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Immunotherapies extend survival for melanoma patients with brain metastases
Since the Food and Drug Administration first approved checkpoint blockade immunotherapy (CBI) and BRAFV600-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 BRAFV600-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 BRAFV600-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.
FROM CANCER IMMUNOLOGY RESEARCH
Key clinical point: Checkpoint blockade immunotherapy and BRAFV600-targeted therapy improve survival for patients with melanoma brain metastases.
Major finding: Patients with melanoma brain metastases receiving first-line checkpoint blockade immunotherapy had an improved 4-year overall survival (28.1% vs. 11.1%; P less than .001) and median overall survival (12.4 months vs. 5.2 months; P less than .001).
Study details: A retrospective study of 2,753 patients with stage IV melanoma and brain metastases, from the National Cancer Database, between 2010 and 2015.
Disclosures: The study was supported by the National Institute of Health, Abbvie, Bristol-Myers Squibb, Merck, and others. No conflicts of interest were reported.
Source: Iorgulescu et al. Cancer Immunol Res. 2018 July 12. doi: 10.1158/2326-6066.CIR-18-0067.
Checkpoint inhibitors in autoimmune disease: More flares, better cancer outcomes
AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.
“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.
These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.
Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.
With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.
The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.
However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.
Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.
Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.
Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.
“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.
The study was not industry funded. Ms. Tison reported no potential conflicts of interest.
SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.
AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.
“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.
These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.
Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.
With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.
The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.
However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.
Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.
Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.
Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.
“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.
The study was not industry funded. Ms. Tison reported no potential conflicts of interest.
SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.
AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.
“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.
These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.
Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.
With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.
The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.
However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.
Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.
Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.
Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.
“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.
The study was not industry funded. Ms. Tison reported no potential conflicts of interest.
SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.
REPORTING FROM THE EULAR 2018 CONGRESS
Key clinical point: Cancer patients who take a checkpoint inhibitor and have a preexisting autoimmune disease were significantly more likely to have a disease flare but also a better cancer outcome than were those without preexisting disease.
Major finding: In those with a disease flare, progression-free and overall survival were significantly improved (P = .016 and P = .004, respectively).
Study details: Retrospective multicenter study.
Disclosures: The study was not industry funded. Ms. Tison reported no potential conflicts of interest.
Source: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.
PFS does not capture the benefit of PD-1 inhibitors
Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.
There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”
Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.
The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.
Median PFS and median OS correlated poorly, with an R2 value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R2 = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).
This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.
Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”
Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.
SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.
Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.
There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”
Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.
The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.
Median PFS and median OS correlated poorly, with an R2 value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R2 = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).
This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.
Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”
Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.
SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.
Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.
There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”
Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.
The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.
Median PFS and median OS correlated poorly, with an R2 value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R2 = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).
This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.
Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”
Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.
SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.
FROM JAMA NETWORK OPEN
Key clinical point: Overall survival should remain the standard endpoint for trials of PD-1 inhibitors.
Major finding: The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).
Study details: Systematic review and meta-analysis of 12 randomized, controlled trials.
Disclosures: Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.
Source: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416
KEYNOTE-427: Pembrolizumab monotherapy shows promise in accRCC
CHICAGO – (accRCC), according to findings from the phase 2 KEYNOTE-427 study.
At a median follow-up of 12 months, the overall response rate in 110 study participants with at least one post-baseline assessment was 38%. Three patients (2.7%) achieved a complete response and 39 (35.5%) achieved a partial response, David F. McDermott, MD, reported at the annual meeting of the American Society of Clinical Oncology.
“The disease control rate was 59%,” he said.
Overall, 67% of the patients experienced a reduction in tumor burden, 14% experienced at least an 80% reduction, and 7% experienced a 100% reduction of their target lesion, said Dr. McDermott of Beth Israel Deaconess Medical Center, Boston.
“Most tumor responses occurred early in the course of therapy,” he noted.
The median time to response was 2.8 months, and the median duration of response was not reached at data cutoff, but 74.8% of responders had a response lasting at least 6 months.
An analysis by International Metastatic Renal Cell Carcinoma Database Criteria (IMDC) category showed a confirmed overall response rate (ORR) of 32% among 41 patients with favorable risk, and 42% in 69 patients with intermediate or poor risk.
“Nine of 17 patients in the poor risk group achieved a major response,” Dr. McDermott noted. “Complete and durable responders were seen in all IMDC subgroups.”
In 46 patients with increased PD-L1 expression or a combined positive score of at least 1 the confirmed ORR was 50.0%, and in 53 patients with low PD-L1 expression and a combined positive score less than 1 it was 26%. The ORR was 45% in the remaining patients in whom PD-L1testing could not be performed.
“Of note, all of the complete responses were seen in the PD-L1-high or CPS-greater-than-1 group,” he said.
Median progression-free survival was 8.7 months, and median overall survival has not been reached.
Tolerability of pembrolizumab in this study was acceptable and consistent with that seen with pembrolizumab monotherapy in other tumor types. Although 80% of patients experienced a treatment-related adverse event, the events mainly included fatigue, pruritus, diarrhea, rash, and arthralgia, occurring in 12.7% to 27.3% of patients, he said.
Grade 3/4 events occurred in 21.8% of patients and one patient experienced a fatal grade 5 case of pneumonitis, he added, noting that 11% of patients discontinued treatment because of a treatment-related adverse event.
Overall, 61 patients discontinued therapy, and 33 of those discontinued because of disease progression.
Programmed death-1 (PD-1) inhibitor-based combination therapies have been shown to have clinical benefit when used first-line in accRCC, but data with respect to the clinical impact of first-line PD-1 inhibitor monotherapy are lacking, Dr. McDermott explained.
KEYNOTE-427 was a single-arm, open-label, two-cohort study evaluating the efficacy and safety of pembrolizumab as first-line monotherapy in accRCC and advanced non–clear cell RCC (anccRCC). Patients had accRCC or anccRCC, measurable disease, no prior systemic therapy and Karnofsky Performance Status score of 70% or greater. They were treated with intravenous pembrolizumab at a dose of 200 mg every 3 weeks, and response was assessed at week 12, then every 6 weeks thereafter until week 54, then every 12 weeks.
The current analysis focused on the accRCC cohort and showed that in treatment-naive patients with histologically confirmed accRCC and measurable disease, pembrolizumab shows promising antitumor activity across IMDC risk groups, he said.
“Encouraging activity was also observed in key subgroups, such as the IMDC intermediate/poor risk group ... and patients with [programmed death-ligand 1]-positive tumors,” he said. “The findings ... provide support for the exploration of pembrolizumab in the adjuvant setting and will allow investigators to put the benefit of anti-PD-1-based combination therapies in better context,” he concluded, noting that KEYNOTE-564, a study of pembrolizumab in the adjuvant setting is currently enrolling, and the current study (KEYNOTE-427) cohort B exploring pembrolizumab monotherapy in anccRCC patients is ongoing.
Merck sponsored the study. Dr. McDermott reported consulting or advisory roles with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. His institution has received research funding from Prometheus Laboratories.
SOURCE: McDermott DF et al., ASCO 2018 Abstract 4500.
CHICAGO – (accRCC), according to findings from the phase 2 KEYNOTE-427 study.
At a median follow-up of 12 months, the overall response rate in 110 study participants with at least one post-baseline assessment was 38%. Three patients (2.7%) achieved a complete response and 39 (35.5%) achieved a partial response, David F. McDermott, MD, reported at the annual meeting of the American Society of Clinical Oncology.
“The disease control rate was 59%,” he said.
Overall, 67% of the patients experienced a reduction in tumor burden, 14% experienced at least an 80% reduction, and 7% experienced a 100% reduction of their target lesion, said Dr. McDermott of Beth Israel Deaconess Medical Center, Boston.
“Most tumor responses occurred early in the course of therapy,” he noted.
The median time to response was 2.8 months, and the median duration of response was not reached at data cutoff, but 74.8% of responders had a response lasting at least 6 months.
An analysis by International Metastatic Renal Cell Carcinoma Database Criteria (IMDC) category showed a confirmed overall response rate (ORR) of 32% among 41 patients with favorable risk, and 42% in 69 patients with intermediate or poor risk.
“Nine of 17 patients in the poor risk group achieved a major response,” Dr. McDermott noted. “Complete and durable responders were seen in all IMDC subgroups.”
In 46 patients with increased PD-L1 expression or a combined positive score of at least 1 the confirmed ORR was 50.0%, and in 53 patients with low PD-L1 expression and a combined positive score less than 1 it was 26%. The ORR was 45% in the remaining patients in whom PD-L1testing could not be performed.
“Of note, all of the complete responses were seen in the PD-L1-high or CPS-greater-than-1 group,” he said.
Median progression-free survival was 8.7 months, and median overall survival has not been reached.
Tolerability of pembrolizumab in this study was acceptable and consistent with that seen with pembrolizumab monotherapy in other tumor types. Although 80% of patients experienced a treatment-related adverse event, the events mainly included fatigue, pruritus, diarrhea, rash, and arthralgia, occurring in 12.7% to 27.3% of patients, he said.
Grade 3/4 events occurred in 21.8% of patients and one patient experienced a fatal grade 5 case of pneumonitis, he added, noting that 11% of patients discontinued treatment because of a treatment-related adverse event.
Overall, 61 patients discontinued therapy, and 33 of those discontinued because of disease progression.
Programmed death-1 (PD-1) inhibitor-based combination therapies have been shown to have clinical benefit when used first-line in accRCC, but data with respect to the clinical impact of first-line PD-1 inhibitor monotherapy are lacking, Dr. McDermott explained.
KEYNOTE-427 was a single-arm, open-label, two-cohort study evaluating the efficacy and safety of pembrolizumab as first-line monotherapy in accRCC and advanced non–clear cell RCC (anccRCC). Patients had accRCC or anccRCC, measurable disease, no prior systemic therapy and Karnofsky Performance Status score of 70% or greater. They were treated with intravenous pembrolizumab at a dose of 200 mg every 3 weeks, and response was assessed at week 12, then every 6 weeks thereafter until week 54, then every 12 weeks.
The current analysis focused on the accRCC cohort and showed that in treatment-naive patients with histologically confirmed accRCC and measurable disease, pembrolizumab shows promising antitumor activity across IMDC risk groups, he said.
“Encouraging activity was also observed in key subgroups, such as the IMDC intermediate/poor risk group ... and patients with [programmed death-ligand 1]-positive tumors,” he said. “The findings ... provide support for the exploration of pembrolizumab in the adjuvant setting and will allow investigators to put the benefit of anti-PD-1-based combination therapies in better context,” he concluded, noting that KEYNOTE-564, a study of pembrolizumab in the adjuvant setting is currently enrolling, and the current study (KEYNOTE-427) cohort B exploring pembrolizumab monotherapy in anccRCC patients is ongoing.
Merck sponsored the study. Dr. McDermott reported consulting or advisory roles with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. His institution has received research funding from Prometheus Laboratories.
SOURCE: McDermott DF et al., ASCO 2018 Abstract 4500.
CHICAGO – (accRCC), according to findings from the phase 2 KEYNOTE-427 study.
At a median follow-up of 12 months, the overall response rate in 110 study participants with at least one post-baseline assessment was 38%. Three patients (2.7%) achieved a complete response and 39 (35.5%) achieved a partial response, David F. McDermott, MD, reported at the annual meeting of the American Society of Clinical Oncology.
“The disease control rate was 59%,” he said.
Overall, 67% of the patients experienced a reduction in tumor burden, 14% experienced at least an 80% reduction, and 7% experienced a 100% reduction of their target lesion, said Dr. McDermott of Beth Israel Deaconess Medical Center, Boston.
“Most tumor responses occurred early in the course of therapy,” he noted.
The median time to response was 2.8 months, and the median duration of response was not reached at data cutoff, but 74.8% of responders had a response lasting at least 6 months.
An analysis by International Metastatic Renal Cell Carcinoma Database Criteria (IMDC) category showed a confirmed overall response rate (ORR) of 32% among 41 patients with favorable risk, and 42% in 69 patients with intermediate or poor risk.
“Nine of 17 patients in the poor risk group achieved a major response,” Dr. McDermott noted. “Complete and durable responders were seen in all IMDC subgroups.”
In 46 patients with increased PD-L1 expression or a combined positive score of at least 1 the confirmed ORR was 50.0%, and in 53 patients with low PD-L1 expression and a combined positive score less than 1 it was 26%. The ORR was 45% in the remaining patients in whom PD-L1testing could not be performed.
“Of note, all of the complete responses were seen in the PD-L1-high or CPS-greater-than-1 group,” he said.
Median progression-free survival was 8.7 months, and median overall survival has not been reached.
Tolerability of pembrolizumab in this study was acceptable and consistent with that seen with pembrolizumab monotherapy in other tumor types. Although 80% of patients experienced a treatment-related adverse event, the events mainly included fatigue, pruritus, diarrhea, rash, and arthralgia, occurring in 12.7% to 27.3% of patients, he said.
Grade 3/4 events occurred in 21.8% of patients and one patient experienced a fatal grade 5 case of pneumonitis, he added, noting that 11% of patients discontinued treatment because of a treatment-related adverse event.
Overall, 61 patients discontinued therapy, and 33 of those discontinued because of disease progression.
Programmed death-1 (PD-1) inhibitor-based combination therapies have been shown to have clinical benefit when used first-line in accRCC, but data with respect to the clinical impact of first-line PD-1 inhibitor monotherapy are lacking, Dr. McDermott explained.
KEYNOTE-427 was a single-arm, open-label, two-cohort study evaluating the efficacy and safety of pembrolizumab as first-line monotherapy in accRCC and advanced non–clear cell RCC (anccRCC). Patients had accRCC or anccRCC, measurable disease, no prior systemic therapy and Karnofsky Performance Status score of 70% or greater. They were treated with intravenous pembrolizumab at a dose of 200 mg every 3 weeks, and response was assessed at week 12, then every 6 weeks thereafter until week 54, then every 12 weeks.
The current analysis focused on the accRCC cohort and showed that in treatment-naive patients with histologically confirmed accRCC and measurable disease, pembrolizumab shows promising antitumor activity across IMDC risk groups, he said.
“Encouraging activity was also observed in key subgroups, such as the IMDC intermediate/poor risk group ... and patients with [programmed death-ligand 1]-positive tumors,” he said. “The findings ... provide support for the exploration of pembrolizumab in the adjuvant setting and will allow investigators to put the benefit of anti-PD-1-based combination therapies in better context,” he concluded, noting that KEYNOTE-564, a study of pembrolizumab in the adjuvant setting is currently enrolling, and the current study (KEYNOTE-427) cohort B exploring pembrolizumab monotherapy in anccRCC patients is ongoing.
Merck sponsored the study. Dr. McDermott reported consulting or advisory roles with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. His institution has received research funding from Prometheus Laboratories.
SOURCE: McDermott DF et al., ASCO 2018 Abstract 4500.
REPORTING FROM ASCO 2018
Key clinical point: Pembrolizumab monotherapy shows promising efficacy and tolerability in accRCC.
Major finding: Overall response rate was 38%.
Study details: The phase 2 KEYNOTE-427 trial of 110 patients from one of two study cohorts.
Disclosures: Merck sponsored the study. Dr. McDermott reported consulting or advisory roles with Array BioPharma, Bristol-Myers Squibb, Exelixis, Genentech/Roche, Merck, Novartis, Pfizer, and X4 Pharma. His institution has received research funding from Prometheus Laboratories.
Source: McDermott DF et al. ASCO 2018, Abstract 4500.
Hints of nivolumab efficacy seen in biliary tract cancers
BARCELONA – The immune checkpoint inhibitor nivolumab (Opdivo) shows activity against biliary tract cancers (BTC) that have progressed on prior systemic therapies, investigators report.
Among 27 patients with intra- and extrahepatic cholangiocarcinoma and cancers of the gallbladder for whom at least one prior line of therapy had failed, the overall response rate with nivolumab monotherapy was 18.5%, reported Richard Kim, MD of Moffitt Cancer Center, in Tampa.
“Nivolumab demonstrated clinical efficacy in BTC patients. It was very well tolerated, with few grade 3 or 4 adverse events,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The worldwide incidence of biliary tract cancers has grown over the last 4 decades.
“It is a very aggressive disease, with 5-year overall survival rate of advance disease of less than 2%,” he said.
The standard of care for first-line treatment of advanced disease is gemcitabine and cisplatin, but there is no standard treatment available for patients for whom first-line therapy fails.
Median survival of patients with biliary tract cancers who are receiving second- or third-line therapies is approximately 6-7 months, Dr. Kim said.
The rationale for using nivolumab in this setting comes from evidence suggesting that cholangiocarcinoma is related to dysregulated immunity, with carcinogenesis linked to autoimmune conditions such as primary sclerosing cholangitis, and to chronic parasitic infections.
“Immune regulatory protein PD-1 is upregulated more in intrahepatic cholangiocarcinoma tissues than in adjacent normal tissue, and patients with memory CD8 T cells had longer relapse-free survival and overall survival in extrahepatic cholangiocarcinoma after resection,” he explained.
To see whether the use of an immune checkpoint inhibitor could provide clinically meaningful benefit in patients with advance biliary tract cancers, the investigators conducted a phase 2, two-stage study. They first accrued 18 patients with histologically confirmed, treatment-refractory biliary tract malignancies and treated them with nivolumab 240 mg IV every 2 weeks for 16 weeks, followed by 480 mg IV every 4 weeks.
According to the study protocol, if one or more patients had a complete or partial response, additional patients would be enrolled. As of May 2018, 34 patients had been treated.
The median patient age was 64.5 years. Two-thirds of the patients (64.7%) had intrahepatic cholangiocarcinoma, 2.9% had extrahepatic cholangiocarcinoma, and 32.4% had tumors of the gallbladder.
Twenty patients were failed by their first-line therapies, and 14 were failed by two or more lines of therapy. All 34 received at least one dose of nivolumab.
Of this group, 10 patients remained on study at the time of Dr. Kim’s presentation. Fifteen were withdrawn for progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) revision 1.1, and 9 due to clinical progression.
Of 27 patients evaluable for investigator-assessed overall responses – the primary endpoint – 5 patients (18.5%) had a partial response, and 11 (40.7%) had stable disease, for a disease-control rate of 59.3%. The remaining 11 evaluable patients had progressive disease.
“Of interest, of our five patients who had a partial response, three had a diagnosis of intrahepatic cholangiocarcinoma, and two had a diagnosis of a gallbladder tumor,” Dr. Kim said.
All five patients remained on treatment at the time of the presentation, with response duration ranging from 24 to 64 weeks. The median duration of response in these patients has not been reached.
Median progression-free survival for all 34 patients treated with at least one dose was 3.5 months. Overall survival with a median follow-up of 9.9 months has not been reached. The 6-months overall survival rate was 73.5%.
Approximately 20% of patients experienced grade 3 or 4 treatment-related adverse events. There were no grade 4 events and no treatment-related deaths.
The most common grade 3 events were hyponatremia in three patients (8.8%), and lymphopenia, colitis, and hyperbilirubinemia in one patient each (2.9%).
The investigators have collected tissues from all patients and plan to present data from biomarker studies at future meetings. Based on the results of this study, they plan to add 20 more patients to the phase 2 trial to confirm efficacy of nivolumab in this setting.
BARCELONA – The immune checkpoint inhibitor nivolumab (Opdivo) shows activity against biliary tract cancers (BTC) that have progressed on prior systemic therapies, investigators report.
Among 27 patients with intra- and extrahepatic cholangiocarcinoma and cancers of the gallbladder for whom at least one prior line of therapy had failed, the overall response rate with nivolumab monotherapy was 18.5%, reported Richard Kim, MD of Moffitt Cancer Center, in Tampa.
“Nivolumab demonstrated clinical efficacy in BTC patients. It was very well tolerated, with few grade 3 or 4 adverse events,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The worldwide incidence of biliary tract cancers has grown over the last 4 decades.
“It is a very aggressive disease, with 5-year overall survival rate of advance disease of less than 2%,” he said.
The standard of care for first-line treatment of advanced disease is gemcitabine and cisplatin, but there is no standard treatment available for patients for whom first-line therapy fails.
Median survival of patients with biliary tract cancers who are receiving second- or third-line therapies is approximately 6-7 months, Dr. Kim said.
The rationale for using nivolumab in this setting comes from evidence suggesting that cholangiocarcinoma is related to dysregulated immunity, with carcinogenesis linked to autoimmune conditions such as primary sclerosing cholangitis, and to chronic parasitic infections.
“Immune regulatory protein PD-1 is upregulated more in intrahepatic cholangiocarcinoma tissues than in adjacent normal tissue, and patients with memory CD8 T cells had longer relapse-free survival and overall survival in extrahepatic cholangiocarcinoma after resection,” he explained.
To see whether the use of an immune checkpoint inhibitor could provide clinically meaningful benefit in patients with advance biliary tract cancers, the investigators conducted a phase 2, two-stage study. They first accrued 18 patients with histologically confirmed, treatment-refractory biliary tract malignancies and treated them with nivolumab 240 mg IV every 2 weeks for 16 weeks, followed by 480 mg IV every 4 weeks.
According to the study protocol, if one or more patients had a complete or partial response, additional patients would be enrolled. As of May 2018, 34 patients had been treated.
The median patient age was 64.5 years. Two-thirds of the patients (64.7%) had intrahepatic cholangiocarcinoma, 2.9% had extrahepatic cholangiocarcinoma, and 32.4% had tumors of the gallbladder.
Twenty patients were failed by their first-line therapies, and 14 were failed by two or more lines of therapy. All 34 received at least one dose of nivolumab.
Of this group, 10 patients remained on study at the time of Dr. Kim’s presentation. Fifteen were withdrawn for progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) revision 1.1, and 9 due to clinical progression.
Of 27 patients evaluable for investigator-assessed overall responses – the primary endpoint – 5 patients (18.5%) had a partial response, and 11 (40.7%) had stable disease, for a disease-control rate of 59.3%. The remaining 11 evaluable patients had progressive disease.
“Of interest, of our five patients who had a partial response, three had a diagnosis of intrahepatic cholangiocarcinoma, and two had a diagnosis of a gallbladder tumor,” Dr. Kim said.
All five patients remained on treatment at the time of the presentation, with response duration ranging from 24 to 64 weeks. The median duration of response in these patients has not been reached.
Median progression-free survival for all 34 patients treated with at least one dose was 3.5 months. Overall survival with a median follow-up of 9.9 months has not been reached. The 6-months overall survival rate was 73.5%.
Approximately 20% of patients experienced grade 3 or 4 treatment-related adverse events. There were no grade 4 events and no treatment-related deaths.
The most common grade 3 events were hyponatremia in three patients (8.8%), and lymphopenia, colitis, and hyperbilirubinemia in one patient each (2.9%).
The investigators have collected tissues from all patients and plan to present data from biomarker studies at future meetings. Based on the results of this study, they plan to add 20 more patients to the phase 2 trial to confirm efficacy of nivolumab in this setting.
BARCELONA – The immune checkpoint inhibitor nivolumab (Opdivo) shows activity against biliary tract cancers (BTC) that have progressed on prior systemic therapies, investigators report.
Among 27 patients with intra- and extrahepatic cholangiocarcinoma and cancers of the gallbladder for whom at least one prior line of therapy had failed, the overall response rate with nivolumab monotherapy was 18.5%, reported Richard Kim, MD of Moffitt Cancer Center, in Tampa.
“Nivolumab demonstrated clinical efficacy in BTC patients. It was very well tolerated, with few grade 3 or 4 adverse events,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
The worldwide incidence of biliary tract cancers has grown over the last 4 decades.
“It is a very aggressive disease, with 5-year overall survival rate of advance disease of less than 2%,” he said.
The standard of care for first-line treatment of advanced disease is gemcitabine and cisplatin, but there is no standard treatment available for patients for whom first-line therapy fails.
Median survival of patients with biliary tract cancers who are receiving second- or third-line therapies is approximately 6-7 months, Dr. Kim said.
The rationale for using nivolumab in this setting comes from evidence suggesting that cholangiocarcinoma is related to dysregulated immunity, with carcinogenesis linked to autoimmune conditions such as primary sclerosing cholangitis, and to chronic parasitic infections.
“Immune regulatory protein PD-1 is upregulated more in intrahepatic cholangiocarcinoma tissues than in adjacent normal tissue, and patients with memory CD8 T cells had longer relapse-free survival and overall survival in extrahepatic cholangiocarcinoma after resection,” he explained.
To see whether the use of an immune checkpoint inhibitor could provide clinically meaningful benefit in patients with advance biliary tract cancers, the investigators conducted a phase 2, two-stage study. They first accrued 18 patients with histologically confirmed, treatment-refractory biliary tract malignancies and treated them with nivolumab 240 mg IV every 2 weeks for 16 weeks, followed by 480 mg IV every 4 weeks.
According to the study protocol, if one or more patients had a complete or partial response, additional patients would be enrolled. As of May 2018, 34 patients had been treated.
The median patient age was 64.5 years. Two-thirds of the patients (64.7%) had intrahepatic cholangiocarcinoma, 2.9% had extrahepatic cholangiocarcinoma, and 32.4% had tumors of the gallbladder.
Twenty patients were failed by their first-line therapies, and 14 were failed by two or more lines of therapy. All 34 received at least one dose of nivolumab.
Of this group, 10 patients remained on study at the time of Dr. Kim’s presentation. Fifteen were withdrawn for progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) revision 1.1, and 9 due to clinical progression.
Of 27 patients evaluable for investigator-assessed overall responses – the primary endpoint – 5 patients (18.5%) had a partial response, and 11 (40.7%) had stable disease, for a disease-control rate of 59.3%. The remaining 11 evaluable patients had progressive disease.
“Of interest, of our five patients who had a partial response, three had a diagnosis of intrahepatic cholangiocarcinoma, and two had a diagnosis of a gallbladder tumor,” Dr. Kim said.
All five patients remained on treatment at the time of the presentation, with response duration ranging from 24 to 64 weeks. The median duration of response in these patients has not been reached.
Median progression-free survival for all 34 patients treated with at least one dose was 3.5 months. Overall survival with a median follow-up of 9.9 months has not been reached. The 6-months overall survival rate was 73.5%.
Approximately 20% of patients experienced grade 3 or 4 treatment-related adverse events. There were no grade 4 events and no treatment-related deaths.
The most common grade 3 events were hyponatremia in three patients (8.8%), and lymphopenia, colitis, and hyperbilirubinemia in one patient each (2.9%).
The investigators have collected tissues from all patients and plan to present data from biomarker studies at future meetings. Based on the results of this study, they plan to add 20 more patients to the phase 2 trial to confirm efficacy of nivolumab in this setting.
REPORTING FROM ESMO GI 2018
Key clinical point: Nivolumab monotherapy appears to have activity in treatment-refractory biliary tract cancers.
Major finding: Five of 27 evaluable patients had partial responses to nivolumab.
Study details: Two-stage phase 2 trial of 34 patients with intrahepatic or extrahepatic cholangiocarcinomas or gallbladder tumors.
Disclosures: Bristol-Myers Squibb sponsored the study. Dr. Kim disclosed honoraria and institutional research funding from that company and others.
Source: Kim R et al. European Society of Medical Oncology World Congress on Gastrointestinal Cancer. Abstract O-009.
Pembrolizumab does not surpass paclitaxel for gastric cancer
BARCELONA – The immune checkpoint inhibitor pembrolizumab (Keytruda) did not significantly improve overall survival of advanced/metastatic gastric or gastroesophageal junction cancer compared with paclitaxel, the results of the KEYNOTE-061 study show.
Among 395 patients with gastric or gastroesophageal junction (GEJ) cancer who had expression of the programmed death ligand 1 (PD-L1) on 1% or more of their tumor cells, lymphocytes, and macrophages, median overall survival (OS) for patients treated with pembrolizumab was 9.1 months, compared with 8.3 months. This translated into a hazard ratio (HR) for death in the pembrolizumab arm of 0.82, but with the 95% confidence interval crossing 1.00, and a P value (.04205) that did not meet the prespecified threshold for significance (P equal to or less than .0135).
Despite the failure of the trial to reach its primary endpoint, “these results may support further research to identify patients likely to benefit from pembrolizumab monotherapy and ongoing development of pembrolizumab-based combination therapy for gastric cancer,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
Pembrolizumab is approved by the Food and Drug Administration for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with tumors confirmed to carry PD-L1 for whom two or more prior lines of therapy had failed.
The approval was based on results of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score (CPS) of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
The drug is also approved for unresectable of metastatic gastric tumors with high levels of microsatellite instability that progressed on prior therapy.
The KEYNOTE-061 study was designed to test the proposition that pembrolizumab could improve on paclitaxel for treatment of patients with adenocarcinoma of the stomach or GEJ that was metastatic or locally advanced and unresectable, and for which first-line therapy with a platinum agent and fluoropyrimidine had failed.
A total of 592 patients from Europe, Israel, North America, Asia, and Australia were enrolled and randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 35 cycles, or paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 4-week cycle. Each treatment was continued until the maximum number of cycles (for pembrolizumab) or until confirmed disease progression, intolerable toxicity, patient withdrawal, or investigator’s decision.
As noted, OS for patients with a CPS score of 1 or greater, the primary endpoint, did not differ between treatment arms, but there was a numerical tilt that appeared to be in favor of pembrolizumab.
For example, the 12-month OS rates were 39.8% in the pembrolizumab groups vs. 27.1% in the paclitaxel group, and respective 18-month OS rates were 25.7% and 14.8%.
In an analysis of protocol-specified subgroups, there were general trends slightly favoring the checkpoint inhibitor over the taxane, but the only significant difference was among patients with GEJ cancers as the primary tumor location (HR, 0.61, 95% confidence interval, 0.41-0.90).
Pembrolizumab offered a small but significant survival advantage among patients with Eastern Cooperative Oncology Group performance status of 0, with a median OS of 12.3 months vs. 9.3 months (HR, 0.69, 95% CI, 0.49-0.97).
Analyses of PFS and OS by CPS score groups (less than 1, 1-10, or 10 and higher) showed no significant differences, however.
Treatment-related adverse events were more frequent with paclitaxel (84.1% vs. 52.7% of patients on pembrolizumab), but pembrolizumab was associated with more treatment-related deaths (three vs. one). Two of the deaths in the pembrolizumab arm were immune mediated. Grade 3 or greater adverse events occurred in 14.3% vs. 34.8%, respectively.
In the question-and-response following Dr. Shitara’s presentation, session comoderator David Cunningham, MD, of Royal Marsden NHS Foundation Trust in Sutton, England, asked why the KEYNOTE-061 investigators did not pit pembrolizumab against the combination of paclitaxel and ramucirumab (Cyramza) “since that’s what many people would use in this situation.”
Dr. Shitara replied that ramucirumab was not available or accepted as an option in many countries when the trial was first planned in 2014. He added that paclitaxel and ramucirumab should be the control arm for clinical trials going forward.
SOURCE: Shitara K. et al. ESMO World Congress on Gastrointestinal Cancer 2018. Abstract LBA-005.
BARCELONA – The immune checkpoint inhibitor pembrolizumab (Keytruda) did not significantly improve overall survival of advanced/metastatic gastric or gastroesophageal junction cancer compared with paclitaxel, the results of the KEYNOTE-061 study show.
Among 395 patients with gastric or gastroesophageal junction (GEJ) cancer who had expression of the programmed death ligand 1 (PD-L1) on 1% or more of their tumor cells, lymphocytes, and macrophages, median overall survival (OS) for patients treated with pembrolizumab was 9.1 months, compared with 8.3 months. This translated into a hazard ratio (HR) for death in the pembrolizumab arm of 0.82, but with the 95% confidence interval crossing 1.00, and a P value (.04205) that did not meet the prespecified threshold for significance (P equal to or less than .0135).
Despite the failure of the trial to reach its primary endpoint, “these results may support further research to identify patients likely to benefit from pembrolizumab monotherapy and ongoing development of pembrolizumab-based combination therapy for gastric cancer,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
Pembrolizumab is approved by the Food and Drug Administration for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with tumors confirmed to carry PD-L1 for whom two or more prior lines of therapy had failed.
The approval was based on results of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score (CPS) of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
The drug is also approved for unresectable of metastatic gastric tumors with high levels of microsatellite instability that progressed on prior therapy.
The KEYNOTE-061 study was designed to test the proposition that pembrolizumab could improve on paclitaxel for treatment of patients with adenocarcinoma of the stomach or GEJ that was metastatic or locally advanced and unresectable, and for which first-line therapy with a platinum agent and fluoropyrimidine had failed.
A total of 592 patients from Europe, Israel, North America, Asia, and Australia were enrolled and randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 35 cycles, or paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 4-week cycle. Each treatment was continued until the maximum number of cycles (for pembrolizumab) or until confirmed disease progression, intolerable toxicity, patient withdrawal, or investigator’s decision.
As noted, OS for patients with a CPS score of 1 or greater, the primary endpoint, did not differ between treatment arms, but there was a numerical tilt that appeared to be in favor of pembrolizumab.
For example, the 12-month OS rates were 39.8% in the pembrolizumab groups vs. 27.1% in the paclitaxel group, and respective 18-month OS rates were 25.7% and 14.8%.
In an analysis of protocol-specified subgroups, there were general trends slightly favoring the checkpoint inhibitor over the taxane, but the only significant difference was among patients with GEJ cancers as the primary tumor location (HR, 0.61, 95% confidence interval, 0.41-0.90).
Pembrolizumab offered a small but significant survival advantage among patients with Eastern Cooperative Oncology Group performance status of 0, with a median OS of 12.3 months vs. 9.3 months (HR, 0.69, 95% CI, 0.49-0.97).
Analyses of PFS and OS by CPS score groups (less than 1, 1-10, or 10 and higher) showed no significant differences, however.
Treatment-related adverse events were more frequent with paclitaxel (84.1% vs. 52.7% of patients on pembrolizumab), but pembrolizumab was associated with more treatment-related deaths (three vs. one). Two of the deaths in the pembrolizumab arm were immune mediated. Grade 3 or greater adverse events occurred in 14.3% vs. 34.8%, respectively.
In the question-and-response following Dr. Shitara’s presentation, session comoderator David Cunningham, MD, of Royal Marsden NHS Foundation Trust in Sutton, England, asked why the KEYNOTE-061 investigators did not pit pembrolizumab against the combination of paclitaxel and ramucirumab (Cyramza) “since that’s what many people would use in this situation.”
Dr. Shitara replied that ramucirumab was not available or accepted as an option in many countries when the trial was first planned in 2014. He added that paclitaxel and ramucirumab should be the control arm for clinical trials going forward.
SOURCE: Shitara K. et al. ESMO World Congress on Gastrointestinal Cancer 2018. Abstract LBA-005.
BARCELONA – The immune checkpoint inhibitor pembrolizumab (Keytruda) did not significantly improve overall survival of advanced/metastatic gastric or gastroesophageal junction cancer compared with paclitaxel, the results of the KEYNOTE-061 study show.
Among 395 patients with gastric or gastroesophageal junction (GEJ) cancer who had expression of the programmed death ligand 1 (PD-L1) on 1% or more of their tumor cells, lymphocytes, and macrophages, median overall survival (OS) for patients treated with pembrolizumab was 9.1 months, compared with 8.3 months. This translated into a hazard ratio (HR) for death in the pembrolizumab arm of 0.82, but with the 95% confidence interval crossing 1.00, and a P value (.04205) that did not meet the prespecified threshold for significance (P equal to or less than .0135).
Despite the failure of the trial to reach its primary endpoint, “these results may support further research to identify patients likely to benefit from pembrolizumab monotherapy and ongoing development of pembrolizumab-based combination therapy for gastric cancer,” he said at the European Society of Medical Oncology World Congress on Gastrointestinal Cancer.
Pembrolizumab is approved by the Food and Drug Administration for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma with tumors confirmed to carry PD-L1 for whom two or more prior lines of therapy had failed.
The approval was based on results of the nonrandomized, open label KEYNOTE-059 trial, which enrolled 259 patients with gastric or GEJ adenocarcinoma that progressed on at least two prior systemic treatments for advanced disease. Of the enrollees, 143 patients had tumors with a PD-L1 Combined Positive Score (CPS) of 1 or greater. The primary trial outcome, the objective response rate for these 143 patients, was 13.3% (95% confidence interval; 8.2-20), with a complete response rate of 1.4% and a partial response rate of 11.9%. The duration of response ranged from at least 2.8 months to at least 19.4 months.
The drug is also approved for unresectable of metastatic gastric tumors with high levels of microsatellite instability that progressed on prior therapy.
The KEYNOTE-061 study was designed to test the proposition that pembrolizumab could improve on paclitaxel for treatment of patients with adenocarcinoma of the stomach or GEJ that was metastatic or locally advanced and unresectable, and for which first-line therapy with a platinum agent and fluoropyrimidine had failed.
A total of 592 patients from Europe, Israel, North America, Asia, and Australia were enrolled and randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for 35 cycles, or paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 4-week cycle. Each treatment was continued until the maximum number of cycles (for pembrolizumab) or until confirmed disease progression, intolerable toxicity, patient withdrawal, or investigator’s decision.
As noted, OS for patients with a CPS score of 1 or greater, the primary endpoint, did not differ between treatment arms, but there was a numerical tilt that appeared to be in favor of pembrolizumab.
For example, the 12-month OS rates were 39.8% in the pembrolizumab groups vs. 27.1% in the paclitaxel group, and respective 18-month OS rates were 25.7% and 14.8%.
In an analysis of protocol-specified subgroups, there were general trends slightly favoring the checkpoint inhibitor over the taxane, but the only significant difference was among patients with GEJ cancers as the primary tumor location (HR, 0.61, 95% confidence interval, 0.41-0.90).
Pembrolizumab offered a small but significant survival advantage among patients with Eastern Cooperative Oncology Group performance status of 0, with a median OS of 12.3 months vs. 9.3 months (HR, 0.69, 95% CI, 0.49-0.97).
Analyses of PFS and OS by CPS score groups (less than 1, 1-10, or 10 and higher) showed no significant differences, however.
Treatment-related adverse events were more frequent with paclitaxel (84.1% vs. 52.7% of patients on pembrolizumab), but pembrolizumab was associated with more treatment-related deaths (three vs. one). Two of the deaths in the pembrolizumab arm were immune mediated. Grade 3 or greater adverse events occurred in 14.3% vs. 34.8%, respectively.
In the question-and-response following Dr. Shitara’s presentation, session comoderator David Cunningham, MD, of Royal Marsden NHS Foundation Trust in Sutton, England, asked why the KEYNOTE-061 investigators did not pit pembrolizumab against the combination of paclitaxel and ramucirumab (Cyramza) “since that’s what many people would use in this situation.”
Dr. Shitara replied that ramucirumab was not available or accepted as an option in many countries when the trial was first planned in 2014. He added that paclitaxel and ramucirumab should be the control arm for clinical trials going forward.
SOURCE: Shitara K. et al. ESMO World Congress on Gastrointestinal Cancer 2018. Abstract LBA-005.
REPORTING FROM ESMO GI 2018
Key clinical point: KEYNOTE-061 did not meet its primary endpoint of a significant survival advantage with pembrolizumab over paclitaxel.
Major finding: There was no significant difference in overall survival between patients with gastric or gastroesophageal junction cancers treated with pembrolizumab or paclitaxel.
Study details: Phase 3 randomized open-label trial in 592 patients with advanced or metastatic and unresectable tumors of the stomach of GEJ.
Disclosures: The trial was supported by Merck. Dr. Shitara has disclosed honoraria from Abbvie, Novartis and Yakult, consulting or advising with Astellas, BMS. Lilly, Ono Pharmaceutical, Pfizer, and Takeda, and institutional research funding from other companies. Dr. Cunningham has disclosed institutional research finding from Merck Serono and others.
Source: Shitara K et al. ESMO World Congress on Gastrointestinal Cancer 2018. Abstract LBA-005.
Blood and tissue TMB help predict checkpoint inhibition response in NSCLC
CHICAGO – according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.
The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.
Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.
“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.
The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.
Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.
In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.
The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.
B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.
Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.
The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.
Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.
This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.
Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.
“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”
The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.
Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.
SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.
CHICAGO – according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.
The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.
Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.
“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.
The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.
Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.
In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.
The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.
B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.
Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.
The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.
Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.
This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.
Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.
“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”
The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.
Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.
SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.
CHICAGO – according to interim findings from the ongoing B-F1RST study and a retrospective analysis of data from several prior studies.
The retrospective analysis also demonstrated the value of tissue tumor mutational burden (tTMB) as a biomarker for checkpoint inhibition benefit in patients with metastatic urothelial carcinoma and melanoma.
Progression-free survival (PFS) at a minimum of 6 months in 58 evaluable NSCLC patients from the single-arm phase 2b B-F1RST study of first-line atezolizumab monotherapy was 9.5 vs. 2.8 months in those with a high (16 or greater mutations/coding sequence) vs. low (less than 16 mutations/coding sequence) blood tumor mutational burden (bTMB) score (hazard ratio, 0.49), Vamsidhar Velcheti, MD, reported during an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
Progression-free survival hazard ratios improved as bTMB scores increased, explained Dr. Velcheti, associate director of the Center for Immuno-Oncology Research at Taussig Cancer Institute, Cleveland Clinic.
“At the prespecified cutoff of 16, the hazard ratio is 0.51 and this suggests strong correlation of bTMB with clinical benefit,” he said.
The objective response rate in these biomarker evaluable patients was 12.1% and the disease control rate was 25.9%; in the high vs. low bTMB patients the overall response rate was 36.4% vs. 6.4%, he noted, adding that the responses in the high bTMB patients were deeper and more durable, and the safety profile of atezolizumab (Tecentriq) in the trial thus far is consistent with the known adverse event profile for the agent.
Further, prior studies, including the randomized phase 3 OAK and phase 2 POPLAR studies of second-line atezolizumab monotherapy, showed that high bTMB was associated with a PFS benefit.
In the current study, bTMB was evaluated prospectively for the first time as a predictive marker for first-line atezolizumab in stage IIIb-IVb locally advanced or metastatic NSCLC using a next-generation sequencing-based panel. Patients were treated with atezolizumab at a dose of 1,200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or loss of clinical benefit.
The findings show preliminary utility of bTMB as a predictive biomarker for PFS and ORR, and further support bTMB selection of patients in the ongoing phase 3 B-FAST study, which is currently enrolling, Dr. Velcheti said, noting that the findings are encouraging, as 30% of patients with NSCLC have inadequate tumor tissue for molecular testing at diagnosis.
B-F1RST is also ongoing, but has completed enrollment at 153 patients. Primary analysis results will be presented later this year, he said.
Similarly, tTMB was associated with checkpoint inhibitor efficacy across tumor types and lines of therapy in the retrospective analysis of data from seven atezolizumab monotherapy trials.
The overall response rate (ORR) in 987 patients from those studies was 16%, but the response rates were 30% vs. 14% in 125 patients with high tTMB scores vs. 812 patients with low tTMB scores, David R. Gandara, MD, reported during the oral abstract session.
Median duration of response (DOR) was 16.6 months overall but was 29 vs. 14 months in those with high vs. low tTMB scores, respectively, added Dr. Gandara, a professor and director of the thoracic oncology program at the University of California, Davis.
This association was not seen in control cohorts of the three randomized studies included in the analysis (OAK, POPLAR, and IMvigor211), he noted, explaining that the pooled overall response rate in controls was 14.9%, and the response rate in those with high vs. low tTMB scores was 14.4% and 15.1%, respectively.
Further, an exploratory analysis of the three randomized studies showed that PFS increased with increasing levels of tumor mutational burden (TMB). The hazard ratio for PFS at TMB greater than or equal to 16 was 0.71, and the association occurred only in patients receiving atezolizumab.
“As has been previously reported from other studies, [high TMB] identifies a patient population which is distinct from [programmed death-ligand 1] immunohistochemistry and yet complementary,” he said, noting that both high tTMB and high PD-L1 have been shown to predict response independently, and in the current study it is the “small proportion of patients with both [high] TMB and PD-L1 ... that have the best response rate.”
The findings, which highlight “the association of high TMB and enrichment of ORR, DOR, and PFS benefit with atezolizumab monotherapy across indications and lines of therapy,” and demonstrate that high TMB may serve as a surrogate for neoantigen load (NAL – a component of TMB that has been linked with immune response) and complement PD-L1 expression in enriching for clinical benefit from immunotherapy, he concluded, noting that harmonization efforts are underway to standardize TMB platforms and computational algorithms.
Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.
SOURCES: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.
REPORTING FROM ASCO 2018
Key clinical point: High bTMB and tTMB may help predict checkpoint inhibition response in NSCLC patients.
Major finding: PFS in NSCLC patients in the B-F1RST study was 9.5 vs. 2.8 months in those with a high vs. low bTMB score (hazard ratio, 0.49).
Study details: The phase 2b B-F1RST study including 58 evaluable patients and a retrospective analysis of 7 studies including 987 evaluable patients.
Disclosures: Dr. Velcheti has reported financial relationships with Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, and many others. He has received research funding to his institution from Alkermes, Altor BioScience, Atreca, Bristol-Myers Squibb, and others. Dr. Gandara reported financial relationships with ARIAD, AstraZeneca, Boehringer Ingelheim, Celgene, and many others. He has received research funding to his institution from AstraZeneca/MedImmune, Bristol-Myers Squibb, Clovis Oncology, Genentech, and others.
Sources: Velcheti V et al. ASCO 2018 Abstract 12001; Legrand FA et al. ASCO 2018 Abstract 12000.
Avelumab does not add punch to ALK inhibitors for ALK+/– NSCLC
CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.
In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.
In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.
“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
Synergism sought
The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.
Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.
Two groups, two TKIs, one PD-L1 inhibitor
Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.
Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.
In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.
There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.
Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.
In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.
Antitumor activity
In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.
In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.
“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.
But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.
“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.
She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.
“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.
The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”
In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.
“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.
She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.
SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.
CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.
In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.
In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.
“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
Synergism sought
The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.
Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.
Two groups, two TKIs, one PD-L1 inhibitor
Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.
Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.
In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.
There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.
Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.
In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.
Antitumor activity
In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.
In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.
“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.
But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.
“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.
She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.
“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.
The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”
In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.
“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.
She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.
SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.
CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.
In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.
In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.
“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.
In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
Synergism sought
The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.
Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.
Two groups, two TKIs, one PD-L1 inhibitor
Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.
Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.
In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.
There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.
Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.
In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.
Antitumor activity
In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.
In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.
“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.
But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.
“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.
She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.
“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.
The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”
In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.
“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.
She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.
SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.
REPORTING FROM ASCO 2018
Key clinical point: Adding an anti-PD-L1 checkpoint inhibitor to an ALK inhibitor did not add efficacy in patients with either ALK-negative or ALK-positive non–small-cell lung cancer.
Major finding: The ORR in patients treated with avelumab/lorlatinib was 46.4%, the same as ORR with lorlatinib alone.
Study details: Phase 1/2 trial of avelumab/crizotinib in 12 patients with ALK-negative NSCLC, and avelumab/lorlatinib in 28 patients with ALK-positive NSCLC.
Disclosures: Pfizer sponsored the trial. Dr. Shaw disclosed consultancy/advisory board membership, researching funding, and honoraria from Pfizer and other companies. Dr. Horn has previously disclosed serving as a consultant to AbbVie, BMS, Genentech, Merck, and AstraZeneca.
Source: Shaw AT et al. ASCO 2018, Abstract 9008.
Novel antibody shifts ‘eat me/don’t eat me’ balance in refractory NHL
CHICAGO – A first-in-class antibody targeting the macrophage checkpoint CD47 is a promising novel immunotherapy in non-Hodgkin lymphoma, according to Ranjana H. Advani, MD, of Stanford (Calif.) Cancer Institute.
Treatment with Hu5F9-G4 (5F9), an antibody designed to overcome the “don’t eat me” signal associated with CD47, produced “encouraging” antitumor activity in a phase 1b study of 22 patients, Dr. Advani said in an oral abstract presentation at the annual meeting of the American Society of Clinical Oncology.
“5F9 was well tolerated in combination with rituximab, with no maximum tolerated dose achieved,” said Dr. Advani, noting that there were complete remissions in 43% of the refractory follicular lymphoma patients and 33% of refractory diffuse large B-cell lymphoma patients in the phase 1b/2 study.
The antibody has an on-target anemia effect that occurs upon administration, but that was mitigated considerably by a priming and maintenance dosing approach, she added.
The study has demonstrated “excellent” response rates in a highly refractory patient population, said Caron A. Jacobson, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston. “Targeting CD47 ... really helps to shift the balance from ‘don’t eat me’ to ‘eat me,’ ” Dr. Jacobson said at the meeting.
“Importantly, we saw very little toxicity in the study, with very few grade 4 adverse events and no immune-related adverse events,” she added.
Most adverse events were grade 1 or 2, with the most common being the expected on-target anemia associated with 5F9. Using an initial priming dose of 5F9 results in a “temporary and mild decline” in hemoglobin due to clearance of aged red blood cells, Dr. Advani said.
The objective response rate in the study was 50%, with efficacy observed in rituximab-refractory patients, Dr. Advani said. With a median follow-up of greater than 6 months, just 1 of 11 responders had progressed. The median duration of response was not reached, with the longest complete remission lasting more than 14 months.
5F9 is able to selectively eliminate cancer cells through blockade of CD47, while rituximab enhances 5F9’s activity via antibody-dependent cellular phagocytosis, according to Dr. Advani.
“CD47 blockade takes the foot off the brakes, while rituximab puts the foot on the accelerator, leading to maximal tumor phagocytosis,” she said.
The Food and Drug Administration recently granted 5F9 a fast track designation for both diffuse large B-cell lymphoma and follicular lymphoma. Phase 2 investigations of 5F9 in these lymphomas are ongoing, Dr. Advani said.
The trial is sponsored by Forty Seven. Dr. Advani reported research funding from Forty Seven, which is developing 5F9, as well as disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Cell Medica, Genentech/Roche, Gilead Sciences, Pharmacyclics, and Seattle Genetics, among others.
SOURCE: Advani RH et al. ASCO 2018, abstract 7504.
CHICAGO – A first-in-class antibody targeting the macrophage checkpoint CD47 is a promising novel immunotherapy in non-Hodgkin lymphoma, according to Ranjana H. Advani, MD, of Stanford (Calif.) Cancer Institute.
Treatment with Hu5F9-G4 (5F9), an antibody designed to overcome the “don’t eat me” signal associated with CD47, produced “encouraging” antitumor activity in a phase 1b study of 22 patients, Dr. Advani said in an oral abstract presentation at the annual meeting of the American Society of Clinical Oncology.
“5F9 was well tolerated in combination with rituximab, with no maximum tolerated dose achieved,” said Dr. Advani, noting that there were complete remissions in 43% of the refractory follicular lymphoma patients and 33% of refractory diffuse large B-cell lymphoma patients in the phase 1b/2 study.
The antibody has an on-target anemia effect that occurs upon administration, but that was mitigated considerably by a priming and maintenance dosing approach, she added.
The study has demonstrated “excellent” response rates in a highly refractory patient population, said Caron A. Jacobson, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston. “Targeting CD47 ... really helps to shift the balance from ‘don’t eat me’ to ‘eat me,’ ” Dr. Jacobson said at the meeting.
“Importantly, we saw very little toxicity in the study, with very few grade 4 adverse events and no immune-related adverse events,” she added.
Most adverse events were grade 1 or 2, with the most common being the expected on-target anemia associated with 5F9. Using an initial priming dose of 5F9 results in a “temporary and mild decline” in hemoglobin due to clearance of aged red blood cells, Dr. Advani said.
The objective response rate in the study was 50%, with efficacy observed in rituximab-refractory patients, Dr. Advani said. With a median follow-up of greater than 6 months, just 1 of 11 responders had progressed. The median duration of response was not reached, with the longest complete remission lasting more than 14 months.
5F9 is able to selectively eliminate cancer cells through blockade of CD47, while rituximab enhances 5F9’s activity via antibody-dependent cellular phagocytosis, according to Dr. Advani.
“CD47 blockade takes the foot off the brakes, while rituximab puts the foot on the accelerator, leading to maximal tumor phagocytosis,” she said.
The Food and Drug Administration recently granted 5F9 a fast track designation for both diffuse large B-cell lymphoma and follicular lymphoma. Phase 2 investigations of 5F9 in these lymphomas are ongoing, Dr. Advani said.
The trial is sponsored by Forty Seven. Dr. Advani reported research funding from Forty Seven, which is developing 5F9, as well as disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Cell Medica, Genentech/Roche, Gilead Sciences, Pharmacyclics, and Seattle Genetics, among others.
SOURCE: Advani RH et al. ASCO 2018, abstract 7504.
CHICAGO – A first-in-class antibody targeting the macrophage checkpoint CD47 is a promising novel immunotherapy in non-Hodgkin lymphoma, according to Ranjana H. Advani, MD, of Stanford (Calif.) Cancer Institute.
Treatment with Hu5F9-G4 (5F9), an antibody designed to overcome the “don’t eat me” signal associated with CD47, produced “encouraging” antitumor activity in a phase 1b study of 22 patients, Dr. Advani said in an oral abstract presentation at the annual meeting of the American Society of Clinical Oncology.
“5F9 was well tolerated in combination with rituximab, with no maximum tolerated dose achieved,” said Dr. Advani, noting that there were complete remissions in 43% of the refractory follicular lymphoma patients and 33% of refractory diffuse large B-cell lymphoma patients in the phase 1b/2 study.
The antibody has an on-target anemia effect that occurs upon administration, but that was mitigated considerably by a priming and maintenance dosing approach, she added.
The study has demonstrated “excellent” response rates in a highly refractory patient population, said Caron A. Jacobson, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston. “Targeting CD47 ... really helps to shift the balance from ‘don’t eat me’ to ‘eat me,’ ” Dr. Jacobson said at the meeting.
“Importantly, we saw very little toxicity in the study, with very few grade 4 adverse events and no immune-related adverse events,” she added.
Most adverse events were grade 1 or 2, with the most common being the expected on-target anemia associated with 5F9. Using an initial priming dose of 5F9 results in a “temporary and mild decline” in hemoglobin due to clearance of aged red blood cells, Dr. Advani said.
The objective response rate in the study was 50%, with efficacy observed in rituximab-refractory patients, Dr. Advani said. With a median follow-up of greater than 6 months, just 1 of 11 responders had progressed. The median duration of response was not reached, with the longest complete remission lasting more than 14 months.
5F9 is able to selectively eliminate cancer cells through blockade of CD47, while rituximab enhances 5F9’s activity via antibody-dependent cellular phagocytosis, according to Dr. Advani.
“CD47 blockade takes the foot off the brakes, while rituximab puts the foot on the accelerator, leading to maximal tumor phagocytosis,” she said.
The Food and Drug Administration recently granted 5F9 a fast track designation for both diffuse large B-cell lymphoma and follicular lymphoma. Phase 2 investigations of 5F9 in these lymphomas are ongoing, Dr. Advani said.
The trial is sponsored by Forty Seven. Dr. Advani reported research funding from Forty Seven, which is developing 5F9, as well as disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Cell Medica, Genentech/Roche, Gilead Sciences, Pharmacyclics, and Seattle Genetics, among others.
SOURCE: Advani RH et al. ASCO 2018, abstract 7504.
REPORTING FROM ASCO 2018
Key clinical point:
Major finding: Complete responses were seen in 43% of follicular lymphoma (FL) patients and 33% of diffuse large B-cell lymphoma (DLBCL) patients.
Study details: Initial reported results from a phase 1b/2 study of 7 patients with FL and 15 patients with DLBCL.
Disclosures: Forty Seven sponsored the trial. Dr. Advani reported research funding from Forty Seven, which is developing 5F9, as well as disclosures related to AstraZeneca, Bayer, Bristol-Myers Squibb, Cell Medica, Genentech/Roche, Gilead Sciences, Pharmacyclics, and Seattle Genetics, among others.
Source: Advani RH et al. ASCO 2018, abstract 7504.
Checkpoint inhibitor shows promise in advanced squamous-cell carcinoma
An immune checkpoint inhibitor that targets the PD-1 receptor has shown “robust” efficacy among patients with advanced cutaneous squamous-cell carcinoma, according to researchers.
A combined phase 1/phase 2 study, published in the New England Journal of Medicine and presented simultaneously at the annual meeting of the American Society of Clinical Oncology, looked at the effect of monoclonal antibody cemiplimab in an expansion cohort of 26 patients with locally-advanced or metastatic cutaneous squamous-cell carcinoma who were not eligible for surgery. The phase 2 component involved 59 patients with metastatic disease.
Patients were treated with intravenous cemiplimab every 2 weeks for 48 weeks in the phase 1 study, and up to 96 weeks – or until unacceptable toxicity or disease progression – in the phase 2 study.
In the phase 1 study, researchers saw a response rate of 50% and a 65% rate of durable disease control, after a median follow-up of 11 months (1.1-17). The median time to response was 2.3 months, and more than half the patients (54%) who showed a response maintained that response past 6 months.
In the phase 2 study in patients with metastatic disease, 47% responded to the treatment – 24 patients showed a partial response and 4 showed a complete response. Of those who responded, 61% showed durable disease control after a median follow-up of 7.9 months.
The median time to response in this group of patients was 1.9 months, and 57% of those who did respond still showed a response at 6 months. However neither median progression-free survival nor median overall survival had been reached at the point of data cut-off.
The treatment showed similar effects in patients with regional and distant metastatic disease.
Advanced cutaneous squamous-cell carcinoma was thought to be an ideal target for immunotherapy because the high mutation burden in the tumor meant it would be sensitive to effector T cell attack, wrote Michael R. Migden, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“In addition, the dramatically increased risk of cutaneous squamous-cell carcinoma among people with immunosuppression pointed to an important role for immune surveillance with this cancer,” the authors wrote.
In the phase 2 study, 29% of patients experienced a serious adverse event – including two cases of pneumonitis – and three patients (5%) discontinued treatment. There were three deaths due to adverse events: One patient died from pneumonia complications, one died in his sleep, and one patient died following hypercalcemia and deep vein thrombosis.
Aside from these, most adverse events were grade 1 or 2. Around one-quarter of patients experienced diarrhea (27%) or fatigue (24%), while the other most common adverse events were nausea (17%), constipation (15%) and rash (15%). The authors noted that these adverse events were similar to those seen in other PD-1 inhibitors.
“Our results are consistent with an emerging theme regarding the high efficacy of immune checkpoint blockade for the treatment of hypermutated cancers, since the mutation burden of cutaneous squamous-cell carcinoma is similar to that reported for advanced solid tumors with microsatellite instability,” the authors wrote.
Cemiplimab is now being tested in a phase 2 trial in patients with advanced basal cell carcinoma.
The study was supported by Regeneron Pharmaceuticals and Sanofi. Eight authors declared funding from Regeneron to conduct the trial. Ten authors were employees of Regeneron. Fifteen authors also declared funding and payments from pharmaceutical companies outside the submitted work. Four had nothing to disclose.
SOURCE: Migden M et al. NEJM, 2018; June 4. doi: 10.1056/NEJMoa1805131.
An immune checkpoint inhibitor that targets the PD-1 receptor has shown “robust” efficacy among patients with advanced cutaneous squamous-cell carcinoma, according to researchers.
A combined phase 1/phase 2 study, published in the New England Journal of Medicine and presented simultaneously at the annual meeting of the American Society of Clinical Oncology, looked at the effect of monoclonal antibody cemiplimab in an expansion cohort of 26 patients with locally-advanced or metastatic cutaneous squamous-cell carcinoma who were not eligible for surgery. The phase 2 component involved 59 patients with metastatic disease.
Patients were treated with intravenous cemiplimab every 2 weeks for 48 weeks in the phase 1 study, and up to 96 weeks – or until unacceptable toxicity or disease progression – in the phase 2 study.
In the phase 1 study, researchers saw a response rate of 50% and a 65% rate of durable disease control, after a median follow-up of 11 months (1.1-17). The median time to response was 2.3 months, and more than half the patients (54%) who showed a response maintained that response past 6 months.
In the phase 2 study in patients with metastatic disease, 47% responded to the treatment – 24 patients showed a partial response and 4 showed a complete response. Of those who responded, 61% showed durable disease control after a median follow-up of 7.9 months.
The median time to response in this group of patients was 1.9 months, and 57% of those who did respond still showed a response at 6 months. However neither median progression-free survival nor median overall survival had been reached at the point of data cut-off.
The treatment showed similar effects in patients with regional and distant metastatic disease.
Advanced cutaneous squamous-cell carcinoma was thought to be an ideal target for immunotherapy because the high mutation burden in the tumor meant it would be sensitive to effector T cell attack, wrote Michael R. Migden, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“In addition, the dramatically increased risk of cutaneous squamous-cell carcinoma among people with immunosuppression pointed to an important role for immune surveillance with this cancer,” the authors wrote.
In the phase 2 study, 29% of patients experienced a serious adverse event – including two cases of pneumonitis – and three patients (5%) discontinued treatment. There were three deaths due to adverse events: One patient died from pneumonia complications, one died in his sleep, and one patient died following hypercalcemia and deep vein thrombosis.
Aside from these, most adverse events were grade 1 or 2. Around one-quarter of patients experienced diarrhea (27%) or fatigue (24%), while the other most common adverse events were nausea (17%), constipation (15%) and rash (15%). The authors noted that these adverse events were similar to those seen in other PD-1 inhibitors.
“Our results are consistent with an emerging theme regarding the high efficacy of immune checkpoint blockade for the treatment of hypermutated cancers, since the mutation burden of cutaneous squamous-cell carcinoma is similar to that reported for advanced solid tumors with microsatellite instability,” the authors wrote.
Cemiplimab is now being tested in a phase 2 trial in patients with advanced basal cell carcinoma.
The study was supported by Regeneron Pharmaceuticals and Sanofi. Eight authors declared funding from Regeneron to conduct the trial. Ten authors were employees of Regeneron. Fifteen authors also declared funding and payments from pharmaceutical companies outside the submitted work. Four had nothing to disclose.
SOURCE: Migden M et al. NEJM, 2018; June 4. doi: 10.1056/NEJMoa1805131.
An immune checkpoint inhibitor that targets the PD-1 receptor has shown “robust” efficacy among patients with advanced cutaneous squamous-cell carcinoma, according to researchers.
A combined phase 1/phase 2 study, published in the New England Journal of Medicine and presented simultaneously at the annual meeting of the American Society of Clinical Oncology, looked at the effect of monoclonal antibody cemiplimab in an expansion cohort of 26 patients with locally-advanced or metastatic cutaneous squamous-cell carcinoma who were not eligible for surgery. The phase 2 component involved 59 patients with metastatic disease.
Patients were treated with intravenous cemiplimab every 2 weeks for 48 weeks in the phase 1 study, and up to 96 weeks – or until unacceptable toxicity or disease progression – in the phase 2 study.
In the phase 1 study, researchers saw a response rate of 50% and a 65% rate of durable disease control, after a median follow-up of 11 months (1.1-17). The median time to response was 2.3 months, and more than half the patients (54%) who showed a response maintained that response past 6 months.
In the phase 2 study in patients with metastatic disease, 47% responded to the treatment – 24 patients showed a partial response and 4 showed a complete response. Of those who responded, 61% showed durable disease control after a median follow-up of 7.9 months.
The median time to response in this group of patients was 1.9 months, and 57% of those who did respond still showed a response at 6 months. However neither median progression-free survival nor median overall survival had been reached at the point of data cut-off.
The treatment showed similar effects in patients with regional and distant metastatic disease.
Advanced cutaneous squamous-cell carcinoma was thought to be an ideal target for immunotherapy because the high mutation burden in the tumor meant it would be sensitive to effector T cell attack, wrote Michael R. Migden, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his coauthors.
“In addition, the dramatically increased risk of cutaneous squamous-cell carcinoma among people with immunosuppression pointed to an important role for immune surveillance with this cancer,” the authors wrote.
In the phase 2 study, 29% of patients experienced a serious adverse event – including two cases of pneumonitis – and three patients (5%) discontinued treatment. There were three deaths due to adverse events: One patient died from pneumonia complications, one died in his sleep, and one patient died following hypercalcemia and deep vein thrombosis.
Aside from these, most adverse events were grade 1 or 2. Around one-quarter of patients experienced diarrhea (27%) or fatigue (24%), while the other most common adverse events were nausea (17%), constipation (15%) and rash (15%). The authors noted that these adverse events were similar to those seen in other PD-1 inhibitors.
“Our results are consistent with an emerging theme regarding the high efficacy of immune checkpoint blockade for the treatment of hypermutated cancers, since the mutation burden of cutaneous squamous-cell carcinoma is similar to that reported for advanced solid tumors with microsatellite instability,” the authors wrote.
Cemiplimab is now being tested in a phase 2 trial in patients with advanced basal cell carcinoma.
The study was supported by Regeneron Pharmaceuticals and Sanofi. Eight authors declared funding from Regeneron to conduct the trial. Ten authors were employees of Regeneron. Fifteen authors also declared funding and payments from pharmaceutical companies outside the submitted work. Four had nothing to disclose.
SOURCE: Migden M et al. NEJM, 2018; June 4. doi: 10.1056/NEJMoa1805131.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: PD-1 inhibitor cemiplimab shows significant response in advanced squamous-cell carcinoma.
Major finding: Around half of patients with advanced squamous-cell carcinoma responded to checkpoint inhibitor cemiplimab.
Study details: Phase 1 expanded cohort study of 26 patients with advanced cutaneous squamous-cell carcinoma and phase 2 study of 59 patients with metastatic squamous-cell carcinoma.
Disclosures: The study was supported by Regeneron Pharmaceuticals and Sanofi. Eight authors declared funding from Regeneron to conduct the trial. Ten authors were employees of Regeneron. Fifteen authors declared funding and payments from pharmaceutical companies outside the submitted work. Four had nothing to disclose.
Source: Migden M et al. N Engl J Med. 2018 June 4. doi: 10.1056/NEJMoa1805131.