Immune System-Activating Drugs in Combination Treatments May Be Next Big Thing for Melanoma


Among solid tumors, the curative potential of immunotherapies has been explored most in melanoma. One reason for this is that melanoma tumors often contain so-called immune infiltrates—patches of T cells, the killer cells of the immune system. It seems that these fighter cells arrive at the ‘battlefield’ to target tumor cells for killing, but instead become ‘frozen,’ unable to attack.  How to activate the tumor-killing potential of T cells has been an area of intense and fruitful research, leading to the development of several immunotherapy drugs.

Melanoma has been shown to respond to several types of immunotherapies. The first to be approved by the U.S. Food and Drug Administration (FDA), in 1998, was high-dose interleukin-2 (IL-2). The drug peginterferon alfa-2b (aka Sylatron) was approved in 2011 for people with stage III melanoma whose tumors were resected (removed by surgery). Another very promising approach is adoptive cell therapy (ACT), whereby patients receive infusions of their own T cells isolated from their tumors or blood and expanded, activated, and sometimes modified in the laboratory. And then, of course, there are the immune checkpoint inhibitors, which release protein ‘brakes’ that keep T cells from attacking tumors. The oldest immune checkpoint inhibitor is ipilimumab (Yervoy), FDA-approved in 2011, which targets the protein CTLA-4 on T cells. The newer immune checkpoint inhibitors target other T cell brake proteins: PD-1 on T cells and PD-L1 on tumor cells. The anti-PD-1 drug Keytruda (formerly known as MK3475 and made by Merck) has just been approved by the FDA for treatment of metastatic melanoma that has not responded to ipilimumab. The other anti-PD-1 drug nivolumab (aka Opdivo, made by Bristol-Myers Squibb) has been approved in Japan for treatment of unresectable melanoma. Two immune checkpoint inhibitors currently being tested in patients in clinical trials target PD-L1: MEDI4736 from MedImmune and MPDL3280A from Genentech.

Ipilimumab causes tumors to disappear in only about 10% of treated patients. Anti-PD-1 blocking agents induce good responses in 30% to 50% of patients. Moreover, combining ipilimumab with nivolumab appears to have a higher level of anti-melanoma activity than giving either drug alone. The combination is being explored in a number of clinical trials (see table below). In a clinical trial, the anti-PD-L1 drug MPDL3280A induced good responses at a rate of about 25%. Clearly, immune system-stimulating treatments fail to benefit most patients, but those who respond well tend to stay disease-free for a long time, measured in years, which is unprecedented for metastatic melanoma.

On the other hand, targeted therapy—either with vemurafenib or dabrafenib combined with trametinib—greatly reduces the tumor burden in a significant percentage of patients, but most patients relapse within 1 year. These drugs are given to people whose melanomas harbor BRAF mutations (about half of all cutaneous melanoma cases).

Is it possible to combine the long-lasting responses seen with immunotherapy drugs with the high rate of responses seen with targeted therapies? This is an area of much excitement in melanoma treatment. Scientific data shows that treatment with vemurafenib may make tumors more responsive to immunotherapies. However, the first attempt to combine ipilimumab and vemurafenib did not bode well for the treatment; the trial was discontinued because patients who received both drugs at the same time developed serious (though reversible) liver toxicity. This did not dampen interest; it just resulted in a modification of scheduling: in new trials, the immunotherapy and targeted drugs are administered not at the same time, but sequentially.

Below, I showcase some of the clinical trials that are exploring various drug combinations that include immune checkpoint inhibitors. In addition to targeted therapies, some trials combine checkpoint inhibitors with other immunotherapy treatments, or even a promising drug called T-VEC, which is injected directly into tumors. Ipilimumab, being an older drug, is being tested in numerous trials in combination with targeted drugs, vaccines, T-VEC, and with radiation treatments or chemotherapy drugs (only a few are shown below). The hope is that combining immune therapies with other treatments will achieve the ultimate goal of providing a high rate of long-lasting responses in melanoma patients, without serious side effects. Explore these trials if you need new treatment options:

NCT number and phase Immunotherapy drug Second drug or treatment Condition and notes
NCT02130466, Phase I, II Keytruda Trametinib and dabrafenib, or trametinib only Cutaneous, stage III unresectable or metastatic melanoma with BRFAV600 mutation (trametinib and dabrafenib) or negative for BRAF mutation (trametinib only)
NCT02112032, Phase I Keytruda Peginterferon/Sylatron Stage III unresectable or metastatic melanoma, cutaneous and mucosal
NCT02089685,Phase I, II Keytruda Peginterferon/Sylatron, ipilimumab, or nothing Stage III unresectable or metastatic melanoma
NCT02263508,Phase I, II Keytruda T-VEC (a drug injected into tumors directly) Cutaneous, stage III unresectable or metastatic melanoma
NCT02224781,Phase III Nivolumab and ipilimumab Trametinib and dabrafenib (sequential treatment in different order) Stage III unresectable or metastatic melanoma with BRAFV600 mutation
NCT01783938, Phase II Nivolumab Ipilimumab Stage III unresectable or metastatic melanoma
NCT01621490,Phase I Nivolumab Ipilimumab or nothing Stage III unresectable or metastatic melanoma
NCT02186249,Expanded access Nivolumab Ipilimumab Stage III unresectable or metastatic melanoma, cutaneous and mucosal

NCT02027961, Phase I, II

 

MEDI4736 Dabrafenib and trametinib, or trametinib only Stage III unresectable or metastatic melanoma, cutaneous and mucosal

NCT01656642, Phase Ib

MPDL3280A Vemurafenib Stage III unresectable or metastatic melanoma with BRAFV600 mutation except uveal
NCT02174172, Phase I MPDL3280A Peginterferon/Sylatron, or ipilimumab Stage III unresectable or metastatic melanoma
NCT01940809, Phase I Ipilimumab Dabrafenib and trametinib, trametinib only, or dabrafenib only Stage III unresectable or metastatic melanoma with BRAFV600 mutation
NCT01767454, Phase I Ipilimumab Dabrafenib and trametinib, or dabrafenib only Cutaneous, stage III unresectable or metastatic melanoma with BRFAV600 mutation
NCT02200562 Ipilimumab Dabrafenib Cutaneous, stage III unresectable or metastatic melanoma with BRFAV600 mutation
NCT01740297 Ipilimumab T-VEC (a drug injected into tumors directly) Cutaneous, stage III unresectable or metastatic melanoma not yet treated
NCT02073123, Phase I, II Ipilimumab Indoximod (drug that targets the immune inhibitory enzyme IDO) Stage III unresectable or metastatic melanoma
NCT01838200,Phase I Ipilimumab BCG vaccine Stage III unresectable or metastatic melanoma
NCT02032810, Phase I Ipilimumab Panobinostat (targeted) Stage III unresectable or metastatic melanoma

NCT02027935, Phase II

Ipilimumab ACT (patients’ own modified T cells) Stage III unresectable or metastatic melanoma