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Sargramostim and immune checkpoint inhibitors: combinatorial therapeutic studies in metastatic melanoma – take a peek behind the paper with an interview with the author

Written by Fiona Garner (Partner Therapeutics Inc.)

metastatic melanoma

Please introduce yourself, your research background and current research interests.

I, Fiona Garner, am the Executive Director of Immuno-Oncology Clinical Development and Translational Medicine at Partner Therapeutics, Inc., a commercial biotech company. At Partner Therapeutics we are developing Leukine® (sargramostim), a glycosylated, yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) in a number of indications including oncology. Leukine is approved by the US FDA and is also held by the US government in the Strategic National Stockpile. Building upon a strong foundation of expertise in oncology, Partner Therapeutics also leads and supports ground-breaking research in infectious disease and other areas of clinical urgency, including treatment of COVID-19. Our research interests center around the immunomodulatory mechanism of action of sargramostim and expanding our clinical development to address unmet medical needs.

What is the current treatment landscape for metastatic melanoma?

In recent years, the treatment landscape for metastatic melanoma has completely transformed due to the advances in targeted therapy and immunotherapy leading to prolonged survival and long-term disease control in many patients. Targeted therapy inhibits tumor cell proliferation by interfering with specific molecular targets. Immunotherapy modulates the body’s innate and/or adaptive immune response to melanoma cells and tumors. Ipilimumab is the first immune checkpoint inhibitor approved by the US FDA for metastatic melanoma. Ipilimumab therapy is commonly used as second-line or subsequent therapy and generates long-term survival in about 20% of patients. For patients with metastatic melanoma, use of immune checkpoint inhibitors and targeted agents over the past 5 years or so has roughly doubled the 5-year overall survival rate, from approximately 27% between 2010–2016 to over 50% today. GM-CSF is an immunomodulatory cytokine that bridges the innate and adaptive immune responses. Sargramostim (yeast-derived rhu GM-CSF) has been evaluated in several clinical trials as a means of boosting immune responses, reversing immune tolerance and enhancing antitumor efficacy, particularly when used in combination with other immune therapies such as ipilimumab. Previous and ongoing studies show the potential of combining sargramostim with immune checkpoint inhibitors to increase efficacy and decrease toxicity for patients with melanoma.

In your opinion, what are the unmet needs in this treatment landscape? What hurdles need to be overcome to meet these needs?

Unfortunately, primary resistance to immunotherapies occurs in up to 50% of patients leading to poor outcomes and reduced survival. Moreover, in many cases, immunotherapy results in significant toxicity, especially immune-related adverse events. These often require dose interruptions or discontinuations, in addition to adverse effects on patient quality of life.

Despite the improvements seen with melanoma therapies, there remains a clear need for treatments that improve survival and reduce treatment-related toxicity.

Please can you give an overview of your recent article published in Immunotherapy and its main conclusions?

In this article, we review clinical studies of sargramostim for treatment of advanced melanoma when used as a monotherapy and in combination with ipilimumab. One such study, the Phase II E1608 study published by Hodi et al., reported significantly improved overall survival in patients with advanced melanoma with the combination of sargramostim and ipilimumab (median OS: 17.5 months [95% CI: 14.9 to not reached] vs 12.7 months [95% CI: 10.0 to not reached]; one-sided p = 0.01) while also reducing pulmonary (p=0.003) and GI (p=0.05) adverse events. We also review the preclinical and translational data demonstrating the potential mechanism of action of sargramostim that synergizes with immune checkpoint inhibitors to enhance efficacy and reduce the associated treatment-related toxicity.

Ongoing trials are incorporating conclusions from the clinical studies discussed in our review to further the study of sargramostim with immune checkpoint inhibitors in melanoma and other solid tumors. The Phase II/III E6141 trial (NCT02339571) is evaluating the triplet regimen of ipilimumab, nivolumab and sargramostim as frontline therapy for patients with unresectable advanced or metastatic disease. An ongoing Phase II trial is assessing sargramostim induction therapy in patients with advanced biliary cancers, followed by treatment with pembrolizumab (NCT02703714). Additionally, a Phase II study is evaluating sargramostim plus maintenance pembrolizumab with or without pemetrexed after completion of first line chemoimmunotherapy in advanced non-small-cell lung cancer (NCT04856176).

Please explain the potential mechanism for efficacy in advanced melanoma of sargramostim in combination with ipilimumab?

The diverse cellular effects of GM-CSF are likely the result of multiple factors, including presence of its receptor, target cell population and signaling strength that depends on the concentration of this cytokine. The antitumor activity of sargramostim might be influenced by the tumor microenvironment, including degree of inflammation and CTLA-4 expression on tumor tissue. Several hypotheses can be postulated to explain potential mechanisms leading to an increase in overall survival with the combination regimen. The survival benefit may be the result of improved antigen presentation by mature dendritic cells, which increases priming and activation of tumor-infiltrating T lymphocytes in tumor-draining lymph nodes and the tumor microenvironment. Another possibility is that sargramostim augments antibody-mediated depletion of intratumoral immunosuppressive Treg cells, although further study is needed to confirm whether ipilimumab can induce such depletion.

How can these conclusions be implemented into the field to help overcome the challenges mentioned above?

The data in this review support the idea that combining sargramostim with ipilimumab results in additive or synergistic enhancement of antitumor activity in advanced melanoma, and this may be true for PD-1 inhibitor-based combinations as well. The ability of sargramostim to ameliorate ipilimumab treatment-related toxicity, and potentially with other immune checkpoint inhibitors, represents a significant clinical benefit, allowing patients to remain on immunotherapy, thus potentially maximizing efficacy while reducing toxicity. Results from ongoing studies for sargramostim combined with immune checkpoint inhibitor therapy in melanoma (E6141; NCT02339571), biliary cancer (NCT02703714) and non-small-cell lung cancer (NCT04856176) are eagerly anticipated.

How do you hope to see the field and treatment landscape evolve over the next 5 years?

The potential benefits of sargramostim when combined with immune checkpoint inhibitors may not be limited to patients with melanoma. There are ongoing studies in other tumor types such as advanced biliary cancers (NCT02703714) and non-small cell lung cancer (NCT04856176) to investigate this further. The therapeutic paradigm for advanced melanoma will likely continue to evolve toward greater use of combination immunotherapy regimens including novel agents like sargramostim, resulting in greater efficacy, reduced toxicities and prolonged survival.

Click below to read the original article:

Click here to read the original study

The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Oncology Central or Future Science Group.

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Fiona Garner is the Executive Director of Immuno-Oncology Clinical Development and Translational Medicine at Partner Therapeutics, Inc., a commercial biotech company.



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