-1 therapies seemed to do a lot better than expected. We wondered whether this was an incidental finding from a few patients, or whether these patients actually responded better to these drugs than other patients with metastatic melanoma.

 

Q: What initial challenges did you face?

A: Because this is such a rare subtype, we knew it would be challenging to find enough patients from one cancer center to come to any meaningful conclusions, so we collaborated with other cancer centers in the United States and Australia. More than 1,000 cases were reviewed and, ultimately, we found 60 patients with advanced desmoplastic melanoma who received treatment with anti-PD-1 or PD-L1 therapies. We then examined these cases with regard to patient characteristics, tumor response rates and survival, and we analyzed tumor samples from these patients if they were available.

 

 

Q: What did you find?

A: We were pleasantly surprised to see that what we thought may have been an anecdotal observation turned out to be accurate. Seventy percent of the 60 patients treated with anti-PD-1/PD-L1 therapies had an objective tumor response. Typically, with anti-PD-1 antibodies alone in metastatic melanoma, we see a 30% to 40% response rate. With the desmoplastic subtype, we found the response was quite higher. Forty-two patients achieved a response. Twenty-three had a partial response and 19 had a complete response. Two-year PFS was 63% and 2-year OS was 74%.

 

Q: Because the study population was small, is it possible to generalize these results?

A: That is a valid point. This is a retrospective data set, and the results definitely should be validated with a prospective trial. There is an ongoing phase 2 clinical trial run through SWOG, led by principal investigator Kari Kendra, MD, PhD, from The Ohio State University. The S1512 study has two cohorts. One cohort, in which patients with metastatic desmoplastic melanoma are receiving the anti-PD-1 agent pembrolizumab (Keytruda, Merck), essentially is the same population as our retrospective cohort. The hope is that, in a prospective clinical trial, the same high response rates and prolonged survival will be observed. However, it is important to note that the SWOG trial has a neoadjuvant cohort for patients with early-stage/primary desmoplastic melanoma, and those patients are receiving three cycles of pembrolizumab prior to surgery. Anti-PD-1 therapies are not commercially available for patients with early-stage melanoma yet. The hypothesis is that patients with primary desmoplastic melanoma treated with anti-PD-1 therapy upfront would require a much smaller surgical resection.

 

Q: What implications might these findings have for clinical practice?

A: Anti-PD-1 drugs are commercially available for patients with metastatic melanoma, but often combinations of two immunotherapy drugs — such as nivolumab (Opdivo, Bristol-Myers Squibb) with ipilimumab (Yervoy, Bristol-Myers Squibb) — are used to try to improve response and PFS rates beyond those seen with single-agent anti-PD-1 therapy. However, these combinations can lead to significantly higher likelihood of severe side effects than anti-PD-1 drugs alone. Our data suggest that upfront single-agent anti-PD-1 therapy may well be sufficient to treat patients with advanced desmoplastic melanoma, and this may potentially spare them the increased toxicities observed with combination immunotherapy regimens. The promising survival data also may help clinicians as they discuss treatment expectations and prognosis with this subgroup of patients. For patients with primary/early-stage desmoplastic melanoma, we will have to see whether it is possible for them to have much less extensive surgeries if they receive a few cycles of anti-PD-1 therapy first.

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Q: Is the goal to eliminate surgery , or will that not be possible?

A: That is a great question. For patients with early-stage desmoplastic melanoma, perhaps it may be possible for many of them avoid surgery if a great pathologic response to neoadjuvant pembrolizumab is observed. However, without having prospective trial data, it is premature to say at this point, so we will have to wait for results of the SWOG study.

 

Q: When might prospective data emerge to answer this question?

A: The SWOG trial has been open to accrual since last year. Within the next couple of years, as the trial nears completing accrual, hopefully the data will come out for both the metastatic and early-stage desmoplastic melanoma cohorts. To obtain the results sooner, we would encourage any site that is part of a cooperative group like SWOG to enroll patients on to that study. – by Rob Volansky

 

Reference:

Eroglu Z, et al. Nature. 2018;doi:10.1038/nature25187.

 

For more information:

Zeynep Eroglu, MD, can be reached Moffitt McKinley Outpatient Center, 10920 McKinley Drive, Tampa, FL 33612; email: zeynep.eroglu@moffitt.org.

 

Disclosure: Eroglu reports no relevant financial disclosures.

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