Sotigalimab Plus Nivolumab in Anti–PD-1/PD-L1–Refractory Melanoma

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Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, but a significant number of patients still fail to respond to anti–PD-1 therapy. The novel combination of sotigalimab, an anti-CD40 monoclonal antibody, and the PD-1 inhibitor nivolumab could help address this unmet clinical need, according to data presented by Weiss et al at the Society for Immunotherapy of Cancer (SITC) 2021 Annual Meeting (Abstract 389).

Results from a phase II study showed that sotigalimab was well tolerated in combination with nivolumab in patients with metastatic melanoma who had progressed on prior anti–PD-1 therapy.

The combination regimen also demonstrated an objective response rate of 15.2% and a stable disease rate of 33% in evaluable patients (n = 33). Moreover, durable responses were observed, with many patients still alive and off therapy, authors of the study reported.

“While a small subset of patients with refractory metastatic melanoma may exhibit delayed tumor shrinkage after continued anti–PD-1 therapy, most will not, and effective treatments for this population represent a critical unmet need,” said senior study author Harriet Kluger, MD, Professor of Medical Oncology at Yale School of Medicine. “These exciting data speak to the promise of sotigalimab-based combinations and their potential to pave the way for novel immuno-oncology strategies that can provide meaningful benefits for patients with anti–PD-1/PD-L1–refractory melanoma.”

As Dr. Kluger explained, there are very few treatment options available for patients with refractory or resistant melanoma. Sotigalimab is a humanized monoclonal antibody that targets CD40 with a very high affinity and is designed to mimic the naturally occurring binding of CD40 to its ligand. In preclinical models, said Dr. Kluger, CD40 agonists have shown to synergize with PD-1 inhibitors in models that are resistant to anti–PD-1 alone.

Study Methods

Dr. Kluger and colleagues conducted a multicenter, open-label, phase Ib/parallel arm phase II trial to evaluate the combination of sotigalimab with nivolumab in subjects with anti–PD-1/PD-L1–refractory metastatic melanoma. Patients received sotigalimab at 0.3 mg/kg combined with nivolumab at 360 mg every 3 weeks. Thirty-eight participants with unresectable or metastatic melanoma who had confirmed progressive disease during treatment with anti–PD-1 therapy were enrolled, and 33 were evaluable for efficacy.


  • The combination of sotigalimab and nivolumab demonstrated treatment benefit in patients with anti–PD-1/PD-L1–refractory melanoma, with an overall favorable safety and tolerability profile.
  • Notably, a subset of patients remains in response off treatment for at least 26 months.

Durable Responses Observed

As Dr. Kluger reported, 42% of patients had elevated lactate dehydrogenase (LDH) at baseline, indicating a “heavily pretreated and ill population” of patients.

Adverse events considered related to sotigalimab or nivolumab occurred in the majority of patients, but were predominantly grade 1 or 2 and transient. The most commonly observed adverse events were pyrexia, chills, nausea, fatigue, pruritus, transaminitis, headache, asthenia, myalgia, rash, vomiting, and arthralgia.

Researchers reported a low incidence of reported infusion reactions and no cytokine-release syndrome. There were no grade 4 or 5 adverse events due to study drugs, and no treatment discontinuations due to adverse events. 

In addition to the overall favorable safety and tolerability profile, Dr. Kluger and colleagues were “encouraged by the results” showing that the novel combination of nivolumab and sotigalimab led to “prolonged tumor response or prolonged disease control.”

Five patients had a response to treatment (15.2%), and among those with stable disease, two patients had stable disease for over 6 months. At completion of therapy and study follow-up, four of five patients remained in partial response without further systemic therapy. Stable disease was observed for up to 14.8 months.

“We were surprised to see the depth of the response and pleased that a therapy given continuously can result in ongoing response after stopping,” said Dr. Kluger.

“Other than stem cell therapy and CTLA-4–containing regimens, there are no regimens known to induce responses that continue after the patients have stopped their therapy,” Dr. Kluger continued. “We therefore conclude that the combination of sotigalimab and nivolumab warrants additional studies.”

Disclosure: Dr. Kluger reported no relevant financial disclosures.