Immuno-oncology

Variations in the clinical presentation of immunotherapy-induced inflammatory arthritis is partly explained by which treatment regimen was used to treat the cancer, a single-center study suggests.

While immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, their use for an ever-widening range of indications had created an increasing population of patients referred to rheumatologists for the management of immune-related adverse events (IrAEs), according to Laura C. Cappelli, MD, and her colleagues at John Hopkins University, Baltimore. 

Well-established guidelines exist for managing adverse events such as colitis and pneumonitis, but there are only preliminary guidelines for evaluating and treating immunotherapy-induced inflammatory arthritis (IA). “This may stem from a lack of consistent reporting of rheumatologic IrAEs in clinical trials, the non–life threatening nature of [inflammatory arthritis], or lack of recognition of musculoskeletal symptoms by treating providers,” they wrote in Seminars in Arthritis and Rheumatism.

Clinical trials have reported ranges of arthralgia in 1%-43% of patients treated with ICIs, but no accurate estimate of the incidence of IA exists. 

The researchers noted that treating patients with ICI-induced IA is complicated by a history of active or recently treated cancer and concerns over using immunosuppression in the context of ICI therapy. 

They set out to evaluate the clinical presentations of 30 patients seen in their clinic with ICI-induced IA. Patients were a median of 59 years old and 12 (40%) were female. Tumor types included metastatic melanoma, non–small cell lung cancer, small cell lung cancer, colorectal cancer, Hodgkin lymphoma, cutaneous lymphoma, renal cell carcinoma, duodenal carcinoma, Merkel cell carcinoma, cutaneous basal cell carcinoma, and cutaneous squamous cell carcinoma.

Sixteen patients were treated with anti–programmed cell death protein 1 (PD-1)/programmed death ligand 1 monotherapy, and 14 were treated with combination anti–CTLA-4/PD-1 therapy. 
Patients on combination therapy were significantly younger (7.5 years, P = 0.01) and were more likely to have metastatic melanoma as their underlying cancer.

Patients who received combination therapy were more likely to present first with knee IA (n = 10) and none had small joint involvement. In contrast, initial small joint involvement was more common in the monotherapy group (n = 6).

Most of the patients in the study had an additional IrAE, with colitis being the most common (n=10), followed by thyroid disease, pneumonitis, and rash. Patients on PD-1 or programmed death ligand 1 monotherapy were more likely to have IA as their first IrAE.

The research team noted that the median time to symptom onset was 5 months after ICI initiation.

Diagnosis of IA following patient-reported symptoms was an average of 5.2 months, with a significant difference in lag time to diagnosis depending on initial joint presentation. For example, patients with initial small joint involvement had a 10 month longer lag time to IA diagnosis than those with knees as the initial joint involved. 

In terms of treatment, 24 patients were treated with systemic corticosteroids and 10 required additional immunosuppression. The need for corticosteroids did not differ by ICI treatment regimen, but those treated with combination therapy were more likely to require additional immunosuppression (P = 0.02).

Tumor necrosis factor inhibitors with or without methotrexate were prescribed for seven patients. All of the patients had a clinical improvement in their arthritis symptoms. Four had a complete tumor response at the time of tumor necrosis factor inhibitor initiation with none having tumor progression.

The three patients treated with methotrexate monotherapy had a complete or sustained partial tumor response to ICI therapy and their cancer did not develop during IA management follow-up.  

The authors went on to look at the persistence of IA after cessation of therapy in a subset of 21 patients. They found that 18 of these patients still had IA symptoms months after stopping treatment. They suggested that the delay in diagnosis and treatment seen in their study might explain the finding. 

The study provides “critical information, not just for rheumatologists as they try to recognize subgroups in ICI-induced IA and diagnose patients with this new entity, but also for oncology providers who are usually first to encounter patients with ICI-induced IA and subsequently refer patients to rheumatology,” Dr. Cappelli and colleagues wrote.

The experience so far with using immunosuppression in ICI-induced IA “has been reassuring in terms of cancer outcomes, but more studies are needed to confirm this finding,” they concluded.

SOURCE: Cappelli LC et al. Semin Arthritis Rheum. doi: 10.1016/j.semarthrit. 2018.02.011.

Variations in the clinical presentation of immunotherapy-induced inflammatory arthritis is partly explained by which treatment regimen was used to treat the cancer, a single-center study suggests.

While immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, their use for an ever-widening range of indications had created an increasing population of patients referred to rheumatologists for the management of immune-related adverse events (IrAEs), according to Laura C. Cappelli, MD, and her colleagues at John Hopkins University, Baltimore. 

Well-established guidelines exist for managing adverse events such as colitis and pneumonitis, but there are only preliminary guidelines for evaluating and treating immunotherapy-induced inflammatory arthritis (IA). “This may stem from a lack of consistent reporting of rheumatologic IrAEs in clinical trials, the non–life threatening nature of [inflammatory arthritis], or lack of recognition of musculoskeletal symptoms by treating providers,” they wrote in Seminars in Arthritis and Rheumatism.

Clinical trials have reported ranges of arthralgia in 1%-43% of patients treated with ICIs, but no accurate estimate of the incidence of IA exists. 

The researchers noted that treating patients with ICI-induced IA is complicated by a history of active or recently treated cancer and concerns over using immunosuppression in the context of ICI therapy. 

They set out to evaluate the clinical presentations of 30 patients seen in their clinic with ICI-induced IA. Patients were a median of 59 years old and 12 (40%) were female. Tumor types included metastatic melanoma, non–small cell lung cancer, small cell lung cancer, colorectal cancer, Hodgkin lymphoma, cutaneous lymphoma, renal cell carcinoma, duodenal carcinoma, Merkel cell carcinoma, cutaneous basal cell carcinoma, and cutaneous squamous cell carcinoma.

Sixteen patients were treated with anti–programmed cell death protein 1 (PD-1)/programmed death ligand 1 monotherapy, and 14 were treated with combination anti–CTLA-4/PD-1 therapy. 
Patients on combination therapy were significantly younger (7.5 years, P = 0.01) and were more likely to have metastatic melanoma as their underlying cancer.

Patients who received combination therapy were more likely to present first with knee IA (n = 10) and none had small joint involvement. In contrast, initial small joint involvement was more common in the monotherapy group (n = 6).

Most of the patients in the study had an additional IrAE, with colitis being the most common (n=10), followed by thyroid disease, pneumonitis, and rash. Patients on PD-1 or programmed death ligand 1 monotherapy were more likely to have IA as their first IrAE.

The research team noted that the median time to symptom onset was 5 months after ICI initiation.

Diagnosis of IA following patient-reported symptoms was an average of 5.2 months, with a significant difference in lag time to diagnosis depending on initial joint presentation. For example, patients with initial small joint involvement had a 10 month longer lag time to IA diagnosis than those with knees as the initial joint involved. 

In terms of treatment, 24 patients were treated with systemic corticosteroids and 10 required additional immunosuppression. The need for corticosteroids did not differ by ICI treatment regimen, but those treated with combination therapy were more likely to require additional immunosuppression (P = 0.02).

Tumor necrosis factor inhibitors with or without methotrexate were prescribed for seven patients. All of the patients had a clinical improvement in their arthritis symptoms. Four had a complete tumor response at the time of tumor necrosis factor inhibitor initiation with none having tumor progression.

The three patients treated with methotrexate monotherapy had a complete or sustained partial tumor response to ICI therapy and their cancer did not develop during IA management follow-up.  

The authors went on to look at the persistence of IA after cessation of therapy in a subset of 21 patients. They found that 18 of these patients still had IA symptoms months after stopping treatment. They suggested that the delay in diagnosis and treatment seen in their study might explain the finding. 

The study provides “critical information, not just for rheumatologists as they try to recognize subgroups in ICI-induced IA and diagnose patients with this new entity, but also for oncology providers who are usually first to encounter patients with ICI-induced IA and subsequently refer patients to rheumatology,” Dr. Cappelli and colleagues wrote.

The experience so far with using immunosuppression in ICI-induced IA “has been reassuring in terms of cancer outcomes, but more studies are needed to confirm this finding,” they concluded.

SOURCE: Cappelli LC et al. Semin Arthritis Rheum. doi: 10.1016/j.semarthrit. 2018.02.011.

Variations in the clinical presentation of immunotherapy-induced inflammatory arthritis is partly explained by which treatment regimen was used to treat the cancer, a single-center study suggests.

While immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, their use for an ever-widening range of indications had created an increasing population of patients referred to rheumatologists for the management of immune-related adverse events (IrAEs), according to Laura C. Cappelli, MD, and her colleagues at John Hopkins University, Baltimore. 

Well-established guidelines exist for managing adverse events such as colitis and pneumonitis, but there are only preliminary guidelines for evaluating and treating immunotherapy-induced inflammatory arthritis (IA). “This may stem from a lack of consistent reporting of rheumatologic IrAEs in clinical trials, the non–life threatening nature of [inflammatory arthritis], or lack of recognition of musculoskeletal symptoms by treating providers,” they wrote in Seminars in Arthritis and Rheumatism.

Clinical trials have reported ranges of arthralgia in 1%-43% of patients treated with ICIs, but no accurate estimate of the incidence of IA exists. 

The researchers noted that treating patients with ICI-induced IA is complicated by a history of active or recently treated cancer and concerns over using immunosuppression in the context of ICI therapy. 

They set out to evaluate the clinical presentations of 30 patients seen in their clinic with ICI-induced IA. Patients were a median of 59 years old and 12 (40%) were female. Tumor types included metastatic melanoma, non–small cell lung cancer, small cell lung cancer, colorectal cancer, Hodgkin lymphoma, cutaneous lymphoma, renal cell carcinoma, duodenal carcinoma, Merkel cell carcinoma, cutaneous basal cell carcinoma, and cutaneous squamous cell carcinoma.

Sixteen patients were treated with anti–programmed cell death protein 1 (PD-1)/programmed death ligand 1 monotherapy, and 14 were treated with combination anti–CTLA-4/PD-1 therapy. 
Patients on combination therapy were significantly younger (7.5 years, P = 0.01) and were more likely to have metastatic melanoma as their underlying cancer.

Patients who received combination therapy were more likely to present first with knee IA (n = 10) and none had small joint involvement. In contrast, initial small joint involvement was more common in the monotherapy group (n = 6).

Most of the patients in the study had an additional IrAE, with colitis being the most common (n=10), followed by thyroid disease, pneumonitis, and rash. Patients on PD-1 or programmed death ligand 1 monotherapy were more likely to have IA as their first IrAE.

The research team noted that the median time to symptom onset was 5 months after ICI initiation.

Diagnosis of IA following patient-reported symptoms was an average of 5.2 months, with a significant difference in lag time to diagnosis depending on initial joint presentation. For example, patients with initial small joint involvement had a 10 month longer lag time to IA diagnosis than those with knees as the initial joint involved. 

In terms of treatment, 24 patients were treated with systemic corticosteroids and 10 required additional immunosuppression. The need for corticosteroids did not differ by ICI treatment regimen, but those treated with combination therapy were more likely to require additional immunosuppression (P = 0.02).

Tumor necrosis factor inhibitors with or without methotrexate were prescribed for seven patients. All of the patients had a clinical improvement in their arthritis symptoms. Four had a complete tumor response at the time of tumor necrosis factor inhibitor initiation with none having tumor progression.

The three patients treated with methotrexate monotherapy had a complete or sustained partial tumor response to ICI therapy and their cancer did not develop during IA management follow-up.  

The authors went on to look at the persistence of IA after cessation of therapy in a subset of 21 patients. They found that 18 of these patients still had IA symptoms months after stopping treatment. They suggested that the delay in diagnosis and treatment seen in their study might explain the finding. 

The study provides “critical information, not just for rheumatologists as they try to recognize subgroups in ICI-induced IA and diagnose patients with this new entity, but also for oncology providers who are usually first to encounter patients with ICI-induced IA and subsequently refer patients to rheumatology,” Dr. Cappelli and colleagues wrote.

The experience so far with using immunosuppression in ICI-induced IA “has been reassuring in terms of cancer outcomes, but more studies are needed to confirm this finding,” they concluded.

SOURCE: Cappelli LC et al. Semin Arthritis Rheum. doi: 10.1016/j.semarthrit. 2018.02.011.

Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.

Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.

Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.

The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.

Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.

Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.

A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.

The authors reported no conflicts of interest.
 

[email protected]

SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.

Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.

Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.

Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.

The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.

Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.

Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.

A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.

The authors reported no conflicts of interest.
 

[email protected]

SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.

Objective response rate (ORR) correlated poorly with overall survival (OS), but 6-month progression-free survival was a better predictor of 12-month OS, according to a systematic review and meta-analysis of phase 2 and phase 3 trials of checkpoint inhibitors in advanced solid cancers.

Six-month progression-free survival is recommended in place of objective response rate as an endpoint in future phase 2 checkpoint-inhibitor trials, investigators wrote. The report was published in JAMA Oncology.

Appropriate selection of a primary endpoint in phase 2 checkpoint-inhibitor trials is critical to proceed to phase 3 testing. In checkpoint inhibitor trials, the validity of ORR, as determined by RECIST, and PFS as surrogates for OS remains unclear.

The investigators conducted a systematic search of electronic databases for trial results from January 2000 to January 2017, identified through PREMEDLINE, MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. In addition, abstracts and conference presentations on the European Society for Medical Oncology and American Society of Clinical Oncology websites were hand-searched, wrote Georgia Ritchie, MBBS, of the Cancer Care Centre, St. George Hospital, Sydney, and associates.

Inclusion criteria comprised trials that used checkpoint inhibitors in advanced solid cancers in single-arm or randomized controlled trials of phase 2 and phase 3 designs.

Within the checkpoint inhibitor arms of the trials, r correlation coefficients between ORR with 6-month PFS, ORR with 12-month OS, and 6-month PFS with 12-month OS were 0.37 (95% confidence interval, −0.06 to 0.95), 0.08 (95% confidence interval, −0.17 to 0.70), and 0.74 (95% confidence interval, 0.57-0.92), respectively, Dr. Ritchie and associates reported. To validate an OS prediction model, the investigators found a good calibration between 6-month PFS and actual and predicted 12-month OS. However, when ORR was used to predict 6-month PFS and 12-month OS rates, the actual vs. predicted rates calibrated poorly, they said.

A strength of the study is its generalizability, because of a heterogeneous population of patients with advanced cancer. “Future phase 2 trials might require a larger sample size, and more resources to report on this result than RECIST ORR,” reported the authors. Further research is required to assess the validity of milestone analysis with 6-month PFS as a potential surrogate for OS in treatment comparisons between checkpoint inhibitors and standard of care therapy, they added.

The authors reported no conflicts of interest.
 

[email protected]

SOURCE: Ritchie G et al., JAMA Oncol. 2018 Feb 22 doi: 10.1001/jamaoncol.2017.5236.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

[email protected]

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

[email protected]

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

[email protected]

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – The expression of major histocompatibility complex class II (MHC-II) molecules on tumor cells can predict response to immune checkpoint blockade, and a recent analysis of MHC-II–positive tumor features provided some insight into the evolution of that response.

The analysis, which involved RNA sequencing on 58 patients with anti–programmed cell death-1 (PD-1)–treated melanoma and lung tumors and on a subset of matched pretreatment specimens at acquired resistance, also highlighted the Fc-receptor–like 6 (FCRL6) molecule as a potential novel immunotherapy target, Justin M. Balko, PharmD, PhD, of Vanderbilt University Medical Center, Nashville, Tenn., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

MHC-II

“MHC-II functions to present class-II restricted antigens to CD4+ T cells, especially T helper cells,” he said, explaining that the expression is typically confined to the professional antigen presenting cell (pAPC) population, but has also previously been shown to be both constitutively and dynamically expressed on tumor cells.

He and his colleagues showed in a 2016 study that MHC-II expression on tumor cells had potential as a biomarker for anti-PD-1 response.

The current study was undertaken to further explore the biological implications of MHC-II expression in tumor cells.

“Importantly here, instead of using mRNA for MHC-II, which could be confounded by other cells in the stroma or microenvironment, we performed immunohistochemistry (IHC) for MHC-II specifically on the tumor compartment within these samples,” Dr. Balko said, noting that he and his colleagues were specifically looking for what was different in gene expression patterns in the MHC-II+ tumor cells.

They compared the gene sets that were enriched in HLA-DR+, or MHC-II+, tumor cells within human tumors with those from melanoma cell lines grown ex vivo in culture (which eliminated any confounding factors of RNA data from contaminating stroma or immune cells), and found substantial gene set overlap.

“These were signatures of innate autoimmunity or inflammation, including those describing allograft rejection gene sets, viral myocarditis, and asthma, suggesting there’s a tumor-intrinsic inflammation signal associated with class II expression on tumor cells,” he said. “We also previously showed in the melanoma data set that HLA-DR expression specifically on tumor cells had a strong association with CD4 infiltrate, and a slightly weaker association with the degree of CD8 infiltration within the tumors.”

Similarly, quantitative immunofluorescence of MHC-II expression in 100 triple negative breast cancer tumors showed that those tumors with HLA-DR or MHC-II expression on tumor cells had a greater degree of CD4 infiltrate than did the negative tumors. CD8 infiltrate was also increased, but enrichment was greater toward the CD4 compartment – an interesting finding given that MHC-II presents antigen to T helper cells, Dr. Balko noted.

Findings in a mouse model

The functional significance of this was explored using an MHC-II–negative orthotopic model cell line unlikely to induce expression of MHC-II when treated with interferon-gamma in culture; MHC-class-II transactivator (CIITA), the master regulator of MHC-II, was used to transduce the cells, resulting in cells that were “constitutively 100% class II+.”

Immunocompetent mice injected with these cells rejected tumors at a much higher rate, but IHC showed more nonregulatory CD4 cells in mice that did not reject the MHC-II+ tumors, Dr. Balko noted.

Gene expression analysis of the rejection-escaped tumors showed more mRNA for PD-1 and LAG-3, similar to what was seen in the study subjects.

“To see if the effect was truly an increase in PD-1 and LAG-3 on lymphocytes within the tumor microenvironment or in lymphoid tissues, we injected immunocompetent mice with either control or CIITA-positive tumors, and then at 7 days harvested either the contralateral lymph node, the spleen, or the proximal or tumor-draining lymph node,” he said.

This showed increased amounts of LAG-3 and PD-1-positive CD4 and CD8 cells in the tumor-draining lymph node, and more LAG-3 PD-1-positive CD8 cells within the tumor itself.

“To perform a therapeutic study, but also to eliminate any confounding factors of the rejecting mice, we waited 14 days after injection of the tumor cells and only enrolled mice with actively growing tumors. We randomized the mice to treatment with either IgG vehicle control, or anti-PD-1, or the combination of anti-PD1 plus LAG-3, and we had a very substantial [75%] complete response rate in the mice with class II–positive tumors treated with the combined PD-1 and LAG-3,” he said. “Importantly, all of the mice in this study were reinoculated with the [MHC-II–negative] cell line and had complete rejection of any subsequent injection of tumor cells.”

To assess whether any other MHC-II receptors could be expressed in the tumor microenvironment, Dr. Balko and his colleagues turned their attention to the FCRL6 molecule, which has previously been shown to be an MHC-II receptor that is expressed on cytolytic cells.
 

FCRL6

“[FCRL6] actually has an [immunoreceptor tyrosine-based inhibitory motif] domain in the intracellular portion of the human ortholog, which suggests that it could have some inhibitory function,” Dr. Balko said, adding that it has been shown to be expressed in a substantial proportion of natural killer cells and CD8 cells, and in a minor fraction of CD4+ T cells, which have been described as “cytotoxic CD4 cells.”

An immortalized FCRL6-negative natural killer cell line know as NK-92 was used to test for inhibitory function.

“We co-cultured it with K562 cells, which are a leukemia cell line that is both class I and class II negative; because they have a missing-self signal, the natural killer cells will naturally lyse the K562 cells, which can be measured by chromium release,” he explained.

When MHC-II was reconstituted on K562 cells, the natural killer cells still had effective lysis of the K562 cells, but when FCRL6 was also transduced on the natural killer cells, this interaction was stopped, and there was suppression of cytotoxic activity, or chromium release, in the co-cultures, suggesting that FCRL6 may have a checkpoint-like functionality, he said.

In the melanoma dataset, a look at FLCR6 mRNA in the tumor microenvironment showed that it was also much more highly expressed in HLA-DR–positive tumors and in the relapsed specimens.

In the tumors with paired specimens (three of which were MHC-II positive and three of which were MHC-II negative), IHC for FCRL6 identified greater enrichment of lymphocytes in the MHC-II–positive tumors, but the difference was not statistically significant.

In the breast cancer samples, where more LAG-3 and FCRL6 was seen in the triple-negative breast tumors, quantitative immunofluorescence showed that FCRL6-postive lymphocytes and LAG-3-positive lymphocytes had a substantial suppression of CD8-sel-positive granzyme B-positive cells within the microenvironment that was more substantial than that observed with PD-L1 expression, he noted.

“So our conclusions are that MHC-II tumors demonstrate enhanced T cell-mediated inflammation and immunity and anti-tumor immunity is circumvented through adaptive resistance by PD-1 and potentially LAG-3/MHC-II engagement in some tumors, and that ... FCRL6 may be a novel MHC-II receptor with inhibitory functionality, and could be a new immunotherapy target,” he said.

MHC-II expression could be useful for stratifying patients to combined anti-PD-1/anti-LAG-3 therapy, and eventually to combined anti-PD-1/anti-FCRL6 therapy, he added.
 

Combined anti-PD-1 and anti-LAG-3 therapy

The findings are of particular interest given recent findings regarding LAG-3 antibodies in development, said invited discussant Antoni Ribas, MD.

In a study reported by Ascierto et al. at ASCO 2017, for example, combined anti-PD-1 and anti-LAG-3 therapy had a 13% overall response rate in metastatic melanoma patients who progressed on anti-PD-1 therapy alone (20% and 7.1% in those with and without LAG-3 expression, respectively), said Dr. Ribas of the University of California, Los Angeles.

[email protected]

SOURCE: Balko J et al., ASCO-SITC abstract 180

SAN FRANCISCO – The expression of major histocompatibility complex class II (MHC-II) molecules on tumor cells can predict response to immune checkpoint blockade, and a recent analysis of MHC-II–positive tumor features provided some insight into the evolution of that response.

The analysis, which involved RNA sequencing on 58 patients with anti–programmed cell death-1 (PD-1)–treated melanoma and lung tumors and on a subset of matched pretreatment specimens at acquired resistance, also highlighted the Fc-receptor–like 6 (FCRL6) molecule as a potential novel immunotherapy target, Justin M. Balko, PharmD, PhD, of Vanderbilt University Medical Center, Nashville, Tenn., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

MHC-II

“MHC-II functions to present class-II restricted antigens to CD4+ T cells, especially T helper cells,” he said, explaining that the expression is typically confined to the professional antigen presenting cell (pAPC) population, but has also previously been shown to be both constitutively and dynamically expressed on tumor cells.

He and his colleagues showed in a 2016 study that MHC-II expression on tumor cells had potential as a biomarker for anti-PD-1 response.

The current study was undertaken to further explore the biological implications of MHC-II expression in tumor cells.

“Importantly here, instead of using mRNA for MHC-II, which could be confounded by other cells in the stroma or microenvironment, we performed immunohistochemistry (IHC) for MHC-II specifically on the tumor compartment within these samples,” Dr. Balko said, noting that he and his colleagues were specifically looking for what was different in gene expression patterns in the MHC-II+ tumor cells.

They compared the gene sets that were enriched in HLA-DR+, or MHC-II+, tumor cells within human tumors with those from melanoma cell lines grown ex vivo in culture (which eliminated any confounding factors of RNA data from contaminating stroma or immune cells), and found substantial gene set overlap.

“These were signatures of innate autoimmunity or inflammation, including those describing allograft rejection gene sets, viral myocarditis, and asthma, suggesting there’s a tumor-intrinsic inflammation signal associated with class II expression on tumor cells,” he said. “We also previously showed in the melanoma data set that HLA-DR expression specifically on tumor cells had a strong association with CD4 infiltrate, and a slightly weaker association with the degree of CD8 infiltration within the tumors.”

Similarly, quantitative immunofluorescence of MHC-II expression in 100 triple negative breast cancer tumors showed that those tumors with HLA-DR or MHC-II expression on tumor cells had a greater degree of CD4 infiltrate than did the negative tumors. CD8 infiltrate was also increased, but enrichment was greater toward the CD4 compartment – an interesting finding given that MHC-II presents antigen to T helper cells, Dr. Balko noted.

Findings in a mouse model

The functional significance of this was explored using an MHC-II–negative orthotopic model cell line unlikely to induce expression of MHC-II when treated with interferon-gamma in culture; MHC-class-II transactivator (CIITA), the master regulator of MHC-II, was used to transduce the cells, resulting in cells that were “constitutively 100% class II+.”

Immunocompetent mice injected with these cells rejected tumors at a much higher rate, but IHC showed more nonregulatory CD4 cells in mice that did not reject the MHC-II+ tumors, Dr. Balko noted.

Gene expression analysis of the rejection-escaped tumors showed more mRNA for PD-1 and LAG-3, similar to what was seen in the study subjects.

“To see if the effect was truly an increase in PD-1 and LAG-3 on lymphocytes within the tumor microenvironment or in lymphoid tissues, we injected immunocompetent mice with either control or CIITA-positive tumors, and then at 7 days harvested either the contralateral lymph node, the spleen, or the proximal or tumor-draining lymph node,” he said.

This showed increased amounts of LAG-3 and PD-1-positive CD4 and CD8 cells in the tumor-draining lymph node, and more LAG-3 PD-1-positive CD8 cells within the tumor itself.

“To perform a therapeutic study, but also to eliminate any confounding factors of the rejecting mice, we waited 14 days after injection of the tumor cells and only enrolled mice with actively growing tumors. We randomized the mice to treatment with either IgG vehicle control, or anti-PD-1, or the combination of anti-PD1 plus LAG-3, and we had a very substantial [75%] complete response rate in the mice with class II–positive tumors treated with the combined PD-1 and LAG-3,” he said. “Importantly, all of the mice in this study were reinoculated with the [MHC-II–negative] cell line and had complete rejection of any subsequent injection of tumor cells.”

To assess whether any other MHC-II receptors could be expressed in the tumor microenvironment, Dr. Balko and his colleagues turned their attention to the FCRL6 molecule, which has previously been shown to be an MHC-II receptor that is expressed on cytolytic cells.
 

FCRL6

“[FCRL6] actually has an [immunoreceptor tyrosine-based inhibitory motif] domain in the intracellular portion of the human ortholog, which suggests that it could have some inhibitory function,” Dr. Balko said, adding that it has been shown to be expressed in a substantial proportion of natural killer cells and CD8 cells, and in a minor fraction of CD4+ T cells, which have been described as “cytotoxic CD4 cells.”

An immortalized FCRL6-negative natural killer cell line know as NK-92 was used to test for inhibitory function.

“We co-cultured it with K562 cells, which are a leukemia cell line that is both class I and class II negative; because they have a missing-self signal, the natural killer cells will naturally lyse the K562 cells, which can be measured by chromium release,” he explained.

When MHC-II was reconstituted on K562 cells, the natural killer cells still had effective lysis of the K562 cells, but when FCRL6 was also transduced on the natural killer cells, this interaction was stopped, and there was suppression of cytotoxic activity, or chromium release, in the co-cultures, suggesting that FCRL6 may have a checkpoint-like functionality, he said.

In the melanoma dataset, a look at FLCR6 mRNA in the tumor microenvironment showed that it was also much more highly expressed in HLA-DR–positive tumors and in the relapsed specimens.

In the tumors with paired specimens (three of which were MHC-II positive and three of which were MHC-II negative), IHC for FCRL6 identified greater enrichment of lymphocytes in the MHC-II–positive tumors, but the difference was not statistically significant.

In the breast cancer samples, where more LAG-3 and FCRL6 was seen in the triple-negative breast tumors, quantitative immunofluorescence showed that FCRL6-postive lymphocytes and LAG-3-positive lymphocytes had a substantial suppression of CD8-sel-positive granzyme B-positive cells within the microenvironment that was more substantial than that observed with PD-L1 expression, he noted.

“So our conclusions are that MHC-II tumors demonstrate enhanced T cell-mediated inflammation and immunity and anti-tumor immunity is circumvented through adaptive resistance by PD-1 and potentially LAG-3/MHC-II engagement in some tumors, and that ... FCRL6 may be a novel MHC-II receptor with inhibitory functionality, and could be a new immunotherapy target,” he said.

MHC-II expression could be useful for stratifying patients to combined anti-PD-1/anti-LAG-3 therapy, and eventually to combined anti-PD-1/anti-FCRL6 therapy, he added.
 

Combined anti-PD-1 and anti-LAG-3 therapy

The findings are of particular interest given recent findings regarding LAG-3 antibodies in development, said invited discussant Antoni Ribas, MD.

In a study reported by Ascierto et al. at ASCO 2017, for example, combined anti-PD-1 and anti-LAG-3 therapy had a 13% overall response rate in metastatic melanoma patients who progressed on anti-PD-1 therapy alone (20% and 7.1% in those with and without LAG-3 expression, respectively), said Dr. Ribas of the University of California, Los Angeles.

[email protected]

SOURCE: Balko J et al., ASCO-SITC abstract 180

SAN FRANCISCO – The expression of major histocompatibility complex class II (MHC-II) molecules on tumor cells can predict response to immune checkpoint blockade, and a recent analysis of MHC-II–positive tumor features provided some insight into the evolution of that response.

The analysis, which involved RNA sequencing on 58 patients with anti–programmed cell death-1 (PD-1)–treated melanoma and lung tumors and on a subset of matched pretreatment specimens at acquired resistance, also highlighted the Fc-receptor–like 6 (FCRL6) molecule as a potential novel immunotherapy target, Justin M. Balko, PharmD, PhD, of Vanderbilt University Medical Center, Nashville, Tenn., reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

MHC-II

“MHC-II functions to present class-II restricted antigens to CD4+ T cells, especially T helper cells,” he said, explaining that the expression is typically confined to the professional antigen presenting cell (pAPC) population, but has also previously been shown to be both constitutively and dynamically expressed on tumor cells.

He and his colleagues showed in a 2016 study that MHC-II expression on tumor cells had potential as a biomarker for anti-PD-1 response.

The current study was undertaken to further explore the biological implications of MHC-II expression in tumor cells.

“Importantly here, instead of using mRNA for MHC-II, which could be confounded by other cells in the stroma or microenvironment, we performed immunohistochemistry (IHC) for MHC-II specifically on the tumor compartment within these samples,” Dr. Balko said, noting that he and his colleagues were specifically looking for what was different in gene expression patterns in the MHC-II+ tumor cells.

They compared the gene sets that were enriched in HLA-DR+, or MHC-II+, tumor cells within human tumors with those from melanoma cell lines grown ex vivo in culture (which eliminated any confounding factors of RNA data from contaminating stroma or immune cells), and found substantial gene set overlap.

“These were signatures of innate autoimmunity or inflammation, including those describing allograft rejection gene sets, viral myocarditis, and asthma, suggesting there’s a tumor-intrinsic inflammation signal associated with class II expression on tumor cells,” he said. “We also previously showed in the melanoma data set that HLA-DR expression specifically on tumor cells had a strong association with CD4 infiltrate, and a slightly weaker association with the degree of CD8 infiltration within the tumors.”

Similarly, quantitative immunofluorescence of MHC-II expression in 100 triple negative breast cancer tumors showed that those tumors with HLA-DR or MHC-II expression on tumor cells had a greater degree of CD4 infiltrate than did the negative tumors. CD8 infiltrate was also increased, but enrichment was greater toward the CD4 compartment – an interesting finding given that MHC-II presents antigen to T helper cells, Dr. Balko noted.

Findings in a mouse model

The functional significance of this was explored using an MHC-II–negative orthotopic model cell line unlikely to induce expression of MHC-II when treated with interferon-gamma in culture; MHC-class-II transactivator (CIITA), the master regulator of MHC-II, was used to transduce the cells, resulting in cells that were “constitutively 100% class II+.”

Immunocompetent mice injected with these cells rejected tumors at a much higher rate, but IHC showed more nonregulatory CD4 cells in mice that did not reject the MHC-II+ tumors, Dr. Balko noted.

Gene expression analysis of the rejection-escaped tumors showed more mRNA for PD-1 and LAG-3, similar to what was seen in the study subjects.

“To see if the effect was truly an increase in PD-1 and LAG-3 on lymphocytes within the tumor microenvironment or in lymphoid tissues, we injected immunocompetent mice with either control or CIITA-positive tumors, and then at 7 days harvested either the contralateral lymph node, the spleen, or the proximal or tumor-draining lymph node,” he said.

This showed increased amounts of LAG-3 and PD-1-positive CD4 and CD8 cells in the tumor-draining lymph node, and more LAG-3 PD-1-positive CD8 cells within the tumor itself.

“To perform a therapeutic study, but also to eliminate any confounding factors of the rejecting mice, we waited 14 days after injection of the tumor cells and only enrolled mice with actively growing tumors. We randomized the mice to treatment with either IgG vehicle control, or anti-PD-1, or the combination of anti-PD1 plus LAG-3, and we had a very substantial [75%] complete response rate in the mice with class II–positive tumors treated with the combined PD-1 and LAG-3,” he said. “Importantly, all of the mice in this study were reinoculated with the [MHC-II–negative] cell line and had complete rejection of any subsequent injection of tumor cells.”

To assess whether any other MHC-II receptors could be expressed in the tumor microenvironment, Dr. Balko and his colleagues turned their attention to the FCRL6 molecule, which has previously been shown to be an MHC-II receptor that is expressed on cytolytic cells.
 

FCRL6

“[FCRL6] actually has an [immunoreceptor tyrosine-based inhibitory motif] domain in the intracellular portion of the human ortholog, which suggests that it could have some inhibitory function,” Dr. Balko said, adding that it has been shown to be expressed in a substantial proportion of natural killer cells and CD8 cells, and in a minor fraction of CD4+ T cells, which have been described as “cytotoxic CD4 cells.”

An immortalized FCRL6-negative natural killer cell line know as NK-92 was used to test for inhibitory function.

“We co-cultured it with K562 cells, which are a leukemia cell line that is both class I and class II negative; because they have a missing-self signal, the natural killer cells will naturally lyse the K562 cells, which can be measured by chromium release,” he explained.

When MHC-II was reconstituted on K562 cells, the natural killer cells still had effective lysis of the K562 cells, but when FCRL6 was also transduced on the natural killer cells, this interaction was stopped, and there was suppression of cytotoxic activity, or chromium release, in the co-cultures, suggesting that FCRL6 may have a checkpoint-like functionality, he said.

In the melanoma dataset, a look at FLCR6 mRNA in the tumor microenvironment showed that it was also much more highly expressed in HLA-DR–positive tumors and in the relapsed specimens.

In the tumors with paired specimens (three of which were MHC-II positive and three of which were MHC-II negative), IHC for FCRL6 identified greater enrichment of lymphocytes in the MHC-II–positive tumors, but the difference was not statistically significant.

In the breast cancer samples, where more LAG-3 and FCRL6 was seen in the triple-negative breast tumors, quantitative immunofluorescence showed that FCRL6-postive lymphocytes and LAG-3-positive lymphocytes had a substantial suppression of CD8-sel-positive granzyme B-positive cells within the microenvironment that was more substantial than that observed with PD-L1 expression, he noted.

“So our conclusions are that MHC-II tumors demonstrate enhanced T cell-mediated inflammation and immunity and anti-tumor immunity is circumvented through adaptive resistance by PD-1 and potentially LAG-3/MHC-II engagement in some tumors, and that ... FCRL6 may be a novel MHC-II receptor with inhibitory functionality, and could be a new immunotherapy target,” he said.

MHC-II expression could be useful for stratifying patients to combined anti-PD-1/anti-LAG-3 therapy, and eventually to combined anti-PD-1/anti-FCRL6 therapy, he added.
 

Combined anti-PD-1 and anti-LAG-3 therapy

The findings are of particular interest given recent findings regarding LAG-3 antibodies in development, said invited discussant Antoni Ribas, MD.

In a study reported by Ascierto et al. at ASCO 2017, for example, combined anti-PD-1 and anti-LAG-3 therapy had a 13% overall response rate in metastatic melanoma patients who progressed on anti-PD-1 therapy alone (20% and 7.1% in those with and without LAG-3 expression, respectively), said Dr. Ribas of the University of California, Los Angeles.

[email protected]

SOURCE: Balko J et al., ASCO-SITC abstract 180

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

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

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

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

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

Lessons from cHL and solid tumors

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

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

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

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

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

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

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

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

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

9p24.1 alterations and checkpoint blockade

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

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

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

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

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

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

Treatment outcomes

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

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

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

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

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

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

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

Recommendations

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

Lessons from cHL and solid tumors

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

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

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

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

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

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

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

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

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

9p24.1 alterations and checkpoint blockade

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

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

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

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

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

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

Treatment outcomes

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

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

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

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

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

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

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

Recommendations

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

Lessons from cHL and solid tumors

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

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

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

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

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

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

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

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

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

9p24.1 alterations and checkpoint blockade

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

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

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

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

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

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

Treatment outcomes

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

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

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

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

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

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

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

Recommendations

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

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

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

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

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

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

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

[email protected]

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

A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.

However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”

Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.

The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 10⁹/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.

Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.

“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.

“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.

Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Findings in context

Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.

“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.

“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”

Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.

SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413

A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.

However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”

Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.

The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 10⁹/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.

Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.

“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.

“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.

Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Findings in context

Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.

“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.

“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”

Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.

SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413

A new model containing six basic laboratory and imaging factors predicts survival of patients with advanced urothelial carcinoma who are given the immune checkpoint inhibitor atezolizumab(Tecentriq), investigators reported in a press briefing in advance of the 2018 Genitourinary Cancers Symposium.

“In the past couple of years, there have been five new programmed death 1 [PD-1] and programmed death ligand 1 [PD-L1] inhibitors [checkpoint-inhibitors] approved by the U.S. FDA [Food and Drug Administration] for patients with advanced urothelial carcinoma that progressed during or after platinum-based chemotherapy, and one of these is atezolizumab,” said lead study author Gregory R. Pond, PhD, of McMaster University, Hamilton, Ont.

However, “there is no available prognostic model for predicting which patients will have improved overall survival in this setting,” he said. “At the moment, we don’t know which therapy to give to which patient. These sorts of prognostic models will help us identify which patients might benefit the most from which therapy.”

Dr. Pond and colleagues analyzed data from patients with advanced urothelial carcinoma treated with atezolizumab in the postplatinum setting. They developed and trained the model in a cohort of 310 patients from the phase 2 IMvigor210 trial and validated it in a cohort of 95 patients from the phase 1 PCD4989g trial.

The model ultimately contained six prognostic factors: elevated neutrophil-lymphocyte ratio (5 or higher), impaired functional status (Eastern Cooperative Oncology Group performance status of 1 or higher), elevated platelet count (400 x 10⁹/L or higher), anemia (hemoglobin level less than 10 g/dL), elevated lactate dehydrogenase level (280 U/L or higher), and the presence of liver metastasis.

Main results showed that median overall survival for patients with 0-1, 2-3, and 4 or more factors was 19.6, 5.9, and 2.8 months in the IMvigor210 cohort, and 19.4, 7.2, and 2.6 months in the PCD4989g cohort, respectively.

“We have developed a prognostic model for overall survival, which we now propose for patients with advanced urothelial carcinoma receiving postplatinum atezolizumab,” Dr. Pond summarized. “The initial results of our study are very promising in both the training and validation datasets.

“The model does require further evaluation and further refinements,” he acknowledged. “For example, we need to look at and evaluate how the model performs in larger sample sizes, and we also want to see how it works with other checkpoint inhibitors.” The investigators also plan to assess its performance relative to that of a PD-L1 immunohistochemical assay.

Full results of the study will be reported later this week at the symposium, which is sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Findings in context

Response of advanced urothelial carcinoma to immune checkpoint inhibitors ranges widely, with one-quarter of patients or fewer seeing tumor shrinkage, and a small proportion seeing longer-term survival, according to ASCO expert and presscast moderator Sumanta K. Pal, MD.

“Until the results of this study, there was no way to easily discern prognosis and identify who might stand to benefit most,” he said. “This easily applied score developed by Dr. Pond and colleagues based on parameters readily available in the patient’s chart provides tremendous input.

“While I would not necessarily withhold therapy on the basis of an anticipated poor prognosis, I would consider using this information in counseling patients who want to be better informed about potential outcomes with immunotherapy,” commented Dr. Pal, who is a medical oncologist and codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif.

Many studies are assessing combinations of immunotherapies with one another and with chemotherapy, he noted. “If these studies are positive, there would be a massive paradigm shift in how we manage advanced bladder cancer. At that point in time, we would have to determine if the model established by Dr. Pond and colleagues remains relevant in that climate.”

Dr. Pond disclosed that an immediate family member is an employee of Roche Canada. Genentech provided data for this study.

SOURCE: Pond GR et al. GU Cancers Symposium, Abstract 413

SAN FRANCISCO – Pembrolizumab immunotherapy with multi-site stereotactic body radiotherapy (SBRT) appears to be a safe and effective treatment in patients with advanced solid tumors, according to findings from a phase 1 study.

Of 79 patients with metastatic solid tumors who progressed on standard treatment and who were enrolled in the study, 68 underwent multi-site SBRT, received at least one cycle of pembrolizumab (Keytruda), and had imaging follow-up. The overall objective response rate in those 68 patients was 13.2%, Jeffrey Lemons, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

[email protected]

SOURCE: Lemons J et al., ASCO-SITC abstract #20.

SAN FRANCISCO – Pembrolizumab immunotherapy with multi-site stereotactic body radiotherapy (SBRT) appears to be a safe and effective treatment in patients with advanced solid tumors, according to findings from a phase 1 study.

Of 79 patients with metastatic solid tumors who progressed on standard treatment and who were enrolled in the study, 68 underwent multi-site SBRT, received at least one cycle of pembrolizumab (Keytruda), and had imaging follow-up. The overall objective response rate in those 68 patients was 13.2%, Jeffrey Lemons, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

[email protected]

SOURCE: Lemons J et al., ASCO-SITC abstract #20.

SAN FRANCISCO – Pembrolizumab immunotherapy with multi-site stereotactic body radiotherapy (SBRT) appears to be a safe and effective treatment in patients with advanced solid tumors, according to findings from a phase 1 study.

Of 79 patients with metastatic solid tumors who progressed on standard treatment and who were enrolled in the study, 68 underwent multi-site SBRT, received at least one cycle of pembrolizumab (Keytruda), and had imaging follow-up. The overall objective response rate in those 68 patients was 13.2%, Jeffrey Lemons, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

[email protected]

SOURCE: Lemons J et al., ASCO-SITC abstract #20.

SAN FRANCISCO – Combined therapy using an experimental programmed cell death protein 1 (PD-1) inhibitor and experimental poly ADP-ribose polymerase (PARP) 1/2 inhibitor was generally well tolerated and showed efficacy in a phase 1 study of patients with advanced solid tumors.

Tislelizumab, the anti–PD-1 agent in development for solid and hematologic malignancies, is a humanized IgG4 monoclonal antibody engineered to have minimal Fc-gamma receptor binding. Pamiparib, the PARP 1/2 inhibitor, is hypothesized to promote neoantigen release that may boost the efficacy of tislelizumab. At the Jan. 4 data cutoff, 2 of 49 patients treated with one of five planned dose levels experienced a complete response, 8 had a confirmed partial response, and 4 had an unconfirmed partial response, Linda Mileshkin, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Thus, the objective response rate was 20%, she said, noting that the clinical benefit rate, which encompasses all those with a response as well as those with durable stable disease after at least 24 weeks, was 39%. The median duration of response was 168.5 days

As of the data cutoff, 11 patients, including all those with a complete or partial response, remained on treatment, and 10 patients remained on treatment beyond 200 days, said Dr. Mileshkin of Peter MacCallum Cancer Centre, Melbourne.

Study participants were 42 women and 7 men, with a mean age of 63 years and measurable disease treated with at least 1 prior line of therapy (median of 4), but with no prior exposure to a PARP inhibitor or PD-1 therapy. Primary tumor sites included ovarian/fallopian tube/peritoneal (34 patients); pancreas, prostate, and breast cancer (3 patients each); and bile duct, bladder, cervix, lung, peripheral nerve sheath, and uterus (1 patient each). For the current dose-finding phase of the study (phase 1a), cohorts of 6-13 patients were treated with either tislelizumab at an intravenous dose of 2 mg/kg every 3 weeks plus either an oral dose of 20, 40, or 60 mg of pamiparib (dose levels 1, 2, and 3, respectively), or with tislelizumab at an intravenous dose of 200 mg every 3 weeks plus pamiparib at an oral dose of 40 or 60 mg twice daily (dose levels 4 and 5, respectively), Dr. Mileshkin said.

Phase 1b will be a disease-specific expansion to evaluate preliminary antitumor activity.

The rationale for combining the two agents was “to prove that we could get some up-regulation of tumor-associated antigens by using a PARP inhibitor that may then allow us to improve the antitumor activity of the checkpoint inhibitor,” she said.

Further, the malignancies in the patients include those likely to harbor DNA damage repair deficiencies, she added.

All patients experienced at least one treatment-emergent adverse event; 21 experienced a serious event, and 23 had immune-related adverse events.

“Despite the number of events, most patients were able to continue therapy,” Dr. Mileshkin said, noting that more discontinuation was associated with the PD-1 therapy than with the PARP inhibitor.

Non–immune-related adverse events related to the PARP inhibitor included mostly grade 1 and 2 nausea, fatigue, and diarrhea. Anemia also occurred and was grade 3 in 12% of patients.

“In terms of the PD-1 therapy, we mostly saw grade 1 or 2 nonimmune adverse events and very few grade 3 and 4 events,” she said.

One or more grade 3 immune-related adverse events occurred in 12 patients, and based on reports from participating centers, there “seemed to be a signal here that we were seeing more hepatic toxicity than we might have expected,” she said, explaining that these included increases in transaminases and hepatitis.

“We ended up with 13 patients who had a hepatic adverse event thought to be related to treatment. The median time to onset was 55 days ... and there were 9 patients in whom these events were grade 3 or 4,” she said.

Ten had grade 2 or higher transaminitis, which was most likely autoimmune in nature.

“All of these patients were treated with corticosteroids, and they all recovered promptly from the event. Subsequently, the protocol was amended to try increase real-time hepatic safety monitoring,” she said, noting that the rate of hepatic events has fallen since these changes were made.

“We need to closely monitor that moving forward to try to understand it better,” she said of the hepatic events.

Dose level 4 (tislelizumab at 200 mg every 3 weeks plus pamiparib at 40 mg twice daily) was determined to be the maximum tolerated dose and is the recommended phase 2 dose, she noted.

“We were pleased to see 10 patients respond, with these responses appearing to be durable with this currently short follow-up period, and we look forward to seeing the results of part B,” she concluded, noting that enrollment of patients into disease-specific cohorts for that next phase is ongoing.

This study is sponsored by BeiGene. Dr. Mileshkin reported receiving payment for travel, accommodations, and/or expenses from BeiGene and Roche.

[email protected]

SOURCE: Friedlander M et al. ASCO-SITC Clinical Immuno-Oncology Symposium 2018, Abstract #48.

SAN FRANCISCO – Combined therapy using an experimental programmed cell death protein 1 (PD-1) inhibitor and experimental poly ADP-ribose polymerase (PARP) 1/2 inhibitor was generally well tolerated and showed efficacy in a phase 1 study of patients with advanced solid tumors.

Tislelizumab, the anti–PD-1 agent in development for solid and hematologic malignancies, is a humanized IgG4 monoclonal antibody engineered to have minimal Fc-gamma receptor binding. Pamiparib, the PARP 1/2 inhibitor, is hypothesized to promote neoantigen release that may boost the efficacy of tislelizumab. At the Jan. 4 data cutoff, 2 of 49 patients treated with one of five planned dose levels experienced a complete response, 8 had a confirmed partial response, and 4 had an unconfirmed partial response, Linda Mileshkin, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Thus, the objective response rate was 20%, she said, noting that the clinical benefit rate, which encompasses all those with a response as well as those with durable stable disease after at least 24 weeks, was 39%. The median duration of response was 168.5 days

As of the data cutoff, 11 patients, including all those with a complete or partial response, remained on treatment, and 10 patients remained on treatment beyond 200 days, said Dr. Mileshkin of Peter MacCallum Cancer Centre, Melbourne.

Study participants were 42 women and 7 men, with a mean age of 63 years and measurable disease treated with at least 1 prior line of therapy (median of 4), but with no prior exposure to a PARP inhibitor or PD-1 therapy. Primary tumor sites included ovarian/fallopian tube/peritoneal (34 patients); pancreas, prostate, and breast cancer (3 patients each); and bile duct, bladder, cervix, lung, peripheral nerve sheath, and uterus (1 patient each). For the current dose-finding phase of the study (phase 1a), cohorts of 6-13 patients were treated with either tislelizumab at an intravenous dose of 2 mg/kg every 3 weeks plus either an oral dose of 20, 40, or 60 mg of pamiparib (dose levels 1, 2, and 3, respectively), or with tislelizumab at an intravenous dose of 200 mg every 3 weeks plus pamiparib at an oral dose of 40 or 60 mg twice daily (dose levels 4 and 5, respectively), Dr. Mileshkin said.

Phase 1b will be a disease-specific expansion to evaluate preliminary antitumor activity.

The rationale for combining the two agents was “to prove that we could get some up-regulation of tumor-associated antigens by using a PARP inhibitor that may then allow us to improve the antitumor activity of the checkpoint inhibitor,” she said.

Further, the malignancies in the patients include those likely to harbor DNA damage repair deficiencies, she added.

All patients experienced at least one treatment-emergent adverse event; 21 experienced a serious event, and 23 had immune-related adverse events.

“Despite the number of events, most patients were able to continue therapy,” Dr. Mileshkin said, noting that more discontinuation was associated with the PD-1 therapy than with the PARP inhibitor.

Non–immune-related adverse events related to the PARP inhibitor included mostly grade 1 and 2 nausea, fatigue, and diarrhea. Anemia also occurred and was grade 3 in 12% of patients.

“In terms of the PD-1 therapy, we mostly saw grade 1 or 2 nonimmune adverse events and very few grade 3 and 4 events,” she said.

One or more grade 3 immune-related adverse events occurred in 12 patients, and based on reports from participating centers, there “seemed to be a signal here that we were seeing more hepatic toxicity than we might have expected,” she said, explaining that these included increases in transaminases and hepatitis.

“We ended up with 13 patients who had a hepatic adverse event thought to be related to treatment. The median time to onset was 55 days ... and there were 9 patients in whom these events were grade 3 or 4,” she said.

Ten had grade 2 or higher transaminitis, which was most likely autoimmune in nature.

“All of these patients were treated with corticosteroids, and they all recovered promptly from the event. Subsequently, the protocol was amended to try increase real-time hepatic safety monitoring,” she said, noting that the rate of hepatic events has fallen since these changes were made.

“We need to closely monitor that moving forward to try to understand it better,” she said of the hepatic events.

Dose level 4 (tislelizumab at 200 mg every 3 weeks plus pamiparib at 40 mg twice daily) was determined to be the maximum tolerated dose and is the recommended phase 2 dose, she noted.

“We were pleased to see 10 patients respond, with these responses appearing to be durable with this currently short follow-up period, and we look forward to seeing the results of part B,” she concluded, noting that enrollment of patients into disease-specific cohorts for that next phase is ongoing.

This study is sponsored by BeiGene. Dr. Mileshkin reported receiving payment for travel, accommodations, and/or expenses from BeiGene and Roche.

[email protected]

SOURCE: Friedlander M et al. ASCO-SITC Clinical Immuno-Oncology Symposium 2018, Abstract #48.

SAN FRANCISCO – Combined therapy using an experimental programmed cell death protein 1 (PD-1) inhibitor and experimental poly ADP-ribose polymerase (PARP) 1/2 inhibitor was generally well tolerated and showed efficacy in a phase 1 study of patients with advanced solid tumors.

Tislelizumab, the anti–PD-1 agent in development for solid and hematologic malignancies, is a humanized IgG4 monoclonal antibody engineered to have minimal Fc-gamma receptor binding. Pamiparib, the PARP 1/2 inhibitor, is hypothesized to promote neoantigen release that may boost the efficacy of tislelizumab. At the Jan. 4 data cutoff, 2 of 49 patients treated with one of five planned dose levels experienced a complete response, 8 had a confirmed partial response, and 4 had an unconfirmed partial response, Linda Mileshkin, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.

Thus, the objective response rate was 20%, she said, noting that the clinical benefit rate, which encompasses all those with a response as well as those with durable stable disease after at least 24 weeks, was 39%. The median duration of response was 168.5 days

As of the data cutoff, 11 patients, including all those with a complete or partial response, remained on treatment, and 10 patients remained on treatment beyond 200 days, said Dr. Mileshkin of Peter MacCallum Cancer Centre, Melbourne.

Study participants were 42 women and 7 men, with a mean age of 63 years and measurable disease treated with at least 1 prior line of therapy (median of 4), but with no prior exposure to a PARP inhibitor or PD-1 therapy. Primary tumor sites included ovarian/fallopian tube/peritoneal (34 patients); pancreas, prostate, and breast cancer (3 patients each); and bile duct, bladder, cervix, lung, peripheral nerve sheath, and uterus (1 patient each). For the current dose-finding phase of the study (phase 1a), cohorts of 6-13 patients were treated with either tislelizumab at an intravenous dose of 2 mg/kg every 3 weeks plus either an oral dose of 20, 40, or 60 mg of pamiparib (dose levels 1, 2, and 3, respectively), or with tislelizumab at an intravenous dose of 200 mg every 3 weeks plus pamiparib at an oral dose of 40 or 60 mg twice daily (dose levels 4 and 5, respectively), Dr. Mileshkin said.

Phase 1b will be a disease-specific expansion to evaluate preliminary antitumor activity.

The rationale for combining the two agents was “to prove that we could get some up-regulation of tumor-associated antigens by using a PARP inhibitor that may then allow us to improve the antitumor activity of the checkpoint inhibitor,” she said.

Further, the malignancies in the patients include those likely to harbor DNA damage repair deficiencies, she added.

All patients experienced at least one treatment-emergent adverse event; 21 experienced a serious event, and 23 had immune-related adverse events.

“Despite the number of events, most patients were able to continue therapy,” Dr. Mileshkin said, noting that more discontinuation was associated with the PD-1 therapy than with the PARP inhibitor.

Non–immune-related adverse events related to the PARP inhibitor included mostly grade 1 and 2 nausea, fatigue, and diarrhea. Anemia also occurred and was grade 3 in 12% of patients.

“In terms of the PD-1 therapy, we mostly saw grade 1 or 2 nonimmune adverse events and very few grade 3 and 4 events,” she said.

One or more grade 3 immune-related adverse events occurred in 12 patients, and based on reports from participating centers, there “seemed to be a signal here that we were seeing more hepatic toxicity than we might have expected,” she said, explaining that these included increases in transaminases and hepatitis.

“We ended up with 13 patients who had a hepatic adverse event thought to be related to treatment. The median time to onset was 55 days ... and there were 9 patients in whom these events were grade 3 or 4,” she said.

Ten had grade 2 or higher transaminitis, which was most likely autoimmune in nature.

“All of these patients were treated with corticosteroids, and they all recovered promptly from the event. Subsequently, the protocol was amended to try increase real-time hepatic safety monitoring,” she said, noting that the rate of hepatic events has fallen since these changes were made.

“We need to closely monitor that moving forward to try to understand it better,” she said of the hepatic events.

Dose level 4 (tislelizumab at 200 mg every 3 weeks plus pamiparib at 40 mg twice daily) was determined to be the maximum tolerated dose and is the recommended phase 2 dose, she noted.

“We were pleased to see 10 patients respond, with these responses appearing to be durable with this currently short follow-up period, and we look forward to seeing the results of part B,” she concluded, noting that enrollment of patients into disease-specific cohorts for that next phase is ongoing.

This study is sponsored by BeiGene. Dr. Mileshkin reported receiving payment for travel, accommodations, and/or expenses from BeiGene and Roche.

[email protected]

SOURCE: Friedlander M et al. ASCO-SITC Clinical Immuno-Oncology Symposium 2018, Abstract #48.

SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.

“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.

Findings in context

“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.

“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”

Study details

In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).

The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.

The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)

Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.

“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
 

Long-term outcomes with monotherapy

In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.

Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).

Findings in context

“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”

The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”

“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”

Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.

[email protected]

SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.

SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.

“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.

Findings in context

“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.

“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”

Study details

In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).

The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.

The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)

Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.

“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
 

Long-term outcomes with monotherapy

In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.

Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).

Findings in context

“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”

The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”

“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”

Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.

[email protected]

SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.

SAN FRANCISCO – Combination immunotherapy is efficacious for treating metastatic colorectal cancer that is deficient in mismatch repair (dMMR), giving rise to high microsatellite instability (MSI-H), according to the first report of results for the full cohort of the CheckMate-142 trial.

“Approximately 4% of patients with metastatic colorectal cancer have a deficiency in the DNA mismatch repair system. These patients benefit less from conventional chemotherapy than other patients,” lead investigator Thierry André, MD, chief of Medical Oncology at the Saint-Antoine Hospital, Paris, said at the 2018 GI Cancers Symposium.

Findings in context

“This is the largest study to date of anti-PD-1 and anti-CTLA-4 inhibitor combination in MSI-H colon cancer,” noted invited discussant Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York. Taken together, the results are promising.

“Is this sufficient evidence that combination therapy is superior to monotherapy with anti–PD-1? No. This trial was not intended for comparison or to show superiority,” she maintained. “This will require a large randomized comparison as has been done, for example, in melanoma. Even then, cost and value become important factors in the decision of whom to select for combination therapy.”

Study details

In CheckMate-142, the 55% overall response rate with the combination of nivolumab and ipilimumab consisted of complete response in 3.4% of patients and partial response in 51.3%, Dr. André reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology. (The overall rate with nivolumab monotherapy at the same median follow-up was 31%, all partial responses.) The disease control rate was 80% with combination therapy (69% with monotherapy).

The combination achieved a similar response rate regardless of tumor PD-L1 expression and BRAF and KRAS mutational status. It was 71% in patients with a history of Lynch syndrome and 48% in those without such history.

The 12-month rates of progression-free survival and overall survival were 71% and 85%, respectively. “The PFS curve shows a plateau,” Dr. André pointed out. “This is a curve we dream about having in the first line. It’s very unusual to have that with a medical therapy in advanced disease.” (The corresponding rates with nivolumab monotherapy were 50% and 73%.)

Patients had significant, clinically meaningful improvements from baseline in quality of life with combination immunotherapy out to 91 weeks. “In my experience, this is really the first time I have had a very large number of patients going back to work in this very advanced disease,” he commented.

“No new safety signals or treatment-related deaths were reported,” Dr. André noted. The rate of treatment-related adverse events of grade 3 or 4 was 32% with the combination therapy (20% with monotherapy). The rate of events leading to discontinuation was 13% (7% with monotherapy).
 

Long-term outcomes with monotherapy

In a related presentation, Michael J. Overman, MD, an associate professor at the University of Texas MD Anderson Cancer Center, Houston, reported long-term outcomes with nivolumab monotherapy on CheckMate-142 according to prior lines of therapy.

Patients given monotherapy were classified as more heavily pretreated (at least three prior therapies, including a fluoropyrimidine, oxaliplatin, and irinotecan) and less heavily pretreated (at most two prior therapies, usually excluding irinotecan).

Findings in context

“This secondary analysis is of interest, but this is an unplanned retrospective subgroup analysis of this data,” commented Dr. Stadler, the discussant. “I think the take-home message here is that both the heavily pretreated and not-so-heavily pretreated groups have clinical benefit from this therapy. Certainly, longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR colorectal cancer.”

The findings for the whole nivolumab monotherapy cohort generally mirror those seen with pembrolizumab (Keytruda), another anti–PD-1 antibody, in this patient population, except for a shorter time to response with the former, she noted. “This suggests that both nivolumab and pembrolizumab are reasonable monotherapies in metastatic MSI-H colorectal cancer.”

“Evaluation of anti–PD-1 therapies in the first-line setting is certainly warranted,” Dr. Stadler concluded. “In fact, the KEYNOTE-177 trial is a phase 3 randomized study of pembrolizumab versus investigator-choice chemotherapy for mismatch repair–deficient colorectal cancer that is already investigating this question and that is nearing completion of accrual.”

Dr. Andre disclosed that he receives honoraria from Baxter, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, MSD Oncology, Novartis, Roche/Genentech, Sanofi, Servier, and Xbiotech; that he has a consulting or advisory role with Amgen, Bristol-Myers Squibb, HalioDX, MSD Oncology, Mundipharma, Roche/Genentech, and Servier; and that he receives travel expenses from Amgen, Bristol-Myers Squibb, and Roche/Genentech. Dr. Overman disclosed that he has a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech, and receives research funding Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche. The trial was sponsored by Bristol-Myers Squibb.

[email protected]

SOURCES: André T et al. GI Cancers Symposium Abstract 553, Overman MJ et al. GI Cancer Symposium Abstract 554.

People with rheumatologic diseases and cancer appear to be at no higher risk of having an adverse event or disease flare if they receive checkpoint inhibitor therapy, compared with the general population, experience from the Mayo Clinic suggests.

In a brief report published in Arthritis and Rheumatology, a team from the Mayo Clinic in Rochester, Minn., reported on 16 patients with rheumatologic diseases who received cancer immunotherapy. They found that only a minority experienced a flare of their disease or another immune-related event.

The rate of severe immune-related adverse effects (IRAEs) with a single immune checkpoint inhibitor (ICI) has been reported to be less than 2% among the average population. However, less is known about patients with underlying rheumatologic disease, largely because initial trials of ICIs had excluded patients with autoimmune diseases for fear the treatment would induce a disease flare, the researchers noted.

Small studies have suggested that people with inflammatory arthritis or connective tissue diseases have higher rates of IRAEs with immunotherapy, but it is unclear how often these events represented flares of their disease or new autoimmune events, and whether the events had any predictive significance for cancer survival.

In this study, researchers performed a retrospective review of medical records and identified 16 patients with rheumatologic diseases who had received checkpoint inhibitor therapy at the Mayo Clinic between 2011 and 2016.

The most common rheumatologic diseases among the 16 patients were rheumatoid arthritis, polymyalgia rheumatica, Sjögren’s syndrome, and systemic lupus erythematosus, and the most common cancers were malignant melanoma, pulmonary malignancies, and non-Hodgkin lymphoma. Seven of the patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatologic disease upon initiation of a checkpoint inhibitor.

Ten patients had received a prior disease-modifying antirheumatic drug, but only two patients were still taking this at the time of ICI initiation.

Results showed that six of the patients (38%) had an IRAE or flare of their rheumatologic disease, two were graded as mild. All of the patients responded well to glucocorticoids and discontinuation of therapy. The most common event was colitis and just one patient had a flare of rheumatologic disease.

“This is consistent with what is currently known about the management of IRAEs,” the research team wrote. “This study adds further support to the emerging notion that the rate of IRAEs is not necessarily higher in this group compared to the general population.”

The type and severity of rheumatologic disease may play an important role in both the risk of disease flare and IRAEs, a factor that they were unable to assess in the current study, the researchers wrote.

“Further large, prospective studies are needed to address the link between the type, severity, and concurrent rheumatologic disease activity on the risk of flare and IRAE. It is possible that patients with more severe or active disease are at higher risk for these complications,” they wrote.

While patients in the study did not appear to have significantly increased incidence or severity of adverse effects, the research team advised that “treatment decisions must factor in clinical judgement.”

They noted that some studies had proposed predictive biomarkers, pretreatment workup, and monitoring, but this advice was based on a small body of evidence.

“Larger, prospective studies will be necessary to validate these findings and establish evidence-based guidelines for appropriate identification and rating of the rheumatologic IRAEs as well as their treatment, such that patients can continue to receive potentially life-saving cancer treatments,” they wrote.

One of the researchers reported advisory board membership with Bristol-Myers Squibb.

[email protected]

SOURCE: Richter M et al. Arthritis Rheumatol. 2018 Jan 24. doi: 10.1002/art.40397.

People with rheumatologic diseases and cancer appear to be at no higher risk of having an adverse event or disease flare if they receive checkpoint inhibitor therapy, compared with the general population, experience from the Mayo Clinic suggests.

In a brief report published in Arthritis and Rheumatology, a team from the Mayo Clinic in Rochester, Minn., reported on 16 patients with rheumatologic diseases who received cancer immunotherapy. They found that only a minority experienced a flare of their disease or another immune-related event.

The rate of severe immune-related adverse effects (IRAEs) with a single immune checkpoint inhibitor (ICI) has been reported to be less than 2% among the average population. However, less is known about patients with underlying rheumatologic disease, largely because initial trials of ICIs had excluded patients with autoimmune diseases for fear the treatment would induce a disease flare, the researchers noted.

Small studies have suggested that people with inflammatory arthritis or connective tissue diseases have higher rates of IRAEs with immunotherapy, but it is unclear how often these events represented flares of their disease or new autoimmune events, and whether the events had any predictive significance for cancer survival.

In this study, researchers performed a retrospective review of medical records and identified 16 patients with rheumatologic diseases who had received checkpoint inhibitor therapy at the Mayo Clinic between 2011 and 2016.

The most common rheumatologic diseases among the 16 patients were rheumatoid arthritis, polymyalgia rheumatica, Sjögren’s syndrome, and systemic lupus erythematosus, and the most common cancers were malignant melanoma, pulmonary malignancies, and non-Hodgkin lymphoma. Seven of the patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatologic disease upon initiation of a checkpoint inhibitor.

Ten patients had received a prior disease-modifying antirheumatic drug, but only two patients were still taking this at the time of ICI initiation.

Results showed that six of the patients (38%) had an IRAE or flare of their rheumatologic disease, two were graded as mild. All of the patients responded well to glucocorticoids and discontinuation of therapy. The most common event was colitis and just one patient had a flare of rheumatologic disease.

“This is consistent with what is currently known about the management of IRAEs,” the research team wrote. “This study adds further support to the emerging notion that the rate of IRAEs is not necessarily higher in this group compared to the general population.”

The type and severity of rheumatologic disease may play an important role in both the risk of disease flare and IRAEs, a factor that they were unable to assess in the current study, the researchers wrote.

“Further large, prospective studies are needed to address the link between the type, severity, and concurrent rheumatologic disease activity on the risk of flare and IRAE. It is possible that patients with more severe or active disease are at higher risk for these complications,” they wrote.

While patients in the study did not appear to have significantly increased incidence or severity of adverse effects, the research team advised that “treatment decisions must factor in clinical judgement.”

They noted that some studies had proposed predictive biomarkers, pretreatment workup, and monitoring, but this advice was based on a small body of evidence.

“Larger, prospective studies will be necessary to validate these findings and establish evidence-based guidelines for appropriate identification and rating of the rheumatologic IRAEs as well as their treatment, such that patients can continue to receive potentially life-saving cancer treatments,” they wrote.

One of the researchers reported advisory board membership with Bristol-Myers Squibb.

[email protected]

SOURCE: Richter M et al. Arthritis Rheumatol. 2018 Jan 24. doi: 10.1002/art.40397.

People with rheumatologic diseases and cancer appear to be at no higher risk of having an adverse event or disease flare if they receive checkpoint inhibitor therapy, compared with the general population, experience from the Mayo Clinic suggests.

In a brief report published in Arthritis and Rheumatology, a team from the Mayo Clinic in Rochester, Minn., reported on 16 patients with rheumatologic diseases who received cancer immunotherapy. They found that only a minority experienced a flare of their disease or another immune-related event.

The rate of severe immune-related adverse effects (IRAEs) with a single immune checkpoint inhibitor (ICI) has been reported to be less than 2% among the average population. However, less is known about patients with underlying rheumatologic disease, largely because initial trials of ICIs had excluded patients with autoimmune diseases for fear the treatment would induce a disease flare, the researchers noted.

Small studies have suggested that people with inflammatory arthritis or connective tissue diseases have higher rates of IRAEs with immunotherapy, but it is unclear how often these events represented flares of their disease or new autoimmune events, and whether the events had any predictive significance for cancer survival.

In this study, researchers performed a retrospective review of medical records and identified 16 patients with rheumatologic diseases who had received checkpoint inhibitor therapy at the Mayo Clinic between 2011 and 2016.

The most common rheumatologic diseases among the 16 patients were rheumatoid arthritis, polymyalgia rheumatica, Sjögren’s syndrome, and systemic lupus erythematosus, and the most common cancers were malignant melanoma, pulmonary malignancies, and non-Hodgkin lymphoma. Seven of the patients were receiving immunosuppressive therapy or glucocorticoids for their rheumatologic disease upon initiation of a checkpoint inhibitor.

Ten patients had received a prior disease-modifying antirheumatic drug, but only two patients were still taking this at the time of ICI initiation.

Results showed that six of the patients (38%) had an IRAE or flare of their rheumatologic disease, two were graded as mild. All of the patients responded well to glucocorticoids and discontinuation of therapy. The most common event was colitis and just one patient had a flare of rheumatologic disease.

“This is consistent with what is currently known about the management of IRAEs,” the research team wrote. “This study adds further support to the emerging notion that the rate of IRAEs is not necessarily higher in this group compared to the general population.”

The type and severity of rheumatologic disease may play an important role in both the risk of disease flare and IRAEs, a factor that they were unable to assess in the current study, the researchers wrote.

“Further large, prospective studies are needed to address the link between the type, severity, and concurrent rheumatologic disease activity on the risk of flare and IRAE. It is possible that patients with more severe or active disease are at higher risk for these complications,” they wrote.

While patients in the study did not appear to have significantly increased incidence or severity of adverse effects, the research team advised that “treatment decisions must factor in clinical judgement.”

They noted that some studies had proposed predictive biomarkers, pretreatment workup, and monitoring, but this advice was based on a small body of evidence.

“Larger, prospective studies will be necessary to validate these findings and establish evidence-based guidelines for appropriate identification and rating of the rheumatologic IRAEs as well as their treatment, such that patients can continue to receive potentially life-saving cancer treatments,” they wrote.

One of the researchers reported advisory board membership with Bristol-Myers Squibb.

[email protected]

SOURCE: Richter M et al. Arthritis Rheumatol. 2018 Jan 24. doi: 10.1002/art.40397.