Wealth of Options Available for Adjuvant Melanoma Therapy

Jeffrey S. Weber, MD, PhD

Immunotherapies and targeted therapies have greatly impacted the treatment of advanced melanoma and are beginning to make their way into earlier settings, with FDA approvals for adjuvant therapies and studies ongoing in the neoadjuvant space, according to a presentation by Jeffrey S. Weber, MD, PhD, at the37th AnnualCFS®.¹

The first adjuvant checkpoint inhibitor approved for patients with melanoma was the CTLA-4 inhibitor ipilimumab (Yervoy), this was followed by the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda), which may soon be joined by the combination of nivolumab and ipilimumab. Additionally, the targeted combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) has also gained approval as an adjuvant treatment forBRAF-mutant melanoma.

“Adjuvant dabrafenib plus trametinib has impressive prolongation of relapse-free survival and overall survival versus placebo in stage III resected disease, especially early,” said Weber, of the Laura and Isaac Perlmutter Cancer Center of NYU Langone Health. “Adjuvant nivolumab has an excellent long-term record of prolonging relapse-free survival in patients with resected stage IIIB/IIIC/IV melanoma. Data on pembrolizumab are less mature but it is an active adjuvant therapy. Adjuvant ipilimumab plus nivolumab appears to be even better than nivolumab alone.”

Single-Agent Adjuvant Therapies

The longest follow-up data available for a modern adjuvant therapy is for ipilimumab in patients with stage III melanoma from the EORTC 18071 study. In a 6.9-year analysis of the study, the estimated 7-year relapse-free survival (RFS) rate was 39.2% for adjuvant ipilimumab compared with 30.9% with placebo (HR, 0.75; 95% CI, 0.63-0.88;P<.001). Overall, 60.0% of patients remained alive in the ipilimumab arm compared with 51.3% in the placebo group at 7 years (HR, 0.73; 95% CI, 0.60-0.89;P= .002).²

Building on this, the phase III CheckMate 238 enrolled patients with both stage III and stage IV melanoma to compare adjuvant nivolumab with ipilimumab. In a 3-year assessment of these data,³the RFS rate with adjuvant nivolumab was 58% compared with 45% for ipilimumab (HR, 0.68; 95% CI, 0.56-0.82;P<.0001). This was seen across disease stages, Weber noted.³

An exploratory end point of distant metastases-free survival (DMFS) was also examined in the study as an early surrogate of overall survival (OS), Weber noted. As patients with stage IV disease had already experienced metastases, this analysis only looked at those with stage III disease. In this group, the 3-year DMFS rate was 66% with nivolumab versus 58% for ipilimumab (HR, 0.78; 95% CI, 0.62-0.99;P= .044).³

Although accepted in the United States, adjuvant ipilimumab was not globally introduced as an adjuvant standard of care. As such, an adjuvant study exploring pembrolizumab, which was conducted primarily in Europe, did not have ipilimumab in the comparator arm. In this study, which was labeled EORTC 1325/KEYNOTE-054, the 18-month RFS rate was 71.4% with pembrolizumab versus 53.2% with placebo (HR, 0.57; 95% CI, 0.43-0.74;P<.001). This trial enrolled patients with stage III disease only.⁴

Adjuvant Combination Therapies

The combination of dabrafenib and trametinib was the first targeted therapy combination approved for advanced melanoma, and quickly found its way into the adjuvant setting. The pivotal study that led to approval of the combination, known as COMBI-AD, was designed prior to the approval of ipilimumab in the adjuvant space, resulting in a placebo control arm. The trial enrolled those withBRAFV600&shy;—mutant stage III melanoma.

In long-term findings from the phase III COMBI-AD study, the 4-year RFS rate was 54% with the combination compared with 38% in the placebo arm (HR, 0.49; 95% CI, 0.40-0.59). The DMFS rate at 4 years was 67% in the dabrafenib/trametinib arm compared with 56% for placebo (HR, 0.53; 95% CI, 0.42-0.67). The OS rate at 3 years was 86% with the combination compared with 77% for placebo (HR, 0.57; 95% CI, 0.42-0.79;P= .0006).⁵

&ldquo;Targeted therapy has major activity in melanoma and is sometimes the treatment of choice for patients with rapidly progressing [tumors], high LDH [lactate dehydrogenase], and high disease burden,&rdquo; said Weber. &ldquo;Early on, it does seem like you do better with targeted therapy, whether that is maintained over time remains to be seen with longer follow-up with pembrolizumab and nivolumab.&rdquo;

In addition to targeted combinations, immunotherapy combinations—such as nivolumab plus ipilimumab which was approved for the treatment of metastatic melanoma in 2015&mdash;are now being tested in the adjuvant setting following the success seen with other checkpoint inhibitors in this space. In early findings from the phase II IMMUNED study, adjuvant treatment with the combination for patients with high-risk stage IV disease demonstrated a 2-year RFS rate of 70% compared with 42% for nivolumab alone (HR, 0.40; 95% CI, 0.22-0.73) and 14% for placebo (HR, 0.23; 95% CI, 0.13-0.41).⁶

One concern with the combination has been adverse events (AEs), which were higher with nivolumab and ipilimumab combined. In the study, treatment-related AEs of grade 3/4 in severity were experienced by 70.9% of patients in the combination group compared with 26.8% with nivolumab and 5.9% of patients in the placebo group.

&ldquo;This looks phenomenal, and these are the patients with the worst outcomes. It&rsquo;s fantastic, looks very good. It&rsquo;s better than any of the other immunotherapy arms looking at 1-year and 2-year [data]. The 2-year data here look as good as the 1-year data for pembrolizumab or nivolumab alone if you were looking at stage III disease, but this is stage IV,&rdquo; said Weber. &ldquo;These data are very promising.&rdquo;

The combination is being examined further in the phase III CheckMate 915 study, Weber said. This trial plans to randomize 1950 patients with stage III or IV disease to either nivolumab plus ipilimumab or nivolumab alone. The primary end point is RFS (NCT03068455). Results from the study are anticipated within the next few years, Weber said.

In addition to this adjuvant study, the combination of nivolumab and ipilimumab is being examined prior to surgery in the phase II OpACIN-neo study, Weber noted. This trial will look at a variety of doses for the combination with a primary end point focused on the occurrence of grade 3/4 immune-related AEs (NCT02977052).

References

1. Weber JS. Adjuvant Therapy for Melanoma. Presented at: 37th Annual CFS, hosted by Physicians&rsquo; Education Resource, LLC; November 6-8, 2019; New York, New York.
2. Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: Long-term follow-up results the EORTC 18071 double-blind phase 3 randomized trial.J Clin Oncol.2019;37(suppl 15;abstr 2512). doi: 10.1200/JCO.2019.37.15_suppl.2512.
3. Weber J, Del Vecchio M, Mandala M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase 3 CheckMate 238 trial. Presented at: European Society for Medical Oncology 2019 Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract 2801. bit.ly/2quxKwo.
4. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma [published online April 15, 2018].N Engl J Med.doi: 10.1056/NEJMoa1802357.
5. Long GV, Hauschild A, Santinami M, et al. Updated relapse-free survival (RFS) and biomarker analysis in the COMBI-AD trial of adjuvant dabrafenib + trametinib (D + T) in patients (pts) with resected BRAF V600—mutant stage III melanoma.Ann Oncol.2018;29(suppl 8;abstr LBA43). doi: 10.1093/annonc/mdy424.053.
6. Schadendorf D, Hassel JC, Fluck M, et al. Adjuvant immunotherapy with nivolumab (NIVO) alone or in combination with ipilimumab (IPI) versus placebo in stage IV melanoma patients with no evidence of disease (NED): A randomized, double-blind phase 2 trial (IMMUNED).Ann Oncol.2019;30(suppl 5;abstr LBA67). doi: 10.1093/annonc/mdy394.064.