Focus Moves to Earlier Settings in Melanoma

Axel Hauschild, MD

Novel systemic therapies in the neoadjuvant and adjuvant settings have shown promising outcomes for locally advanced melanoma and may reduce the proportion of patients who need complete lymphadenectomy. Optimizing systemic therapy to maximize efficiency and minimize adverse events (AEs) will be the next step moving forward, according to panelists who participated in an OncLive Peer Exchange^® panel.

The panelists discussed recent clinical trial results showing high rates of pathologic response with neoadjuvant therapy that targets BRAF and MEK and agents that modulate the immune system, lack of improvement in overall survival (OS) with complete lymphnode dissection for sentinel node metastases, and substantial improvements in relapsefree survival (RFS) with adjuvant BRAF- plus MEK-targeted therapy and PD-1 targeted therapy. Although the panelists agreed that systemic therapy should play a key role in the treatment of locally advanced disease, determining the optimal agents and duration of therapy will require head-to-head trials comparing the regimens. Effective treatment approaches also will involve combinations of agents, according to Axel Hauschild, MD, PhD.

Role of Surgery in Locoregional Disease

The trend in melanoma therapy has been toward combinations, and Hauschild said he expects that to continue. Sequencing drugs correctly will be important, he noted.Neoadjuvant Therapy

Traditionally, the standard of care for patients with stage III melanoma has included surgical removal and possible adjuvant treatment. However, recent data on the effectiveness of different systemic therapies have raised questions about the relative roles of surgery and neoadjuvant therapy for locoregional management of stage III melanoma, according to Michael A. Postow, MD.

Multiple clinical trials have investigated the efficacy of BRAF and MEK inhibitors, single-agent PD-1 inhibitor therapy, or combinations of ipilimumab (Yervoy) and PD-1 inhibitors for reducing tumor size to improve resectablity and treating micrometastatic disease that leads to recurrence. Neoadjuvant trials showed high rates of pathologic response with dabrafenib (Tafinlar) plus trametinib (Mekinist) for resectable stage IIIB/C BRAF V600-mutated melanoma¹ and ipilimumab plus nivolumab (Opdivo) for stage IIIB/C melanoma.² However, Caroline Robert, MD, PhD, said that the optimal duration of treatment is unknown.

“These patients with big, palpable stage III disease…the reality is that we think they might be stage IV,” she said. “We’re in a situation of a very small burden of [stage IV] disease, so how long to treat...is the real question.”

Complete Lymphadenectomy

Complete lymph-node dissection, which involves removal of the regional lymph nodes after excision of the sentinel node, is often recommended for patients with sentinel node metastases. However, retrospective analyses of the utility of complete lymph-node dissection are inconclusive, and the procedure is associated with considerable morbidities and complications.

Findings from the recently published prospective MSLT-II trial³ show that complete lymph-node dissection led to a slightly improved disease-free survival (DFS; attributed to the reduced rate of nodal recurrence after dissection) but did not improve the primary endpoint of OS in patients with sentinel lymph node metastases. These results could affect surgical paradigms at institutions, according to Reinhard G. Dummer, MD. For patients with a tumor burden ≤1 mm, he and his colleagues perform ultrasonography with close follow-up instead of a complete lymphadenectomy, which has reduced the number of surgeries by approximately 70% in his clinic. However, he performs a complete staging of patients with nodal involvement >1 mm. “If you don’t do it, then you have no information about the stages of the other nodes.” However, Dummer noted that some of the new trials for adjuvant therapy do not mandate lymphadenectomy for inclusion, perhaps acknowledging the lack of OS benefit in the MSLT-II trial.

Adjuvant Therapy

Nevertheless, Hauschild pointed out that ultrasonography surveillance of lymph nodes alone could miss some cases that require surgery because approximately 18% of the patients in the MSLT-II study had positive nonsentinel lymph nodes that were only found with complete lymphadenectomy. Hauschild and moderator Jeffrey S. Weber, MD, PhD, agreed that identifying the small subgroup of patients likely to have a high tumor load— such as those with a high tumor burden in the sentinel node or extracapsular spread—and discussing the benefits and consequences of complete lymphadenectomy, as well as options for adjuvant therapy, are important to select patients most likely to benefit from surgery.BRAF- and MEK-targeted and immunetargeted therapies have been shown to improve OS in nonresectable and metastatic melanoma, and multiple studies of their roles in the adjuvant setting have recently shown promising outcomes in stage III resected melanoma.

The phase III double-blind, placebo-controlled COMBI-AD trial⁴ showed that dabrafenib plus trametinib significantly improved RFS and OS in patients with completely resected stage III melanoma with BRAF V600E or V600K mutations, with hazard ratios (HRs) of 0.47 for relapse or death and 0.57 for death. According to Hauschild, these were, “the best results I have ever seen in an adjuvant trial in melanoma.” The FDA has granted a priority review for a supplemental new drug application for use of the dabrafenib/ trametinib combination in this setting.

However, Hauschild noted that the treatment discontinuation rate was unusually high (24%), even though the incidence of grade 3 or 4 toxicities was typical for the patient population. Although the reason for the high discontinuation rate was unclear, Hauschild suggested that the perceived lack of urgency for adjuvant therapy in phase III melanoma may lead patients to opt out of systemic therapy.

The results of the phase III CheckMate-238 trial⁵ demonstrated significant improvement in RFS with nivolumab over ipilimumab in patients with resected stage IIIB/C and IV melanoma and led to FDA approval of adjuvant nivolumab monotherapy on December 21, 2017. ⁶ According to Weber, the high efficacy of nivolumab for preventing recurrence may reduce the role of the surgeon for management of locally advanced disease.

Nivolumab was also associated with substantially less toxicity than ipilimumab in the CheckMate-238 trial, with treatment-related grade 3 or 4 AEs reported in 14.4% of patients in the nivolumab group and 45.9% of patients in the ipilimumab group. Based on these data, Postow predicted that ipilimumab will likely be replaced by nivolumab in the adjuvant setting.

“If you’re going to be giving adjuvant immunotherapy, you’ll choose adjuvant nivolumab. If you’re going to be considering targeted therapy, it would be the BRAF and MEK combination of dabrafenib and trametinib for stage III patients,” he said.

However, Postow noted that the choice of adjuvant therapy for a patient with BRAF-mutated stage III melanoma is unclear because there are no randomized data to compare adjuvant nivolumab with dabrafenib plus trametinib. The panelists also cautioned against comparing the trial results of the 2 therapeutic regimens because of the different patient populations studied, although Hauschild pointed out that data for dabrafenib plus trametinib were consistent for every subgroup factor (patients were stratified based on V600E versus V600K, as well as stage IIIA, IIIB, or IIIC), indicating that the combination likely works similarly well across all subgroups.

Vemurafenib (Zelboraf), a first-in-class BRAF kinase inhibitor, has robust clinical activity against the BRAF V600E mutation and is approved by the FDA for unresectable or metastatic melanoma. Data presented at the 2017 ESMO Congress7 showed that adjuvant vemurafenib improved DFS in patients with fully resected stage IIC, IIIA, or IIIB melanoma, and Postow noted that it appeared to reduce disease recurrence beyond the period during which patients were on active treatment. “There may be something immunologic happening or maybe something more permanent that happens when patients are on somewhat of a limited course of targeted therapy,” said Postow. “And we don’t really completely understand what’s going on there.”

Robert also noted that adjuvant pembrolizumab (Keytruda) could be another treatment option. Although data from the phase III EORTC1325/KEYNOTE-054 trial were not available at the time of the panel discussion, an online publication8 by Merck reported that adjuvant pembrolizumab reduced risk for recurrence by 43% compared with placebo in patients with resected stage III melanoma at high risk for recurrence and did not introduce any additional safety concerns.

However, Weber pointed out that data from the CheckMate-238, COMBI-AD, and EORTC trials will likely introduce controversy over which agent is superior for adjuvant therapy.

Reducing Toxicity

“Each trial may change the parameter,” said Weber. “We had a few years where we used [ipilimumab]. Now we’ll have a time where we use BRAF/MEK [inhibitors] or nivolumab and who knows what it will be.”Considering the high toxicity of ipilimumab, Hauschild also suggested conducting trials that test shorter durations of therapy, such as a 3-month regimen instead of a 12-month regimen for certain patients. However, Robert pointed out that whether the lack of efficacy of a shorter regimen is due to the duration of treatment or the agents themselves would be unclear.

Key to Future Progress

Weber also stated that in his pilot studies of adjuvant ipilimumab plus nivolumab, patients with stage IIIB/ IIIC disease did not tolerate high doses of ipilimumab. Considering these patients may have a 50% risk for relapse, the toxicity of highdose ipilimumab is “a tough sell,” according to Weber. A regimen lower in ipilimumab (1 mg/kg) and higher in nivolumab (3 mg/kg) improved tolerability over a regimen of 3 mg/ kg ipilimumab plus 1 mg/kg nivolumab. Weber noted that spacing out the doses may also reduce toxicity. In 2015, the FDA approved adjuvant ipilimumab at a dosage of 10 mg/kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity.The panelists concluded by stating that the rapid progress in the treatment of melanoma and its position as the pioneer of immunotherapy and targeted therapy were due to a strong research community that encourages open sharing of the latest data. Postow also acknowledged the important role of patient participation in clinical trials. “This is the reason we know what we know about all of our drugs right now. And as happy as we’ve been with all of our advances, until we get to 100%, there’s more work to be done,” he said.

References

1. Menzies AM, Gonzalez M, Guminski A, et al. Phase 2 study of neoadjuvant dabrafenib + trametinib (D+T) for resectable stage IIIB/C BRAF V600 mutant melanoma. Abstract presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 1220PD. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/Phase-2-study-of-neoadjuvant-dabrafenib-trametinib-D-T-for-resectable-stage-IIIB-C-BRAF-V600-mutant-melanoma.
2. Rozeman EA, Fanchi L, van Akkooi ACJ, et al. (Neo-)adjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage 3 melanoma — updated relapse free survival (RFS) data from the OpACIN trial. Abstract presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 1221PD. academic.oup.com/annonc/article/28/suppl_5/mdx377.008/4109295.
3. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med. 2017;376(23):2211-2222. doi: 10.1056/NEJMoa1613210.
4. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-1823. doi: 10.1056/NEJMoa1708539.
5. Weber J, Mandala M, Del Vecchio M, et al; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835. doi: 10.1056/NEJMoa1709030.
6. FDA grants regular approval to nivolumab for adjuvant treatment of melanoma [press release]. Silver Spring, MD: FDA; December 21, 2017.www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590004.htm. Accessed January 18, 2018.
7. Lewis K, Maio M, Demidov L, Mandala M, et al. BRIM8: a randomized, double-blind, placebo-controlled study of adjuvant vemurafenib in patients (pts) with completely resected, BRAFV600+ melanoma. Abstract presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA7_PR. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/BRIM8-a-randomized-double-blind-placebo-controlled-study-of-adjuvant-vemurafenib-in-patients-pts-with-completely-resected-BRAFV600-melanoma-at-high-risk-for-recurrence.
8. Merck’s Keytruda (pembrolizumab) significantly improved recurrence-free survival compared to placebo as adjuvant therapy in patients with stage 3 resected high-risk melanoma (EORTC1325/KEYNOTE-054) [press release]. Kenilworth, NJ: Merck; January 8, 2018. mrknewsroom.com/news-release/oncology/mercks-keytruda-pembrolizumab-significantly-improved-recurrence-free-survival-. Accessed January 18, 2018.