Review of adjuvant treatment in Stage III melanoma and "death knell" for ipi and interferon in that role!!!!

Those who have read this blog for half a minute know that I have been yelling about the need for adjuvant treatment in melanoma that is NOT interferon....and after the response rates we know we can attain with anti-PD-1 products and BRAF/MEKi...NOT ipi either!!!  Here is a recent post with links to more within:

Adjuvant treatments in melanoma - They WORK!!! Now, let's make sure people can get them!!!!!

Now there's this:

Dabrafenib/Trametinib Combination and Nivolumab New Adjuvant Treatment Options for Stage III Melanoma. Prime Line, October 5, 2017.

The current adjuvant treatment options for high-risk patients with resectable melanoma include interferon and the cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab. Compared to placebo, ipilimumab (10 mg/kg) prolonged relapse free survival (RFS) and showed significant 5-year survival benefit in high-risk patients with melanoma, but at the cost of serious toxicity. In the metastatic setting, combinations of BRAF/MEK inhibitors in patients harboring BRAF mutations, and immunotherapy with programmed death receptor 1 (PD-1) inhibitors (± ipilimumab) regardless of BRAF status are standard of care based on evidence of survival benefit and manageable toxicity. The efficacy of these regimens has, thus, been investigated in the adjuvant setting, and results from two of these studies presented at the third Presidential Session at the 2017 European Society for Medical Oncology (ESMO) Congress are practice changing.

The COMBI-AD trial (N = 870), presented by Axel Hauschild, MD, PhD (University Hospital Schleswig-Holstein, Kiel, Germany), compared the combination of dabrafenib (150 mg twice daily) and trametinib (2 mg daily) to placebo in patients with resected, high-risk, stage IIIA-C melanoma with BRAF V600E/Kmutation. At 2.8 years follow-up, the combination of dabrafenib and trametinib had significantly improved RFS compared to placebo (not reached vs 16.6 months). The 3-year RFS rate was 58% with the combination compared to 39% with placebo. The benefit of dabrafenib plus trametinib adjuvant therapy was seen across all patient subgroups, regardless of disease stage or risk factors. Furthermore, combination therapy significantly improved overall survival (OS), with 3-year OS rates of 86% with combination versus 77% with placebo. Dabrafenib plus trametinib was associated with an increase in adverse events (AEs) compared to placebo (grade 3/4: 41% vs 14%), but there were no deaths due to AE. A greater number of patients receiving the combination discontinued treatment due to AE (26% vs 3%), with the most common reasons being pyrexia and chills. In his conclusion, Dr Hauschild highlighted the RFS and OS benefits of dabrafenib plus trametinib, along with the manageable safety profile, indicating that this combination should become a new treatment option for patients with resected, stage III, BRAF-mutated melanoma. Results from the COMBI-AD trial were simultaneously published in The New England Journal of Medicine.

Jeffery Weber, MD, PhD (New York University, New York, New York, United States), presented results from the phase III CheckMate-238 trial (N = 906), which compared one year of adjuvant therapy with nivolumab (3 mg/kg IV every 2 weeks) to ipilimumab (10 mg/kg IV every 3 weeks for 4 doses, then every 12 weeks) in patients with resected stage III/IV melanoma. Significantly more patients treated with nivolumab remained relapse-free at 18 months compared to ipilimumab (66% vs 53%). Relapse-free survival benefit favored nivolumab regardless of PD-L1 expression level, disease stage, or BRAF mutation status. Adjuvant treatment with nivolumab was more tolerable than ipilimumab. There were fewer grade 3/4 treatment-related AEs in the nivolumab arm (14% vs 46%), and fewer patients treated with nivolumab experienced a treatment-related AE leading to discontinuation (8% vs 42%). There were no treatment-related deaths in the nivolumab group, while 2 patients in the ipilimumab group died due to AE. Dr Weber concluded that nivolumab should be considered as a new standard treatment option for patients with resected stage IIIB/IIIC/IV melanoma, regardless of BRAF mutation status. Results from this trial were also simultaneously published in The New England Journal of Medicine.

In their discussions of these studies, Alexander Eggermont, MD, PhD (Gustave Roussy, Villejuif, France), and Reinhard Dummer, MD, PhD (Cancer Center Zurich, Zurich, Switzerland), indicated that these trials represent the death knell for both ipilimumab and interferon as adjuvant therapies for melanoma. Moving forward, either nivolumab or dabrafenib plus trametinib will be the adjuvant therapy of choice for stage III melanoma, with treatment choice dependent on BRAF mutation status and physician and patient preference.

Additional reiteration (if you're into redundant redundancy) was noted in an editorial by Lynn Schuchter M.D. in The New England Journal of Medicine, published today:

Adjuvant Melanoma Therapy - Head-Spinning Progress

There she states, in part:

"Every year in the United States, approximately 87,000 patients receive the diagnosis of melanoma. Although most of these patients are cured with simple excision, those with node-positive, stage III melanoma are at increased risk for distant metastasis and death. To date, the Food and Drug Administration (FDA) has approved three adjuvant therapies for such patients, all of which are immunotherapies: high-dose interferon alfa-2b, pegylated interferon alfa, and high-dose ipilimumab (10 mg per kilogram of body weight).  Concerns about the marginal efficacy of these drugs (especially the interferon-based agents) and considerable toxicity (all three drugs) have limited their use. Therefore, the current standard of care for patients with node-positive melanoma includes observation without therapy, the use of one of the approved adjuvant therapies, or participation in a clinical trial."

She goes on to note the approval of "8 new drugs for the treatment of melanoma, seven of which have improved survival" - noting specifically the use of BRAF/MEK inhibitors and immunotherapy over the past 5 years - continuing:   "With these new approaches, some patients have been cured and many have seen remarkable improvements in symptoms...and duration of life.  The median overall survival of patients with disseminated melanoma has increased from 9 months before 2011 to 2 years or more."

As does the report above, she notes the results of the Weber presentation of the CheckMate 238 trial and the COMBI-AD trial.  Stating further:   "How do these results compare with those currently approved adjuvant therapies in patients with node-positive melanoma?  High-dose interferon...was approved more than 20 years ago and has been extensively studied...and showed no benefit in overall survival.  [It] has been associated with substantial toxic effects...the majority of patients... [fail to complete] 1 year of therapy, and the frequency of Grade 3/4 events has been more than 65%. 

Adjuvant high-dose ipilimumab was approved by the FDA 2 years ago on the basis of the results of EORTC 18071, which compared ipi with placebo...[and] significant benefit of overall survival was reported [with ipi]...Although high dose ipi has been shown to be effective, the toxicity of ipi at a dose of 10 mg/kg continues to pose a major challenge as an adjuvant therapy.

...Adjuvant therapy with nivo in patients with node-positive melanoma may now be considered a new standard of care, regardless of BRAF status.  On the basis of efficacy and safety, nivolumab, unequivocally, is a better choice than interferon or high-dose ipilimumab.  Adjuvant combination therapy with dabrafenib and trametiib is also an option for patients with node-positive BRAF-mutated melanoma.  Testing of melanoma tumors for the presence of BRAF mutations may now become standard in patients with node-positive, stage III melanoma.  There is no longer a role for adjuvant interferon in patients with  node-positive melanoma."

So, there!!!

Come on, FDA peeps!!!  If you or your loved one were affected...these therapies...not the crap you approved years ago....are the ones YOU would want!!! - c