Adjuvant Immunotherapy Combinations on Horizon for Melanoma

Quickly following on the approval of single agents, adjuvant immunotherapy combinations are quickly progressing through development, with promising signs of clinical activity seen in phase II studies, according to a presentation by Jeffrey S. Weber, MD, PhD, at the 37th Annual CFS®.

Jeffrey Weber, MD, PhD

Quickly following on the approval of single agents, adjuvant immunotherapy combinations are quickly progressing through development, with promising signs of clinical activity seen in phase II studies, according to a presentation by Jeffrey S. Weber, MD, PhD, at the 37th Annual CFS®.1

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) 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 (Yervoy) in the adjuvant space, resulting in a placebo control arm. The trial enrolled those with BRAF V600—mutant stage III melanoma.

“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,” said Weber, of the Laura and Isaac Perlmutter Cancer Center of NYU Langone Health. “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.”

In long-term findings from the phase III COMBI-AD study,2 the 4-year relapse-free survival (RFS) rate was 54% with the combination compared with 38% in the placebo arm (HR, 0.49; 95% CI, 0.40-0.59). The distant metastases-free survival 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).

In addition to targeted combinations, immunotherapy combinations—such as nivolumab plus ipilimumab which was approved for the treatment of metastatic melanoma in 2015—are now being tested in the adjuvant setting. In early findings from the phase II IMMUNED study,3 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).

“This looks phenomenal, and these are the patients with the worst outcomes. It’s fantastic, looks very good. It’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,” said Weber. “These data are very promising.”

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.

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’ Education Resource®, LLC; November 6-8, 2019; New York, New York.
  2. 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.
  3. 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.

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