Standards evolve for adjuvant therapy of melanoma
NEW YORK — A strong rationale exists for offering adjuvant therapy to certain patients with melanoma, but several aspects of treatment remain controversial, according to a presenter at HemOnc Today New York.
“Regardless of the treatment advances we have seen, metastatic melanoma is still a disease worthy of respect,” meeting co-chair Sanjiv S. Agarwala, MD, chief of medical oncology and hematology at St. Luke’s Cancer Center and professor of medicine at Temple University, said during his presentation. “For every 40% response rate, we have a 60% nonresponse rate, and we can’t forget that.”
Early intervention in the adjuvant setting may lead to improved long-term cure rates. Prognostic factors for assessing recurrence risk are becoming more clearly defined, and patient selection also is key, as most melanoma-related deaths occur among patients initially diagnosed with stage II or stage III disease, Agarwala said.
Checkpoint inhibitors are one option for adjuvant therapy.
The EORTC 18071/CA184-029 trial showed the CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb) prolonged RFS (HR = 0.76; 95% CI, 0.64-0.89) and OS (HR = 0.72; 95% CI, 0.58-0.88) in the adjuvant setting compared with placebo.
However, a higher percentage of patients who received ipilimumab than placebo experienced grade 3/grade 4 adverse events (54.1% vs. 26.2%) and discontinued therapy due to grade 3/grade 4 adverse events (32.9% vs. 0.6%).
Five patients (1.1%) in the ipilimumab group died — three due to colitis, one due to myocarditis, and one who had multiorgan failure with Guillain-Barré syndrome.
“That is unacceptable [in cases when] they are surgically cured and you’re giving them a drug that they may not even need,” Agarwala said.
A rationale existed for adjuvant therapy with anti-PD-1 agents — such as pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb) — because they were more effective than and less toxic than ipilimumab for patients with metastatic melanoma.
The CheckMate 238 study compared nivolumab with high-dose ipilimumab for patients with high-risk, completely resected stage IIIB/IIIC or stage IV melanoma who received no prior systemic therapy and had ECOG performance status of 0 or 1.
Results showed prolonged median RFS in the nivolumab group (30.8 moths vs. 24.1 months; HR = 0.66; 95% CI, 0.54-0.81).
Nivolumab also exhibited a favorable toxicity profile, with fewer patients in that group experiencing treatment-related grade 3/grade 4 adverse events (14% vs. 46%) or discontinuing therapy due to any treatment-related adverse event (8% vs. 42%).
No treatment-related deaths occurred in the nivolumab group. Two treatment-related deaths occurred in the ipilimumab group. Both deaths — one due to colitis and the other due to marrow aplasia — occurred more than 100 days after the final ipilimumab dose.
“Anti-PD-1 agents work in adjuvant therapy also,” Agarwala said. “They are better than ipilimumab and they are less toxic and, therefore, they are a new standard of care. Note that I don’t say the new standard of care, because there are other options for certain patients.”
Those options include targeted therapy.
Approximately 40% of patients with melanoma have BRAF-positive disease, and combinations of BRAF and MEK inhibitors work well in metastatic melanoma.
The COMBI-AD study evaluated this approach in the adjuvant setting for patients with completely resected, high-risk stage IIIA, IIIB or IIIC cutaneous melanoma with BRAF V600E or V600K mutations. All patients had ECOG performance status of 0 or 1 and had received no prior systemic therapy.
Researchers randomly assigned 438 patients to the BRAF inhibitor dabrafenib (Tafinlar, Novartis) dosed at 150 mg twice daily plus the MEK inhibitor trametinib (Mekinist, Novartis) dosed at 2 mg once daily. The other 432 patients received matching placebos. RFS served as the primary endpoint.
Researchers reported a significantly higher 3-year RFS rate in the dabrafenib-trametinib group (58% vs. 39%; HR = 0.47; 95% CI, 0.39-0.58).
Patients assigned the experimental regimen experienced higher rates of pyrexia (any grade, 66% vs. 11%; grade 3/grade 4, 5% vs. < 1%), fatigue (any grade, 47% vs. 26%; grade 3/grade 4, 4% vs. < 1%), nausea, headache, chills, diarrhea, vomiting, arthralgia and rash.
“Targeted therapy with BRAF/MEK combinations work in adjuvant therapy,” Agarwala said. “Toxicity is as expected, [and this approach] also is a new standard of care for BRAF-positive patients.”
Agarwala and his team offer anti-PD-1 therapy with nivolumab or pembrolizumab in the adjuvant setting to patients with BRAF V600-negative disease. Those who have BRAF V600 mutation-positive disease can receive either anti-PD-1 therapy or the dabrafenib-trametinib combination.
“So how do you decide what to do?” Agarwala said. “Is there a randomized trial to tell us what to do? No, there is not, so it’s a clinical judgment right now.”
Considerations include IV administration of anti-PD-1 therapy every 2 to 4 weeks vs. daily oral administration of BRAF/MEK therapy.
Toxicity also varies. It is chronic but manageable with BRAF/MEK inhibitors and stops during treatment breaks. Toxicity is less frequent with anti-PD-1 therapy but can be severe if it occurs, and it does not always stop with a treatment break.
Other controversies surrounding adjuvant therapy exist.
For example, all available data are from the era of completion lymphadenectomy, but that is no longer the standard of care.
“Can we extrapolate? We’re going to have to, but I’m a little uncomfortable with that,” Agarwala said.
In addition, metastatic melanoma may be curable for some patients.
“Are we curing the same patients in the adjuvant setting, and the price of that is treating everybody rather than just those who need it,” Agarwala said. “Another question is, can we afford adjuvant therapy? This is not cheap.”
Agarwala concluded by outlining questions that still must be addressed in current or future trials. These include the efficacy and safety of ipilimumab plus nivolumab, whether adjuvant treatment should be considered for patients with earlier-stage disease or for those with resected stage IV disease, and the potential role of neoadjuvant therapy. – by Mark Leiser
Agarwala SS. Curing melanoma with adjuvant therapy: Are we there yet? Presented at: HemOnc Today New York; March 21-23, 2019; New York.
Disclosure: Agarwala reports consultant fees from Merck.