Discussing Rationale for Combination Therapy in Metastatic Melanoma


During a Targeted Oncology™ Case-Based Roundtable™ event, Hussein A. Tawbi, MD, PhD, and participants discussed which first-line therapy they would recommend for a 78-year-old patient with metastatic melanoma and no BRAF-activating mutation. This is the first of 2 articles based on this event.


Hussein A. Tawbi, MD, PhD

Professor and Deputy Chair

Department of Melanoma Medical Oncology

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX


A 78-year-old man with a history of stage III melanoma underwent surgical resection 12 years ago; his lymph node dissection (LND) was positive for nodal involvement. The patient declined complete LND and adjuvant systemic therapy. He remained active since his surgery and maintained regular follow-up appointments.

On routine follow-up, the patient presented with moderate asthenia that limited his daily activities. His ECOG performance status was 1, and his physical examination was unremarkable. Notable laboratory findings included lactate dehydrogenase (LDH) level of 380 U/L (reference range, 110-240 U/L). A full-body CT scan revealed pulmonary and hepatic nodules but no evidence of brain metastases. He underwent core-needle biopsy of the largest hepatic lesion in segment IVb without any complications. Pathology revealed metastatic melanoma.

What first-line therapy are you most likely to recommend for this patient with metastatic melanoma and no BRAF-activating mutation?

Nivolumab + ipilimumab
Nivolumab + relatlimab-rmbw
Pembrolizumab + low-dose ipilimumab


  • Beyond the absence of an actionable BRAF mutation, what factors influence first-line selection of immunotherapy (IO) monotherapy versus dual IO therapy?
    • For example: biomarkers, baseline LDH, disease burden, pace of disease progression, performance status, symptoms, comorbidities, psychosocial support, other.

HUSSEIN A. TAWBI, MD, PHD: What first line therapy are most likely to recommend for this patient?

I see that 63% of you chose ipilimumab [Yervoy] plus nivolumab [Opdivo], 25% chose nivolumab/relatlimab [Opdualag], and 13% chose low-dose ipilimumab plus pembrolizumab [Keytruda]. There was not a single vote for single-agent nivolumab or pembrolizumab.

As you think about this patient, and the fact that they don't have a BRAF mutation, what were the factors that you thought through in terms of choosing a combination? Not a single one of you chose single-agent PD-1 inhibitor, which I support. What are the reasons you thought of this?

MAGDALENA FLEJSIEROWICZ, MD: I think all these [factors] on the list are very relevant. I would make my decision based on everything we do…PD-L1 [expression], if it is a high-burden vs low-burden disease, brain metastases, the performance status of the patient, and [whether he is able to tolerate] a combination.

TAWBI: Those are good points. Why [might you choose] ipilimumab/nivolumab in this patient over nivolumab/relatlimab or low-dose ipilimumab plus pembrolizumab?

UMASANKAR RAMADOSS, MD: I chose low-dose ipilimumab and pembrolizumab mostly for the scheduling [and] because there is a long-term benefit of ipilimumab in these patients. If there were a brain metastasis, I would have gone with ipilimumab. I think all 3 combination choices are good. Even a single-agent choice is good for this patient, given that he is older.

TAWBI: When you chose low-dose ipilimumab plus pembrolizumab, was it [because of] the efficacy or was toxicity part of this decision?

RAMADOSS: The toxicity [was important]. Low-dose ipilimumab is very well tolerated along with pembrolizumab. Even the low-dose ipilimumab with the [higher] dose of nivolumab is well tolerated.

TAWBI: Those are great points. This patient has elevated LDH. He has 2 sites of disease, but no brain metastasis we know of. Single-agent PD-1 [inhibitor] is appropriate for toxicity purposes, but…the data…show that from an efficacy perspective, I think you all chose appropriately to go with combinations.

It's true that we have data for brain metastases with ipilimumab and nivolumab, but only for high-dose ipilimumab.1 Low-dose [ipilimumab] has not been studied for the brain, nor has nivolumab/relatlimab [so] we don't know if it works well or not. We just have very strong data for ipilimumab/nivolumab.

If you compare a low-dose ipilimumab/pembrolizumab to nivolumab/relatlimab, do you think they have the same toxicity or does one has more or less toxicity than the other?

RAMADOSS: My experience is really good with nivolumab/relatlimab.

1. Tawbi HA, Forsyth PA, Hodi FS, et al. Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204). Neuro Oncol. 2021;23(11):1961-1973. doi:10.1093/neuonc/noab094
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