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Uveal melanoma: NCCN provides first pathway-based guidelines
ORLANDO – Uveal melanoma has little in common with it’s cutaneous namesake, and its distinct characteristics necessitated the development of specific guidelines for diagnosis and management, which were released earlier this year by the National Comprehensive Cancer Network (NCCN).
Unlike cutaneous melanoma, uveal melanoma is usually treated with radiotherapy rather than surgery, and primary treatment is based on tumor size, according to Christopher A. Barker, MD, a radiation oncologist and director of clinical investigations in the department of radiation at Memorial Sloan Kettering Cancer Center, New York.
Further, molecular testing aids in prognosis in uveal melanoma but not in predicting treatment response as it can in cutaneous disease, and recurrences of uveal melanoma are typically distant – usually occurring in the liver – rather than in the skin or lymph nodes as with cutaneous melanoma.
These and other diagnosis- and treatment-related issues are outlined in the new guidelines, which are the first developed by the NCCN for uveal melanoma.
Guidelines exist in several countries, including Australia, the United Kingdom, Canada, and the United States (published by The American Brachytherapy Society), but until now none have provided pathway-based strategies for the management of all stages of this rare disease that affects about 1 in 200,000 Americans, typically Caucasians in their 50s, 60s, or 70s, Dr. Barker, a member of the NCCN Melanoma guidelines panel and the uveal melanoma subcommittee, said at the NCCN’s annual meeting where he presented the guidelines.
The median age of diagnosis is 60 years, he noted.
The NCCN guidelines specifically address melanoma arising in the choroid and ciliary body of the uvea. The choroid is the predominant site of uveal melanoma origin, and tumors arising there may involve the ciliary body as well, although the latter is a rare site of melanoma origin. The iris is also a rare site of origin, and tumors arising there are typically indolent in nature and thus are not part of the new guidelines, he explained.
Risk factors include choroidal nevi, ocular melanocytosis, and familial uveal melanoma associated with germline BAP1 mutation, neurofibromatosis, or dysplastic nevus syndrome; cutaneous melanoma is not a risk factor, he said.
The guidelines address clinical presentation, diagnostic work-up, and staging; primary treatments; and metastatic risks and follow-up imaging.
Presentation, diagnosis, and staging
About two-thirds of patients with uveal melanoma present because of changes in their vision, and about a third present with no new symptoms and are diagnosed during routine evaluation, Dr. Barker said.
“History and physical exam, and specifically attention to any prior malignancies, is important,” he said. “A comprehensive eye examination is absolutely vital to the evaluation and staging of patients with uveal melanoma.”
Numerous additional testing options, including autofluorescence of the ocular fundus, retinal fluorescein angiography of the ocular fundus, and transillumination, among others, are listed in the guidelines, which note that MRI is sometimes needed to confirm diagnosis.
Biopsies, however, are generally only performed to confirm diagnosis if needed or for prognostic analysis for risk stratification.
Staging is determined mainly by tumor size, which is known to be associated with outcomes in patients with uveal melanoma, and is based on criteria from both the Collaborative Ocular Melanoma Study (COMS) staging system and the American Joint Committee on Cancer (AJCC) staging manual, Dr. Barker said.
The COMS system was developed based on separate studies of small, medium, and large tumors and helped define primary tumor management and establish existing standards of care. The AJCC system was developed subsequently and focuses more on tumor features that may improve clinical predictions.
Primary treatments
Options for primary treatment for small tumors (largest diameter 5-16 mm and thickness less than 2.5 mm) include plaque brachytherapy, partical beam radiation, and laser ablation in highly select patients. For medium tumors (18mm or less at largest diameter and thickness of 2.5-10 mm), they include plaque brachytherapy, particle beam radiation, and enucleation, according to the guidelines.
Large tumors can be treated with radiotherapy (preferably particle beam radiation, Dr. Barker said) or enucleation. Large tumors are those greater than 18mm with any thickness, those with thickness greater than 10mm with any diameter, and those with thickness greater than 8mm with optic nerve involvement.
In patients for whom surgical removal is selected, “ there are a few unusual situations where additional local adjuvant therapy might be considered,” Dr. Barker said, explaining, for example, that the presence of microscopically positive or close margins after enucleation without evidence of gross residual disease in the orbit may be observed or may warrant map biopsy and/or particle beam or photon beam radiotherapy to the orbit.
For visible extraocular tumors or suspicion of gross disease in the orbit, biopsy of the extraocular tissue is recommended when possible, along with either intraoperative cryotherapy, orbital exenteration, or particle beam or photon beam radiotherapy to the orbit, he added.
Metastatic risks and follow-up imaging
Recent studies, including Cancer Genome Atlas Research Network studies, have elucidated the genomics of both uveal and cutaneous melanomas, and they show “a completely different mutation spectrum” for uveal melanoma, Dr. Barker said.
These genomic studies demonstrate that cutaneous melanoma involves mutations that predict response to certain treatments, while those found in uveal melanoma do not, but they are, however, associated with the probability of metastasis, he said.
For example, various studies have shown that BRAF mutation in cutaneous melanoma predicts response to RAF or MEK inhibition and that the overall number of mutations in cutaneous melanoma may predict response to immunotherapy.
In uveal melanoma, alterations in ElFAX1, SF3B1, or BAP1 have been shown to indicate low, intermediate, and high risk of metastasis, respectively.
Other factors associated with the risk of metastasis after primary tumor treatment in uveal melanoma include clinical factors (tumor size, ciliary body involvement, and extraocular extension); histopathologic factors (spindle or epithelioid cell type); and cytogenetics (status of chromosomes 3, 6, and 8), he said.
An AJCC Ophthalmic Oncology Task Force study published in 2015, for example, showed that the 5-year metastasis-free survival was 97% for AJCC stage T1 disease, 85% for stage T2, 77% for stage T3, and 61% for stage T4. T-stage modifiers, which are based on particular tumor characteristics, such as ciliary body involvement (CBI) and extraocular extension (EXE), were also associated with the risk of distant metastasis: 5-year metastasis-free survival was 90%, 72%, 54% and 33% for AJCC T_a (no CBI or EXE), T_b (CBI only), T_c (EXE only), and T_d tumors (CBI and EXE), respectively.
Follow-up imaging after primary tumor treatment should be based on the most likely site of metastatic recurrence, which is the liver in 90% of uveal melanoma metastases.
“For this reason, surveillance of high-risk patients with uveal melanoma should include specific imaging of the liver,” Dr. Barker said, who noted that the NCCN risk stratification–based surveillance guidelines categorize patients as either low, medium, or high risk for metastasis based on the various characteristics that can affect risk.
“These risk groups help clinicians identify how often imaging should be performed in their surveillance strategy,” he said, adding that those who are high risk based on BAP1 mutation, PRAME mutation, CBI, or EXE, for example, should undergo imaging to evaluate signs or symptoms every 3-6 months for 5 years, every 6-12 months for 10 years, and then as clinically indicated thereafter.
The guideline calls for less stringent imaging for low- and medium-risk patients.
“Now, what happens when distant metastases are identified? Unfortunately there is no single systemic therapy that has proven to be most effective for uveal melanoma,” he said. “For this reason, the NCCN guideline encourages clinical trial participation whenever possible for patients who develop distant metastasis.”
This is because drugs effective for cutaneous melanoma are far less effective for uveal melanoma, but do elicit response in some patients and can be considered, he explained.
“Moreover, because the liver is the site of metastasis most often, and is often the exclusive site of metastasis, liver metastasis–directed therapy is considered part of the management of patients with uveal melanoma,” he said, adding that this can involve resection, ablation, chemo/radio embolization, or regional perfusion.”
The NCCN Uveal Melanoma Guidelines were developed by a panel of experts from various institutions based on the available evidence and on consensus; they are category 2A (based on lower-level evidence with uniform NCCN consensus that the intervention is appropriate).
Dr. Barker reported receiving clinical research support from Amgen, Bristol-Myers Squibb, Elekta, Merck, University of California San Francisco, and University of Florida Health Cancer Center Orlando, and serving as an advisor, consultant, or expert witness for Pfizer.
ORLANDO – Uveal melanoma has little in common with it’s cutaneous namesake, and its distinct characteristics necessitated the development of specific guidelines for diagnosis and management, which were released earlier this year by the National Comprehensive Cancer Network (NCCN).
Unlike cutaneous melanoma, uveal melanoma is usually treated with radiotherapy rather than surgery, and primary treatment is based on tumor size, according to Christopher A. Barker, MD, a radiation oncologist and director of clinical investigations in the department of radiation at Memorial Sloan Kettering Cancer Center, New York.
Further, molecular testing aids in prognosis in uveal melanoma but not in predicting treatment response as it can in cutaneous disease, and recurrences of uveal melanoma are typically distant – usually occurring in the liver – rather than in the skin or lymph nodes as with cutaneous melanoma.
These and other diagnosis- and treatment-related issues are outlined in the new guidelines, which are the first developed by the NCCN for uveal melanoma.
Guidelines exist in several countries, including Australia, the United Kingdom, Canada, and the United States (published by The American Brachytherapy Society), but until now none have provided pathway-based strategies for the management of all stages of this rare disease that affects about 1 in 200,000 Americans, typically Caucasians in their 50s, 60s, or 70s, Dr. Barker, a member of the NCCN Melanoma guidelines panel and the uveal melanoma subcommittee, said at the NCCN’s annual meeting where he presented the guidelines.
The median age of diagnosis is 60 years, he noted.
The NCCN guidelines specifically address melanoma arising in the choroid and ciliary body of the uvea. The choroid is the predominant site of uveal melanoma origin, and tumors arising there may involve the ciliary body as well, although the latter is a rare site of melanoma origin. The iris is also a rare site of origin, and tumors arising there are typically indolent in nature and thus are not part of the new guidelines, he explained.
Risk factors include choroidal nevi, ocular melanocytosis, and familial uveal melanoma associated with germline BAP1 mutation, neurofibromatosis, or dysplastic nevus syndrome; cutaneous melanoma is not a risk factor, he said.
The guidelines address clinical presentation, diagnostic work-up, and staging; primary treatments; and metastatic risks and follow-up imaging.
Presentation, diagnosis, and staging
About two-thirds of patients with uveal melanoma present because of changes in their vision, and about a third present with no new symptoms and are diagnosed during routine evaluation, Dr. Barker said.
“History and physical exam, and specifically attention to any prior malignancies, is important,” he said. “A comprehensive eye examination is absolutely vital to the evaluation and staging of patients with uveal melanoma.”
Numerous additional testing options, including autofluorescence of the ocular fundus, retinal fluorescein angiography of the ocular fundus, and transillumination, among others, are listed in the guidelines, which note that MRI is sometimes needed to confirm diagnosis.
Biopsies, however, are generally only performed to confirm diagnosis if needed or for prognostic analysis for risk stratification.
Staging is determined mainly by tumor size, which is known to be associated with outcomes in patients with uveal melanoma, and is based on criteria from both the Collaborative Ocular Melanoma Study (COMS) staging system and the American Joint Committee on Cancer (AJCC) staging manual, Dr. Barker said.
The COMS system was developed based on separate studies of small, medium, and large tumors and helped define primary tumor management and establish existing standards of care. The AJCC system was developed subsequently and focuses more on tumor features that may improve clinical predictions.
Primary treatments
Options for primary treatment for small tumors (largest diameter 5-16 mm and thickness less than 2.5 mm) include plaque brachytherapy, partical beam radiation, and laser ablation in highly select patients. For medium tumors (18mm or less at largest diameter and thickness of 2.5-10 mm), they include plaque brachytherapy, particle beam radiation, and enucleation, according to the guidelines.
Large tumors can be treated with radiotherapy (preferably particle beam radiation, Dr. Barker said) or enucleation. Large tumors are those greater than 18mm with any thickness, those with thickness greater than 10mm with any diameter, and those with thickness greater than 8mm with optic nerve involvement.
In patients for whom surgical removal is selected, “ there are a few unusual situations where additional local adjuvant therapy might be considered,” Dr. Barker said, explaining, for example, that the presence of microscopically positive or close margins after enucleation without evidence of gross residual disease in the orbit may be observed or may warrant map biopsy and/or particle beam or photon beam radiotherapy to the orbit.
For visible extraocular tumors or suspicion of gross disease in the orbit, biopsy of the extraocular tissue is recommended when possible, along with either intraoperative cryotherapy, orbital exenteration, or particle beam or photon beam radiotherapy to the orbit, he added.
Metastatic risks and follow-up imaging
Recent studies, including Cancer Genome Atlas Research Network studies, have elucidated the genomics of both uveal and cutaneous melanomas, and they show “a completely different mutation spectrum” for uveal melanoma, Dr. Barker said.
These genomic studies demonstrate that cutaneous melanoma involves mutations that predict response to certain treatments, while those found in uveal melanoma do not, but they are, however, associated with the probability of metastasis, he said.
For example, various studies have shown that BRAF mutation in cutaneous melanoma predicts response to RAF or MEK inhibition and that the overall number of mutations in cutaneous melanoma may predict response to immunotherapy.
In uveal melanoma, alterations in ElFAX1, SF3B1, or BAP1 have been shown to indicate low, intermediate, and high risk of metastasis, respectively.
Other factors associated with the risk of metastasis after primary tumor treatment in uveal melanoma include clinical factors (tumor size, ciliary body involvement, and extraocular extension); histopathologic factors (spindle or epithelioid cell type); and cytogenetics (status of chromosomes 3, 6, and 8), he said.
An AJCC Ophthalmic Oncology Task Force study published in 2015, for example, showed that the 5-year metastasis-free survival was 97% for AJCC stage T1 disease, 85% for stage T2, 77% for stage T3, and 61% for stage T4. T-stage modifiers, which are based on particular tumor characteristics, such as ciliary body involvement (CBI) and extraocular extension (EXE), were also associated with the risk of distant metastasis: 5-year metastasis-free survival was 90%, 72%, 54% and 33% for AJCC T_a (no CBI or EXE), T_b (CBI only), T_c (EXE only), and T_d tumors (CBI and EXE), respectively.
Follow-up imaging after primary tumor treatment should be based on the most likely site of metastatic recurrence, which is the liver in 90% of uveal melanoma metastases.
“For this reason, surveillance of high-risk patients with uveal melanoma should include specific imaging of the liver,” Dr. Barker said, who noted that the NCCN risk stratification–based surveillance guidelines categorize patients as either low, medium, or high risk for metastasis based on the various characteristics that can affect risk.
“These risk groups help clinicians identify how often imaging should be performed in their surveillance strategy,” he said, adding that those who are high risk based on BAP1 mutation, PRAME mutation, CBI, or EXE, for example, should undergo imaging to evaluate signs or symptoms every 3-6 months for 5 years, every 6-12 months for 10 years, and then as clinically indicated thereafter.
The guideline calls for less stringent imaging for low- and medium-risk patients.
“Now, what happens when distant metastases are identified? Unfortunately there is no single systemic therapy that has proven to be most effective for uveal melanoma,” he said. “For this reason, the NCCN guideline encourages clinical trial participation whenever possible for patients who develop distant metastasis.”
This is because drugs effective for cutaneous melanoma are far less effective for uveal melanoma, but do elicit response in some patients and can be considered, he explained.
“Moreover, because the liver is the site of metastasis most often, and is often the exclusive site of metastasis, liver metastasis–directed therapy is considered part of the management of patients with uveal melanoma,” he said, adding that this can involve resection, ablation, chemo/radio embolization, or regional perfusion.”
The NCCN Uveal Melanoma Guidelines were developed by a panel of experts from various institutions based on the available evidence and on consensus; they are category 2A (based on lower-level evidence with uniform NCCN consensus that the intervention is appropriate).
Dr. Barker reported receiving clinical research support from Amgen, Bristol-Myers Squibb, Elekta, Merck, University of California San Francisco, and University of Florida Health Cancer Center Orlando, and serving as an advisor, consultant, or expert witness for Pfizer.
ORLANDO – Uveal melanoma has little in common with it’s cutaneous namesake, and its distinct characteristics necessitated the development of specific guidelines for diagnosis and management, which were released earlier this year by the National Comprehensive Cancer Network (NCCN).
Unlike cutaneous melanoma, uveal melanoma is usually treated with radiotherapy rather than surgery, and primary treatment is based on tumor size, according to Christopher A. Barker, MD, a radiation oncologist and director of clinical investigations in the department of radiation at Memorial Sloan Kettering Cancer Center, New York.
Further, molecular testing aids in prognosis in uveal melanoma but not in predicting treatment response as it can in cutaneous disease, and recurrences of uveal melanoma are typically distant – usually occurring in the liver – rather than in the skin or lymph nodes as with cutaneous melanoma.
These and other diagnosis- and treatment-related issues are outlined in the new guidelines, which are the first developed by the NCCN for uveal melanoma.
Guidelines exist in several countries, including Australia, the United Kingdom, Canada, and the United States (published by The American Brachytherapy Society), but until now none have provided pathway-based strategies for the management of all stages of this rare disease that affects about 1 in 200,000 Americans, typically Caucasians in their 50s, 60s, or 70s, Dr. Barker, a member of the NCCN Melanoma guidelines panel and the uveal melanoma subcommittee, said at the NCCN’s annual meeting where he presented the guidelines.
The median age of diagnosis is 60 years, he noted.
The NCCN guidelines specifically address melanoma arising in the choroid and ciliary body of the uvea. The choroid is the predominant site of uveal melanoma origin, and tumors arising there may involve the ciliary body as well, although the latter is a rare site of melanoma origin. The iris is also a rare site of origin, and tumors arising there are typically indolent in nature and thus are not part of the new guidelines, he explained.
Risk factors include choroidal nevi, ocular melanocytosis, and familial uveal melanoma associated with germline BAP1 mutation, neurofibromatosis, or dysplastic nevus syndrome; cutaneous melanoma is not a risk factor, he said.
The guidelines address clinical presentation, diagnostic work-up, and staging; primary treatments; and metastatic risks and follow-up imaging.
Presentation, diagnosis, and staging
About two-thirds of patients with uveal melanoma present because of changes in their vision, and about a third present with no new symptoms and are diagnosed during routine evaluation, Dr. Barker said.
“History and physical exam, and specifically attention to any prior malignancies, is important,” he said. “A comprehensive eye examination is absolutely vital to the evaluation and staging of patients with uveal melanoma.”
Numerous additional testing options, including autofluorescence of the ocular fundus, retinal fluorescein angiography of the ocular fundus, and transillumination, among others, are listed in the guidelines, which note that MRI is sometimes needed to confirm diagnosis.
Biopsies, however, are generally only performed to confirm diagnosis if needed or for prognostic analysis for risk stratification.
Staging is determined mainly by tumor size, which is known to be associated with outcomes in patients with uveal melanoma, and is based on criteria from both the Collaborative Ocular Melanoma Study (COMS) staging system and the American Joint Committee on Cancer (AJCC) staging manual, Dr. Barker said.
The COMS system was developed based on separate studies of small, medium, and large tumors and helped define primary tumor management and establish existing standards of care. The AJCC system was developed subsequently and focuses more on tumor features that may improve clinical predictions.
Primary treatments
Options for primary treatment for small tumors (largest diameter 5-16 mm and thickness less than 2.5 mm) include plaque brachytherapy, partical beam radiation, and laser ablation in highly select patients. For medium tumors (18mm or less at largest diameter and thickness of 2.5-10 mm), they include plaque brachytherapy, particle beam radiation, and enucleation, according to the guidelines.
Large tumors can be treated with radiotherapy (preferably particle beam radiation, Dr. Barker said) or enucleation. Large tumors are those greater than 18mm with any thickness, those with thickness greater than 10mm with any diameter, and those with thickness greater than 8mm with optic nerve involvement.
In patients for whom surgical removal is selected, “ there are a few unusual situations where additional local adjuvant therapy might be considered,” Dr. Barker said, explaining, for example, that the presence of microscopically positive or close margins after enucleation without evidence of gross residual disease in the orbit may be observed or may warrant map biopsy and/or particle beam or photon beam radiotherapy to the orbit.
For visible extraocular tumors or suspicion of gross disease in the orbit, biopsy of the extraocular tissue is recommended when possible, along with either intraoperative cryotherapy, orbital exenteration, or particle beam or photon beam radiotherapy to the orbit, he added.
Metastatic risks and follow-up imaging
Recent studies, including Cancer Genome Atlas Research Network studies, have elucidated the genomics of both uveal and cutaneous melanomas, and they show “a completely different mutation spectrum” for uveal melanoma, Dr. Barker said.
These genomic studies demonstrate that cutaneous melanoma involves mutations that predict response to certain treatments, while those found in uveal melanoma do not, but they are, however, associated with the probability of metastasis, he said.
For example, various studies have shown that BRAF mutation in cutaneous melanoma predicts response to RAF or MEK inhibition and that the overall number of mutations in cutaneous melanoma may predict response to immunotherapy.
In uveal melanoma, alterations in ElFAX1, SF3B1, or BAP1 have been shown to indicate low, intermediate, and high risk of metastasis, respectively.
Other factors associated with the risk of metastasis after primary tumor treatment in uveal melanoma include clinical factors (tumor size, ciliary body involvement, and extraocular extension); histopathologic factors (spindle or epithelioid cell type); and cytogenetics (status of chromosomes 3, 6, and 8), he said.
An AJCC Ophthalmic Oncology Task Force study published in 2015, for example, showed that the 5-year metastasis-free survival was 97% for AJCC stage T1 disease, 85% for stage T2, 77% for stage T3, and 61% for stage T4. T-stage modifiers, which are based on particular tumor characteristics, such as ciliary body involvement (CBI) and extraocular extension (EXE), were also associated with the risk of distant metastasis: 5-year metastasis-free survival was 90%, 72%, 54% and 33% for AJCC T_a (no CBI or EXE), T_b (CBI only), T_c (EXE only), and T_d tumors (CBI and EXE), respectively.
Follow-up imaging after primary tumor treatment should be based on the most likely site of metastatic recurrence, which is the liver in 90% of uveal melanoma metastases.
“For this reason, surveillance of high-risk patients with uveal melanoma should include specific imaging of the liver,” Dr. Barker said, who noted that the NCCN risk stratification–based surveillance guidelines categorize patients as either low, medium, or high risk for metastasis based on the various characteristics that can affect risk.
“These risk groups help clinicians identify how often imaging should be performed in their surveillance strategy,” he said, adding that those who are high risk based on BAP1 mutation, PRAME mutation, CBI, or EXE, for example, should undergo imaging to evaluate signs or symptoms every 3-6 months for 5 years, every 6-12 months for 10 years, and then as clinically indicated thereafter.
The guideline calls for less stringent imaging for low- and medium-risk patients.
“Now, what happens when distant metastases are identified? Unfortunately there is no single systemic therapy that has proven to be most effective for uveal melanoma,” he said. “For this reason, the NCCN guideline encourages clinical trial participation whenever possible for patients who develop distant metastasis.”
This is because drugs effective for cutaneous melanoma are far less effective for uveal melanoma, but do elicit response in some patients and can be considered, he explained.
“Moreover, because the liver is the site of metastasis most often, and is often the exclusive site of metastasis, liver metastasis–directed therapy is considered part of the management of patients with uveal melanoma,” he said, adding that this can involve resection, ablation, chemo/radio embolization, or regional perfusion.”
The NCCN Uveal Melanoma Guidelines were developed by a panel of experts from various institutions based on the available evidence and on consensus; they are category 2A (based on lower-level evidence with uniform NCCN consensus that the intervention is appropriate).
Dr. Barker reported receiving clinical research support from Amgen, Bristol-Myers Squibb, Elekta, Merck, University of California San Francisco, and University of Florida Health Cancer Center Orlando, and serving as an advisor, consultant, or expert witness for Pfizer.
EXPERT ANALYSIS FROM THE NCCN ANNUAL CONFERENCE
Checkpoint inhibition less toxic than antiangiogenic therapy in NSCLC
ORLANDO – , a systematic review and meta-analysis suggests.
In 16,810 patients from 37 trials included in the analysis, first-line treatment with nivolumab or pembrolizumab, compared with first-line sorafenib plus platinum doublets, for example, was associated with less combined direct and indirect toxicity (odds ratios, 0.08 and 0.12, respectively), Chin-Chuan Hung, MD, and her colleagues reported in a poster at the annual conference of the National Comprehensive Cancer Network.
For subsequent therapy, nivolumab showed lower risk than most antiangiogenic therapies, particularly combination ramucirumab and docetaxel (OR, 0.06), said Dr. Hung of China Medical University Hospital in Taichung, Taiwan.
The findings are notable because tolerability is an essential selection criterion for patients with advanced stage disease, and while checkpoint inhibitors – including nivolumab, pembrolizumab, and atezolizumab – and antiangiogenic agents – including bevacizumab, ramucirumab, and nintedanib – have become the treatments of choice, direct comparisons with respect to tolerability are lacking, she noted.
The investigators performed a systematic review using Bayesian-model network meta-analysis of studies conducted through July 2017 comparing first-line and subsequent regimens containing chemotherapy, antiangiogenic therapy, and/or immune checkpoint inhibitors. Chemotherapy agents studied included cisplatin, carboplatin, oxaliplatin, gemcitabine, paclitaxel, docetaxel, and pemetrexed; antiangiogenic agents included bevacizumab, aflibercept, ramucirumab, nintedanib, axitinib, sorafenib, vandetanib, and sunitinib; and immune checkpoint inhibitors included ipilimumab, pembrolizumab, nivolumab, and atezolizumab.
Direct and indirect data for all grade 3-5 adverse events were combined using random-effects network meta-analysis.
“The results indicated that [checkpoint] inhibitors can be preferred choices for less toxicity to treat advanced stage NSCLC compared with antiangiogenic therapies in first-line and subsequent settings,” Dr. Hung and her associates concluded.
This study was supported by the China Medical University Beigang Hospital.
sworcester@frontlinemedcom.com
SOURCE: Hsu C et al. NCCN poster 13
ORLANDO – , a systematic review and meta-analysis suggests.
In 16,810 patients from 37 trials included in the analysis, first-line treatment with nivolumab or pembrolizumab, compared with first-line sorafenib plus platinum doublets, for example, was associated with less combined direct and indirect toxicity (odds ratios, 0.08 and 0.12, respectively), Chin-Chuan Hung, MD, and her colleagues reported in a poster at the annual conference of the National Comprehensive Cancer Network.
For subsequent therapy, nivolumab showed lower risk than most antiangiogenic therapies, particularly combination ramucirumab and docetaxel (OR, 0.06), said Dr. Hung of China Medical University Hospital in Taichung, Taiwan.
The findings are notable because tolerability is an essential selection criterion for patients with advanced stage disease, and while checkpoint inhibitors – including nivolumab, pembrolizumab, and atezolizumab – and antiangiogenic agents – including bevacizumab, ramucirumab, and nintedanib – have become the treatments of choice, direct comparisons with respect to tolerability are lacking, she noted.
The investigators performed a systematic review using Bayesian-model network meta-analysis of studies conducted through July 2017 comparing first-line and subsequent regimens containing chemotherapy, antiangiogenic therapy, and/or immune checkpoint inhibitors. Chemotherapy agents studied included cisplatin, carboplatin, oxaliplatin, gemcitabine, paclitaxel, docetaxel, and pemetrexed; antiangiogenic agents included bevacizumab, aflibercept, ramucirumab, nintedanib, axitinib, sorafenib, vandetanib, and sunitinib; and immune checkpoint inhibitors included ipilimumab, pembrolizumab, nivolumab, and atezolizumab.
Direct and indirect data for all grade 3-5 adverse events were combined using random-effects network meta-analysis.
“The results indicated that [checkpoint] inhibitors can be preferred choices for less toxicity to treat advanced stage NSCLC compared with antiangiogenic therapies in first-line and subsequent settings,” Dr. Hung and her associates concluded.
This study was supported by the China Medical University Beigang Hospital.
sworcester@frontlinemedcom.com
SOURCE: Hsu C et al. NCCN poster 13
ORLANDO – , a systematic review and meta-analysis suggests.
In 16,810 patients from 37 trials included in the analysis, first-line treatment with nivolumab or pembrolizumab, compared with first-line sorafenib plus platinum doublets, for example, was associated with less combined direct and indirect toxicity (odds ratios, 0.08 and 0.12, respectively), Chin-Chuan Hung, MD, and her colleagues reported in a poster at the annual conference of the National Comprehensive Cancer Network.
For subsequent therapy, nivolumab showed lower risk than most antiangiogenic therapies, particularly combination ramucirumab and docetaxel (OR, 0.06), said Dr. Hung of China Medical University Hospital in Taichung, Taiwan.
The findings are notable because tolerability is an essential selection criterion for patients with advanced stage disease, and while checkpoint inhibitors – including nivolumab, pembrolizumab, and atezolizumab – and antiangiogenic agents – including bevacizumab, ramucirumab, and nintedanib – have become the treatments of choice, direct comparisons with respect to tolerability are lacking, she noted.
The investigators performed a systematic review using Bayesian-model network meta-analysis of studies conducted through July 2017 comparing first-line and subsequent regimens containing chemotherapy, antiangiogenic therapy, and/or immune checkpoint inhibitors. Chemotherapy agents studied included cisplatin, carboplatin, oxaliplatin, gemcitabine, paclitaxel, docetaxel, and pemetrexed; antiangiogenic agents included bevacizumab, aflibercept, ramucirumab, nintedanib, axitinib, sorafenib, vandetanib, and sunitinib; and immune checkpoint inhibitors included ipilimumab, pembrolizumab, nivolumab, and atezolizumab.
Direct and indirect data for all grade 3-5 adverse events were combined using random-effects network meta-analysis.
“The results indicated that [checkpoint] inhibitors can be preferred choices for less toxicity to treat advanced stage NSCLC compared with antiangiogenic therapies in first-line and subsequent settings,” Dr. Hung and her associates concluded.
This study was supported by the China Medical University Beigang Hospital.
sworcester@frontlinemedcom.com
SOURCE: Hsu C et al. NCCN poster 13
REPORTING FROM THE NCCN ANNUAL CONFERENCE
Key clinical point: Checkpoint blockade appears less toxic than antiangiogenic therapies in advanced NSCLC
Major finding: Less toxicity was seen with first-line nivolumab or pembrolizumab vs. sorafenib + platinum doublets (odds ratios, 0.08 and 0.12, respectively).
Study details: A systematic review and meta-analysis of 37 trials involving 16,810 patients.
Disclosures: The study was supported by the China Medical University Beigang Hospital.
Source: Hsu C et al. NCCN poster 13.
HDAC inhibition may boost immune therapy efficacy in breast cancer
ORLANDO – The novel combination of entinostat and nivolumab with or without ipilimumab showed encouraging safety, tolerability, and antitumor activity in early results from an ongoing phase 1 trial of patients with advanced breast cancer.
Of 30 patients who were enrolled and treated in the dose-escalation phase of the study as of Feb. 24, 2018, 20 had evaluable responses, and of those, 3 had a partial response for an overall response rate of 15%. An additional 12 had stable disease, and 5 had disease progression, Roisin M. Connolly, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.
Responses were seen in all 3 DL1 patients, 12 of 14 DL2 patients, 3 of 4 DL3 patients, and 2 of 9 (with 4 pending first restaging) DL4 patients. Dose-limiting toxicities included one case of pneumonitis at DL2 and an allergic reaction in one DL4 patient, said Dr. Connolly of Johns Hopkins University, Baltimore.
The most common treatment-associated adverse events occurring in 6 or more patients included anemia, fatigue, neutropenia, nausea, and rash, with each occurring in 12 to 22 patients, including grade 3 anemia in 7 patients, grade 3 fatigue in 4 patients, and grade 3 neutropenia in 5 patients. Grade 4 adverse events included lymphopenia in one patient and elevated lipase in one patient, she said.
Possible immune-related adverse events included hypothyroidism in 2 DL2 patients and 3 DL3 patients, hyperthyroidism in 1 DL3 patient, colitis in 1 DL2 and 1 DL3 patient, pneumonitis in 4 DL2 patients, rash in 10 DL2-DL4 patients, and meningoencephalitis and myasthenia gravis in 1 DL3 patient.
Study participants were adults with a mean age of 60 years with metastatic or unresectable solid tumors for which standard treatments did not exist or were no longer effective, or for which treatment with anti–programmed cell death ligand1/cytotoxic T-lymphocyte antigen 4 treatment was appropriate. All had good performance status and adequate organ and pulmonary function, less than 30% liver involvement, and any brain metastases were stable. Those with active autoimmune disease or a history of autoimmune disease that might recur were excluded, as were patients treated within 14 days of enrollment.
“The rationale for the study was based on preclinical work suggesting that epigenetic modifiers might be able to enhance the efficacy of immune therapies, and this would be particularly important for ‘colder’ tumor types like breast cancer that might not have the same sort of responses that we see in other tumor types,” Dr. Connolly explained in an interview. “The lab work suggested, for example, that the [histone deacetylase] inhibitor entinostat might affect myeloid-derived suppressor and regulatory T cells that might prevent cytotoxic T cells from fighting the cancer.”
There may be other mechanisms for this activity as well, she noted.
The run-in period with entinostat alone allowed collection of pre- and posttreatment biopsies to examine the effects on the tissues, such as whether treatment affects T cells, myeloid-derived suppressor cells, or their pathways, she said.
“We’re seeing [the] same types of toxicities seen with combination immune-oncology strategies, and we’re seeing some tumor responses that are of interest. Now we will delve into the tissue biopsies and blood samples we’ve collected to explore the mechanisms in more detail. In the near future we will open our breast cancer expansion cohort to look in more detail at what these drugs might be doing in breast cancer,” she added.
Specifically, she and her colleagues are evaluating the effects of treatment on immune-related biomarkers, measuring tumor-specific mutations and mutant neoantigens recognized by patient T cells in tumor biopsies, evaluating changes in the frequency of T cells recognizing tumor-specific mutant neoantigens in peripheral blood lymphocytes pre- and posttherapy, and looking at epigenetic changes pre- and posttherapy.
These preliminary findings suggest that the combination of entinostat and nivolumab with or without ipilimumab is safe and tolerable, with expected rates of immune-related adverse events, Dr. Connolly said, noting that the recommended phase 2 dose to be used in the dose expansion phase of the study has yet to be determined.
The findings, should they be confirmed as the trial progresses, could have important implications because immune checkpoint inhibitors, which work best in patients with immunogenic cancers that naturally attract T-cell infiltration into their tumor microenvironment, have limited single-agent activity in tumors, such as breast cancer, that are not believed to be immunogenic, she reported. Such cancers have thus far had only modest responses to single-agent immune checkpoint inhibition in advanced triple-negative and HER2+ breast cancer, with overall response rates of 5%-20%.
However, women who do respond to immune checkpoint inhibition tend to have durable and sustainable responses, she said, explaining that suboptimal immune responsiveness is likely a result of a lack of tumor antigen expression and/or recognition, as well as multiple suppressive signals in the tumor microenvironment.
Should the novel strategy tested in this study for converting breast cancers into immune responsive tumors facilitate improved response to immune checkpoint agents, it has the potential to significantly extend survival in breast cancer patients, she concluded.
This study was funded by grants from the National Institutes of Health, Bloomberg Kimmel Institute for Immunotherapy, NCCN, and the Mary Kay Foundation, as well as a V Foundation award. Dr. Connolly reported having no disclosures
SOURCE: Connolly RM et al. NCCN, Poster 3.
ORLANDO – The novel combination of entinostat and nivolumab with or without ipilimumab showed encouraging safety, tolerability, and antitumor activity in early results from an ongoing phase 1 trial of patients with advanced breast cancer.
Of 30 patients who were enrolled and treated in the dose-escalation phase of the study as of Feb. 24, 2018, 20 had evaluable responses, and of those, 3 had a partial response for an overall response rate of 15%. An additional 12 had stable disease, and 5 had disease progression, Roisin M. Connolly, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.
Responses were seen in all 3 DL1 patients, 12 of 14 DL2 patients, 3 of 4 DL3 patients, and 2 of 9 (with 4 pending first restaging) DL4 patients. Dose-limiting toxicities included one case of pneumonitis at DL2 and an allergic reaction in one DL4 patient, said Dr. Connolly of Johns Hopkins University, Baltimore.
The most common treatment-associated adverse events occurring in 6 or more patients included anemia, fatigue, neutropenia, nausea, and rash, with each occurring in 12 to 22 patients, including grade 3 anemia in 7 patients, grade 3 fatigue in 4 patients, and grade 3 neutropenia in 5 patients. Grade 4 adverse events included lymphopenia in one patient and elevated lipase in one patient, she said.
Possible immune-related adverse events included hypothyroidism in 2 DL2 patients and 3 DL3 patients, hyperthyroidism in 1 DL3 patient, colitis in 1 DL2 and 1 DL3 patient, pneumonitis in 4 DL2 patients, rash in 10 DL2-DL4 patients, and meningoencephalitis and myasthenia gravis in 1 DL3 patient.
Study participants were adults with a mean age of 60 years with metastatic or unresectable solid tumors for which standard treatments did not exist or were no longer effective, or for which treatment with anti–programmed cell death ligand1/cytotoxic T-lymphocyte antigen 4 treatment was appropriate. All had good performance status and adequate organ and pulmonary function, less than 30% liver involvement, and any brain metastases were stable. Those with active autoimmune disease or a history of autoimmune disease that might recur were excluded, as were patients treated within 14 days of enrollment.
“The rationale for the study was based on preclinical work suggesting that epigenetic modifiers might be able to enhance the efficacy of immune therapies, and this would be particularly important for ‘colder’ tumor types like breast cancer that might not have the same sort of responses that we see in other tumor types,” Dr. Connolly explained in an interview. “The lab work suggested, for example, that the [histone deacetylase] inhibitor entinostat might affect myeloid-derived suppressor and regulatory T cells that might prevent cytotoxic T cells from fighting the cancer.”
There may be other mechanisms for this activity as well, she noted.
The run-in period with entinostat alone allowed collection of pre- and posttreatment biopsies to examine the effects on the tissues, such as whether treatment affects T cells, myeloid-derived suppressor cells, or their pathways, she said.
“We’re seeing [the] same types of toxicities seen with combination immune-oncology strategies, and we’re seeing some tumor responses that are of interest. Now we will delve into the tissue biopsies and blood samples we’ve collected to explore the mechanisms in more detail. In the near future we will open our breast cancer expansion cohort to look in more detail at what these drugs might be doing in breast cancer,” she added.
Specifically, she and her colleagues are evaluating the effects of treatment on immune-related biomarkers, measuring tumor-specific mutations and mutant neoantigens recognized by patient T cells in tumor biopsies, evaluating changes in the frequency of T cells recognizing tumor-specific mutant neoantigens in peripheral blood lymphocytes pre- and posttherapy, and looking at epigenetic changes pre- and posttherapy.
These preliminary findings suggest that the combination of entinostat and nivolumab with or without ipilimumab is safe and tolerable, with expected rates of immune-related adverse events, Dr. Connolly said, noting that the recommended phase 2 dose to be used in the dose expansion phase of the study has yet to be determined.
The findings, should they be confirmed as the trial progresses, could have important implications because immune checkpoint inhibitors, which work best in patients with immunogenic cancers that naturally attract T-cell infiltration into their tumor microenvironment, have limited single-agent activity in tumors, such as breast cancer, that are not believed to be immunogenic, she reported. Such cancers have thus far had only modest responses to single-agent immune checkpoint inhibition in advanced triple-negative and HER2+ breast cancer, with overall response rates of 5%-20%.
However, women who do respond to immune checkpoint inhibition tend to have durable and sustainable responses, she said, explaining that suboptimal immune responsiveness is likely a result of a lack of tumor antigen expression and/or recognition, as well as multiple suppressive signals in the tumor microenvironment.
Should the novel strategy tested in this study for converting breast cancers into immune responsive tumors facilitate improved response to immune checkpoint agents, it has the potential to significantly extend survival in breast cancer patients, she concluded.
This study was funded by grants from the National Institutes of Health, Bloomberg Kimmel Institute for Immunotherapy, NCCN, and the Mary Kay Foundation, as well as a V Foundation award. Dr. Connolly reported having no disclosures
SOURCE: Connolly RM et al. NCCN, Poster 3.
ORLANDO – The novel combination of entinostat and nivolumab with or without ipilimumab showed encouraging safety, tolerability, and antitumor activity in early results from an ongoing phase 1 trial of patients with advanced breast cancer.
Of 30 patients who were enrolled and treated in the dose-escalation phase of the study as of Feb. 24, 2018, 20 had evaluable responses, and of those, 3 had a partial response for an overall response rate of 15%. An additional 12 had stable disease, and 5 had disease progression, Roisin M. Connolly, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.
Responses were seen in all 3 DL1 patients, 12 of 14 DL2 patients, 3 of 4 DL3 patients, and 2 of 9 (with 4 pending first restaging) DL4 patients. Dose-limiting toxicities included one case of pneumonitis at DL2 and an allergic reaction in one DL4 patient, said Dr. Connolly of Johns Hopkins University, Baltimore.
The most common treatment-associated adverse events occurring in 6 or more patients included anemia, fatigue, neutropenia, nausea, and rash, with each occurring in 12 to 22 patients, including grade 3 anemia in 7 patients, grade 3 fatigue in 4 patients, and grade 3 neutropenia in 5 patients. Grade 4 adverse events included lymphopenia in one patient and elevated lipase in one patient, she said.
Possible immune-related adverse events included hypothyroidism in 2 DL2 patients and 3 DL3 patients, hyperthyroidism in 1 DL3 patient, colitis in 1 DL2 and 1 DL3 patient, pneumonitis in 4 DL2 patients, rash in 10 DL2-DL4 patients, and meningoencephalitis and myasthenia gravis in 1 DL3 patient.
Study participants were adults with a mean age of 60 years with metastatic or unresectable solid tumors for which standard treatments did not exist or were no longer effective, or for which treatment with anti–programmed cell death ligand1/cytotoxic T-lymphocyte antigen 4 treatment was appropriate. All had good performance status and adequate organ and pulmonary function, less than 30% liver involvement, and any brain metastases were stable. Those with active autoimmune disease or a history of autoimmune disease that might recur were excluded, as were patients treated within 14 days of enrollment.
“The rationale for the study was based on preclinical work suggesting that epigenetic modifiers might be able to enhance the efficacy of immune therapies, and this would be particularly important for ‘colder’ tumor types like breast cancer that might not have the same sort of responses that we see in other tumor types,” Dr. Connolly explained in an interview. “The lab work suggested, for example, that the [histone deacetylase] inhibitor entinostat might affect myeloid-derived suppressor and regulatory T cells that might prevent cytotoxic T cells from fighting the cancer.”
There may be other mechanisms for this activity as well, she noted.
The run-in period with entinostat alone allowed collection of pre- and posttreatment biopsies to examine the effects on the tissues, such as whether treatment affects T cells, myeloid-derived suppressor cells, or their pathways, she said.
“We’re seeing [the] same types of toxicities seen with combination immune-oncology strategies, and we’re seeing some tumor responses that are of interest. Now we will delve into the tissue biopsies and blood samples we’ve collected to explore the mechanisms in more detail. In the near future we will open our breast cancer expansion cohort to look in more detail at what these drugs might be doing in breast cancer,” she added.
Specifically, she and her colleagues are evaluating the effects of treatment on immune-related biomarkers, measuring tumor-specific mutations and mutant neoantigens recognized by patient T cells in tumor biopsies, evaluating changes in the frequency of T cells recognizing tumor-specific mutant neoantigens in peripheral blood lymphocytes pre- and posttherapy, and looking at epigenetic changes pre- and posttherapy.
These preliminary findings suggest that the combination of entinostat and nivolumab with or without ipilimumab is safe and tolerable, with expected rates of immune-related adverse events, Dr. Connolly said, noting that the recommended phase 2 dose to be used in the dose expansion phase of the study has yet to be determined.
The findings, should they be confirmed as the trial progresses, could have important implications because immune checkpoint inhibitors, which work best in patients with immunogenic cancers that naturally attract T-cell infiltration into their tumor microenvironment, have limited single-agent activity in tumors, such as breast cancer, that are not believed to be immunogenic, she reported. Such cancers have thus far had only modest responses to single-agent immune checkpoint inhibition in advanced triple-negative and HER2+ breast cancer, with overall response rates of 5%-20%.
However, women who do respond to immune checkpoint inhibition tend to have durable and sustainable responses, she said, explaining that suboptimal immune responsiveness is likely a result of a lack of tumor antigen expression and/or recognition, as well as multiple suppressive signals in the tumor microenvironment.
Should the novel strategy tested in this study for converting breast cancers into immune responsive tumors facilitate improved response to immune checkpoint agents, it has the potential to significantly extend survival in breast cancer patients, she concluded.
This study was funded by grants from the National Institutes of Health, Bloomberg Kimmel Institute for Immunotherapy, NCCN, and the Mary Kay Foundation, as well as a V Foundation award. Dr. Connolly reported having no disclosures
SOURCE: Connolly RM et al. NCCN, Poster 3.
REPORTING FROM THE NCCN ANNUAL CONFERENCE
Key clinical point:
Major finding: Three patients had a partial response, 12 had stable disease, 5 progressed.
Study details: A phase 1 dose-expansion study involving 30 patients.
Disclosures: This study was funded by grants from the National Institutes of Health, Bloomberg Kimmel Institute for Immunotherapy, NCCN, and the Mary Kay Foundation, and by a V Foundation award. Dr. Connolly reported having no disclosures.
Source: Connolly RM et al. NCCN, Poster 3.
CBC data can predict immunotherapy responses in NSCLC
ORLANDO – Information readily available on complete blood count can help predict response to immunotherapy and outcomes in patients with advanced non–small cell lung cancer, according to findings from a review of 157 cases.
Specifically, absolute monocyte count of 0.63 or greater and absolute neutrophil count/absolute lymphocyte count of 5.9 or greater at baseline were significantly associated with poor progression-free survival (hazard ratios, 1.50 and 1.61, respectively) and overall survival (HRs, 1.71 and 1.87, respectively) in patients treated with anti–programmed death-1 (PD-1) antibodies, Aixa E. Soyano, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.
Additionally, absolute neutrophil count of at least 7.5 and myeloid to lymphoid ratio of at least 11.3 at baseline were associated with poor overall survival (HRs, 1.86 and 2.31, respectively), according to Dr. Soyano of the Mayo Clinic, Jacksonville, Fla.
“The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies,” she and her colleagues wrote.
Cases included in the review involved advanced non–small cell lung cancer (NSCLC) patients with a median age of 66 years who were treated with nivolumab or pembrolizumab at the Mayo Clinic from January 2010 to April 2017. Most (91%) were white, 4.5% were African American, 1.9% were Asian, 0.6% were native Hawaiian/Pacific Islander, and 1.9% were other ethnicities. Slightly more than half (53%) were men, and diagnoses included adenocarcinoma (69%), squamous disease (29%) and other (3%). Half had one prior line of chemotherapy, 22% had two prior lines, and 10% had three or more prior lines. The majority (72%) had Eastern Cooperative Oncology Group performance status of 1 or 2, and 34% had CNS disease.
Pembrolizumab was given intravenously at a dose of 2 mg/kg every 21 days (11 patients), and nivolumab was given intravenously at a dose of 3 mg/kg every 14 days (146 patients). Clinical response was assessed every 8-12 weeks by CT of the chest, abdomen and pelvis, and also – in some cases – by brain MRI.
The findings are notable because, although combination chemotherapy with a platinum-based doublet has, for the last decade, been the backbone of initial systemic therapy for patients whose tumor does not have driver mutations, monoclonal antibodies targeting PD-1 or its ligand PD-L1 have shown improvements in progression-free survival and overall survival in certain patients with metastatic or locally advanced lung cancer, the investigators explained.
Prior studies in melanoma patients treated with immunotherapy targeting the cytotoxic T-lymphocyte antigen 4 pathway and PD-1/PD-L1 pathways have identified predictive or prognostic hematological markers of outcomes. However, data with respect to hematologic markers in lung cancer are sparse, and given the high cost, significant immune-related side effects, and rapidly expanding number of indications for immunotherapy in NSCLC, there is a need for reliable biomarkers to help predict response and outcomes, they said.
In a separate presentation at the NCCN conference, John A. Thompson, MD, of the Fred Hutchinson Cancer Research Center, Seattle, noted that some progress has been made in the area of predicting response to immune checkpoint inhibitors in NSCLC patients. Namely, the value of tumor PD-L1 expression and tumor mutation burden for predicting outcomes was highlighted in a recent study by Rizvi et al., who concluded that “the incorporation of both TMB [tumor mutation burden] and PD-L1 expression into multivariable predictive models should result in greater predictive power.” .
“This is a first step in our evolution and our progress toward a better biomarker. I think when we add in other factors like gene expression, we may be able to develop an even more robust biomarker that will help us select appropriate patients for therapy,” he said.
Dr. Soyano and her colleagues noted, however, that these measures, as well as tumor infiltrating immune cells, which have also been shown to have predictive value, require special testing and/or processing.
Furthermore, the optimal cutoff with PD-L1 expression is debatable, they said.
CBC data is more readily available, and also appears to have predictive and prognostic value, they said, concluding that the findings warrant further investigation in a larger, prospective study.
The authors reported having no disclosures.
sworcester@frontlinemedcom.com
SOURCE: Soyano A et al. NCCN Poster 075.
ORLANDO – Information readily available on complete blood count can help predict response to immunotherapy and outcomes in patients with advanced non–small cell lung cancer, according to findings from a review of 157 cases.
Specifically, absolute monocyte count of 0.63 or greater and absolute neutrophil count/absolute lymphocyte count of 5.9 or greater at baseline were significantly associated with poor progression-free survival (hazard ratios, 1.50 and 1.61, respectively) and overall survival (HRs, 1.71 and 1.87, respectively) in patients treated with anti–programmed death-1 (PD-1) antibodies, Aixa E. Soyano, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.
Additionally, absolute neutrophil count of at least 7.5 and myeloid to lymphoid ratio of at least 11.3 at baseline were associated with poor overall survival (HRs, 1.86 and 2.31, respectively), according to Dr. Soyano of the Mayo Clinic, Jacksonville, Fla.
“The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies,” she and her colleagues wrote.
Cases included in the review involved advanced non–small cell lung cancer (NSCLC) patients with a median age of 66 years who were treated with nivolumab or pembrolizumab at the Mayo Clinic from January 2010 to April 2017. Most (91%) were white, 4.5% were African American, 1.9% were Asian, 0.6% were native Hawaiian/Pacific Islander, and 1.9% were other ethnicities. Slightly more than half (53%) were men, and diagnoses included adenocarcinoma (69%), squamous disease (29%) and other (3%). Half had one prior line of chemotherapy, 22% had two prior lines, and 10% had three or more prior lines. The majority (72%) had Eastern Cooperative Oncology Group performance status of 1 or 2, and 34% had CNS disease.
Pembrolizumab was given intravenously at a dose of 2 mg/kg every 21 days (11 patients), and nivolumab was given intravenously at a dose of 3 mg/kg every 14 days (146 patients). Clinical response was assessed every 8-12 weeks by CT of the chest, abdomen and pelvis, and also – in some cases – by brain MRI.
The findings are notable because, although combination chemotherapy with a platinum-based doublet has, for the last decade, been the backbone of initial systemic therapy for patients whose tumor does not have driver mutations, monoclonal antibodies targeting PD-1 or its ligand PD-L1 have shown improvements in progression-free survival and overall survival in certain patients with metastatic or locally advanced lung cancer, the investigators explained.
Prior studies in melanoma patients treated with immunotherapy targeting the cytotoxic T-lymphocyte antigen 4 pathway and PD-1/PD-L1 pathways have identified predictive or prognostic hematological markers of outcomes. However, data with respect to hematologic markers in lung cancer are sparse, and given the high cost, significant immune-related side effects, and rapidly expanding number of indications for immunotherapy in NSCLC, there is a need for reliable biomarkers to help predict response and outcomes, they said.
In a separate presentation at the NCCN conference, John A. Thompson, MD, of the Fred Hutchinson Cancer Research Center, Seattle, noted that some progress has been made in the area of predicting response to immune checkpoint inhibitors in NSCLC patients. Namely, the value of tumor PD-L1 expression and tumor mutation burden for predicting outcomes was highlighted in a recent study by Rizvi et al., who concluded that “the incorporation of both TMB [tumor mutation burden] and PD-L1 expression into multivariable predictive models should result in greater predictive power.” .
“This is a first step in our evolution and our progress toward a better biomarker. I think when we add in other factors like gene expression, we may be able to develop an even more robust biomarker that will help us select appropriate patients for therapy,” he said.
Dr. Soyano and her colleagues noted, however, that these measures, as well as tumor infiltrating immune cells, which have also been shown to have predictive value, require special testing and/or processing.
Furthermore, the optimal cutoff with PD-L1 expression is debatable, they said.
CBC data is more readily available, and also appears to have predictive and prognostic value, they said, concluding that the findings warrant further investigation in a larger, prospective study.
The authors reported having no disclosures.
sworcester@frontlinemedcom.com
SOURCE: Soyano A et al. NCCN Poster 075.
ORLANDO – Information readily available on complete blood count can help predict response to immunotherapy and outcomes in patients with advanced non–small cell lung cancer, according to findings from a review of 157 cases.
Specifically, absolute monocyte count of 0.63 or greater and absolute neutrophil count/absolute lymphocyte count of 5.9 or greater at baseline were significantly associated with poor progression-free survival (hazard ratios, 1.50 and 1.61, respectively) and overall survival (HRs, 1.71 and 1.87, respectively) in patients treated with anti–programmed death-1 (PD-1) antibodies, Aixa E. Soyano, MD, reported in a poster at the annual conference of the National Comprehensive Cancer Network.
Additionally, absolute neutrophil count of at least 7.5 and myeloid to lymphoid ratio of at least 11.3 at baseline were associated with poor overall survival (HRs, 1.86 and 2.31, respectively), according to Dr. Soyano of the Mayo Clinic, Jacksonville, Fla.
“The potential predictive value of these readily available biomarkers might help with risk stratification and treatment strategies,” she and her colleagues wrote.
Cases included in the review involved advanced non–small cell lung cancer (NSCLC) patients with a median age of 66 years who were treated with nivolumab or pembrolizumab at the Mayo Clinic from January 2010 to April 2017. Most (91%) were white, 4.5% were African American, 1.9% were Asian, 0.6% were native Hawaiian/Pacific Islander, and 1.9% were other ethnicities. Slightly more than half (53%) were men, and diagnoses included adenocarcinoma (69%), squamous disease (29%) and other (3%). Half had one prior line of chemotherapy, 22% had two prior lines, and 10% had three or more prior lines. The majority (72%) had Eastern Cooperative Oncology Group performance status of 1 or 2, and 34% had CNS disease.
Pembrolizumab was given intravenously at a dose of 2 mg/kg every 21 days (11 patients), and nivolumab was given intravenously at a dose of 3 mg/kg every 14 days (146 patients). Clinical response was assessed every 8-12 weeks by CT of the chest, abdomen and pelvis, and also – in some cases – by brain MRI.
The findings are notable because, although combination chemotherapy with a platinum-based doublet has, for the last decade, been the backbone of initial systemic therapy for patients whose tumor does not have driver mutations, monoclonal antibodies targeting PD-1 or its ligand PD-L1 have shown improvements in progression-free survival and overall survival in certain patients with metastatic or locally advanced lung cancer, the investigators explained.
Prior studies in melanoma patients treated with immunotherapy targeting the cytotoxic T-lymphocyte antigen 4 pathway and PD-1/PD-L1 pathways have identified predictive or prognostic hematological markers of outcomes. However, data with respect to hematologic markers in lung cancer are sparse, and given the high cost, significant immune-related side effects, and rapidly expanding number of indications for immunotherapy in NSCLC, there is a need for reliable biomarkers to help predict response and outcomes, they said.
In a separate presentation at the NCCN conference, John A. Thompson, MD, of the Fred Hutchinson Cancer Research Center, Seattle, noted that some progress has been made in the area of predicting response to immune checkpoint inhibitors in NSCLC patients. Namely, the value of tumor PD-L1 expression and tumor mutation burden for predicting outcomes was highlighted in a recent study by Rizvi et al., who concluded that “the incorporation of both TMB [tumor mutation burden] and PD-L1 expression into multivariable predictive models should result in greater predictive power.” .
“This is a first step in our evolution and our progress toward a better biomarker. I think when we add in other factors like gene expression, we may be able to develop an even more robust biomarker that will help us select appropriate patients for therapy,” he said.
Dr. Soyano and her colleagues noted, however, that these measures, as well as tumor infiltrating immune cells, which have also been shown to have predictive value, require special testing and/or processing.
Furthermore, the optimal cutoff with PD-L1 expression is debatable, they said.
CBC data is more readily available, and also appears to have predictive and prognostic value, they said, concluding that the findings warrant further investigation in a larger, prospective study.
The authors reported having no disclosures.
sworcester@frontlinemedcom.com
SOURCE: Soyano A et al. NCCN Poster 075.
REPORTING FROM THE NCCN ANNUAL CONFERENCE
Key clinical point:
Major finding: Hazard ratios for progression-free survival were 1.50 and 1.61 with absolute monocyte count of 0.63 or greater, absolute neutrophil count/absolute lymphocyte of 5.9 or greater at baseline.
Study details: A review of 157 NSCLC cases.
Disclosures: The authors reported having no disclosures.
Source: Soyano AE et al. NCCN poster 075.