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Expert Critique

FROM THE ASCO Reading Room

Danielle Elise Zimmerman, MD Hematology/Oncology fellow University of Florida Health

Immune checkpoint therapy has led to substantial improvement in survival for metastatic melanoma, and so its use is being examined in stage 3 melanoma as well. Two recent small studies aimed to show the efficacy and safety of either nivolumab alone or nivolumab and ipilimumab together in the neoadjuvant setting.

The OPACIN trial is a phase Ib study of 20 patients receiving either ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks for three cycles prior to regional lymph node dissection (RLND), followed by two cycles of the same ipilimumab and nivolumab combination; or ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks for four cycles following RLND. Seven of nine patients in the neoadjuvant therapy arm achieved both pathological and clinical CR (so two relapses in the neoadjuvant arm, compared with four relapses in the adjuvant arm), but nine of 10 patients in both groups experienced significant toxicity.

Another study looked at a similar idea: a phase II open label trial of 30 patients with either stage 3 or 4 melanoma aimed to answer if neoadjuvant therapy with nivolumab 3 mg/kg every 2 weeks for four cycles resulted in a different pathological CR rate compared with neoadjuvant ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks for three cycles. Path CR was 25% vs 45% and ORR was 25% vs 73%. There was a large difference in significant toxicity as anticipated: there were grade 3 side effects in 8% of the nivolumab arm and in 73% of the combination arm.

These studies do provide preliminary evidence that neoadjuvant treatment with nivolumab and ipilimumab combination therapy can be effective and may lead to improvements in survival, however, with a cost of significant side effects.

As the dosing recommendation for ipilimumab/nivolumab combination therapy in stage 4 melanoma was changed from 3 mg/kg and 1 mg/kg, respectively, to 1 mg/kg and 3 mg/kg after significant toxicity was reported in this similar setting, it would be reasonable to assess the efficacy of the ipilimumab 1 mg/kg and nivolumab 3 mg/kg regimen in the neoadjuvant setting. As most of the toxicity from this combination is thought to come from the higher dose of the more potent ipilimumab, a lower dose of ipilimumab could be anticipated to result in less toxicity in the stage 3 neoadjuvant setting as well. Studies to prove this are currently ongoing.

Full Critique

Neoadjuvant checkpoint inhibitor therapy may be superior to adjuvant therapy for patients with high-risk stage III melanoma, but the clinical benefits come with severe side effects. Similarly, patients with stage IV melanoma show significant benefit from checkpoint blockade, but with significant toxicity. For stage III melanoma, the standard of care has been upfront surgery with adjuvant therapy, but with a high risk of relapse, a significant proportion of these patients die of the disease.

significantly increased event-free survival with high pathological complete response (CR) rates compared with standard care in patients with high-risk melanoma in a phase II clinical trial. Those who achieved a CR showed long-term, durable benefit.

This led to two randomized neoadjuvant clinical trials of immune checkpoint blockade for advanced melanoma patients. In a randomized, phase II trial, in 23 patients with high-risk resectable melanoma. Patients received neoadjuvant therapy with the programmed death-1 inhibitor nivolumab at 3 mg/kg for up to four doses or the cytotoxic T-lymphocyte protein 4 inhibitor ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg for up to three doses. The patients were then restaged for surgery, and received adjuvant nivolumab for 6 months.

Treatment with combined ipilimumab and nivolumab yielded high response rates, with overall response rates (ORRs) of 73% and pathological CRs of 45%, but with substantial toxicity -- a 73% rate of grade 3 treatment-related adverse events. Nivolumab monotherapy yielded modest responses (ORR 25%, pathological CR 25%) and low toxicity (8% grade 3 treatment-related adverse events). Two patients in the monotherapy arm progressed to have stage IV metastatic disease and could not go on to have surgery.

The overall survival rate was 100% at 24 months in the combination arm and 75% in the nivolumab arm.

"We showed it is feasible to treat stage III melanoma with neoadjuvant immunotherapy, with the caveat of significant side effects," the study's senior author, Jennifer Wargo, MD, of the University of Texas MD Anderson Cancer Center in Houston, told the Reading Room.

The second study randomized 20 patients with palpable stage III melanoma to receive ipilimumab at 3 mg/kg and nivolumab at 1 mg kg, as either four courses after surgery or two courses before surgery and two courses post-surgery. The researchers, co-led by Christian Blank, MD, PhD, and Ton Schumacher, PhD, both of the Netherlands Cancer Institute, also found that , with all patients undergoing surgery at the preplanned time point.

The researchers reported that after a median follow-up of 25.6 months, seven of nine patients (78%) treated in the neoadjuvant arm achieved a pathological CR, and that none of these patients have relapsed so far. However, in both groups, nine of 10 patients had at least one grade 3/4 adverse event.

Expanded More Tumor-Resistant T-Cell Clones

Importantly, the team said, neoadjuvant ipilimumab plus nivolumab expanded more tumor-resistant T-cell clones than adjuvant therapy. "The findings in their trial are provocative, demonstrating that a higher number of tumor-resident T-cell receptors expanded in the peripheral blood of patients receiving neoadjuvant as opposed to adjuvant checkpoint blockade – supportive of what was seen in preclinical models – and suggests that the neoadjuvant approach may be superior," said Wargo.

She said clinicians should think about neoadjuvant therapy rather than upfront surgery for patients with bulky stage III melanoma. "We need to shift the entire community and not send these patients straight to surgery. Ideally, they should be enrolled in a clinical trial with targeted therapy or neoadjuvant immunotherapy," Wargo said. "If patients have a BRAF mutation, I treat with targeted therapy first. If they do not have a BRAF mutation, I offer neoadjuvant checkpoint blockade before surgery."

The neoadjuvant approach also allows for identification of biomarkers of response and resistance. "We have embraced longitudinal blood samples to look for predictive biomarkers of response and therapeutic targets," she said. "Correlations of pathologic CR with biomarkers may lead to more developments. As expected, we found that patients who had higher CD8 counts and hot tumors were more likely to respond." Baseline infiltration of tumors by lymphoid cells and total mutational burden were also associated with response to therapy.

In addition, her group found that B cells also matter: "Those with a higher density of B cells that were organized alongside T cells were more likely to respond."

Alternative Dosing

To further optimize neoadjuvant immunotherapy, researchers are investigating alternative dosing patterns and different dosing regimens. For example, Wargo said, the MD Anderson group has re-designed a study to explore the safety and efficacy of nivolumab plus relatlimab, an inhibitor of the LAG3 immune checkpoint, a combination that may be more effective than nivolumab alone with a better side effects profile than combination therapy.

"Neoadjuvant therapy also gives us a window into whether therapy is working and if the patient should continue on this therapy," she said.

In addition, an international neoadjuvant melanoma consortium, composed of regulators, pharmaceutical representatives, and patient advocates, are working together to standardize clinical trial protocols and tissue collection, to identify what trials should enroll patients and share data together.

So how do clinicians balance the potential for significant benefit with immunotherapy with the risks of potentially serious side effects? "I don't say combination adjuvant therapy is for everyone," Wargo said. "I take into consideration if the patient has so-so performance status, the ability to tolerate toxicity, and the length of the disease. Monotherapy is good, but is not the right approach for all patients. A subset of patients will benefit. To better predict who needs combination versus single-agent immunotherapy, we need more translational research."