Neoadjuvant (before-surgery) treatments for resectable melanoma
Neoadjuvant treatments are the mainstay in the care of patients with breast, colon, and other cancers, but have not traditionally been used in melanoma. This has changed now, with the publication of a report showing that patients with resectable stage III or IV BRAF-mutant melanoma benefit from treatment with the BRAF/MEK inhibitor drugs dabrafenib and trametinib prior to (and continued after) surgery. The randomized clinical trial that produced these findings was small, but the benefits were so obvious that the researchers had to close the control group—those patients who received a placebo instead of neoadjuvant treatment. 71% of the 14 patients in the trial who received BRAF/MEK inhibitors prior to surgery were disease-free after 18 months, whereas all seven patients in the control group experienced a recurrence. The trial is continuing without the control group: all patients will receive treatment prior to surgery
Adjuvant (after-surgery) treatments
Melanoma patients whose tumors are surgically removed experience a very high rate of recurrence. Until recently, adjuvant treatments to prevent recurrences were limited to the drug interferon alpha-2B and, more recently, ipilimumab (brand name Yervoy), an anti-CTLA-4 immune checkpoint drug approved by the U.S. Food and Drug Administration (FAD) for adjuvant treatment in 2015. Interferon treatment is extremely harsh, with many adverse effects, and is not often used anymore. Yervoy is often associated with autoimmune side effects, which are sometimes quite serious.
Enter nivolumab (Opdivo) the anti-PD-1 checkpoint drug approved by the FDA to treat metastatic melanoma and other cancers. A clinical trial showed that the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% compared to 52.7% for ipilimumab (Yervoy) in patients with resected stage IIIB/C or IV melanoma. This amounts to a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor. Not the least important factor is the much lower rate of side effects seen with nivolumab compared to ipilimumab. Nivolumab is now approved by the FDA as an adjuvant treatment after surgical resection of melanoma.
Pembrolizumab, a competing anti-PD-1 drug, also showed encouraging results in a randomized trial for stage III melanoma. The stakes in this trial were lower, since the control arm received a placebo (not ipilimumab!). Risk reduction was 43%, according to preliminary results of the trial.
For patients with BRAF-mutant stage III melanoma, adjuvant treatment with the BRAF/MEK inhibitors dabrafenib and trametinib was just recently granted a priority review by the FDA, signaling a likely approval soon. Recurrence-free 3-year survival was 58% for the combination versus 39% for placebo.
New treatments for metastatic melanoma
A Knowledge Blog post from last summer described new combination treatments for metastatic melanoma. There have been significant developments since then.
Several trials combined PD-1 blockers (pembrolizumab or nivolumab) with small molecules known as IDO inhibitors. The latter help shut down the activity of immune system cells known as regulatory T cells (T regs), which dampen the immune response triggered by anti-PD-1 drugs. Combination of pembrolizumab with the IDO inhibitor epacadostat increased the rate of responses to pembrolizumab from 32% to 56%. This is very comparable to the response rate seen with the FDA-approved combination of nivolumab and ipilimumab. However, the significant toxicities seen with addition of ipilimumab are not observed when IDO inhibitors are added. Several other competing IDO inhibitors are currently in trials with both pembrolizumab and nivolumab. Importantly, there is also hope that these drug combinations may abolish resistance to PD-1 blockers in previously treated melanoma patients.
Another promising combination has been tested in a small clinical trial of nivolumab with NKTR-214, a specifically modified form of the protein IL-2, which is a strong activator of the immune system. High-dose IL-2 is a drug that has long been approved for metastatic melanoma but is rarely used because of the extremely serious adverse effects. NKTR-214 is a modified (PEGylated) IL-2 that has much reduced side effects, and does not activate inhibitory T regs. Clinical trial results have been released for 11 melanoma patients treated with the combination. Of the patients enrolled, 73% have experienced objective responses, which is obviously much higher than what is seen with nivolumab alone. This trial is now enrolling patients who have or have not already been treated with immune drugs.
Patients who were treated with anti-PD-1 drugs and experience progression may consider enrolling in trials that add relatlimab (an anti-LAG3 immune drug) to nivolumab. In a trial that enrolled heavily pretreated patients who failed on previous treatment with anti-PD-1 drugs, the rate of response was 11.5%, but many more patients (38%) have achieved stable disease. The presence of LAG3 protein (but not PD-L1 protein) in the tumors was predictive of response.
There are other new drugs to watch. TLR9 agonists (activators) have shown early promising results in melanoma. TLR is a group of receptors that are strongly involved in innate immunity. A recent publication showed that intratumoral injection of a TLR9 activator with an antibody to OX40 (a protein on T cells) has extraordinary activity in a mouse cancer model. Trials that combine anti-OX40 and TLR9 agonists are forthcoming. However, two TLR9 agonists, SD-101 and IMO-2125, have shown very promising results in combination with anti-PD-1 or anti-CTLA4 drugs.
The other drug with early promise is ImmunoPulse IL-12 (pIL-12). In combination with pembrolizumab, it induced responses in 43% of patients who had not been previously treated with immune drugs. The important point is that patients in this trial were specifically selected to have a tumor profile that is associated with lack of response to pembrolizumab. pIL-12 is injected into tumors, so this intervention is appropriate for patients who have injectable tumors.
New BRAF/MEK inhibitors for melanoma have emerged: encorafenib and binimetinib produced a 3-year overall survival rate that is twice as high as seen with vemurafenib, a BRAF inhibitor. The comparison is not exactly meaningful because vemurafenib is not used as a single drug in BRAF-mutant melanoma these days, but this phase III trial was initiated back in 2013, prior to the approval of other BRAF/MEK combinations. The new combination may be approved mid-2018.
The triplet combinations for BRAF-mutant melanoma should be mentioned (immune plus targeted drugs). A trial that combined dabrafenib and trametinib with pembrolizumab reported early success, with a confirmed response rate of 67% in 15 patients who received the combination.