CNS/Brain Cancer

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Treatment with nivolumab plus ipilimumab resulted in clinically meaningful efficacy for melanoma patients with asymptomatic, previously untreated brain metastases, results of an open-label, multicenter, phase 2 study have shown.

The combination of these two immune checkpoint inhibitors produced intracranial responses in more than half of the patients treated, and perhaps more importantly, according to the study investigators, the combination treatment prevented intracranial progression for more than 6 months in 64% of the study population.

“These results are relevant in a population in whom progression can quickly result in substantial neurologic symptoms, functional impairment, and the need for glucocorticoid therapy,” the study investigators wrote in the New England Journal of Medicine.

The investigators, led by Hussein A. Tawbi, MD, PhD, of the University of Texas MD Anderson Cancer, Houston, initially enrolled 101 patients with histologically confirmed melanoma and metastases to the brain that were asymptomatic. All patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had not received systemic glucocorticoid therapy within 10 days of study treatment.

The primary endpoint of the study was the rate of intracranial benefit, defined as the percentage of patients with complete response, partial response, or stable disease for at least 6 months after starting treatment.

For 94 patients with at least 6 months of follow-up at the time of analysis (median follow-up, 14 months), the rate of intracranial benefit was 57%, including complete responses in 26%, partial responses in 30%, and stable disease in 2%, the investigators reported. The rate of extracranial benefit was similar, at 56%.

The 6-month rate of progression-free survival was 64.2% for intracranial assessments, while the 6-month overall survival rate was 92.3%, according to results of an initial assessment.

Grade 3 or 4 adverse events thought to be related to treatment occurred in 55% of patients and led to treatment discontinuation in 20%; the most common were increased levels of ALT and AST.

Dr. Tawbi and his colleagues said that, while cross-trial comparisons have inherent limitations, the rate of intracranial response seen in this trial is similar to what was seen in the COMBI-MB study of dabrafenib plus trametinib in patients with BRAF-mutant melanoma and brain metastases. However, in that study, published in 2017 in the Lancet, the combination of a BRAF inhibitor and MEK inhibitor had rates of intracranial response and progression-free survival that were “substantially shorter” than the rates of extracranial response and progression-free survival.

“In our study, the use of immunotherapy seemed capable of inducing intracranial responses that were very similar to extracranial responses in character, depth, and duration,” they wrote.

Dr. Tawbi and his coinvestigators enrolled an additional 20 symptomatic patients with brain metastases following a study protocol amendment; however, results from that cohort are not being reported yet because of inadequate follow-up length, they said.

The study was supported by Bristol-Myers Squibb and a grant from the National Cancer Institute. Dr. Tawbi reported disclosures related to Bristol-Myers Squibb, Merck, Genentech, and Novartis. His coauthors reported additional disclosures related to MedImmune, AstraZeneca, Dynavax Technologies, Genoptix, Exelixis, Acceleron Pharma, and Eisai, among others.

SOURCE: Tawbi HA et al. N Engl J Med. 2018 Aug 23. doi: 10.1056/NEJMoa1805453.

Among scenarios where immune checkpoint inhibitors (ICIs) might be combined, particular caution is needed in the setting of brain metastases, according to authors of a recent clinical review.

While evidence to date is mixed, some studies do suggest that adding ICIs to high-dose stereotactic intracranial radiotherapy for brain metastases might increase the risk of treatment-related brain necrosis, the authors said.

By contrast, the balance of evidence suggests ICIs can be safely combined with palliative radiotherapy without site-specific increases in adverse events, they added.

Likewise, in patients with non–small-cell lung cancer, ICIs do not appear to increase incidence of grade 3 or greater pneumonitis when given after definitive chemoradiotherapy, in both retrospective and prospective investigations.

Nevertheless, the addition of ICIs to radiotherapy requires careful further study because of the potential for increased type or severity of toxicities, including the immune-related adverse events associated with ICIs, wrote corresponding author Jay S. Loeffler, MD, of Massachusetts General Hospital, Boston, and his colleagues.

“Caution is warranted when combining radiotherapy and ICI, especially with intracranial radiotherapy,” the researchers wrote. Their report is in Nature Reviews Clinical Oncology.

Some studies have indicated a higher rate of treatment-associated brain necrosis when ICIs are combined with intracranial radiotherapy, while others have shown no such trend, the authors said.

In one single-institution experience involving 180 patients with brain metastases undergoing stereotactic radiotherapy, incidence of treatment-associated brain necrosis was significantly higher in patients receiving an ICI, with an odds ratio of 2.4 (95% confidence interval, 1.06-5.44; P = .03).

Similarly, a retrospective single institution 480-patient study showed an incidence of treatment-associated brain necrosis of 20% for ICIs plus stereotactic radiotherapy versus 7% for radiotherapy alone (P less than .001), but substantial differences in baseline characteristics between groups limited the strength of the study’s conclusions, according to the researchers.

Increased risk is primarily in the form of asymptomatic or minimally symptomatic episodes in some series, the authors noted. A retrospective, 54-patient report showed a rate of treatment-associated brain necrosis of 30% when ICIs were combined with stereotactic radiotherapy, versus 21% for radiotherapy alone (P = .08), but the incidence of symptomatic cases was 15% in both groups, they noted.

“Intriguingly, the findings of several studies have demonstrated an association between [treatment-associated brain necrosis] and improved survival outcomes in patients with melanoma brain metastases that is similar to the independent observations of an analogous relationship between risk of [immune-related adverse events] in general and responsiveness to ICI,” the researchers wrote.

Most of the Food and Drug Administration–approved indications for ICIs are in the metastatic setting, where palliative radiotherapy is frequently important, the authors noted.

In two retrospective studies of patients with metastatic cancers receiving palliative radiotherapy with ICIs, there was a lack of clear association between the irradiated site and specific immune-related adverse events; that lack of association suggests that any toxicities arising from interactions between palliative radiotherapy and ICIs are mainly systemic, rather than local, the authors wrote.

Several retrospective series in advanced-stage melanoma patients have suggested that palliative radiotherapy plus ICIs is safe and does not significantly increase incidence of immune-related adverse events. However, findings from one series showed a correlation between both the ICI and radiotherapy dose given and the incidence of immune-related adverse events.

Prospective studies will be essential to optimize the balance between disease control and risk of morbidity associated with ICIs and radiotherapy combinations, the authors concluded.

The researchers declared no competing interests related to their review article.

SOURCE: Hwang WL, et al. Nat Rev Clin Oncol. 2018 Aug;15(8):477-494.

Among scenarios where immune checkpoint inhibitors (ICIs) might be combined, particular caution is needed in the setting of brain metastases, according to authors of a recent clinical review.

While evidence to date is mixed, some studies do suggest that adding ICIs to high-dose stereotactic intracranial radiotherapy for brain metastases might increase the risk of treatment-related brain necrosis, the authors said.

By contrast, the balance of evidence suggests ICIs can be safely combined with palliative radiotherapy without site-specific increases in adverse events, they added.

Likewise, in patients with non–small-cell lung cancer, ICIs do not appear to increase incidence of grade 3 or greater pneumonitis when given after definitive chemoradiotherapy, in both retrospective and prospective investigations.

Nevertheless, the addition of ICIs to radiotherapy requires careful further study because of the potential for increased type or severity of toxicities, including the immune-related adverse events associated with ICIs, wrote corresponding author Jay S. Loeffler, MD, of Massachusetts General Hospital, Boston, and his colleagues.

“Caution is warranted when combining radiotherapy and ICI, especially with intracranial radiotherapy,” the researchers wrote. Their report is in Nature Reviews Clinical Oncology.

Some studies have indicated a higher rate of treatment-associated brain necrosis when ICIs are combined with intracranial radiotherapy, while others have shown no such trend, the authors said.

In one single-institution experience involving 180 patients with brain metastases undergoing stereotactic radiotherapy, incidence of treatment-associated brain necrosis was significantly higher in patients receiving an ICI, with an odds ratio of 2.4 (95% confidence interval, 1.06-5.44; P = .03).

Similarly, a retrospective single institution 480-patient study showed an incidence of treatment-associated brain necrosis of 20% for ICIs plus stereotactic radiotherapy versus 7% for radiotherapy alone (P less than .001), but substantial differences in baseline characteristics between groups limited the strength of the study’s conclusions, according to the researchers.

Increased risk is primarily in the form of asymptomatic or minimally symptomatic episodes in some series, the authors noted. A retrospective, 54-patient report showed a rate of treatment-associated brain necrosis of 30% when ICIs were combined with stereotactic radiotherapy, versus 21% for radiotherapy alone (P = .08), but the incidence of symptomatic cases was 15% in both groups, they noted.

“Intriguingly, the findings of several studies have demonstrated an association between [treatment-associated brain necrosis] and improved survival outcomes in patients with melanoma brain metastases that is similar to the independent observations of an analogous relationship between risk of [immune-related adverse events] in general and responsiveness to ICI,” the researchers wrote.

Most of the Food and Drug Administration–approved indications for ICIs are in the metastatic setting, where palliative radiotherapy is frequently important, the authors noted.

In two retrospective studies of patients with metastatic cancers receiving palliative radiotherapy with ICIs, there was a lack of clear association between the irradiated site and specific immune-related adverse events; that lack of association suggests that any toxicities arising from interactions between palliative radiotherapy and ICIs are mainly systemic, rather than local, the authors wrote.

Several retrospective series in advanced-stage melanoma patients have suggested that palliative radiotherapy plus ICIs is safe and does not significantly increase incidence of immune-related adverse events. However, findings from one series showed a correlation between both the ICI and radiotherapy dose given and the incidence of immune-related adverse events.

Prospective studies will be essential to optimize the balance between disease control and risk of morbidity associated with ICIs and radiotherapy combinations, the authors concluded.

The researchers declared no competing interests related to their review article.

SOURCE: Hwang WL, et al. Nat Rev Clin Oncol. 2018 Aug;15(8):477-494.

Among scenarios where immune checkpoint inhibitors (ICIs) might be combined, particular caution is needed in the setting of brain metastases, according to authors of a recent clinical review.

While evidence to date is mixed, some studies do suggest that adding ICIs to high-dose stereotactic intracranial radiotherapy for brain metastases might increase the risk of treatment-related brain necrosis, the authors said.

By contrast, the balance of evidence suggests ICIs can be safely combined with palliative radiotherapy without site-specific increases in adverse events, they added.

Likewise, in patients with non–small-cell lung cancer, ICIs do not appear to increase incidence of grade 3 or greater pneumonitis when given after definitive chemoradiotherapy, in both retrospective and prospective investigations.

Nevertheless, the addition of ICIs to radiotherapy requires careful further study because of the potential for increased type or severity of toxicities, including the immune-related adverse events associated with ICIs, wrote corresponding author Jay S. Loeffler, MD, of Massachusetts General Hospital, Boston, and his colleagues.

“Caution is warranted when combining radiotherapy and ICI, especially with intracranial radiotherapy,” the researchers wrote. Their report is in Nature Reviews Clinical Oncology.

Some studies have indicated a higher rate of treatment-associated brain necrosis when ICIs are combined with intracranial radiotherapy, while others have shown no such trend, the authors said.

In one single-institution experience involving 180 patients with brain metastases undergoing stereotactic radiotherapy, incidence of treatment-associated brain necrosis was significantly higher in patients receiving an ICI, with an odds ratio of 2.4 (95% confidence interval, 1.06-5.44; P = .03).

Similarly, a retrospective single institution 480-patient study showed an incidence of treatment-associated brain necrosis of 20% for ICIs plus stereotactic radiotherapy versus 7% for radiotherapy alone (P less than .001), but substantial differences in baseline characteristics between groups limited the strength of the study’s conclusions, according to the researchers.

Increased risk is primarily in the form of asymptomatic or minimally symptomatic episodes in some series, the authors noted. A retrospective, 54-patient report showed a rate of treatment-associated brain necrosis of 30% when ICIs were combined with stereotactic radiotherapy, versus 21% for radiotherapy alone (P = .08), but the incidence of symptomatic cases was 15% in both groups, they noted.

“Intriguingly, the findings of several studies have demonstrated an association between [treatment-associated brain necrosis] and improved survival outcomes in patients with melanoma brain metastases that is similar to the independent observations of an analogous relationship between risk of [immune-related adverse events] in general and responsiveness to ICI,” the researchers wrote.

Most of the Food and Drug Administration–approved indications for ICIs are in the metastatic setting, where palliative radiotherapy is frequently important, the authors noted.

In two retrospective studies of patients with metastatic cancers receiving palliative radiotherapy with ICIs, there was a lack of clear association between the irradiated site and specific immune-related adverse events; that lack of association suggests that any toxicities arising from interactions between palliative radiotherapy and ICIs are mainly systemic, rather than local, the authors wrote.

Several retrospective series in advanced-stage melanoma patients have suggested that palliative radiotherapy plus ICIs is safe and does not significantly increase incidence of immune-related adverse events. However, findings from one series showed a correlation between both the ICI and radiotherapy dose given and the incidence of immune-related adverse events.

Prospective studies will be essential to optimize the balance between disease control and risk of morbidity associated with ICIs and radiotherapy combinations, the authors concluded.

The researchers declared no competing interests related to their review article.

SOURCE: Hwang WL, et al. Nat Rev Clin Oncol. 2018 Aug;15(8):477-494.

Since the Food and Drug Administration first approved checkpoint blockade immunotherapy (CBI) and BRAF^V600-targeted therapy in 2011, survival times for patients with melanoma brain metastases (MBMs) have significantly improved, with a 91% increase in 4-year overall survival (OS) from 7.4% to 14.1%.

“The management of advanced melanoma has traditionally been tempered by limited responses to conventional therapies, resulting in a median overall survival (OS) of less than 1 year,” wrote J. Bryan Iorgulescu, MD, of Brigham and Women’s Hospital in Boston, and his colleagues. The report was published in Cancer Immunology Research. “The landscape of advanced melanoma treatment was revolutionized” by the approval of immunotherapy agents, beginning in 2011.

The current, retrospective study involved 2,753 patients with stage IV melanoma. Patient data were drawn from the National Cancer Database, with diagnoses made between 2010 and 2015. Patient management, overall survival, and disease characteristics were evaluated.

During initial review, the researchers found that 35.8% of patients with stage IV melanoma had brain involvement. These patients were further categorized by those with MBM only (39.7%) versus those with extracranial metastatic disease (60.3%), which included involvement of lung (82.9%), liver (8.1%), bone (6.0%), and lymph nodes or distant subcutaneous skin (3%). MBM-only disease was independently predicted by both younger age and geographic location.

Patients receiving first-line CBI therapy demonstrated improved 4-year OS (28.1% vs. 11.1%; P less than.001) and median OS (12.4 months vs. 5.2 months; P less than .001).

Improvements with CBI were most dramatic in patients with MBM-only disease. In these cases, 4-year OS improved from 16.9% to 51.5% (P less than .001), while median OS jumped from 7.7 months to 56.4 months (P less than .001).

Improved OS was also associated with fewer comorbidities, younger age, management at an academic cancer center, single-fraction stereotactic radiosurgery, and resection of the MBM.

“Our findings help bridge the gaps in early clinical trials of CBIs that largely excluded stage IV melanoma patients with MBMs, with checkpoint immunotherapy demonstrating a more than doubling of the median and 4-year OS of MBMs,” the authors concluded.

SOURCE: Iorgulescu et al. Cancer Immunol Res. 2018 July 12 doi: 10.1158/2326-6066.CIR-18-0067.

Since the Food and Drug Administration first approved checkpoint blockade immunotherapy (CBI) and BRAF^V600-targeted therapy in 2011, survival times for patients with melanoma brain metastases (MBMs) have significantly improved, with a 91% increase in 4-year overall survival (OS) from 7.4% to 14.1%.

“The management of advanced melanoma has traditionally been tempered by limited responses to conventional therapies, resulting in a median overall survival (OS) of less than 1 year,” wrote J. Bryan Iorgulescu, MD, of Brigham and Women’s Hospital in Boston, and his colleagues. The report was published in Cancer Immunology Research. “The landscape of advanced melanoma treatment was revolutionized” by the approval of immunotherapy agents, beginning in 2011.

The current, retrospective study involved 2,753 patients with stage IV melanoma. Patient data were drawn from the National Cancer Database, with diagnoses made between 2010 and 2015. Patient management, overall survival, and disease characteristics were evaluated.

During initial review, the researchers found that 35.8% of patients with stage IV melanoma had brain involvement. These patients were further categorized by those with MBM only (39.7%) versus those with extracranial metastatic disease (60.3%), which included involvement of lung (82.9%), liver (8.1%), bone (6.0%), and lymph nodes or distant subcutaneous skin (3%). MBM-only disease was independently predicted by both younger age and geographic location.

Patients receiving first-line CBI therapy demonstrated improved 4-year OS (28.1% vs. 11.1%; P less than.001) and median OS (12.4 months vs. 5.2 months; P less than .001).

Improvements with CBI were most dramatic in patients with MBM-only disease. In these cases, 4-year OS improved from 16.9% to 51.5% (P less than .001), while median OS jumped from 7.7 months to 56.4 months (P less than .001).

Improved OS was also associated with fewer comorbidities, younger age, management at an academic cancer center, single-fraction stereotactic radiosurgery, and resection of the MBM.

“Our findings help bridge the gaps in early clinical trials of CBIs that largely excluded stage IV melanoma patients with MBMs, with checkpoint immunotherapy demonstrating a more than doubling of the median and 4-year OS of MBMs,” the authors concluded.

SOURCE: Iorgulescu et al. Cancer Immunol Res. 2018 July 12 doi: 10.1158/2326-6066.CIR-18-0067.

Since the Food and Drug Administration first approved checkpoint blockade immunotherapy (CBI) and BRAF^V600-targeted therapy in 2011, survival times for patients with melanoma brain metastases (MBMs) have significantly improved, with a 91% increase in 4-year overall survival (OS) from 7.4% to 14.1%.

“The management of advanced melanoma has traditionally been tempered by limited responses to conventional therapies, resulting in a median overall survival (OS) of less than 1 year,” wrote J. Bryan Iorgulescu, MD, of Brigham and Women’s Hospital in Boston, and his colleagues. The report was published in Cancer Immunology Research. “The landscape of advanced melanoma treatment was revolutionized” by the approval of immunotherapy agents, beginning in 2011.

The current, retrospective study involved 2,753 patients with stage IV melanoma. Patient data were drawn from the National Cancer Database, with diagnoses made between 2010 and 2015. Patient management, overall survival, and disease characteristics were evaluated.

During initial review, the researchers found that 35.8% of patients with stage IV melanoma had brain involvement. These patients were further categorized by those with MBM only (39.7%) versus those with extracranial metastatic disease (60.3%), which included involvement of lung (82.9%), liver (8.1%), bone (6.0%), and lymph nodes or distant subcutaneous skin (3%). MBM-only disease was independently predicted by both younger age and geographic location.

Patients receiving first-line CBI therapy demonstrated improved 4-year OS (28.1% vs. 11.1%; P less than.001) and median OS (12.4 months vs. 5.2 months; P less than .001).

Improvements with CBI were most dramatic in patients with MBM-only disease. In these cases, 4-year OS improved from 16.9% to 51.5% (P less than .001), while median OS jumped from 7.7 months to 56.4 months (P less than .001).

Improved OS was also associated with fewer comorbidities, younger age, management at an academic cancer center, single-fraction stereotactic radiosurgery, and resection of the MBM.

“Our findings help bridge the gaps in early clinical trials of CBIs that largely excluded stage IV melanoma patients with MBMs, with checkpoint immunotherapy demonstrating a more than doubling of the median and 4-year OS of MBMs,” the authors concluded.

SOURCE: Iorgulescu et al. Cancer Immunol Res. 2018 July 12 doi: 10.1158/2326-6066.CIR-18-0067.

Treatment with the recombinant poliovirus vaccine PVSRIPO in patients with recurrent glioblastoma can be delivered at a safe dose with efficacy that compares favorably with historical data, recently reported results of a phase 1, nonrandomized study suggest.

The survival rate at 36 months after intratumoral infusion of PVSRIPO was 21%, versus 4% in a control group of patients who would have met the study’s eligibility criteria, investigators wrote in the New England Journal of Medicine.

There was no evidence of virus shedding or viral neuropathogenicity in the study, which included 61 patients with recurrent World Health Organization grade IV malignant glioma. “Further investigations are warranted,” wrote Annick Desjardins, MD, of Duke University, Durham, N.C., and her coauthors.

The prognosis of WHO grade IV malignant glioma remains dismal despite aggressive therapy and decades of research focused on advanced surgery, radiation, chemotherapy, and targeted agents, Dr. Desjardins and her colleagues said.

Accordingly, they sought to evaluate the potential of PVSRIPO, a live-attenuated poliovirus type 1 vaccine with its viral internal ribosome entry site replaced by one of human rhinovirus type. The engineered virus gains entry via the CD155 receptor, which is upregulated in solid tumors such as glioblastomas and expressed in antigen-presenting cells.

“Tumor cytotoxic effects, interferon-dominant activation of antigen-presenting cells, and the profound inflammatory response to poliovirus may counter tumor-induced immunosuppression and instigate antitumor immunity,” the investigators wrote.

With a median follow-up of 27.6 months, the median overall survival for PVSRIPO-treated patients was 12.5 months, longer than the 11.3 months seen in the historical control group. It was also longer than the 6.6 months found in a second comparison group of patients who underwent therapy with tumor-treating fields, which involves application of alternating electrical current to the head.

Survival hit a “plateau” in the PVSRIPO-treated patients, investigators said, with an overall survival rate of 21% at both 24 and 36 months. That stood in contrast to a decline in the historical control group from 14% at 24 months to 4% at 36 months, and a decline from 8% to 3% in the tumor-treating-fields group.

The phase 1 study had a dose-escalation phase including 9 patients and a dose-expansion phase with 52 patients. In the dose-expansion phase, 19% of patients had grade 3 or greater adverse events attributable to PVSRIPO, according to the report.

Of all 61 patients, 69% had a vaccine-related grade 1 or 2 event as their most severe adverse event.

One patient death caused by complications from an intracranial hemorrhage was attributed to bevacizumab. As part of a study protocol amendment, bevacizumab at half the standard dose was allowed to control symptoms of locoregional inflammation, investigators said.

In an ongoing, phase 2, randomized trial, PVSRIPO is being evaluated alone or with lomustine in patients with recurrent WHO grade IV malignant glioma. The Food and Drug Administration granted breakthrough therapy designation to PVSRIPO in May 2016.

Seven study authors reported equity in Istari Oncology, a biotechnology company that is developing PVSRIPO. Authors also reported disclosures related to Genentech/Roche, Celgene, Celldex, and Eli Lilly, among other entities. The study was supported by grants from the Brain Tumor Research Charity, the Tisch family through the Jewish Communal Fund, the National Institutes of Health, and others.

SOURCE: Desjardins A et al .N Engl J Med. 2018 Jun 26. doi: 10.1056/NEJMoa1716435.

Treatment with the recombinant poliovirus vaccine PVSRIPO in patients with recurrent glioblastoma can be delivered at a safe dose with efficacy that compares favorably with historical data, recently reported results of a phase 1, nonrandomized study suggest.

The survival rate at 36 months after intratumoral infusion of PVSRIPO was 21%, versus 4% in a control group of patients who would have met the study’s eligibility criteria, investigators wrote in the New England Journal of Medicine.

There was no evidence of virus shedding or viral neuropathogenicity in the study, which included 61 patients with recurrent World Health Organization grade IV malignant glioma. “Further investigations are warranted,” wrote Annick Desjardins, MD, of Duke University, Durham, N.C., and her coauthors.

The prognosis of WHO grade IV malignant glioma remains dismal despite aggressive therapy and decades of research focused on advanced surgery, radiation, chemotherapy, and targeted agents, Dr. Desjardins and her colleagues said.

Accordingly, they sought to evaluate the potential of PVSRIPO, a live-attenuated poliovirus type 1 vaccine with its viral internal ribosome entry site replaced by one of human rhinovirus type. The engineered virus gains entry via the CD155 receptor, which is upregulated in solid tumors such as glioblastomas and expressed in antigen-presenting cells.

“Tumor cytotoxic effects, interferon-dominant activation of antigen-presenting cells, and the profound inflammatory response to poliovirus may counter tumor-induced immunosuppression and instigate antitumor immunity,” the investigators wrote.

With a median follow-up of 27.6 months, the median overall survival for PVSRIPO-treated patients was 12.5 months, longer than the 11.3 months seen in the historical control group. It was also longer than the 6.6 months found in a second comparison group of patients who underwent therapy with tumor-treating fields, which involves application of alternating electrical current to the head.

Survival hit a “plateau” in the PVSRIPO-treated patients, investigators said, with an overall survival rate of 21% at both 24 and 36 months. That stood in contrast to a decline in the historical control group from 14% at 24 months to 4% at 36 months, and a decline from 8% to 3% in the tumor-treating-fields group.

The phase 1 study had a dose-escalation phase including 9 patients and a dose-expansion phase with 52 patients. In the dose-expansion phase, 19% of patients had grade 3 or greater adverse events attributable to PVSRIPO, according to the report.

Of all 61 patients, 69% had a vaccine-related grade 1 or 2 event as their most severe adverse event.

One patient death caused by complications from an intracranial hemorrhage was attributed to bevacizumab. As part of a study protocol amendment, bevacizumab at half the standard dose was allowed to control symptoms of locoregional inflammation, investigators said.

In an ongoing, phase 2, randomized trial, PVSRIPO is being evaluated alone or with lomustine in patients with recurrent WHO grade IV malignant glioma. The Food and Drug Administration granted breakthrough therapy designation to PVSRIPO in May 2016.

Seven study authors reported equity in Istari Oncology, a biotechnology company that is developing PVSRIPO. Authors also reported disclosures related to Genentech/Roche, Celgene, Celldex, and Eli Lilly, among other entities. The study was supported by grants from the Brain Tumor Research Charity, the Tisch family through the Jewish Communal Fund, the National Institutes of Health, and others.

SOURCE: Desjardins A et al .N Engl J Med. 2018 Jun 26. doi: 10.1056/NEJMoa1716435.

Treatment with the recombinant poliovirus vaccine PVSRIPO in patients with recurrent glioblastoma can be delivered at a safe dose with efficacy that compares favorably with historical data, recently reported results of a phase 1, nonrandomized study suggest.

The survival rate at 36 months after intratumoral infusion of PVSRIPO was 21%, versus 4% in a control group of patients who would have met the study’s eligibility criteria, investigators wrote in the New England Journal of Medicine.

There was no evidence of virus shedding or viral neuropathogenicity in the study, which included 61 patients with recurrent World Health Organization grade IV malignant glioma. “Further investigations are warranted,” wrote Annick Desjardins, MD, of Duke University, Durham, N.C., and her coauthors.

The prognosis of WHO grade IV malignant glioma remains dismal despite aggressive therapy and decades of research focused on advanced surgery, radiation, chemotherapy, and targeted agents, Dr. Desjardins and her colleagues said.

Accordingly, they sought to evaluate the potential of PVSRIPO, a live-attenuated poliovirus type 1 vaccine with its viral internal ribosome entry site replaced by one of human rhinovirus type. The engineered virus gains entry via the CD155 receptor, which is upregulated in solid tumors such as glioblastomas and expressed in antigen-presenting cells.

“Tumor cytotoxic effects, interferon-dominant activation of antigen-presenting cells, and the profound inflammatory response to poliovirus may counter tumor-induced immunosuppression and instigate antitumor immunity,” the investigators wrote.

With a median follow-up of 27.6 months, the median overall survival for PVSRIPO-treated patients was 12.5 months, longer than the 11.3 months seen in the historical control group. It was also longer than the 6.6 months found in a second comparison group of patients who underwent therapy with tumor-treating fields, which involves application of alternating electrical current to the head.

Survival hit a “plateau” in the PVSRIPO-treated patients, investigators said, with an overall survival rate of 21% at both 24 and 36 months. That stood in contrast to a decline in the historical control group from 14% at 24 months to 4% at 36 months, and a decline from 8% to 3% in the tumor-treating-fields group.

The phase 1 study had a dose-escalation phase including 9 patients and a dose-expansion phase with 52 patients. In the dose-expansion phase, 19% of patients had grade 3 or greater adverse events attributable to PVSRIPO, according to the report.

Of all 61 patients, 69% had a vaccine-related grade 1 or 2 event as their most severe adverse event.

One patient death caused by complications from an intracranial hemorrhage was attributed to bevacizumab. As part of a study protocol amendment, bevacizumab at half the standard dose was allowed to control symptoms of locoregional inflammation, investigators said.

In an ongoing, phase 2, randomized trial, PVSRIPO is being evaluated alone or with lomustine in patients with recurrent WHO grade IV malignant glioma. The Food and Drug Administration granted breakthrough therapy designation to PVSRIPO in May 2016.

Seven study authors reported equity in Istari Oncology, a biotechnology company that is developing PVSRIPO. Authors also reported disclosures related to Genentech/Roche, Celgene, Celldex, and Eli Lilly, among other entities. The study was supported by grants from the Brain Tumor Research Charity, the Tisch family through the Jewish Communal Fund, the National Institutes of Health, and others.

SOURCE: Desjardins A et al .N Engl J Med. 2018 Jun 26. doi: 10.1056/NEJMoa1716435.

Despite having more extensive metastases at presentation, breast cancer patients had outcomes after brain-directed therapy similar to those of lung cancer patients, results of a retrospective, single-center study show.

The breast cancer patients had larger and more numerous brain metastases compared with the non-small-cell lung cancer (NSCLC) patients, according to study results published in JAMA Oncology.

However, median survival was not statistically different between groups, at 1.45 years for the breast cancer patients and 1.09 years for NSCLC patients (P = .06), wrote Daniel N. Cagney, MD, of Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, and his coauthors.

“This finding suggests that intracranial disease in patients with breast cancer was not more aggressive or resistant to treatment, but rather was diagnosed at a later stage,” noted Dr. Cagney and his colleagues.

They described a retrospective analysis of 349 patients with breast cancer and 659 patients with NSCLC, all treated between 2000 and 2015 at Dana-Farber/Brigham and Women’s Cancer Center.

Median metastasis diameter at presentation was 17 mm for the breast cancer patients, compared with 14 mm for the lung cancer patients (P less than .001). Breast cancer patients were significantly more likely to be symptomatic, have seizures, harbor brainstem involvement, and have leptomeningeal disease at the time of diagnosis, the researchers wrote.

“After initial brain-directed therapy, no significant differences in recurrence or treatment-based intracranial outcomes were found between the two groups,” they noted. However, neurological death was seen in 37.3% of the breast cancer group versus 19.9% of the lung cancer group (P less than .001).

SOURCE: Cagney DN et al. JAMA Oncol. 2018 May 17. doi: 10.1001/jamaoncol.2018.0813.

Despite having more extensive metastases at presentation, breast cancer patients had outcomes after brain-directed therapy similar to those of lung cancer patients, results of a retrospective, single-center study show.

The breast cancer patients had larger and more numerous brain metastases compared with the non-small-cell lung cancer (NSCLC) patients, according to study results published in JAMA Oncology.

However, median survival was not statistically different between groups, at 1.45 years for the breast cancer patients and 1.09 years for NSCLC patients (P = .06), wrote Daniel N. Cagney, MD, of Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, and his coauthors.

“This finding suggests that intracranial disease in patients with breast cancer was not more aggressive or resistant to treatment, but rather was diagnosed at a later stage,” noted Dr. Cagney and his colleagues.

They described a retrospective analysis of 349 patients with breast cancer and 659 patients with NSCLC, all treated between 2000 and 2015 at Dana-Farber/Brigham and Women’s Cancer Center.

Median metastasis diameter at presentation was 17 mm for the breast cancer patients, compared with 14 mm for the lung cancer patients (P less than .001). Breast cancer patients were significantly more likely to be symptomatic, have seizures, harbor brainstem involvement, and have leptomeningeal disease at the time of diagnosis, the researchers wrote.

“After initial brain-directed therapy, no significant differences in recurrence or treatment-based intracranial outcomes were found between the two groups,” they noted. However, neurological death was seen in 37.3% of the breast cancer group versus 19.9% of the lung cancer group (P less than .001).

SOURCE: Cagney DN et al. JAMA Oncol. 2018 May 17. doi: 10.1001/jamaoncol.2018.0813.

Despite having more extensive metastases at presentation, breast cancer patients had outcomes after brain-directed therapy similar to those of lung cancer patients, results of a retrospective, single-center study show.

The breast cancer patients had larger and more numerous brain metastases compared with the non-small-cell lung cancer (NSCLC) patients, according to study results published in JAMA Oncology.

However, median survival was not statistically different between groups, at 1.45 years for the breast cancer patients and 1.09 years for NSCLC patients (P = .06), wrote Daniel N. Cagney, MD, of Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, and his coauthors.

“This finding suggests that intracranial disease in patients with breast cancer was not more aggressive or resistant to treatment, but rather was diagnosed at a later stage,” noted Dr. Cagney and his colleagues.

They described a retrospective analysis of 349 patients with breast cancer and 659 patients with NSCLC, all treated between 2000 and 2015 at Dana-Farber/Brigham and Women’s Cancer Center.

Median metastasis diameter at presentation was 17 mm for the breast cancer patients, compared with 14 mm for the lung cancer patients (P less than .001). Breast cancer patients were significantly more likely to be symptomatic, have seizures, harbor brainstem involvement, and have leptomeningeal disease at the time of diagnosis, the researchers wrote.

“After initial brain-directed therapy, no significant differences in recurrence or treatment-based intracranial outcomes were found between the two groups,” they noted. However, neurological death was seen in 37.3% of the breast cancer group versus 19.9% of the lung cancer group (P less than .001).

SOURCE: Cagney DN et al. JAMA Oncol. 2018 May 17. doi: 10.1001/jamaoncol.2018.0813.

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

PITTSBURGH – Genetic analysis of circulating free DNA (cfDNA) from pediatric solid tumors can noninvasively identify somatic mutations and copy number alterations that could be used to identify therapeutic targets, investigators reported.

An analysis of tumor specimens and plasma samples from children with neuroblastoma, osteosarcoma, and Wilms tumor revealed in cfDNA both somatic mutations and copy number alterations that had already been detected in the solid tumors, and new, potentially targetable mutations, reported Prachi Kothari, DO, and her colleagues from Memorial Sloan Kettering Cancer Center in New York.

Neil Osterweil/MDedge News

“Circulating free DNA is much less invasive than a tumor biopsy, and you can do it throughout the patient’s entire timeline of treatment, so you get real-time information or after they relapse to see what’s going on if you’re not able to get a tumor biopsy,” Dr. Kothari said at annual meeting of the American Society of Pediatric Hematology/Oncology.

So-called “liquid biopsy” using cfDNA has been used for molecular profiling of adults malignancies, but there are few data on its use in pediatric tumors, Dr. Kothari said.

To see whether the technique could provide useful clinical information for the management of pediatric tumors, the investigators examined tumor samples taken at diagnosis or at the time of disease progression from 15 patients with neuroblastoma, 10 with osteosarcoma, and 5 with Wilms tumor. They analyzed the tumor samples using targeted next-generation sequencing (NGS), and cfDNA using three different genomic analysis techniques, including NGS, MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets), and shallow whole genome sequencing.

For each of the tumor types studies, cfDNA analysis with the MSK-IMPACT platform identified key drivers of malignancy, including MYCN, ALK, and ATRX in neuroblastoma; CDKN2A and MDM2 in osteosarcoma; and DICER1 and AMER1 in Wilms tumor.

The cfDNA samples also revealed somatic mutations and copy number alterations previously reported in the tumors of 8 of the 15 patients with neuroblastoma, as well as potentially targetable new mutations in 6 of the 15 patients, including NRAS, MLL2, ARID1B, and IDH2.

In 5 of the 10 patients with osteosarcoma, cfDNA detected mutations that had been seen in the tumor samples, including mutations in ATRX and NOTCH3, and copy number alterations such as CDK4 amplification,

Of the five patients with Wilms tumors, cfDNA analysis was performed on two samples, one of which showed the same mutation as the tumor. Additionally, for the three patients without tumor analysis, cfDNA showed recurrent driver mutations such as AMER1 and DICER1.

SOURCE: Kothari P et al. ASPHO 2018. Abstract #809.

CHICAGO – Patients with adrenal cortical carcinoma (ACC) who opt for surgery are predicted to survive significantly longer than those who choose chemotherapy or radiation at all stages, according to a study presented at the annual meeting of the Endocrine Society.

These findings, uncovered using the largest cancer registry in the United States, will help give physicians insight into what the best course of action is for treating their patients, according to presenters.

“Surgical resection of the primary tumor improved survival in all stages of disease, whereas adjuvant therapy with chemotherapy or radiation improved overall survival only in stage IVpatients,” said Sri Harsha Tella, MD, endocrinologist at the University of South Carolina, Columbia. “These results may help the prognostication of patients in treatment decision making.”

Investigators conducted a retrospective study of 3,185 pathologically confirmed cases of ACC, registered into the National Cancer Database between 2004 and 2015.

[email protected]

SOURCE: Tella SH et al. Endo 2018.

CHICAGO – Patients with adrenal cortical carcinoma (ACC) who opt for surgery are predicted to survive significantly longer than those who choose chemotherapy or radiation at all stages, according to a study presented at the annual meeting of the Endocrine Society.

These findings, uncovered using the largest cancer registry in the United States, will help give physicians insight into what the best course of action is for treating their patients, according to presenters.

“Surgical resection of the primary tumor improved survival in all stages of disease, whereas adjuvant therapy with chemotherapy or radiation improved overall survival only in stage IVpatients,” said Sri Harsha Tella, MD, endocrinologist at the University of South Carolina, Columbia. “These results may help the prognostication of patients in treatment decision making.”

Investigators conducted a retrospective study of 3,185 pathologically confirmed cases of ACC, registered into the National Cancer Database between 2004 and 2015.

[email protected]

SOURCE: Tella SH et al. Endo 2018.

CHICAGO – Patients with adrenal cortical carcinoma (ACC) who opt for surgery are predicted to survive significantly longer than those who choose chemotherapy or radiation at all stages, according to a study presented at the annual meeting of the Endocrine Society.

These findings, uncovered using the largest cancer registry in the United States, will help give physicians insight into what the best course of action is for treating their patients, according to presenters.

“Surgical resection of the primary tumor improved survival in all stages of disease, whereas adjuvant therapy with chemotherapy or radiation improved overall survival only in stage IVpatients,” said Sri Harsha Tella, MD, endocrinologist at the University of South Carolina, Columbia. “These results may help the prognostication of patients in treatment decision making.”

Investigators conducted a retrospective study of 3,185 pathologically confirmed cases of ACC, registered into the National Cancer Database between 2004 and 2015.

[email protected]

SOURCE: Tella SH et al. Endo 2018.

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

SAN FRANCISCO – Amplification of programmed death-ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274), is rare in most solid tumors, but findings from an analysis in which a majority of patients with the alteration experienced durable responses to PD-1/PD-L1 blockade suggest that testing for it may be warranted.

Of 117,344 deidentified cancer patient samples from a large database, only 0.7% had PD-L1 amplification, which was defined as 6 or more copy number alterations (CNAs). The CNAs were found across more than 100 tumor histologies, Aaron Goodman, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Of a subset of 2,039 clinically annotated patients from the database, who were seen at the University of California, San Diego (UCSD) Center for Personalized Cancer Therapy, 13 (0.6%) had PD-L1 CNAs, and 9 were treated with immune checkpoint blockade, either alone or in combination with another immunotherapeutic or targeted therapy, after a median of four prior systemic therapies.

The PD-1/PD-L1 blockade response rate in those nine patients was 67%, and median progression-free survival was 15.2 months; three objective responses were ongoing for at least 15 months, said Dr. Goodman of UCSD.

The findings are notable, because in unselected patients, the rates of response to immune checkpoint blockade range from 10% to 20%.
 

Lessons from cHL and solid tumors

“Over the past few years, investigators have identified numerous biomarkers that can select subgroups of patients with increased likelihoods of responding to PD-1 blockade,” he said, adding that biomarkers include PD-L1 expression by immunohistochemistry, microsatellite instability – with microsatellite instability–high tumors responding extremely well to immunotherapy, tumor mutational burden measured by whole exome sequencing and next generation sequencing, and possibly PD-L1 amplification.

Of note, response rates are high in patients with classical Hodgkin lymphoma (cHL). In general, cHL patients respond well to treatment, with the majority being cured by way of multiagent chemotherapy and radiation.

“But for the subpopulation that fails to respond to chemotherapy or relapses, outcomes still remain suboptimal. Remarkably, in the relapsed/refractory population of Hodgkin lymphoma ... response rates to single agent nivolumab and pembrolizumab were 65% to 87% [in recent studies],” he said. “Long-term follow-up demonstrates that the majority of these responses were durable and lasted over a year.”

The question is why relapsed/refractory cHL patients treated with immune checkpoint blockade have such a higher response rate than is typically seen in patients with solid tumors.

One answer might lie in the recent finding that nearly 100% of cHL tumors harbor amplification of 9p24.1; the 9p24.1 amplicon encodes the genes PD-L1, PD-L2, and JAK2, (and thus is also known as the PDJ amplicon), he explained, adding that “through gene dose-dependent increased expression of PD-L1 ligand on the Hodgkin lymphoma Reed-Sternberg cells, there is also JAK-STAT mediation of further expression of PD-L1 on the Reed-Sternberg cells.

An encounter with a patient with metastatic basal cell carcinoma – a “relatively unusual situation, as the majority of patients are cured with local therapy”– led to interest in looking at 9p24.1 alterations in solid tumors.

The patient had extensive metastatic disease, and had progressed through multiple therapies. Given his limited treatment options, next generation sequencing was performed on a biopsy from his tumor, and it revealed the PTCH1 alteration typical in basal cell carcinoma, as well as amplification of 9p24.1 with PD-L1, PD-L2, and JAK2 amplification. Nivolumab monotherapy was initiated.

“Within 2 months, he had an excellent partial response to therapy, and I’m pleased to say that he’s in an ongoing complete response 2 years later,” Dr. Goodman said.

It was that case that sparked the idea for the current study.

9p24.1 alterations and checkpoint blockade

“With my interest in hematologic malignancies, I was unaware that [9p24.1] amplification could occur in solid tumors, so the first aim was to determine the prevalence of chromosome 9p24.1 alterations in solid tumors. The next was to determine if patients with solid tumors and chromosome 9p24.1 alterations respond to PD-1/PD-L1 checkpoint blockade.

“What is astounding is [that PD-L1 amplification] was found in over 100 unique tumor histologies, although rare in most histologies,” Dr. Goodman said, noting that histologies with a statistically increased prevalence of PD-L1 amplification included breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and soft tissue sarcoma.

There also were some rare histologies with increased prevalence of PD-L1 amplification, including nasopharyngeal carcinoma, renal sarcomatoid carcinoma, bladder squamous cell carcinoma, and liver mixed hepatocellular cholangiocarcinoma, he said.

Tumors with a paucity of PD-L1 amplification included colorectal cancer, pancreatic cancer, and cutaneous melanoma, although even these still harbored a few patients with amplification, he said.

A closer look at the mutational burden in amplified vs. unamplified tumors showed a median of 7.4 vs. 3.6 mut/mb, but in the PD-L1 amplified group, 85% still had a low-to intermediate mutational burden of 1-20 mut/mb.

“Microsatellite instability and PD-L1 amplification were not mutually exclusive, but a rare event. Five of the 821 cases with PD-L1 amplification were microsatellite high; these included three carcinomas of unknown origin and two cases of gastrointestinal cancer,” he noted.
 

Treatment outcomes

In the 13 UCSD patients with PD-L1 amplification, nine different malignancies were identified, and all patients had advanced or metastatic disease and were heavily pretreated. Of the nine treated patients, five received anti-PD-1 monotherapy, one received anti-CTLA4/anti-PD-1 combination therapy, and three received a PD-1/PD-L1 inhibitor plus an investigational agent, which was immunotherapeutic, Dr. Goodman said.

The 67% overall response rate was similar to that seen in Hodgkin lymphoma, and many of the responses were durable; median overall survival was not reached.

Of note, genomic analysis in the 13 UCSD patients found to have PD-L1 amplification showed there were 143 total alterations in 70 different genes. All but one patient had amplification of PD-L1, PD-L2, and JAK2, and that one had amplification of PD-L1 and PD-L2.

Of six tumors with tissue available to test for PD-L1 expression by immunohistochemistry, four (67%) tested positive. None were microsatellite high, and tumor-infiltrating lymphocytes were present in five cases.

The tumors that tested negative for PD-L1 expression were from the patient with the rare basal cell cancer, and another with glioblastoma. Both responded to anti-PD1/PD-L1 therapy.

The glioblastoma patient was a 40-year-old man with progressive disease, who underwent standard surgical debulking followed by concurrent radiation therapy plus temozolomide. He progressed soon after completing the concurrent chemoradiation therapy, and genomic profiling revealed 12 alterations, including 9p24.1 amplification, Dr. Goodman said, adding that nivolumab therapy was initiated.

“By week 12, much of the tumor mass had started to resolve, and by week 26 it continued to decrease further. He continues to be in an ongoing partial response at 5.2 months,” he said.
 

Recommendations

The findings of this study demonstrate that PD-Ll amplification is rare in solid tumors.

“However, PD-L1 amplification appears to be tissue agnostic, as we have seen in over 100 tumor histologies. We also noted that PD-L1 amplification was enriched in many rare tumors with limited treatment options, including anaplastic thyroid cancer, sarcomatoid carcinoma, and some sarcomas. We believe testing for PD-L1 amplification may be warranted given the frequent responses that were durable and seemed to be independent of mutational burden,” he concluded.

Ravindra Uppaluri, MD, session chair and discussant for Dr. Goodman’s presentation, said that Dr. Goodman’s findings should be considered in the context of “the complex biology [of PD-L1/PD-L2] that has evolved over the last few years.”

He specifically mentioned the two patients without PD-L1 expression despite amplification, but with response to immune checkpoint blockade, and noted that “there are several things going on here ... and we really want to look at all these things.”

The PDJ amplicon, especially given “the ability to look at this with the targeted gene panels that many patients are getting,” is clearly contributing to biomarker stratification, said Dr. Uppaluri of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston.

However, it should be assessed as part of a “global biomarker” that includes tumor-infiltrating lymphocytes and tumor mutational burden, he said.

Dr. Goodman reported having no disclosures. Dr. Uppaluri has received grant/research support from NIH/NIDCR, Merck, and V Foundation, and has received honoraria from Merck.

[email protected]

SOURCE: Goodman A et al. ASCO-SITC, Abstract 47

Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.

The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.

The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

Gadolinium-based contrast agents (GBCAs) used for MRI will now carry a warning regarding their potential retention in the bodies and brains of treated patients, according to the Food and Drug Administration.

The FDA is requiring the new class warning, along with other safety measures, based on evidence showing that trace amounts of gadolinium can be retained in the body for months to years after treatment.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.

Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.

Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.

[email protected]

The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.

Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.

Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.

[email protected]

The Food and Drug Administration has approved a biosimilar to bevacizumab (Avastin) for the treatment of certain colorectal, lung, brain, kidney, and cervical cancers.

Bevacizumab-awwb is the first biosimilar approved in the United States for the treatment of cancer, the FDA said in a press release.

Approval is based on structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data, and other clinical safety and effectiveness data that demonstrate bevacizumab-awwb is biosimilar to bevacizumab, the FDA said.

[email protected]