On 2014 Dec 29, David Keller commented:

Might the addition of sargramostim to combination checkpoint inhibition reduce adverse events?

Recently, Hodi et al demonstrated that addition of sargramostim (GM-CSF) to high-dose ipilimumab monotherapy (10 mg/kg) resulted in significantly improved median overall survival, and also significant reduction in the rate of adverse effects compared with high-dose ipilimumab alone (1). It seems imperative to test the proposition that sargramostim might provide similar increase in benefit and decrease in risk when administered with combination checkpoint inhibition.

Reference

1: Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. doi: 10.1001/jama.2014.13943. PubMed PMID: 25369488.

On 2013 Jun 20, Martin Fenner commented:

The systemic therapy for metastatic melanoma changed dramatically in 2010 when ipilimumab, an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4], was shown PMCID: PMC3549297 to improve survival in patients previously treated with chemotherapy. In 2011 ipilimumab was shown Robert C, 2011 to also improve survival when given in combination with dacarbazine compared to dacarbazine alone in previously untreated metastatic melanoma patients.

The present study is a dose-finding phase Ib study looking at the combination of ipilimumab and nivolumab, an antibody against the programmed death 1 [PD-1] receptor. Fifty-five patients received concurrent therapy of the two drugs, whereas 33 patients previously treated with ipilimumab were given nivolumab (sequential therapy). The objective response rate in the 55 patients treated with combination therapy was 40% with 53% of patients experiencing grade 3 or 4 adverse events. In the 33 patients treated with sequential therapy, 20% showed an objective response and 18% had adverse events related to therapy.

The study results demonstrate clinical activity of the combination therapy with manageable adverse events (although the rate of adverse events was increased in the concurrent therapy group). What the publication unfortunately fails to do is to clearly describe the study design. According to the information at ClinicalTrials.gov the primary endpoint of the trial was safety (as expected for a phase I trial), and this primary endpoint is mentioned neither in the abstract nor the methods section. What the publication also fails to mention is that according to the Clinicaltrials.gov information this is an ongoing trial with an estimated enrollment of 136 patients and an estimated study completion in August 2014. With all the excitement about new treatment options for metastatic melanoma patients we shouldn't forget best practices of reporting clinical trial results.

On 2013 Jun 20, Martin Fenner commented:

The systemic therapy for metastatic melanoma changed dramatically in 2010 when ipilimumab, an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4], was shown PMCID: PMC3549297 to improve survival in patients previously treated with chemotherapy. In 2011 ipilimumab was shown Robert C, 2011 to also improve survival when given in combination with dacarbazine compared to dacarbazine alone in previously untreated metastatic melanoma patients.

The present study is a dose-finding phase Ib study looking at the combination of ipilimumab and nivolumab, an antibody against the programmed death 1 [PD-1] receptor. Fifty-five patients received concurrent therapy of the two drugs, whereas 33 patients previously treated with ipilimumab were given nivolumab (sequential therapy). The objective response rate in the 55 patients treated with combination therapy was 40% with 53% of patients experiencing grade 3 or 4 adverse events. In the 33 patients treated with sequential therapy, 20% showed an objective response and 18% had adverse events related to therapy.

The study results demonstrate clinical activity of the combination therapy with manageable adverse events (although the rate of adverse events was increased in the concurrent therapy group). What the publication unfortunately fails to do is to clearly describe the study design. According to the information at ClinicalTrials.gov the primary endpoint of the trial was safety (as expected for a phase I trial), and this primary endpoint is mentioned neither in the abstract nor the methods section. What the publication also fails to mention is that according to the Clinicaltrials.gov information this is an ongoing trial with an estimated enrollment of 136 patients and an estimated study completion in August 2014. With all the excitement about new treatment options for metastatic melanoma patients we shouldn't forget best practices of reporting clinical trial results.

On 2014 Dec 29, David Keller commented:

Might the addition of sargramostim to combination checkpoint inhibition reduce adverse events?

Recently, Hodi et al demonstrated that addition of sargramostim (GM-CSF) to high-dose ipilimumab monotherapy (10 mg/kg) resulted in significantly improved median overall survival, and also significant reduction in the rate of adverse effects compared with high-dose ipilimumab alone (1). It seems imperative to test the proposition that sargramostim might provide similar increase in benefit and decrease in risk when administered with combination checkpoint inhibition.

Reference

1: Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA, Leming P, Puzanov I, Shin D, Kirkwood JM. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA. 2014 Nov 5;312(17):1744-53. doi: 10.1001/jama.2014.13943. PubMed PMID: 25369488.