Updates from Melanoma Trials Demonstrate New Roles for Adjuvant/Neoadjuvant Treatment

Sapna Patel, MD

Varying therapies for the neoadjuvant and adjuvant treatment of melanoma based on staging continue to be explored with pembrolizumab (Keytruda) a common agent in both settings, according to Sapna Patel, MD.

Patel’s presentation at the 40th Annual CFS^® meeting, “Neoadjuvant and Adjuvant Therapeutic Approaches for Melanoma” highlighted clinical trials such as phase 2 S1801 (NCT03698019) and discussed the role of pembrolizumab as well as agents nivolumab (Opdivo) plus ipilimumab (Yervoy) in the treatment paradigm.

In an interview with OncLive^®, Patel, chair of the SWOG melanoma committee and an associate professor at The University of Texas MD Anderson Cancer Center in Houston, reviewed several key studies across stages of melanoma and emerging targeted therapies for patients with BRAF mutations.

Please discuss the top-level findings from S1801?

[At CFS^®] I presented data from S1801 which was a randomized phase 2 study for participants with resectable stage IIIB to IV melanoma [who] were [randomly assigned] 1:1 to either upfront surgery followed by adjuvant anti–PD-1 flat-dose therapy for 1 year or neoadjuvant pembrolizumab [for] 3 doses followed by surgery [and] adjuvant pembrolizumab 15 additional doses to complete 1 year of treatment.

In the neoadjuvant setting, S1801 was practice changing because if you have resectable melanoma, you could do the traditional [resection] and give patients adjuvant therapy, but you have a demonstrable benefit by doing some medicine upfront with single agent PD-1; it is minimally toxic and minimally disruptive to quality of life. The next question is would combination immunotherapy do better?

Combination immunotherapy has a stronger response rate in metastatic melanoma, but it also has more toxicity. That toxicity in the neoadjuvant setting could lead to delays in surgery and loss of a surgical window and it could lead to disease progression. If you hold therapy [and] give steroids that melanoma could certainly progress.

What was the significance of the IMMUNED (NCT02523313) trial?

For [patients with] stage IV metastatic melanoma, if you can resect the oligometastatic disease or a small volume of the disease, [you can ask]: Should you be giving systemic therapy in this adjuvant setting.

IMMUNED randomly assigned participants to receive either nivolumab with ipilimumab [followed by] nivolumab [alone], or double placebo, and [investigators] found that nivolumab plus ipilimumab with maintenance nivolumab for up to 2 years of therapy did have a significant improvement in [recurrence-free survival] RFS or disease recurrence compared with nivolumab and the placebo arm. If a [patient has] stage IV disease [and after resection has] no evidence of disease [NED] or who gets radiation for their stage IV lesion within 8 weeks of that rendering of NED, nivolumab/ipilimumab should be considered for them for a 2-year duration to improve survival. Strikingly, the benefit in the BRAF-mutated patients is very high; if you have a patient with a BRAF-mutation this should be considered for them.

How has targeted therapy been integrated into treatment for patients with BRAF mutations?

The DREAMseq [NCT02224781] trial in metastatic melanoma established that we should start most patients on combination immunotherapy rather than BRAF/MEK [inhibitor] therapy except for those who do poorly starting [on that therapy]. In the neoadjuvant space it may be similar. [Results of a] pooled analysis from the International Neoadjuvant Melanoma Consortium found that pathologic [complete responses] CRs and major CRs to immunotherapy were long lasting, whereas pathologic CRs and major complete pathologic responses to BRAF/MEK therapy still [resulted in] relapse or disease recurrence. In the neoadjuvant space we will also be swinging to immunotherapy over targeted therapy. Head-to-head trials have not been performed and that certainly could be designed.

Multiple studies that have demonstrated the efficacy [of adjuvant anti–PD-1 thereapy]. There is also COMBI-AD [NCT01682083], which demonstrated the efficacy of targeted BRAF/MEK therapy for BRAF-mutated melanoma. It’s a question of where do you think your cure fraction is? An important real-world piece of evidence is that [for] patients who receive adjuvant PD-1 therapy in the real world a number of recurrences that happen on therapy. In that 1 year of adjuvant therapy, as many as 20% to 30% of people will relapse.

Very few relapses in the real world happen on adjuvant BRAF/MEK [therapy and] in the year that patients are receiving adjuvant BRAF/MEK inhibition, patients are not likely to experience a relapse, but upon discontinuation the relapses occur. If you [review] real-world evidence you may find yourself wanting to prescribe BRAF/MEK in the adjuvant setting and that makes sense where you have the potential to cure patients and then if they’re metastatic you have frontline immunotherapy.

What was your main take home message for colleagues regarding all the updates in these 2 spaces?

In the resectable setting, you now have the opportunity to use single agent PD-1 therapy. Once those data are published and [incorporated] into clinical guidelines, we’ll have more help with getting insurance approval for that regimen. For stage II melanoma we now have adjuvant therapy using single agent PD-1, for stage IIIB and up we have clear evidence of either single agent immunotherapy for stage IIIB, IIIC, IV melanoma, and for stage IV adjuvant ipilimumab with nivolumab. There is no role for adjuvant ipilimumab with nivolumab outside of resected stage IV and the key for stage IIIA patients is that that risk is so minimal, it’s unclear that the use of adjuvant therapy improves survival at this point.