With the report in HealthDay News breaking Nov. 4 and the actual study: Ipilimumab plus sargramostim vs ipilmumab alone for the treatment of metastatic melanoma: a randomized clinical trial (Hodi, Lee, McDermott, et al.) being published in JAMA on the fifth....questions on melanoma blogs and forums have gone through the roof!!!
So....here's my best interpretation of what it all means. First of all, let's back up a step! Yes, the magical "sargramostim" is the same thing as GM-CSF, leukine and used in OncoVex. It is an immunostimulator used most often to help grow new white cells after a bone marrow transplant or when they have been depleted by conventional chemo in diseases like leukemia.
OR....here's what I noted before in a post about the intralesional therapy OncoVEX:
"OncoVEX is a 2nd generation herpes virus embedded with GM-CSF...a substance that causes the body to make more white cells. (GM-CSF can be given to premature babies and leukemia patients with low white cell counts to help build them back up....and reverse immune suppression.) But, in OncoVEX, it is thought to only replicate in the tumor cells. The white cells produced in the process kill off the tumor cells. In a phase 2 trial reported in 2012, 20% of patients achieved a complete response and 28% gained an overall response. 92% of the responses were durable to at least 6 months, and the majority were ongoing with a range of 18-40 months. Responses were found in patients with all stages and systemic tumors were eradicated in some patients."
OR...here's where Ribas and Weber discussed T-VEC vs GM-CSF and an abstract of a study that used GM-CSF and IL-2 as an injectable therapy
Ribas: ...a randomized trial of an injectable virus called T-VEC compared with granulocyte-macrophage colony stimulating factor (GM-CSF).
Weber: ...the responses were 16% vs 2%. Obviously you don't expect any responses with GM-CSF, so 2% would be essentially zero. A 16% response rate overall in a patient with injectable local-regional disease plus systemic disease is pretty modest....
Tumor response and patient survival after intralesional therapy with low-dose GM-CSF and IL-2 in metastatic and primary cutaneous melanoma: An exploratory study. Elisas & Sharma
Patients with dermal and subdermal mets, no matter the extent of their disease or previous therapy, were given intralesional GM-CSF once a week for 4-6 weeks. If no complete clinical response was noted at the injection sites, they were then given intralesional IL-2 for the same length of time. Results: 4 patients with more than 126 small in-transit mets, each lesion measured a few mm to up to 1 cm. All had a complete response confirmed pathologically 6-8 weeks after cessation of therapy, with disease free survival of 37-54 months. Another 3 patients with large sclerotic skin lesions failed to respond to either cytokine. One of 2 patients with distant mets who also had palpable subdermal tumors had complete response of all mets. This patient is alive and disease free for over 48 months. Conclusion: [After examination of the tissues resected after treatment...] Intralesional therapy seemed to utilize the tumor site as a source for tumor-specific antigens giving rise to autoimmunization with strong antitumor response...
Clearly, this drug is not unknown to oncology or even melanoma world...it has been used as a control, combined with IL-2 and with a viral vector as an injectable therapy. The story now is that Hodi et al., wanted to see if, when given systemically WITH ipi, would the immune stimulating effects of GM-CSF boost the patient's response to ipi??? A randomized clinical trial with 245 stage III or IV unresectable melanoma patients (12/2010 - 7/2011) were given either ipi at 10mg/kg plus sargramostim 250ug subcutaneously or ipi alone. RESULTS: Median OS for combo was 17.5 months vs 12.7 months for ipi alone. 1 year survival for combo was 68.9% vs 52.9% for ipi. PFS was only 3.1 months for both groups. Grade 3/5 adverse events occurred in 44.9% of the combo group but even more frequently in the ipi only group at 58.3%.
So....GM-CSF decreased side effects when combined with ipi and resulted in longer overall survival, but provided no additional benefit in progression free survival.
In Reinberg's report in HealthDay, he indicated that Dr. Doris Day (I know!!! Her parents didn't like her!!!) had a rather positive view of the results while Hodi (lead researcher in the study) didn't "know whether starting combination therapy before melanoma spread will improve survival." Reinberg concluded his report with a quote from Dr. Mario Sznol, "Overall, these are interesting results..., but the field has moved so quickly, that it may be difficult to follow up..." Noting also that pembro and nivo alone will probably be more effective and less toxic. Finally, Sznol stated, "So these results, even if confirmed, are not as important as they would have been several years ago."
- Yes, I think here, as with all immunotherapies, we've learned enough to know that starting them sooner, rather than later, with the least tumor burden possible, is better. How much better would this turn out to be? We don't know.
- Nobody is giving ipi at 10mg/kg anymore....at least not in anything other than a clinical trial. And even there, we've learned that when using ipi combinations...ipi is the bad boy in terms of adverse effects. That is why many of the ipi/nivo combo trials have 'flipped' their dosages...giving a smaller dose of ipi and a larger one of nivo...creating a much better side effect profile and as good or better results. What would the results of this study have been if ipi had been dosed at the now FDA approved 3mg/kg?
- As I've noted in several prior posts...there are many ongoing/developing studies looking at immunotherapy combinations: ipi and nivo, ipi and TVEC, ipi and INCBO24360 (an IDO inhibitor)....not to mention...Pembro and TVEC, Pembro and an IDO inhibitor, Pembro and BRAFi, Nivo and antiCD137, Nivo and anti-LAG-3...etc. I fear Sznol may be right. While these results would have looked incredibly good to me when I needed treatment in 2010, thankfully, with the current anti-PD1 drugs and other immunotherapy combinations....ipi and Sargramostim may not work as well as some of the options currently available or rapidly on their way.