On 2014 Sep 06, David Keller commented:

Are melanoma patients with pre-existing autoimmune disease at increased risk of severe immune reaction to ipilimumab?

Patients with pre-existing autoimmune disease were excluded from this clinical trial. Even so, Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab. Is the rate of immune-related adverse events (IRAE) even higher in patients with pre-existing autoimmune disease who are treated with ipilimumab for melanoma? Clinical trials of immune checkpoint inhibitors all exclude such patients, but post-approval data on adverse events could supply an estimate of their relative risk ratio (RRR) with the following equation:

RRR = ( IRAEp / IRAEt ) / (prevalence of AIDM)

where RRR is the relative risk ratio for a severe adverse event in a melanoma patient with preexisting autoimmune disease who is treated with ipilimumab, and IRAEp is the number of immune related adverse events in patients with prior autoimmune disease, IRAEt is the total number of reported immune related adverse events, and the denominator is the prevalence of autoimmune diseases in melanoma patients.

If patients with preexisting autoimmune disease are found to have a significantly elevated relative risk ratio for severe autoimmune reactions to ipilimumab compared with other melanoma patients, they should have access to that information in order to help them make difficult treatment decisions. Each melanoma patient will have their own cut-off of acceptable values for RRR.

Recently, an anti-PD1 immune checkpoint inhibitor, pembrolizumab, was approved by the FDA for advanced melanoma patients who have failed on ipilimumab. It has been suggested that the anti-PD1 agents have a milder autoimmune adverse event profile than anti-CTLA-4 agents like ipilimumab (1,2). If this is true, it may be a reason for patients with active autoimmune diseases to be treated with the former, skipping the latter. If the RRR for a patient with preexisting autoimmune disease is found to be 5, 10 or even 20 times higher than for average patients, then this data could be used to justify treating them with pembrolizumab first-line and off-label.

This question cannot be answered using data from the controlled clinical trials, because patients with active autoimmune diseases were excluded from these studies.

When the FDA approved Yervoy (ipilimumab) in 2011, they mandated a risk mitigation program, including a database of all reported post-approval adverse reactions to Yervoy. In order to obtain full access to the information in that database, one must file a separate request with the FDA, under the Freedom of Information Act (FOIA), for each reported adverse reaction. The number of reports of serious adverse events associated with Yervoy filed from March 2011 through September 2014 totals nearly 4000. Since the cost of filing an FOIA request for each report is over $50, the cost to perform a detailed analysis of the entire database of adverse events is over $20,000. This fee is prohibitive, and defeats the purpose of the risk mitigation program. FDA should provide free access to this data, in order to stimulate and facilitate research into the effects of Yervoy on patient populations which were excluded from the controlled clinical trials.

References

1: Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007 Jul;12(7):864-72. Review. PubMed PMID: 17673617.

2: Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013 Jun;18(6):733-43. doi: 10.1634/theoncologist.2012-0483. Epub 2013 Jun 17. Review. PubMed PMID: 23774827; PubMed Central PMCID: PMC4063401.

On 2014 Sep 06, David Keller commented:

Are melanoma patients with pre-existing autoimmune disease at increased risk of severe immune reaction to ipilimumab?

Patients with pre-existing autoimmune disease were excluded from this clinical trial. Even so, Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab. Is the rate of immune-related adverse events (IRAE) even higher in patients with pre-existing autoimmune disease who are treated with ipilimumab for melanoma? Clinical trials of immune checkpoint inhibitors all exclude such patients, but post-approval data on adverse events could supply an estimate of their relative risk ratio (RRR) with the following equation:

RRR = ( IRAEp / IRAEt ) / (prevalence of AIDM)

where RRR is the relative risk ratio for a severe adverse event in a melanoma patient with preexisting autoimmune disease who is treated with ipilimumab, and IRAEp is the number of immune related adverse events in patients with prior autoimmune disease, IRAEt is the total number of reported immune related adverse events, and the denominator is the prevalence of autoimmune diseases in melanoma patients.

If patients with preexisting autoimmune disease are found to have a significantly elevated relative risk ratio for severe autoimmune reactions to ipilimumab compared with other melanoma patients, they should have access to that information in order to help them make difficult treatment decisions. Each melanoma patient will have their own cut-off of acceptable values for RRR.

Recently, an anti-PD1 immune checkpoint inhibitor, pembrolizumab, was approved by the FDA for advanced melanoma patients who have failed on ipilimumab. It has been suggested that the anti-PD1 agents have a milder autoimmune adverse event profile than anti-CTLA-4 agents like ipilimumab (1,2). If this is true, it may be a reason for patients with active autoimmune diseases to be treated with the former, skipping the latter. If the RRR for a patient with preexisting autoimmune disease is found to be 5, 10 or even 20 times higher than for average patients, then this data could be used to justify treating them with pembrolizumab first-line and off-label.

This question cannot be answered using data from the controlled clinical trials, because patients with active autoimmune diseases were excluded from these studies.

When the FDA approved Yervoy (ipilimumab) in 2011, they mandated a risk mitigation program, including a database of all reported post-approval adverse reactions to Yervoy. In order to obtain full access to the information in that database, one must file a separate request with the FDA, under the Freedom of Information Act (FOIA), for each reported adverse reaction. The number of reports of serious adverse events associated with Yervoy filed from March 2011 through September 2014 totals nearly 4000. Since the cost of filing an FOIA request for each report is over $50, the cost to perform a detailed analysis of the entire database of adverse events is over $20,000. This fee is prohibitive, and defeats the purpose of the risk mitigation program. FDA should provide free access to this data, in order to stimulate and facilitate research into the effects of Yervoy on patient populations which were excluded from the controlled clinical trials.

References

1: Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007 Jul;12(7):864-72. Review. PubMed PMID: 17673617.

2: Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013 Jun;18(6):733-43. doi: 10.1634/theoncologist.2012-0483. Epub 2013 Jun 17. Review. PubMed PMID: 23774827; PubMed Central PMCID: PMC4063401.