Immunotherapy

TOPLINE:

A systematic review of 69 economic evaluations revealed that adjuvant immunotherapy was cost-effective in 58% of studies, with higher Quality-Adjusted Life-Year gains reported in 91% of cases. Cost-effectiveness varied significantly by cancer type, treatment strategy, and healthcare system context, with industry-funded studies more likely to report favorable outcomes.

METHODOLOGY:

• Multiple phase 3 trials have shown improved survival and reduced recurrence with adjuvant immunotherapy in various cancers. But the high cost of immunotherapy treatments, often exceeding $100,000 per patient, has raised questions about their economic value and affordability across different healthcare systems.
• Researchers conducted a systematic review of 69 economic evaluations published between January 2015 and January 2025, focusing on adjuvant immunotherapy across various cancer types.
• Analysis included studies from PubMed, Embase, Scopus, Web of Science, and Cochrane Library, with most evaluations conducted in the US (26 studies) and China (20 studies).
• Quality assessment utilized the Criteria for Health Economic Quality Evaluation tool, evaluating 48 attributes across methodologic and reporting quality dimensions.
• Markov modeling dominated the analytical approach (46 studies [67%]), with EuroQol Five-Dimensions being the most commonly used health utility instrument (56 studies [81%]).

TAKEAWAY:

• Of 69 studies analyzed, 58% concluded that adjuvant immunotherapy was cost-effective, with stronger evidence in non-small cell lung cancer and melanoma, particularly in early-stage and high-risk populations.
• Industry-funded studies more frequently reported cost-effective outcomes (17 of 20 studies [85%]) than nonindustry funded studies (13 of 28 studies [46%]).
• Higher Quality-Adjusted Life-Year/Life-Year gains were consistently reported in the adjuvant immunotherapy group (63 studies [91%]), especially for non-small cell lung cancer and combination regimens.
• Cost-effectiveness results varied significantly by cancer type, model assumptions, drug pricing, funding organizations, and country-specific willingness-to-pay thresholds.

IN PRACTICE:

“From a policy standpoint, the findings of this systematic review support the use of structured, context-specific health technology assessment frameworks to evaluate adjuvant immunotherapies. For health systems under financial constraints, prioritizing subgroups with the highest absolute benefit may be a viable approach to ensure sustainable access,” the authors of the review wrote.

SOURCE:

The systematic review was led by Rashidul Alam Mahumud, PhD, MCncrSc, MPH, MSc, Health Economics and Health Technology Assessment Unit, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney in Camperdown, Australia. It was published online on January 22 in JAMA Oncology.

LIMITATIONS:

The methodologic heterogeneity across studies presents a significant limitation, with variations in time horizons, discounting methods, survival data extrapolation, and health utility measurements affecting result comparability. Geographic distribution primarily focused on high-income countries, limiting generalizability to low- and middle-income settings. Few evaluations incorporated adaptive pricing schemes or managed entry agreements that increasingly influence clinical reimbursement decisions.

DISCLOSURES:

Mahumud had full access to all study data and takes responsibility for data integrity and analysis accuracy. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

A systematic review of 69 economic evaluations revealed that adjuvant immunotherapy was cost-effective in 58% of studies, with higher Quality-Adjusted Life-Year gains reported in 91% of cases. Cost-effectiveness varied significantly by cancer type, treatment strategy, and healthcare system context, with industry-funded studies more likely to report favorable outcomes.

METHODOLOGY:

• Multiple phase 3 trials have shown improved survival and reduced recurrence with adjuvant immunotherapy in various cancers. But the high cost of immunotherapy treatments, often exceeding $100,000 per patient, has raised questions about their economic value and affordability across different healthcare systems.
• Researchers conducted a systematic review of 69 economic evaluations published between January 2015 and January 2025, focusing on adjuvant immunotherapy across various cancer types.
• Analysis included studies from PubMed, Embase, Scopus, Web of Science, and Cochrane Library, with most evaluations conducted in the US (26 studies) and China (20 studies).
• Quality assessment utilized the Criteria for Health Economic Quality Evaluation tool, evaluating 48 attributes across methodologic and reporting quality dimensions.
• Markov modeling dominated the analytical approach (46 studies [67%]), with EuroQol Five-Dimensions being the most commonly used health utility instrument (56 studies [81%]).

TAKEAWAY:

• Of 69 studies analyzed, 58% concluded that adjuvant immunotherapy was cost-effective, with stronger evidence in non-small cell lung cancer and melanoma, particularly in early-stage and high-risk populations.
• Industry-funded studies more frequently reported cost-effective outcomes (17 of 20 studies [85%]) than nonindustry funded studies (13 of 28 studies [46%]).
• Higher Quality-Adjusted Life-Year/Life-Year gains were consistently reported in the adjuvant immunotherapy group (63 studies [91%]), especially for non-small cell lung cancer and combination regimens.
• Cost-effectiveness results varied significantly by cancer type, model assumptions, drug pricing, funding organizations, and country-specific willingness-to-pay thresholds.

IN PRACTICE:

“From a policy standpoint, the findings of this systematic review support the use of structured, context-specific health technology assessment frameworks to evaluate adjuvant immunotherapies. For health systems under financial constraints, prioritizing subgroups with the highest absolute benefit may be a viable approach to ensure sustainable access,” the authors of the review wrote.

SOURCE:

The systematic review was led by Rashidul Alam Mahumud, PhD, MCncrSc, MPH, MSc, Health Economics and Health Technology Assessment Unit, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney in Camperdown, Australia. It was published online on January 22 in JAMA Oncology.

LIMITATIONS:

The methodologic heterogeneity across studies presents a significant limitation, with variations in time horizons, discounting methods, survival data extrapolation, and health utility measurements affecting result comparability. Geographic distribution primarily focused on high-income countries, limiting generalizability to low- and middle-income settings. Few evaluations incorporated adaptive pricing schemes or managed entry agreements that increasingly influence clinical reimbursement decisions.

DISCLOSURES:

Mahumud had full access to all study data and takes responsibility for data integrity and analysis accuracy. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

A systematic review of 69 economic evaluations revealed that adjuvant immunotherapy was cost-effective in 58% of studies, with higher Quality-Adjusted Life-Year gains reported in 91% of cases. Cost-effectiveness varied significantly by cancer type, treatment strategy, and healthcare system context, with industry-funded studies more likely to report favorable outcomes.

METHODOLOGY:

• Multiple phase 3 trials have shown improved survival and reduced recurrence with adjuvant immunotherapy in various cancers. But the high cost of immunotherapy treatments, often exceeding $100,000 per patient, has raised questions about their economic value and affordability across different healthcare systems.
• Researchers conducted a systematic review of 69 economic evaluations published between January 2015 and January 2025, focusing on adjuvant immunotherapy across various cancer types.
• Analysis included studies from PubMed, Embase, Scopus, Web of Science, and Cochrane Library, with most evaluations conducted in the US (26 studies) and China (20 studies).
• Quality assessment utilized the Criteria for Health Economic Quality Evaluation tool, evaluating 48 attributes across methodologic and reporting quality dimensions.
• Markov modeling dominated the analytical approach (46 studies [67%]), with EuroQol Five-Dimensions being the most commonly used health utility instrument (56 studies [81%]).

TAKEAWAY:

• Of 69 studies analyzed, 58% concluded that adjuvant immunotherapy was cost-effective, with stronger evidence in non-small cell lung cancer and melanoma, particularly in early-stage and high-risk populations.
• Industry-funded studies more frequently reported cost-effective outcomes (17 of 20 studies [85%]) than nonindustry funded studies (13 of 28 studies [46%]).
• Higher Quality-Adjusted Life-Year/Life-Year gains were consistently reported in the adjuvant immunotherapy group (63 studies [91%]), especially for non-small cell lung cancer and combination regimens.
• Cost-effectiveness results varied significantly by cancer type, model assumptions, drug pricing, funding organizations, and country-specific willingness-to-pay thresholds.

IN PRACTICE:

“From a policy standpoint, the findings of this systematic review support the use of structured, context-specific health technology assessment frameworks to evaluate adjuvant immunotherapies. For health systems under financial constraints, prioritizing subgroups with the highest absolute benefit may be a viable approach to ensure sustainable access,” the authors of the review wrote.

SOURCE:

The systematic review was led by Rashidul Alam Mahumud, PhD, MCncrSc, MPH, MSc, Health Economics and Health Technology Assessment Unit, National Health and Medical Research Council Clinical Trials Centre, The University of Sydney in Camperdown, Australia. It was published online on January 22 in JAMA Oncology.

LIMITATIONS:

The methodologic heterogeneity across studies presents a significant limitation, with variations in time horizons, discounting methods, survival data extrapolation, and health utility measurements affecting result comparability. Geographic distribution primarily focused on high-income countries, limiting generalizability to low- and middle-income settings. Few evaluations incorporated adaptive pricing schemes or managed entry agreements that increasingly influence clinical reimbursement decisions.

DISCLOSURES:

Mahumud had full access to all study data and takes responsibility for data integrity and analysis accuracy. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

Background

The rise in the number of T-cell engager therapies highlights their importance in modern cancer treatment paradigms. Having recognized the need for, and complexities of, administering these innovative medications to our patients, our team assessed our institution’s capability to provide these therapies to our patients. We identified that our facility was wellequipped for implementation of T-cell engager therapy due to inpatient administration capabilities, an outpatient infusion center, on-hand supportive care medications (tocilizumab), and access to higher levels of care. Key players included medical oncologists, pharmacists, inpatient and infusion nurses, staff physicians, critical care practitioners, and care coordinators.

Clinical Practice Initiative

Barriers identified: education, toxicity concerns, formulary management, and logistics. To overcome these obstacles, comprehensive plans for procurement, hospital admission, monitoring, and training were developed as a facility-specific standard operating procedure (SOP). All available Tcell engager therapies were presented to the formulary committee and received local approval. Physician and pharmacist champions were registered for the associated risk evaluation and mitigation strategies (REMS) programs. Recorded webinars were done to provide education on REMS requirements, medication logistics, and adverse event management.

An admission plan was formulated to outline admission criteria, medication administration, and safety logistics. Order sets created by pharmacists, encompassed pre, post, and as needed medications for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. To facilitate safe discharge and meet REMS criteria, patients received wallet cards, dexamethasone and acetaminophen PRNs with detailed instructions for use, and direction for seeking emergency care with consideration of local tocilizumab availability.

Conclusions

Our SOP has enabled administration of six T-cell engager therapies for six diseases. The primary limitation for some of these agents is the need for inpatient monitoring at initiation, which may not be available at smaller centers. Facilities that lack these capabilities could utilize community care or partner with a neighboring Veterans Affairs medical center for initial administration, then transition back for continued treatment. Facilities that lack inpatient oncology nursing could administer the drug in the infusion center followed by admission for monitoring and toxicity management. Our implementation plan serves as a scalable model for improving veteran access to novel therapies.

Background

The rise in the number of T-cell engager therapies highlights their importance in modern cancer treatment paradigms. Having recognized the need for, and complexities of, administering these innovative medications to our patients, our team assessed our institution’s capability to provide these therapies to our patients. We identified that our facility was wellequipped for implementation of T-cell engager therapy due to inpatient administration capabilities, an outpatient infusion center, on-hand supportive care medications (tocilizumab), and access to higher levels of care. Key players included medical oncologists, pharmacists, inpatient and infusion nurses, staff physicians, critical care practitioners, and care coordinators.

Clinical Practice Initiative

Barriers identified: education, toxicity concerns, formulary management, and logistics. To overcome these obstacles, comprehensive plans for procurement, hospital admission, monitoring, and training were developed as a facility-specific standard operating procedure (SOP). All available Tcell engager therapies were presented to the formulary committee and received local approval. Physician and pharmacist champions were registered for the associated risk evaluation and mitigation strategies (REMS) programs. Recorded webinars were done to provide education on REMS requirements, medication logistics, and adverse event management.

An admission plan was formulated to outline admission criteria, medication administration, and safety logistics. Order sets created by pharmacists, encompassed pre, post, and as needed medications for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. To facilitate safe discharge and meet REMS criteria, patients received wallet cards, dexamethasone and acetaminophen PRNs with detailed instructions for use, and direction for seeking emergency care with consideration of local tocilizumab availability.

Conclusions

Our SOP has enabled administration of six T-cell engager therapies for six diseases. The primary limitation for some of these agents is the need for inpatient monitoring at initiation, which may not be available at smaller centers. Facilities that lack these capabilities could utilize community care or partner with a neighboring Veterans Affairs medical center for initial administration, then transition back for continued treatment. Facilities that lack inpatient oncology nursing could administer the drug in the infusion center followed by admission for monitoring and toxicity management. Our implementation plan serves as a scalable model for improving veteran access to novel therapies.

Background

The rise in the number of T-cell engager therapies highlights their importance in modern cancer treatment paradigms. Having recognized the need for, and complexities of, administering these innovative medications to our patients, our team assessed our institution’s capability to provide these therapies to our patients. We identified that our facility was wellequipped for implementation of T-cell engager therapy due to inpatient administration capabilities, an outpatient infusion center, on-hand supportive care medications (tocilizumab), and access to higher levels of care. Key players included medical oncologists, pharmacists, inpatient and infusion nurses, staff physicians, critical care practitioners, and care coordinators.

Clinical Practice Initiative

Barriers identified: education, toxicity concerns, formulary management, and logistics. To overcome these obstacles, comprehensive plans for procurement, hospital admission, monitoring, and training were developed as a facility-specific standard operating procedure (SOP). All available Tcell engager therapies were presented to the formulary committee and received local approval. Physician and pharmacist champions were registered for the associated risk evaluation and mitigation strategies (REMS) programs. Recorded webinars were done to provide education on REMS requirements, medication logistics, and adverse event management.

An admission plan was formulated to outline admission criteria, medication administration, and safety logistics. Order sets created by pharmacists, encompassed pre, post, and as needed medications for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. To facilitate safe discharge and meet REMS criteria, patients received wallet cards, dexamethasone and acetaminophen PRNs with detailed instructions for use, and direction for seeking emergency care with consideration of local tocilizumab availability.

Conclusions

Our SOP has enabled administration of six T-cell engager therapies for six diseases. The primary limitation for some of these agents is the need for inpatient monitoring at initiation, which may not be available at smaller centers. Facilities that lack these capabilities could utilize community care or partner with a neighboring Veterans Affairs medical center for initial administration, then transition back for continued treatment. Facilities that lack inpatient oncology nursing could administer the drug in the infusion center followed by admission for monitoring and toxicity management. Our implementation plan serves as a scalable model for improving veteran access to novel therapies.

Background

Immune-related adverse events (irAEs) associated with checkpoint inhibitors can involve virtually any organ system. Optic neuritis is a rare but potentially reversible toxicity, with limited reports in the literature.

Case Presentation

A 57-year-old male with Stage IV poorly-differentiated neuroendocrine carcinoma presented with progressive bilateral vision loss following a near-complete response to four cycles of atezolizumab, carboplatin, and etoposide chemotherapy, and one cycle of maintenance atezolizumab. Symptoms began in the right eye and progressed to the left over 12 days. Neurological and ophthalmological evaluations included brain and orbital MRI, autoimmune panels, and infectious workup, all of which were unrevealing. The clinical picture remained consistent with isolated, immunemediated optic neuritis.

Discussion

High-dose intravenous methylprednisolone was initiated, resulting in gradual improvement and partial visual recovery by day four. An oral prednisone taper was prescribed for continued treatment. This is the second reported case of isolated optic neuritis associated with PD-L1 inhibitor therapy and the second with negative imaging findings. The rarity of this irAE and the absence of radiographic abnormalities may delay diagnosis and treatment.

Conclusions

Checkpoint-inhibitor-induced optic neuritis should be considered in patients with visual symptoms on immunotherapy, even in the setting of negative imaging. Early recognition and corticosteroid therapy are critical in preserving visual function.

Background

Immune-related adverse events (irAEs) associated with checkpoint inhibitors can involve virtually any organ system. Optic neuritis is a rare but potentially reversible toxicity, with limited reports in the literature.

Case Presentation

A 57-year-old male with Stage IV poorly-differentiated neuroendocrine carcinoma presented with progressive bilateral vision loss following a near-complete response to four cycles of atezolizumab, carboplatin, and etoposide chemotherapy, and one cycle of maintenance atezolizumab. Symptoms began in the right eye and progressed to the left over 12 days. Neurological and ophthalmological evaluations included brain and orbital MRI, autoimmune panels, and infectious workup, all of which were unrevealing. The clinical picture remained consistent with isolated, immunemediated optic neuritis.

Discussion

High-dose intravenous methylprednisolone was initiated, resulting in gradual improvement and partial visual recovery by day four. An oral prednisone taper was prescribed for continued treatment. This is the second reported case of isolated optic neuritis associated with PD-L1 inhibitor therapy and the second with negative imaging findings. The rarity of this irAE and the absence of radiographic abnormalities may delay diagnosis and treatment.

Conclusions

Checkpoint-inhibitor-induced optic neuritis should be considered in patients with visual symptoms on immunotherapy, even in the setting of negative imaging. Early recognition and corticosteroid therapy are critical in preserving visual function.

Background

Immune-related adverse events (irAEs) associated with checkpoint inhibitors can involve virtually any organ system. Optic neuritis is a rare but potentially reversible toxicity, with limited reports in the literature.

Case Presentation

A 57-year-old male with Stage IV poorly-differentiated neuroendocrine carcinoma presented with progressive bilateral vision loss following a near-complete response to four cycles of atezolizumab, carboplatin, and etoposide chemotherapy, and one cycle of maintenance atezolizumab. Symptoms began in the right eye and progressed to the left over 12 days. Neurological and ophthalmological evaluations included brain and orbital MRI, autoimmune panels, and infectious workup, all of which were unrevealing. The clinical picture remained consistent with isolated, immunemediated optic neuritis.

Discussion

High-dose intravenous methylprednisolone was initiated, resulting in gradual improvement and partial visual recovery by day four. An oral prednisone taper was prescribed for continued treatment. This is the second reported case of isolated optic neuritis associated with PD-L1 inhibitor therapy and the second with negative imaging findings. The rarity of this irAE and the absence of radiographic abnormalities may delay diagnosis and treatment.

Conclusions

Checkpoint-inhibitor-induced optic neuritis should be considered in patients with visual symptoms on immunotherapy, even in the setting of negative imaging. Early recognition and corticosteroid therapy are critical in preserving visual function.

Background

Immune checkpoint inhibitors, including pembrolizumab, are associated with a spectrum of immune-related adverse events (irAEs), including immune- mediated hepatitis. Typically, this toxicity manifests within the first 14 weeks of therapy. Delayed presentations beyond one year are exceedingly rare and pose diagnostic challenges.

Case Presentation

We report an elderly patient (over 90 years old) with stage IVa squamous cell carcinoma of the lung and high microsatellite instability (MSI) who had been receiving pembrolizumab since 2023. In 2024—13 months into therapy—he presented with subjective fevers, weakness, and altered mental status. Laboratory evaluation revealed cholestatic jaundice with AST 310 U/L, ALT 291 U/L, alkaline phosphatase 860 U/L, and total bilirubin 5.7 mg/dL. Infectious workup was negative. Imaging via MRCP showed multiple scattered hepatic cysts and a small pancreatic cyst, without biliary obstruction.

Further evaluation, including serologies for hepatitis B and C, CMV, HSV, autoimmune hepatitis panel, iron studies, and ceruloplasmin, was unremarkable except for mildly elevated alpha-1 antitrypsin. Scattered liver cysts were seen on an MRI. The overall findings were most consistent with immune-related hepatitis, as pembrolizumab is known to cause both hepatocellular and cholestatic patterns of liver injury.

The patient was started on high-dose prednisone, resulting in rapid clinical and biochemical improvement. Two weeks post-discharge, liver function tests (LFTs) had markedly improved (bilirubin 1.3, AST 19, ALT 40, ALP 193). Given the severity of transaminitis and hyperbilirubinemia (AST >8x ULN, bilirubin >3x ULN), pembrolizumab was permanently discontinued. LFTs normalized after completion of the steroid taper.

Conclusions

This case highlights a rare instance of delayed immune-related hepatitis occurring over a year after initiation of pembrolizumab, far beyond the typical window of onset. Clinicians should maintain a high index of suspicion for irAEs even in late stages of immunotherapy, particularly when common etiologies are excluded. Prompt recognition and corticosteroid treatment can lead to favorable outcomes, even in older patients.

Background

Immune checkpoint inhibitors, including pembrolizumab, are associated with a spectrum of immune-related adverse events (irAEs), including immune- mediated hepatitis. Typically, this toxicity manifests within the first 14 weeks of therapy. Delayed presentations beyond one year are exceedingly rare and pose diagnostic challenges.

Case Presentation

We report an elderly patient (over 90 years old) with stage IVa squamous cell carcinoma of the lung and high microsatellite instability (MSI) who had been receiving pembrolizumab since 2023. In 2024—13 months into therapy—he presented with subjective fevers, weakness, and altered mental status. Laboratory evaluation revealed cholestatic jaundice with AST 310 U/L, ALT 291 U/L, alkaline phosphatase 860 U/L, and total bilirubin 5.7 mg/dL. Infectious workup was negative. Imaging via MRCP showed multiple scattered hepatic cysts and a small pancreatic cyst, without biliary obstruction.

Further evaluation, including serologies for hepatitis B and C, CMV, HSV, autoimmune hepatitis panel, iron studies, and ceruloplasmin, was unremarkable except for mildly elevated alpha-1 antitrypsin. Scattered liver cysts were seen on an MRI. The overall findings were most consistent with immune-related hepatitis, as pembrolizumab is known to cause both hepatocellular and cholestatic patterns of liver injury.

The patient was started on high-dose prednisone, resulting in rapid clinical and biochemical improvement. Two weeks post-discharge, liver function tests (LFTs) had markedly improved (bilirubin 1.3, AST 19, ALT 40, ALP 193). Given the severity of transaminitis and hyperbilirubinemia (AST >8x ULN, bilirubin >3x ULN), pembrolizumab was permanently discontinued. LFTs normalized after completion of the steroid taper.

Conclusions

This case highlights a rare instance of delayed immune-related hepatitis occurring over a year after initiation of pembrolizumab, far beyond the typical window of onset. Clinicians should maintain a high index of suspicion for irAEs even in late stages of immunotherapy, particularly when common etiologies are excluded. Prompt recognition and corticosteroid treatment can lead to favorable outcomes, even in older patients.

Background

Immune checkpoint inhibitors, including pembrolizumab, are associated with a spectrum of immune-related adverse events (irAEs), including immune- mediated hepatitis. Typically, this toxicity manifests within the first 14 weeks of therapy. Delayed presentations beyond one year are exceedingly rare and pose diagnostic challenges.

Case Presentation

We report an elderly patient (over 90 years old) with stage IVa squamous cell carcinoma of the lung and high microsatellite instability (MSI) who had been receiving pembrolizumab since 2023. In 2024—13 months into therapy—he presented with subjective fevers, weakness, and altered mental status. Laboratory evaluation revealed cholestatic jaundice with AST 310 U/L, ALT 291 U/L, alkaline phosphatase 860 U/L, and total bilirubin 5.7 mg/dL. Infectious workup was negative. Imaging via MRCP showed multiple scattered hepatic cysts and a small pancreatic cyst, without biliary obstruction.

Further evaluation, including serologies for hepatitis B and C, CMV, HSV, autoimmune hepatitis panel, iron studies, and ceruloplasmin, was unremarkable except for mildly elevated alpha-1 antitrypsin. Scattered liver cysts were seen on an MRI. The overall findings were most consistent with immune-related hepatitis, as pembrolizumab is known to cause both hepatocellular and cholestatic patterns of liver injury.

The patient was started on high-dose prednisone, resulting in rapid clinical and biochemical improvement. Two weeks post-discharge, liver function tests (LFTs) had markedly improved (bilirubin 1.3, AST 19, ALT 40, ALP 193). Given the severity of transaminitis and hyperbilirubinemia (AST >8x ULN, bilirubin >3x ULN), pembrolizumab was permanently discontinued. LFTs normalized after completion of the steroid taper.

Conclusions

This case highlights a rare instance of delayed immune-related hepatitis occurring over a year after initiation of pembrolizumab, far beyond the typical window of onset. Clinicians should maintain a high index of suspicion for irAEs even in late stages of immunotherapy, particularly when common etiologies are excluded. Prompt recognition and corticosteroid treatment can lead to favorable outcomes, even in older patients.

Background

Immune related adverse events (irAE) are a well-known complication in the treatment of nonsmall cell lung cancer (NSCLCA) with checkpoint inhibitors and have been shown to improve overall survival (OS) and progression free survival (PFS) across multiple studies. However, studies have shown that the prognosis of NSCLCA differs depending on the type of immune related adverse event and the grade of the irAE. For instance, patients who experienced endocrine irAEs like thyroid, or adrenal insufficiency tended to have an improved OS and PFS, whereas patients who developed pneumonitis that required discontinuation of checkpoint inhibitors had worse OS and PFS. While the literature describes the prognostic impacts of irAEs on NSCLCA, there is still a dearth of information on the implications of HLA supertypes on the prognosis of NSCLCA following irAEs.

Case Presentation

To address this point and to ask a question, we would like to share the case of a patient with a 10-year history of inflammatory arthropathy related to HLA-B27 antigen prior to his diagnosis of T2bN2M1b adenosquamous lung cancer with liver metastases. The tumor was 100% PD-L1 expressive and the patient was treated with pembrolizumab. The patient developed central adrenal insufficiency 10 months after pembrolizumab was initiated which was treated with physiologic dosing of hydrocortisone. The patient later developed a grade 3 pneumonitis 62 months after initiation of pembrolizumab and was treated with systemic glucocorticoids. Due to recurrent hospitalizations for pneumonitis, pembrolizumab was discontinued at 70 months post initiation. At the time of discontinuation PET was positive. However, there was a decrease in hyperactivity of the primary tumor at 4 months post discontinuation of pembrolizumab and there have been serial negative PETS from 7 months to 13 months post discontinuation. This led us to ask the question of whether HLA-B27 is protective of the poor prognostic immune related pneumonitis in this patient?

Background

Immune related adverse events (irAE) are a well-known complication in the treatment of nonsmall cell lung cancer (NSCLCA) with checkpoint inhibitors and have been shown to improve overall survival (OS) and progression free survival (PFS) across multiple studies. However, studies have shown that the prognosis of NSCLCA differs depending on the type of immune related adverse event and the grade of the irAE. For instance, patients who experienced endocrine irAEs like thyroid, or adrenal insufficiency tended to have an improved OS and PFS, whereas patients who developed pneumonitis that required discontinuation of checkpoint inhibitors had worse OS and PFS. While the literature describes the prognostic impacts of irAEs on NSCLCA, there is still a dearth of information on the implications of HLA supertypes on the prognosis of NSCLCA following irAEs.

Case Presentation

To address this point and to ask a question, we would like to share the case of a patient with a 10-year history of inflammatory arthropathy related to HLA-B27 antigen prior to his diagnosis of T2bN2M1b adenosquamous lung cancer with liver metastases. The tumor was 100% PD-L1 expressive and the patient was treated with pembrolizumab. The patient developed central adrenal insufficiency 10 months after pembrolizumab was initiated which was treated with physiologic dosing of hydrocortisone. The patient later developed a grade 3 pneumonitis 62 months after initiation of pembrolizumab and was treated with systemic glucocorticoids. Due to recurrent hospitalizations for pneumonitis, pembrolizumab was discontinued at 70 months post initiation. At the time of discontinuation PET was positive. However, there was a decrease in hyperactivity of the primary tumor at 4 months post discontinuation of pembrolizumab and there have been serial negative PETS from 7 months to 13 months post discontinuation. This led us to ask the question of whether HLA-B27 is protective of the poor prognostic immune related pneumonitis in this patient?

Background

Immune related adverse events (irAE) are a well-known complication in the treatment of nonsmall cell lung cancer (NSCLCA) with checkpoint inhibitors and have been shown to improve overall survival (OS) and progression free survival (PFS) across multiple studies. However, studies have shown that the prognosis of NSCLCA differs depending on the type of immune related adverse event and the grade of the irAE. For instance, patients who experienced endocrine irAEs like thyroid, or adrenal insufficiency tended to have an improved OS and PFS, whereas patients who developed pneumonitis that required discontinuation of checkpoint inhibitors had worse OS and PFS. While the literature describes the prognostic impacts of irAEs on NSCLCA, there is still a dearth of information on the implications of HLA supertypes on the prognosis of NSCLCA following irAEs.

Case Presentation

To address this point and to ask a question, we would like to share the case of a patient with a 10-year history of inflammatory arthropathy related to HLA-B27 antigen prior to his diagnosis of T2bN2M1b adenosquamous lung cancer with liver metastases. The tumor was 100% PD-L1 expressive and the patient was treated with pembrolizumab. The patient developed central adrenal insufficiency 10 months after pembrolizumab was initiated which was treated with physiologic dosing of hydrocortisone. The patient later developed a grade 3 pneumonitis 62 months after initiation of pembrolizumab and was treated with systemic glucocorticoids. Due to recurrent hospitalizations for pneumonitis, pembrolizumab was discontinued at 70 months post initiation. At the time of discontinuation PET was positive. However, there was a decrease in hyperactivity of the primary tumor at 4 months post discontinuation of pembrolizumab and there have been serial negative PETS from 7 months to 13 months post discontinuation. This led us to ask the question of whether HLA-B27 is protective of the poor prognostic immune related pneumonitis in this patient?

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

TOPLINE:

For patients with early-stage ERBB2 (formerly HER2)–positive breast cancer, injections of increasing doses of autologous conventional type 1 dendritic cells (cDC1) combined with ERBB2-targeted antibodies demonstrate safety and effectiveness in enhancing immune response. The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.

METHODOLOGY:

• ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
• A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
• Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
• Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m²) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
• Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.

TAKEAWAY:

• IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
• Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
• Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
• Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.

IN PRACTICE:

“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.

SOURCE:

The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.

LIMITATIONS:

Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.

DISCLOSURES:

This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

For patients with early-stage ERBB2 (formerly HER2)–positive breast cancer, injections of increasing doses of autologous conventional type 1 dendritic cells (cDC1) combined with ERBB2-targeted antibodies demonstrate safety and effectiveness in enhancing immune response. The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.

METHODOLOGY:

• ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
• A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
• Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
• Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m²) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
• Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.

TAKEAWAY:

• IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
• Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
• Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
• Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.

IN PRACTICE:

“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.

SOURCE:

The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.

LIMITATIONS:

Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.

DISCLOSURES:

This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

For patients with early-stage ERBB2 (formerly HER2)–positive breast cancer, injections of increasing doses of autologous conventional type 1 dendritic cells (cDC1) combined with ERBB2-targeted antibodies demonstrate safety and effectiveness in enhancing immune response. The higher dose (100 million cells) shows enhanced immune effector recruitment and significant tumor regression before chemotherapy initiation.

METHODOLOGY:

• ERBB2-positive breast cancer survival has improved with anti-ERBB2 antibodies trastuzumab and pertuzumab, but for a pathologic complete response, chemotherapy remains necessary, which comes with significant toxic effects.
• A phase 1, nonrandomized clinical trial enrolled 12 patients with early-stage ERBB2-positive breast cancer in Tampa, Florida, from October 2021 to October 2022.
• Participants received intratumoral (IT) cDC1 injections weekly for 6 weeks at two dose levels (50 million cells for dose level 1 and 100 million cells for dose level 2), with six patients in each group.
• Starting from day 1 of the cDC1 injections, treatment included trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) administered intravenously every 3 weeks for six cycles, followed by paclitaxel (80 mg/m²) weekly for 12 weeks and surgery with lumpectomy or mastectomy.
• Primary outcomes measured safety and immune response of increasing doses of cDC1 combined with anti-ERBB2 antibodies before neoadjuvant chemotherapy; secondary outcomes assessed antitumor efficacy through breast MRI and residual cancer burden at surgery.

TAKEAWAY:

• IT delivery of ERBB2 cDC1 was safe and not associated with any dose-limiting toxic effects. The most frequent adverse events attributed to cDC1 were grade 1-2 chills (50%), fatigue (41.7%), headache (33%), and injection-site reactions (33%).
• Dose level 2 showed enhanced recruitment of adaptive CD3, CD4, and CD8 T cells and B cells within the tumor microenvironment (TME), along with increased innate gamma delta T cells and natural killer T cells.
• Breast MRI revealed nine objective responses, including six partial responses and three complete responses, with three cases of stable disease.
• Following surgery, 7 of 12 patients (58%) achieved a pathologic complete response, including all 3 hormone receptor–negative patients and 4 of the 9 hormone receptor–positive patients.

IN PRACTICE:

“Overall, the clinical data shown here demonstrate the effects of combining ERBB2 antibodies with IT [intratumoral] delivery of targeted cDC1 to enhance immune cell infiltration within the TME [tumor microenvironment] and subsequently induce tumor regression before chemotherapy,” wrote the authors, who noted they will be testing the higher dose for an ongoing phase 2 trial with an additional 41 patients.

SOURCE:

The study was led by Hyo S. Han, MD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. It was published online on December 5, 2024, in JAMA Oncology.

LIMITATIONS:

Because only two dose levels of cDC1 were tested, it remains unclear whether higher doses or different administration schedules could further enhance immune response. Additionally, the nonrandomized design prevents definitive conclusions about whether the clinical benefits were solely from the anti-ERBB2 antibodies. The small sample size also makes it difficult to determine if the pathologic complete responses were primarily due to the 12 weeks of trastuzumab/pertuzumab/paclitaxel treatment.

DISCLOSURES:

This study was funded by the Moffitt Breast Cancer Research Fund, Shula Fund, and Pennies in Action. Several authors reported research support and personal and consulting fees from US funding agencies and multiple pharmaceutical companies outside of the submitted work, as well as related intellectual property and patents.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

A version of this article first appeared on Medscape.com.

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

A version of this article first appeared on Medscape.com.

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

A version of this article first appeared on Medscape.com.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

A version of this article first appeared on Medscape.com.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

A version of this article first appeared on Medscape.com.

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

A version of this article first appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.

WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found. 

Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.

“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.

Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events. 

“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.

Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.” 

 

No Difference in Mortality for Those With and Without Autoimmune Disease

Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.

Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use. 

At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00). 

The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said. 

 

Some Caveats About the Data

Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited. 

Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease. 

“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.

“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.

Challener and Jeffries had no relevant disclosures. 
 

A version of this article appeared on Medscape.com.