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CHICAGO -- Combination neoadjuvant immunotherapy for resectable melanoma reduced recurrence and other clinical events by two-thirds versus adjuvant therapy, a randomized trial showed.

Patients treated with nivolumab (Opdivo) and ipilimumab (Yervoy) and response-guided adjuvant nivolumab had an overall event rate of 13% versus 34% with adjuvant nivolumab. The difference translated into a 68% improvement in the hazard ratio for event-free survival (EFS), including a difference of 83% vs 57% at 12 months. The benefit was consistent across major subgroups, including BRAF mutation status.

Almost 60% of the neoadjuvant arm achieved a major pathologic response (MPR), which was associated with a 12-month EFS of 95%, reported Christian U. Blank, MD, of the Netherlands Cancer Institute in Amsterdam, at the American Society of Clinical Oncology (ASCO) meeting.

"Together with the SWOG 1801, I think the trial, defines that neoadjuvant immunotherapy is the new standard of care for macroscopic stage III melanoma, which means that all trials that are currently ongoing need to be amended from adjuvant comparators to neoadjuvant comparators," said Blank. "It is a new template for other malignancies, implementing a neoadjuvant immunotherapy regimen, followed by response, to adjuvant therapy."

"I think we see at the moment only sandwich design [neoadjuvant followed by adjuvant], and this is more sales driven than patient driven, because what you have seen is if the patient achieves a really deep response, the patient doesn't need the adjuvant part," he added.

ASCO expert Michael Lowe, MD, of Emory University in Atlanta, agreed that the trial confirms the superiority of neoadjuvant therapy for resectable stage III melanoma.

"The study also confirms that giving two immunotherapy drugs before surgery results in excellent responses," said Lowe. But he cautioned that "all patients got two immunotherapies, so we cannot make a comparison [with SWOG 1801 with pembrolizumab (Keytruda) alone]. But [NADINA] confirms with consistency that patients who receive ipilimumab and nivolumab have superior responses compared with single-agent immunotherapy."

"Also, all patients had all of their lymph nodes removed, so this should remain the standard of care in terms of surgical approach," Lowe continued. "Lastly, for patients with major pathologic responses, [the adjuvant therapy] that they are being given after surgery, was omitted. It is too early to tell if some patients may have benefited from that adjuvant therapy."

ASCO chief medical officer Julie Gralow, MD, noted that "60% of patients did not require nonstop therapy, so really tremendous results. I think we do have a new standard of care here. We'll have some discussion about whether we should keep the tumor intact when giving immunotherapy in the early-stage setting to get more immune response and not do surgery first, and then try to stimulate the immune system when you've taken out all of the tumor and antigen."

Patients with macroscopic stage III melanoma have poor outcomes despite adjuvant therapy, with a 5-year relapse-free survival of 30% and OS of 50%, said Blank. Trials of adjuvant therapy have shown improved RFS but not an OS benefit, creating a need for novel, more effective therapeutic strategies.

An of adjuvant nivolumab-ipilimumab versus sandwich immunotherapy showed that the strategy with a neoadjuvant component more effectively destroyed malignant clones. Subsequently, the SWOG 1801 trial showed a 24-month EFS of 72% in patients who received immunotherapy before and after surgery versus 49% in those who received pembrolizumab only after surgery.

The rationale for the NADINA trial included evidence that achieved higher pCR rates and EFS as compared with neoadjuvant single-agent PD-1 inhibition. Use of of the combination improved safety and tolerability without sacrificing efficacy.

The NADINA protocol incorporated following evidence that patients with major pathologic response (≤10% residual viable tumor) to neoadjuvant therapy have excellent long-term outcomes without adjuvant therapy. For patients who do not achieve an MPR, the appears to improve outcomes.

In the NADINA trial, patients randomized to neoadjuvant therapy received two courses of the combination, followed by resection and lymph node dissection. Patients who achieved MPR received no further treatment, whereas those who had less than MPR received additional systemic therapy with or without radiotherapy (RT). In the control arm, patients had upfront resection and lymph node dissection followed by 12 courses of nivolumab with or without adjuvant RT.

The primary endpoint was EFS, and OS was a key secondary endpoint. Data analysis included 423 randomized patients, who were well balanced for clinical and demographic variables.

The primary analysis showed that the neoadjuvant strategy produced a hazard ratio of 0.32 versus adjuvant therapy (95% CI 0.15-0.66, P<0.0001). Outcomes were similar for patients with BRAF mutations (HR 0.29, 95% CI 0.11-0.79, P<0.0001) and those with wild-type BRAF (HR 0.35, 95% CI 0.12-1.03, P=0.0014).

Patients who achieved MPR with the two cycles of neoadjuvant therapy finished systemic treatment in 6 weeks.

"I think this is very interesting in times of scarce resources, not only financially but also healthcare professionals," said Blank. "You have treatments for our patients that are, in my view, highly potentially effective but don't use so much of the resources of our healthcare system."

Quality-of-life outcomes were similar between the two arms. The major adverse effects on quality of life come from the surgery, he said.

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