It has been over a year since I last wrote about new developments in treatment of melanoma, and it is time for an update. There is certainly some good news for melanoma patients!
Neoadjuvant (before surgery) treatments for resectable melanoma
Stage III—and more rarely, stage IV—melanoma tumors that have not spread widely can be sometimes treated surgically. Last year a small clinical trial showed that, in BRAF-mutant melanoma, treatment with the BRAF/MEK inhibitors dabrafenib and trametinib (D/T) before and after surgery provides a significant improvement over just post-surgery treatment, by preventing later recurrence.
Later in 2018, researchers reported that using the immune checkpoint drugs nivolumab and ipilimumab prior to surgery led to tumor reduction in 73% of patients treated in a clinical trial. After surgery, they remained disease-free for 2 years (the reported time of observation). Treatment with nivolumab alone was not nearly as active in this randomized trial, with only 25% of patients responding to neoadjuvant nivolumab; still, 75% were disease-free within the 2-year observation period.
An interesting trial tested a single dose of the drug pembrolizumab given three weeks prior to surgery. Of 27 patients who received this single infusion, eight (29%) had a complete or major pathological response, meaning that their tumors were reduced by 90% or more. These eight patients continued on pembrolizumab after surgery and were disease-free for over 2 years.
Adjuvant (after surgery) treatments
One year ago, some encouraging results emerged for new adjuvant treatments given to patients after surgical removal (resection) of stage-III melanoma tumors. Since then, important developments have surfaced. First, the U.S. Food and Drug Administration (FDA) approved adjuvant treatment with BRAF/MEK inhibitors D/T in resected BRAF-mutant melanoma. This approval was based on clinical trial results showing significantly improved rates of recurrence-free survival within 3 years after surgery: 58% for patients who received D/T versus 39% for those who received a placebo. Vemurafenib, the first FDA-approved BRAF inhibitor, did not do well in a trial testing it in the adjuvant setting. This is not surprising, considering that dabrafenib and trametinib have displaced vemurafenib as a treatment of choice in metastatic melanoma.
Back in 2017, the FDA approved nivolumab, an immune checkpoint anti-PD-1 drug, as an adjuvant treatment for resected stage III-IV melanoma. In February of this year, the ever-competing pembrolizumab was approved based on positive results in the adjuvant setting. Both drugs are effective in reducing the risk of recurrence after surgery.
New treatments for metastatic melanoma
Last year saw quite a lot of excitement over the addition of the IDO inhibitor epacadostat to pembrolizumab, but this turned to be a big disappointment. Preliminary clinical trial findings suggested a significant improvement in response rate without increased side effects, but the results of a phase III trial failed to confirm this. The failure of drugs in phase III after promising results in earlier-phase trials is, unfortunately, common, but nevertheless worrisome.
Better results were reported this year for treatment with the immunostimulatory cytokine IL-12, which is injected directly into a tumor (intratumoral injection). This drug was previously known as Immunopulse IL-12, and is now called TAVO (or, for those who prefer, tavokinogene telseplasmid). In a clinical trial, 30% of patients experienced objective tumor regressions, including in lesions that were not injected, and 47% had stable disease. Other trials are now testing TAVO in combination with pembrolizumab.
Continuing with cytokines—immune-system proteins that can be produced in a lab to help fight cancer—the clinical development of NKTR-214 seems to hit a wall. NKTR-214 is a modified form of IL-2, a cytokine approved long ago by the FDA for melanoma, but not much used because of low efficacy and very harsh side effects. NKTR-214 was designed to retain the immune system-stimulating properties of IL-2 without activating immune cells known as inhibitory T cells. Its combination with nivolumab was initially hailed as more effective than the FDA-approved combo of nivolumab with ipilimumab, without the serious side effects associated with this dual checkpoint blockade. However, results reported in November 2018 gave no reason for continuing optimism.
Still, patients with BRAF-mutant melanoma now have a new treatment option: encorafenib (a BRAF inhibitor) with binimetinib (a MEK inhibitor). The duration of response to this treatment in a pivotal trial was 16.6 months, and responses were seen in 63% of patients. Compared to the previously FDA-approved combination of dabrafenib and trametinib (D/T), the new drugs appear to have similar response rates, but a longer duration of response. However, a direct comparison of the two combinations in a clinical trial will be needed to make a solid conclusion about the comparative efficacy of the two treatments.
Meanwhile, some new data have emerged on triple-drug combinations for BRAF-mutant melanoma. Preliminary results from a trial of spartalizumab (a new anti-PD-1 antibody) with D/T in previously untreated melanoma patients reported responses in all nine patients. These included three complete responses, but side effects were frequent and sometimes serious. However, results from a different trial with D/T and pembrolizumab failed to show a significant improvement over D/T alone. The reason for this difference between the two anti-PD-1 drugs is unclear. We will need to wait for more mature results from the trial with spartalizumab in order to make meaningful conclusions.
And here is the latest on drugs that are currently the bright new hope in immunotherapy of melanoma: TLR9 agonists, the subject of a Knowledge Blog post last year. These drugs activate the innate immune system, and are injected intratumorally, including into deep visceral tumors. Preliminary results are now available for three of these drugs:
- SD-101: In combination with prembrolizumab in a small clinical trial, SD-101 produced responses in 78% of patients who had not received immunotherapy drugs previously—a truly remarkable rate of responses. In patients who had previously been treated with anti-PD-1 drugs, the response rate was much lower, at 15%. This certainly indicates that combination of SD-101 with anti-PD-1 drugs could be considered as a first line of treatment, once more data are accumulated in trials.
- CMP-001: This TLR9 agonist was tested in combination with pembrolizimab in a trial for melanoma patients who had previously been treated with an anti-PD-1 drug without responding. In this difficult-to-treat population, the response rate was around 30%, meaning that resistance to anti-PD-1 was overcome in almost one third of patients.
- IMO-2125: When given in combination with ipilimumab, this TLR-9 agonist showed encouraging results in patients who had not previously responded to anti-PD-1 drugs. Thirty eight percent of the patients in this trial had objective responses to the treatment, and the overall disease control rate was 71%.
Some interesting data have also emerged for certain specific BRAF mutations, which are found in at least 40% of cutaneous melanoma. There is a tendency to not specify the type of BRAF mutation a patient has, but in reality between 70% and 80% of melanomas have BRAF V600E mutations, and between 20% and 30% have BRAF V600K mutations. It turns out that the response to BRAF/MEK inhibitors in BRAF V600K-mutant melanoma is not nearly as good as in BRAF V600E melanoma; both the rate of responses and their duration are inferior. However, V600K patients have a better response to immune checkpoint blockade. This indicates strongly that immunotherapy should be the preferred option for treating patients with BRAF V600K mutations.
All in all, this past year brought new FDA approvals and new approaches in treatment of melanoma, confirming that the pace of drug development in this previously deadly cancer is transforming it into a treatable and even curable disease.
