Adjuvant Options Arrive for Melanoma

Hussein A. Tawbi, MD, PhD

The treatment armamentarium for adjuvant melanoma has expanded rapidly, which has left the treatment challenge of selecting between immunotherapy and targeted therapy without any head-to-head comparative data. When picking a type of therapy, Hussein Tawbi, MD, PhD, recommended communicating the relative merits and risks of both options to patients and making a shared decision.

“First, I insist that BRAF testing be done before I start giving adjuvant therapy,” Tawbi, director of Melanoma Clinical Research and Early Drug Development in the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, in Houston, Texas, said during a presentation at the 36th Annual CFS^®. “I think patients need to know whether they have the option of going with BRAF therapy or immunotherapy, and then I share with them the results and the toxicity profiles. A lot of the times we let them choose.”

Older therapies were replaced by ipilimumab (Yervoy); however, this agent carries the potential for high toxicity, Tawbi said. More recently, the PD-1 inhibitor nivolumab (Opdivo) gained approval along with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist). Each of these agents carries a milder side effect profile compared with ipilimumab.

In a study of ipilimumab (10 mg/kg) versus placebo as adjuvant therapy for high-risk stage III melanoma, ipilimumab showed significantly higher rates of recurrence-free survival (RFS) and overall survival (OS); however, immune-related adverse events were high. The 5-year RFS rate was 40.8% for the ipilimumab group versus 30.3% for placebo (HR, 0.76; 95% CI, 0.64-0.89; P <.001). OS at 5 years was 65.4% versus 54.4%, respectively (HR, 0.72; 95.1% CI, 0.58-0.88; P = .001). Grade 3/4 adverse events occurred in 41.6% of the ipilimumab population, versus 2.7% in the placebo cohort.¹

“We all look at ipilimumab and we feel a little nervous about starting our patients on it; in the adjuvant setting even more so—obviously because of the high dose&mdash;but also we know that in this population we have a high risk of toxicity,” Tawbi said.

CheckMate-238 compared nivolumab with ipilimumab in resected stage III or IV melanoma and delivered a “hands-down” win in the adjuvant setting, Tawbi said. The 12-month RFS rate was 70.5% for nivolumab versus 60.8% for ipilimumab (HR, 0.65; 97.56% CI, 0.51-0.83; P <.001). In addition, grade 3/4 AEs were significantly lower for nivolumab versus ipilimumab: 14.4% versus 45.9%.²

COMBI-AD tested adjuvant dabrafenib and trametinib in high-risk BRAF V600 mutation-positive melanoma. Enrollment was restricted to patients with stage III nonmetastatic melanoma, 20% of whom were stage IIIa. Tawbi noted a “pretty massive difference” between active treatment and placebo. The RFS rate was 59% versus 40% at 3 years for dabrafenib plus trametinib versus placebo and 54% versus 38% at 4 years, respectively (HR, 0.49; 95% CI, 0.40-0.59).³

“In all honesty, I think we should apply the same metrics we use in breast cancer. We know that in breast cancer time and again it has been proven that patients prefer not to have a relapse. Living within the rubric of metastatic disease is not easy and it affects quality of life, and we still lose a lot of our patients to metastatic disease. Immunotherapy really is safe, and we use it frequently. Targeted therapy very definitely has a role,” he said.

A look at the toxicities and trial discontinuation in COMBI-AD and CheckMate-238 was revealing, although the patient populations were different, Tawbi noted. Grade 3/4 events experienced by 31% for targeted therapy versus 14.4% with immunotherapy. Additionally, discontinuation because of toxicity was lower with immunotherapy versus targeted therapy (9.7% vs 26%).^2,3

“The rates of toxicity are lower with immunotherapy, but the character of toxicity is different,” he said. “We always think do we want to give our patients toxicity that lasts forever, like with neuropathies, or do we want to give them toxicities that stop the minute therapy is stopped?”

Adding to the trial data, guidelines for staging melanoma are now more helpful for treatment decisions in the adjuvant setting, given that stages are redefined in greater detail, he said. The American Joint Committee on Cancer (AJCC) Eighth Edition Cancer Staging System provides greater separation between stages IIIa through IIId. Stage IIIa now includes all T1b tumors previously classified as stage IIIb.

Also, 5-year survival rates by AJCC guideline criteria have changed. Stage IIIa melanoma-specific 5-year survival is defined as 93% as opposed to 78% in the Seventh Edition. The stage IIIc numbers are 69% for the updated version versus 40%. Stage IIId has been introduced for T4b tumors with any N3 nodal involvement, which were classified previously as stage IIIc. The 5-year survival for stage IIId by AJCC guidelines is 32%.

“High-risk melanoma is truly high risk because those patients truly die of melanoma if you don’t treat them. There’s a lot of discussion whether you should wait until they relapse, because now we do so well for our metastatic patients,” said Tawbi.

Tawbi concluded by saying that ongoing trials in the stage III setting may deliver combinations that will lead to cures. One such trial, known as TRIDeNT, is exploring a triplet of nivolumab with dabrafenib and trametinib for patients with stage III-IV BRAF-mutant melanoma. The trial hopes to have initial results by the end of 2021 (NCT02910700).

References

1. Eggermont AMM, Chiario-Sileni V, Grob JJ, et al. Prolonged survival in stage iii melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845—1855. doi: 10.1056/NEJMoa1611299
2. Webber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824-1835. doi: 10.1056/NEJMoa1709030
3. Hauschild A, Dummer R, Schadendorf D, et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF V600—mutant stage III melanoma. J Clin Oncol. Published online October 22, 2018. doi: 10.1200/JCO.18.01219