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Dual Neoadjuvant Checkpoint Blockade Feasible in Melanoma

<ѻý class="mpt-content-deck">— Good survival outcomes, but high rates of toxicities, with ipilimumab-nivolumab combo
MedpageToday

Combination neoadjuvant immune checkpoint blockade therapy yielded promising outcomes in high-risk resectable melanoma, although toxicity was an issue, according to a phase II trial.

The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) led to improved progression-free survival (PFS), distant metastasis-free survival (DMFS), and overall survival (OS) versus neoadjuvant nivolumab monotherapy in 23 patients with high-risk resectable melanoma, reported Jennifer A. Wargo, MD, of MD Anderson Cancer Center in Houston, and colleagues in

Outcomes were as follows:

  • PFS: 82% (95% CI 45%-95%) at 17.2 months with ipilimumab-nivolumab combo versus 58% (95% CI 27%-80%) at 22.6 months with monotherapy (P=0.19)
  • DMFS: 91% (95% CI 51%-99%) at 17.2 months versus 67% (95% CI 34%–86%) at 22.6 months (P=0.17)
  • OS: 100% (95% CI 100%-100%) at 24.4 months versus 76% (95% CI 31%-94%) at 22.6 months (P=0.18)

"The advantage of a neoadjuvant approach in this setting is that it enables an interval evaluation of the tumor cells after therapy to determine the extent to which those tumor cells responded to the therapy in real time, and predict which patients are likely to experience durable responses going forward," co-author Michael Tetzlaff, MD, PhD, also of MD Anderson, said in a news release.

However, toxicity rates differed significantly between arms, with grade ≥3 treatment-related adverse events (TRAEs) reported in 8% (1/12; tumor-related pain) of patients treated with monotherapy but 73% (8/11) of patients treated with combo therapy. No grade 4 TRAEs occurred.

The researchers noted that 40 patients were planned for accrual, but the trial was stopped early for two reasons, one of which was the high rates of grade 3 TRAEs with combo therapy.

For the study, 11 patients were randomized to combo therapy and 12 patients were randomized to nivolumab monotherapy. They had clinical stage IIIB disease, stage IIIC disease, or oligometastatic stage IV disease. The median follow-up was 15.6 months for the combo therapy arm and 15 months for the monotherapy arm.

Patients were randomized to one of two 8- or 9-week immune checkpoint inhibitor regimens used in unresectable melanoma: PD-1 blockade with nivolumab 3 mg/kg-1 every 2 weeks or CTLA-4 blockade with ipilimumab 3 mg/kg-1 plus nivolumab 1 mg/kg-1 every 3 weeks.

RECIST overall response was documented in three of 12 patients on monotherapy versus eight of 11 patients on combo therapy.

In 73% of patients on combo therapy, tumors shrank and 45% of these patients had no evidence of disease at time of surgery. In comparison, monotherapy yielded an overall and pathological response rate of 25%.

Two patients with progressive disease on monotherapy were unable to have definitive surgical resection after developing synchronous metastatic disease and local progression.

"This was an unexpected finding," Wargo told ѻý. "Some patients on monotherapy did have a pathologic complete response ... suggesting that, for some patients, monotherapy is perfectly okay but not for all."

Grade 3 TRAEs with combo therapy included transaminitis (27%), colitis (18%), hyperthyroidism (9%), pneumonia (18%), arthralgias (9%), myositis and/or myalgias (9%), electrolyte abnormalities (hypokalemia 9%; hyponatremia 18%), hyperglycemia (9%), fall (9%), and sinus tachycardia (9%).

Dose delays were required in 64% of patients (7/11) on combo therapy, while no delays were required with monotherapy. During the postoperative and adjuvant periods, serious adverse events occurred in two patients in the nivolumab arm (one grade 3 colitis; one grade 4 diabetic ketoacidosis in one patient) and an additional one patient in the combo arm (hypophysitis).

"This was a pretty aggressive regimen, so we're looking at altering doses, perhaps giving a single dose of ipilimumab followed by two doses of nivolumab," Wargo explained.

The inclusion of patients with stage IV oligometastatic disease was a study limitation, making the study participants "relatively heterogeneous," the authors noted, thereby decreasing the generalizability of the results to a stage III population.

The researchers have designed a new 40-patient study, in collaboration with Memorial Sloan Kettering Cancer Center in New York City, to explore the safety and efficacy of neoadjuvant nivolumab plus the investigational treatment relatlimab, an inhibitor of the LAG-3 immune checkpoint.

"This combination may be more effective than nivolumab alone and less toxic than combined CTLA-4 and PD-1 blockade," she said.

In BRAF-mutated melanoma, a previous small study by Wargo's group showed that targeted combination therapy before and after surgery for high-risk disease melanoma yielded a more than six-fold improvement in event-free survival (EFS) compared with surgery alone. Patients receiving combination dabrafenib (Tafinlar) plus trametinib (Mekinist) had a median EFS of 19.7 months versus 2.9 months for patients who had surgery alone.

"Patients with resectable high-risk melanoma can now have effective treatment before surgery. If you go straight to surgery, there's a high risk of relapse," Wargo said, adding that murine studies have suggested neoadjuvant treatment may induce an antigenic response.

A German study found using two agents significantly reduced melanoma recurrence versus placebo. After almost 3 years' follow-up, patients treated with dabrafenib (Tafinlar) and trametinib (Mekinist) combination therapy had relapse-free survival of 58% versus 39% for patients treated with surgery alone.

The MD Anderson group is also working with an international melanoma consortium to harmonize the study of neoadjuvant therapies. "We're teaming up with other research centers, the FDA, the pharmaceutical industry, patients, and advocacy groups in order to make a big difference," Wargo said.

  • author['full_name']

    Diana Swift is a freelance medical journalist based in Toronto.

Disclosures

This study was funded by Bristol-Myers Squibb (BMS).

Wargo disclosed relevant relationships with BMS, Dava Oncology, GlaxoSmithKline, Roche/Genentech, Novartis, and AstraZeneca, as well as holding a U.S. patent. Tetzlaff disclosed relevant relationships with Myriad Genetics, Seattle Genetics, and Novartis. Co-authors disclosed multiple relevant relationships with industry.

Primary Source

Nature Medicine

Amaria RN, et al “Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma” Nat Med 2018; DOI:10.1038/s41591-018-0197-1