Immunotherapy Combinations Reign Supreme in Upfront Melanoma Management

Doublet immunotherapy remains the preferred first-line option for patients with melanoma regardless of BRAF mutation status; however, according to long-term findings from several key clinical and sequencing trials, administering targeted therapy alone or before and after immunotherapy may be appropriate for select patients with high disease burden, visceral crisis, or symptomatic brain metastases, according to Teresa Petrella, MD, MHSc, FRCPC.

In an interview with OncLive® regarding her presentation at the 21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies, Petrella discusses long-term survival and sequencing data that inform frontline treatment selection between immunotherapy and targeted therapies for metastatic melanoma. This included findings from the phase 2 SECOMBIT (NCT02631447) and phase 3 DREAMseq (NCT02224781) trials, as well as long-term data from the phase 3 KEYNOTE-006 (NCT01866319), CheckMate 067 (NCT01844505) and COLUMBUS (NCT01909453) trials.

​“There have been several trials [confirming the superiority of] nivolumab [Opdivo] plus ipilimumab [Yervoy] compared with single-agent nivolumab or ipilimumab,” said Petrella in the interview. “Then we have the sequencing trials, DREAMseq and SECOMBIT, which have told us that [patients treated with] combination immunotherapy up front [have better outcomes] than if they are given targeted therapy first. Based on all those data, [immunotherapy has] become our [optimal] first-line [choice] for patients with metastatic melanoma.”

Petrella also outlined toxicities of note when selecting between checkpoint inhibitor– vs targeted therapy–based approaches. Additionally, she highlighted ongoing trials evaluating checkpoint inhibitor combinations, triplet regimens, and novel pan-RAF and brain-penetrant inhibitors in melanoma.

Petrella is a medical oncologist and affiliate scientist as part of the Evaluative Clinical Sciences platform of the Odette Cancer Research Program at Sunnybrook Research Institute, as well as an associate professor in the Department of Medicine at the University of Toronto in Canada.

OncLive: What long-term data have influenced the use of combination immunotherapy vs monotherapy or targeted therapy as first-line treatment for metastatic melanoma?

Petrella: We now have 10-year data for nivolumab plus ipilimumab compared with single-agent [checkpoint inhibition from CheckMate 067] that still show a benefit [with the doublet] over 10 years. Those data leveled out from year 3 onward. [Among the overall population of] patients who received nivolumab plus ipilimumab, the [melanoma-specific survival rate] was 52% at 10 years compared with 44% with single-agent nivolumab and 20% with single-agent ipilimumab.

Additionally, with nivolumab plus relatlimab-rmbw [Opdualag], we have 3-year data [showing that] there’s still an [overall survival (OS)] advantage [with the doublet] over nivolumab by itself.

What did findings from the DREAMseq and SECOMBIT trials indicate about long-term survival benefits with upfront immunotherapy prior to targeted therapy?

The DREAMseq trial either [treated patients with] nivolumab plus ipilimumab up front then targeted therapy upon progression, or vice versa. It showed that there was a 20.3% OS rate benefit for patients initially treated with immunotherapy as opposed to targeted therapy.

The SECOMBIT trial [was] similar [to DREAMseq] in that [patients in the] first 2 arms either received immuno-oncology up front and then targeted therapy [after] progressing, or vice versa. However, [this trial] also added a third arm, which is called the ‘sandwich’ arm. [In this arm,] targeted therapy [was administered] up front with encorafenib [Braftovi] and binimetinib [Mektovi] for 8 weeks. Once the 8 weeks were completed, patients went on to receive nivolumab plus ipilimumab and then [could receive targeted therapy again] upon progression. That [study] showed that patients who received immunotherapy up front or who were in the ‘sandwich’ arm did best overall compared with patients who received targeted therapy up front.

In which clinical scenarios should targeted therapy be prioritized over combination immunotherapy for patients with BRAF-mutant melanoma?

Based on all those data, the best [plan] is to give immunotherapy up front, regardless of BRAF mutation status. However, there are several subgroups of patients that would potentially benefit from using targeted therapy up front, whether by itself or in a sandwich approach. These would be patients who present with a high burden of disease that’s rapidly progressing, are very symptomatic from their disease, are in a visceral crisis, or have high lactate dehydrogenase [LDH] levels—which is a reflection of how much tumor burden they have. There are data suggesting that these patients may [have] better [outcomes] receiving targeted therapy up front, even if it’s for a limited amount of time, and then using immunotherapy afterward to try and get their symptoms under control and decrease the tumor burden.

The other group [of patients who might] benefit from that [approach] would be patients who have symptomatic brain metastases. [Based on all] the data [from studies that treated] patients with brain metastases with either immunotherapy or targeted therapy, patients who were asymptomatic did well on immunotherapy, but those who were symptomatic or had to use steroids did not do very well on immunotherapy. That was not the case with targeted therapy. When you use targeted therapy, it doesn’t make a difference whether [patients have] symptomatic or asymptomatic brain metastases; response rates are approximately 60% regardless of whether they have symptoms or are receiving steroids. Unfortunately, the progression-free survival rates are short when you use targeted therapy. A better approach for those patients is to use a sandwich approach, [first administering] targeted therapies to get them off the steroids or to decrease their symptoms so they can go on to receive immunotherapy [and achieve] a long-term benefit.

How do long-term data from the KEYNOTE-006, COLUMBUS, and CheckMate 067 trials reinforce the benefit of upfront checkpoint inhibitor combinations vs monotherapy in melanoma?

For all 3 of those trials, we now have long-term data. We now have 7-year data from the KEYNOTE-006 trial of pembrolizumab [Keytruda] and the COLUMBUS [trial evaluating encorafenib plus binimetinib]. We also now have 10-year data from CheckMate 067, which is unheard of for many different types of cancers. This trial investigated nivolumab plus ipilimumab compared with nivolumab alone or ipilimumab alone [and showed] that there’s still a benefit to receiving combination therapy. Most of us think nivolumab and pembrolizumab are pretty interchangeable, [since] they’re both anti–PD-1 agents and have almost identical toxicity profiles. There’s still a benefit to using a doublet over single-agent immunotherapy.

The 7-year OS rate [with encorafenib plus binimetinib in] the COLUMBUS trial was 27.4%. We try to avoid cross-trial comparisons, but that’s still a big difference from using the combination of nivolumab and ipilimumab. Any time we can use doublet immunotherapy, that’s the preferred treatment. Then we treat patients on a case-by-case basis depending on their characteristics and comorbidities.

Does PD-L1 expression influence the choice of first-line therapy in melanoma? What other biomarkers could be relevant in guiding treatment selection?

In most countries, approvals for the anti–PD-1 agents or combinations are not based on PD-1/PD-L1 expression, except for the approval of nivolumab plus relatlimab in Europe. When we look at all the different clinical trials that have compared PD-1–positive or –high patients with PD-1– low or –negative patients, there does not appear to be more benefit [in one group] over the other; even patients with low PD-1 expression can do well on immunotherapy.

In Europe, [oncologists] use the serum S100 biomarker. Some oncologists are using circulating tumor DNA to guide their [therapeutic decision-making], and LDH levels [can them help determine] when to switch therapy or whether patients are benefiting from therapy. However, we currently don’t have a standard biomarker [for clinical] use.

What are the key toxicity considerations when choosing between nivolumab plus ipilimumab and targeted therapy in melanoma?

[This decision is] determined on a case-by-case basis. We consider the patient’s comorbidity, tumor factors, and other factors to make the best possible decision. Because of the toxicity [associated with] nivolumab and ipilimumab, knowing that [over half] of patients [will experience] grade 3/4 toxicities on these therapies, I always ask myself: Does this patient have enough reserve that if they were to experience very bad toxicity, they could manage and get through the rest of their treatment?

Targeted therapies [are associated with] their own toxicities. Any patient with severe cardiac dysfunction [is not a good candidate] for targeted therapies. The other [factor] we would look at is whether patients have autoimmune diseases that are not well controlled. Often, we do not like to give immunotherapy to those patients.

What are some emerging immunotherapy combinations and targeted therapies of interest for patients with melanoma?

There are lots of different upcoming trials [with immunotherapy] in melanoma. Many of them are going to be evaluating combinations with other checkpoint inhibitors, such as TIGIT. There are also triplet combinations coming down the pipeline. [These can be comprised of] 3 different immunotherapies, such as nivolumab plus ipilimumab plus relatlimab, or [consist of] both targeted therapies and immunotherapies.

There are also new pan-RAF inhibitors and new brain-penetrant inhibitors for BRAF-mutated disease. These are in early clinical trials. Hopefully some of those will move on to larger trials. There’s also work [ongoing to develop] pan-RAF inhibitors and MEK inhibitors for the NRAS-mutant patient population.

Reference

Petrella T. Targeted therapy and its placement in melanoma treatment. Presented at: 21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies; February 8, 2025. Cranbury, New Jersey.