Janice M. Mehnert, MD, is a professor in the Department of Medicine at NYU Grossman School of Medicine, director of the Melanoma Medical Oncology Program, and associate director of Clinical Research at Perlmutter Cancer Center in New York City.

Dr Mehnert on Next Steps for the Evaluation of Quadruplet Therapy in Advanced Melanoma

"Putting everything together in context, we’re seeing an interesting signal that by adding IL-6 inhibition [to an ICI backbone], we don’t sacrifice response; if anything, we gain a little there. However, we [also] gain an advantage on the toxicity front, and that’s important."

Janice M. Mehnert, MD, a professor in the Department of Medicine at NYU Grossman School of Medicine, director of the Melanoma Medical Oncology Program, and associate director of Clinical Research at Perlmutter Cancer Center, discussed next steps for the investigation of sarilumab (Kevzara) plus ipilimumab (Yervoy), nivolumab and relatlimab-rmbw (Opdualag) in unresectable stage III or IV melanoma and contextualizes the regimen's efficacy and safety profile with that of other combination regimens for this patient population.

Findings from a phase 2 study (NCT05428007) presented at the 

 showed a 24-week overall response rate (ORR) of 63.6% (n = 21/33) with the combination. In contrast, the ORR was 45.6% (n = 82/180) in the phase 3 Checkmate-511 trial (NCT02714218) and 58.7% (n = 27/46) in the phase 1/2 Relativity-048 trial (NCT03459222). Additionally, at a median follow-up of 9.8 months, the 24-week clinical benefit rate in the phase 2 study was 78.8% (95% CI, 61.1%-91%).

Mehnert discussed the "interesting signal" observed in the phase 2 study, which suggests that adding IL-6 inhibition to an immune checkpoint inhibitor backbone potentially enhances rather than diminish responses. Crucially, Mehnert highlighted that this addition also offers an advantage in terms of toxicity, which she considers to be an important benefit.

The next steps to verify these initial findings involve a randomized phase 2 cohort study, she stated. This study will compare 30 patients receiving the quadruplet regimen against 30 patients treated solely with ipilimumab, nivolumab, and relatlimab. This randomized comparison is designed to help researchers understand the contribution of IL-6 inhibition to the overall efficacy and safety profile of the treatment, Mehnert said. Readout of data from this study is anticipated in June, 2026.

Videos

Janice M. Mehnert, MD, discusses the ongoing investigation of sarilumab plus ipilimumab, nivolumab, and relatlimab in unresectable stage III/IV melanoma.

Dr Mehnert on the Rationale for Adding IL-6 Blockade to Checkpoint Inhibition in Melanoma

"Our idea in designing this trial was to try to inhibit the signaling of IL-6, since this is known to be a pathway that drives both resistance to therapy, as well as toxicity from therapy, with the hope that we could both improve response rates and decrease toxicity."

Janice Mehnert, MD, a professor in the Department of Medicine at the New York University Grossman School of Medicine, director of the Melanoma Medical Oncology Program, and associate director of clinical research at the Perlmutter Cancer Center, explained the clinical rationale for combining IL-6 receptor blockade with checkpoint inhibitors to potentially enhance antitumor efficacy and reduce immune-related toxicity in advanced melanoma.

Although current checkpoint blockade regimens have transformed treatment outcomes, a substantial percentage of patients either fail to respond or develop significant immune-mediated adverse effects. Preclinical and translational evidence indicates that elevated IL-6 signaling contributes to both treatment resistance and immunotoxicity by promoting a suppressive tumor microenvironment and enhancing inflammatory pathways. Based on this rationale, IL-6 receptor inhibition may dampen detrimental inflammation while simultaneously improving responsiveness to immune checkpoint blockade.

In a phase 2 trial (NCT05428007), investigators evaluated an IL-6 receptor antagonist plus checkpoint inhibitors in 33 patients with unresectable stage III or IV melanoma. Findings presented at the 

 demonstrated favorable antitumor activity, with an overall response rate of 63.6% at 24 weeks—including one complete response and 20 partial responses. Importantly, toxicity was manageable: grade 3/4 adverse effects occurred in 48.4% of patients, treatment-related events in 21.2%, and immune-related effects in 12.1%. No grade 5 toxicities were observed.

Mehnert noted that the dual goal of the regimen is to improve outcomes for those unlikely to benefit from standard immunotherapies while mitigating toxicities that can limit their use. By targeting IL-6 signaling, the approach seeks to reprogram the tumor microenvironment to restore sensitivity to checkpoint blockade and lessen excessive immune activation. If efficacy and safety are confirmed in larger trials, IL-6 receptor blockade could offer a new combination backbone for patients with advanced melanoma—particularly those at higher risk for resistance or immune-related toxicity with current treatment options.

Janice Mehnert, MD, discusses the rationale for incorporating IL-6 receptor blockade into a combination with checkpoint inhibition for patients with advanced melanoma. 

Janice M. Mehnert, MD, discusses the efficacy and safety profile of sarilumab plus ipilimumab, nivolumab, and relatimab in unresectable melanoma.

Dr Mehnert on the Efficacy of Sarilumab Plus Ipilimumab, Nivolumab, and Relatlimab in Unresectable Melanoma

“We were able to observe a best overall response rate of 63.6% and that's exciting, because it is one of the highest response rates we've seen in studies of immune checkpoint inhibition in melanoma to date.”

Janice M. Mehnert, MD, a professor in the Department of Medicine at NYU Grossman School of Medicine, director of the Melanoma Medical Oncology Program, and associate director of Clinical Research at Perlmutter Cancer Center, discussed the efficacy and safety profile of sarilumab (Kevzara) plus ipilimumab (Yervoy), nivolumab (Opdivo), and relatlimab for the treatment of patients with unresectable stage III or IV melanoma.

A phase 2 study (NCT05428007) evaluated the efficacy and safety of sarilumab added to ipilimumab, nivolumab, and relatlimab, findings of which were presented at the 

. Of note, the 24-week overall response rate (ORR) was 63.6% (n = 21/33), Mehnert began. She noted that this finding was significant, as it was one of the highest response rates demonstrated compared with other studies assessing immune checkpoint inhibitors in patients with melanoma. Specifically, the ORR was 45.6% (n = 82/180) in the phase 3 Checkmate-511 trial (NCT02714218), and 58.7% (n = 27/46) in the phase 1/2 Relativity-048 trial (NCT03459222). At a median follow-up of 9.8 months, the 24-week clinical benefit rate was 78.8% (95% CI, 61.1%-91%) in the phase 2 study presented during the 2025 ASCO Annual Meeting.

Furthermore, there were no unexpected toxicities associated with the regimen, according to Mehnert. At week 24, grade 3/4 immune-related adverse effects (irAEs) occurred in 12.1% of patients, and any grade irAEs occurred in 93.9% of patients. Mehnert emphasized that the 24-week period was chosen for the coprimary end point of grade 3 to 5 irAEs because sarilumab was given for 24 weeks during the study. In a similar trend to ORR, she explained that the observed rate of grade 3/4 irAEs was lower than that observed in other studies that include anti–CTLA-4 in the regimen. Specifically, in Checkmate-511 and Relativity-048, the grade 3 to 5 irAEs occurred in 34% and 43% of patients, respectively. 

Director, Phase I/Investigational Therapeutics

Director, Melanoma and Soft Tissue Oncology Program

Squamous cell carcinoma of the skin (SCCS) is an increasingly common diagnosis and is the second most common type of skin cancer worldwide.

 The number of cases of SCCS has increased consistently over the past 20 years. This observation may be related to improved detection of skin cancer, increased exposure to UV radiation (including tanning bed exposure), and the aging of the US population, because the incidence of SCCS increases dramatically with age.

With a 10% decrease in stratospheric ozone annually and the continued growth of the aging US population, locally advanced and metastatic squamous cancers arising from a skin primary are likely to continue to increase annually in coming years, particularly in geographic areas with significant sun exposure.

 These cancers also plague patients who are immunosuppressed, such as recipients of solid organ transplants or patients with chronic infections (eg, HIV)—populations that are living longer in recent years and are therefore becoming more likely to develop troublesome SCCS.

	Most often, SCCS and its precursor lesions are localized and amenable to resection. However, larger and more invasive lesions often require multimodality care, with 10-year survival rates dramatically impacted by the development of regional lymph node involvement and distant metastases.

	Relatively little has been done to develop a generalized management plan for these patients.

 Even the development of a widely accepted staging system has been challenging, as the current AJCC system does not easily identify high-risk cancers, with most poor outcomes occurring in stage T2 cases. While alternate staging systems have been proposed to stratify T2 tumors based on poor prognostic factors such as poor differentiation, perineural invasion, tumor diameter ≥2 cm, and invasion beyond subcutaneous fat,

 the lack of validated systems and clear guidelines leads to confusion for practitioners and variability in treatment.

	Questions persist not only about which patients should be defined as high risk, but also what the initial surgical management of high-risk patients should be, particularly the role of sentinel lymph node. There are no high-level data to guide the decision to use this staging tool, although smaller published reports indicate that a select group of patients with high-risk SCCS may benefit from sentinel lymph node biopsy to identify occult nodal metastases, with a suggested cutoff threshold of 10% risk.

 The need to conduct further clinical trials in this area has been identified.

	Not surprisingly, there is also a lack of high-level data on treatment options for SCCS not amenable to resection. Published case reports have demonstrated responses to platinum-based chemotherapy with occasional complete responses.

There are no data from prospective phase III studies available, and only one prospective phase II study examining the use of platinum-based chemotherapy in this population has been reported. Cisplatin, either as a single agent or combined with 5-FU, has occasionally produced meaningful responses, but again, data supporting efficacy is limited. In general, extrapolation of regimens from squamous tumors of the head and neck are employed, despite the fact that these tumors are likely to be biologically distinct. Further investigation is limited by a lack of available trials for SCCS, and by the frequent exclusion of SCCS patients from trials for head and neck cancer patients.

	Because the EGFR is highly expressed in many epithelial tumors, including SCCS,

and EGFR-directed therapy is often a component of treatment for squamous tumors of the head and neck, the use of anti-EGFR therapies for SCCS is increasing. The largest prospective study to date by Maubec et al

 examined the EGFR inhibitor cetuximab. They enrolled 36 poor-prognosis SCCS patients whose tumors expressed EGFR and demonstrated a disease control rate of 69%.

	A smaller, 16-patient study of the EGFR inhibitor panitumumab in patients who received prior local and/or systemic treatment showed antitumor activity with a response rate of 31%, including 3 partial responses and 2 complete responses.

	Furthermore, a trial evaluating the neoadjuvant use of the EGFR tyrosine kinase inhibitor gefinitib enrolled 22 evaluable patients and demonstrated a 18.2% complete and 27.3% partial response rate and did not interfere with subsequent local therapy, indicating antitumor activity worthy of further exploration.

 Due to their availability as FDA-approved agents, and the lack of competing attractive therapeutic options, cetuximab or panitumumab are increasingly employed to treat locally advanced or metastatic SCCS, and EGFR inhibition is now part of NCCN guidelines for treatment of advanced disease. While this may be a useful therapeutic approach, if these patients are not enrolled as part of rigorous randomized studies, practice-changing information cannot be gathered, and many important questions will remain unanswered.

	For example, could preoperative systemic and/ or radiation therapy reduce the morbidity and extent of the subsequent surgical procedure? Does combining chemotherapy with EGFR inhibitors improve clinical outcomes and increase the pathologic complete response rate? In this era of personalized medicine, are there genomic predictors of response and resistance? Finally, is there a role for immunotherapy in this disease? These are questions we routinely ask in other malignancies; the time has come to include SCCS in these investigations.

	In summary, advanced SCCS continues to be a treatment challenge given the aggressive behavior of a subset of cases and the absence of randomized clinical trials to provide guidelines for therapy. Multidisciplinary clinical trials and collaborative efforts are necessary to advance the care of this growing patient population.

				Alam M and Ratner D. Cutaneous squamous-cell carcinoma. 

				Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell carcinoma of the skin with cetuximab. 

				Karia PS, Han J, Schmults CD. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. 

				Gaffney DC, Soyer HP, Simpson F. The epidermal growth factor receptor in squamous cell carcinoma: an emerging drug target. 

				Schmults CD, Karia PS, Carter JB, et al. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. 

				Navarrete-Dechent C, Veness MJ, Droppelmann N, Uribe P. Highrisk cutaneous squamous cell carcinoma and the emerging role of sentinel lymph node biopsy: literature review.” 

				Lawson JD, Otto K, Chen A, et al. Concurrent platinum-based chemotherapy and simultaneous modulated accelerated radiation therapy for locally advanced squamous cell carcinoma of the tongue base. 

				Nakamura K, Okuyama R, Saida T, Uhara H. Platinum and anthracycline therapy for advanced cutaneous squamous cell carcinoma. 

				DeConti RC. Chemotherapy of squamous cell carcinoma of the skin. 

				Maubec E, Petrow P, Scheer-Senyarich I, et al. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. 

				Foote MC, McGrath M, Guminski A, et al. Phase II study of single-agent panitumumab in patients with incurable cutaneous squamous cell carcinoma. 

				Lewis CM, Glisson BS, Feng L, et al. A phase II study of gefitinib for aggressive cutaneous squamous cell carcinoma of the head and neck. 

Articles

Advanced SCCS continues to be a treatment challenge given the aggressive behavior of a subset of cases and the absence of randomized clinical trials to provide guidelines for therapy.

Janice M. Mehnert, MD

Articles

Dr Mehnert on Next Steps for the Evaluation of Quadruplet Therapy in Advanced Melanoma

Dr Mehnert on the Rationale for Adding IL-6 Blockade to Checkpoint Inhibition in Melanoma

Dr Mehnert on the Efficacy of Sarilumab Plus Ipilimumab, Nivolumab, and Relatlimab in Unresectable Melanoma

Advanced Squamous Carcinoma of the Skin: A Persistent, Growing Challenge