Ipilimumab (Yervoy) was first approved by the U.S. Food and Drug Administration (FDA) in 2011 on the basis of an improvement in overall survival compared with gp100 vaccine in patients with advanced melanoma.1 Response rates with ipilimumab have been modest at best—10% to 15% using 3 mg/kg and 15% using 10 mg/kg1,2—and higher doses have been associated with greater toxicity.
ECOG E1608
The Eastern Cooperative Oncology Group (ECOG) E1608 phase II study recently reported by Hodi et al3 in JAMA and reviewed in this issue of The ASCO Post represents an important benchmark for ipilimumab in melanoma: making treatment more effective while minimizing toxicity. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine has been shown to enhance the effect of CTLA-4 blockade in an in vivo model, specifically augmenting the ratio of intratumoral effector T cells to regulatory T cells associated with tumor rejection.4 On the basis of this preclinical work, ECOG E1608 randomly assigned patients to receive intravenous ipilimumab at 10 mg/kg on day 1 plus subcutaneous GM-CSF (sargramostim [Leukine]) at 250 μg on days 1 to 14 or ipilimumab alone in 21-day cycles.
The study met its primary endpoint of improvement in overall survival (17.5 months for ipilimumab plus sargramostim vs 12.7 months for ipilimumab alone, P = .01) while also demonstrating a statistically significant decrease in grade 3 to 5 adverse events (44.9% for ipilimumab plus sargramostim vs 58.3% for ipilimumab alone, P = .04). The overall response rate in both arms was 15%. Diarrhea occurred in 13% of both arms, and colitis was seen in 6% of patients on the ipilimumab-plus-sargramostim arm and 8% of patients receiving ipilimumab alone.
Previous Ipilimumab Studies
This is not the first study to add an agent to ipilimumab and show an improvement in clinical outcomes while decreasing toxicity. A phase II single-arm study of ipilimumab at 10 mg/kg on day 1 plus temozolomide at 200 mg/m2 on days 1 to 4 demonstrated a 30% confirmed objective response rate.5 This enhanced response is suspected to occur via preferential reduction in regulatory T cells due to temozolomide.6,7 Additionally, temozolomide improved the toxicity profile of ipilimumab; notably, nausea and constipation were the most common gastrointestinal toxicities, as compared with diarrhea and colitis in other ipilimumab studies. The rates of grade 3 or 4 diarrhea and colitis with ipilimumab plus temozolomide were 9% and 1.5%, respectively.
NIBIT-M1, a European study of ipilimumab and the nitrosourea alkylating agent fotemustine (not FDA approved), similarly showed an improvement in overall response to 29%, with only a 5% rate of colitis/diarrhea. Unlike temozolomide, however, fotemustine toxicity is notable for a 43% rate of grade 3 to 4 myelotoxicity.8
Further E1608 Findings
Hodi and colleagues noted that the addition of sargramostim had an uncoupling effect on progression-free survival and overall survival. While no benefit was seen in progression-free survival in patients receiving the combination, at a median follow-up of 13.3 months, a significant improvement in overall survival was seen.
This uncoupling may have to do with the protracted effect of sargramostim on enhancing antigen presentation to dendritic cells and macrophages or with the delayed effect of immunotherapy in general; or, it may be reflective of rudimentary radiographic criteria that are unable to differentiate inflammation and immune cell infiltration from disease progression.
The authors give plausible scientific rationale for the decrease in serious gastrointestinal and pulmonary toxicity seen in the combination arm. In particular, they point to GM-CSF knockout mice that develop severe colitis and pulmonary alveolar proteinosis. These effects are prevented with the administration of GM-CSF. These knockout murine models suggest GM-CSF is involved in both pulmonary and gastrointestinal homeostasis.
The authors also noted that GM-CSF
is involved in gastrointestinal mucosal repair and that patients with inflammatory bowel disease often show decreased GM-CSF receptors in the bowel or high titers of circulating GM-CSF neutralizing antibodies. There is level 2B evidence for off-label use of sargramostim in patients with Crohn’s disease and pulmonary alveolar proteinosis.
Closing Thoughts
The addition of sargramostim as a strategy to improve clinical outcome and reduce toxicity is not without concern for cost. Insurance coverage for sargramostim in the real world is yet to be determined, specifically for patients without cytopenia and for a duration of 14 days in each cycle. Nevertheless, the cost-effectiveness of such a regimen could be studied prospectively.
Getting the most out of ipilimumab involves improving patient selection possibly through the use of predictive biomarkers, along with enhancing response rate and clinical outcome while minimizing toxicity. With newer therapies including anti–PD-1–blocking antibodies demonstrating a higher response rate and lower serious toxicity rate,9,10 the attempt to derive the greatest benefit from ipilimumab by using it in combination with agents that can augment the risk:benefit ratio is a step in the right direction. ■
Disclosure: Dr. Patel has received research support from Bristol-Myers Squibb, Novartis, GlaxoSmithKline, and Prometheus and has served as a scientific advisor for Amgen and Genentech and as a speaker for Merck & Co.
References
1. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711-723, 2010.
2. Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517-2526, 2011.
3. Hodi FS, Lee S, McDermott DF, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312:1744-1753, 2014.
4. Quezada SA, Peggs KS, Curran MA, et al: CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest 116:1935-1945, 2006.
5. Patel SP, Hwu W-J, Kim KB, et al: Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma. J Clin Oncol 30(suppl):Abstract 8514, 2012.
6. Banissi C, Ghiringhelli F, Chen L, et al: Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother 58:1627-1634, 2009.
7. Ridolfi L, Petrini M, Granato AM, et al: Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients. J Transl Med 11:135, 2013.
8. Di Giacomo AM, Ascierto PA, Pilla L, et al: Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): An open-label, single-arm phase 2 trial. Lancet Oncol 13:879-886, 2012.
9. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet 384:1109-1117, 2014.
10. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443-2454, 2012.
Dr. Patel is Assistant Professor in the Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.
