Role of Single-Agent vs Dual IO Evolves in Metastatic Melanoma

FOR MANY PATIENTS with metastatic or unresectable melanoma, immune checkpoint inhibition (ICI) is the preferred frontline treatment option based on favorable efficacy and tolerability in this setting. However, now that multiple immunotherapy (IO) agents have been approved, considerations related to efficacy, tolerability, and administration influence how physicians use these agents.

Preferred first-line options include single-agent nivolumab (Opdivo) and pembrolizumab (Keytruda) as well as combination nivolumab plus ipilimumab (Yervoy), and most recently the combination of nivolumab plus relatlimab (Opdualag).¹ Nivolumab plus ipilimumab has demonstrated superior efficacy vs single-agent nivolumab, but combination regimens come with added toxicity of immune-related adverse events (irAEs) such as pneumonitis, colitis, and atrial fibrillation that can be serious and lead to discontinuation of one or both [treatments].²

Another decision concerning IO comes in patients with BRAF mutations, who make up approximately half of the metastatic cutaneous melanoma population and may be treated with BRAF/MEK inhibitors.¹ These patients may still be treated with ICIs before targeted therapy because evidence of sequencing is limited.

At 2 virtual Targeted Oncology Case-Based Roundtable events, physicians discussed in which situations they would use single-agent IO vs combinations in the metastatic setting, how they approach patients who could receive either approach, and their challenges with managing irAEs.

PROS AND CONS OF COMBINATION IO

Most physicians in the events favored nivolumab/ipilimumab because of its clear overall survival (OS) benefit² but agreed that patients who have poorer performance status or are older may do better receiving single-agent ICI because of its lower toxicity.

At an event moderated by Alan Tan, MD, director of genitourinary medical oncology at RUSH University Cancer Center in Chicago, Illinois, physicians discussed these issues. Mukund Nadipuram, MD, of MercyOne Waterloo Cancer Center in Iowa, said he would prefer a single agent in older patients. Tan noted that such patients have differing performance statuses. He said that when counseling patients, he uses the example of former President Jimmy Carter receiving single-agent pembrolizumab for melanoma metastatic to the liver and brain at age 91 years and tolerating it well.³

“I think we’ve all given at least single-agent IO to someone who was not in the best shape, and they’ve usually tolerated it quite well,” Tan said. “They don’t usually go downhill unless they have a grade 3 or grade 4 AE.”

Physicians discussed autoimmune comorbidities such as inflammatory bowel disease as factors for using monotherapy. At the other event—moderated by Douglas B. Johnson, MD, MSCI, assistant professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee—Johnson said that in some cases, patients with low-volume metastatic disease could receive a single agent because of their lower risk, although he acknowledged that they may also be better off receiving the most efficacious therapy first.

Tan said he has treated patients with kidney transplants who have a high risk of losing their grafted organ with single-agent IO; however, he stressed that they will otherwise die of metastatic melanoma. Other reasons to be cautious with dual IO included lack of caregiver support and monitoring, which could endanger patients if they experience a severe irAE.

“Nivolumab/ipilimumab is great, but you have to have the right patient, and caregiver support is very important,” Kalyani Narra, MD, of Acclaim Multi-Specialty Group in Fort Worth, Texas, stated in Johnson’s group. “I had one patient whose daughter lives in Canada and the patient is by herself. What happens if I give nivolumab/ipilimumab in a patient who is [older]?”

Narra stressed that hospitalization for any reason can be detrimental to older patients, and Johnson agreed that this is an issue. “I’ve had several patients [who] didn’t have a toxic irAE death, but at the same time…they ended up in the hospital with colitis, then they got atrial fibrillation and hospital-acquired pneumonia, [and] then they ended up in rehab and never make it out,” Johnson said.

Narra added that in the case of patients with comorbidities, the reduced toxicity of nivolumab/ relatlimab may be an advantage over nivolumab/ ipilimumab. “This is where [nivolumab plus] relatlimab fills in the need, where I don’t want to give nivolumab by itself…and I want to give a little bit more, but not as much toxicity as nivolumab/ipilimumab. I think that’s where the balance comes in.”

Additionally, ease of administration is an issue that could lead physicians to choose a less intensive regimen. Pembrolizumab may now be given every 6 weeks at a higher dose instead of every 3 weeks, which is more practical for patients who need to travel longer distances to the oncologist’s practice.⁴

APPROACHES TO AVOIDING IMMUNE TOXICITY

The unpredictability of irAEs is a challenge for physicians deciding to use IO. “Compared [with] what happens with chemotherapy, the toxicity from IO is highly unpredictable and not dose related. It may happen very early after 1 dose or very late after 12, and it may never disappear,” Giancarlo Moscol, MD, of The University of Texas MD Anderson Cancer Center in Houston, said in Johnson’s group. He explained that there is a dire need for better ways to screen patients for severe toxicities such as encephalitis. Physicians may use a low threshold for dose interruption for certain AEs.

“We have no biomarkers that are validated to help predict who is going to have these [AEs],” Tan said, although he added that several such biomarkers are under investigation, including IL-6 and C-reactive protein.5 Different dosing approaches have been investigated as ways to make combination IO more valuable.

“Flip dosing” with 3 mg/kg nivolumab plus 1 mg/kg ipilimumab instead of 1 mg/kg nivolumab and 3 mg/kg ipilimumab every 3 weeks was investigated in the phase 3b/4 CheckMate 511 trial (NCT02714218).6 Grade 3 to 5 treatment-related AEs (TRAEs) were reported in 33.9% of patients with the flip dosing vs 48.3% with the previously used dosing schedule.

Even so, in Tan’s group, Leo Shunyakov, MD, of Central Care Cancer Center in Bolivar, Missouri, noted that the efficacy data of this trial are not conclusive and if physicians are concerned with preventing death by disease rather than irAEs, they may stay with the higher ipilimumab dose.

Another tactic is discontinuing ipilimumab early. Johnson discussed the phase 2 ADAPT-IT study (NCT03122522), in which patients received 2 doses each of 1 mg/kg nivolumab plus 3 mg/kg ipilimumab followed by CT scan at week 6, with early responders not receiving the 2 additional doses of ipilimumab.⁷ Although he noted that the evidence for stopping ipilimumab early is limited, these data give confidence to physicians who are already considering fewer doses to avoid added toxicity.

Using nivolumab/relatlimab instead of nivolumab/ipilimumab is another approach that oncologists consider when concerned about toxicity in patients whose performance status or comorbidities are a concern.

While the 2 combinations have not been compared head-to-head, nivolumab/ipilimumab had a rate of grade 3 or higher TRAEs of 59% vs 21% with nivolumab monotherapy in the phase 3 CheckMate 067 trial (NCT01844505).⁸ In the phase 2/3 RELATIVITY-047 trial (NCT03470922), nivolumab/relatlimab had a rate of grade 3 or higher TRAEs of 18.9% vs 9.7% with nivolumab alone.⁹

“For most patients, some sort of dual therapy is the way to go. The data for tolerance for nivolumab/relatlimab [were] pretty good. It didn’t seem that much more toxic than nivolumab alone, and so for those patients who are borderline, that would be the option I would go with,” Peter J. Oppelt, MD, of Washington University School of Medicine in St Louis, Missouri, said in Tan’s group. “But with that said, for patients who are mostly fit, it’s still mostly nivolumab/ipilimumab that I’m going with in the front line.”

“We’ve had an extremely favorable experience with [nivolumab/ relatlimab],” Shunyakov said, although he acknowledged his experience is limited. “I don’t remember any significant toxicities in 3 or 4 patients… maybe a little bit of rash and itching. It’s like night and day compared with [nivolumab/ipilimumab], where at least half of the patients are going to have significant AEs.” He said it is more tolerable than the flip-dosed nivolumab/ ipilimumab as well, based on the rate of TRAEs in CheckMate 511.

CHALLENGES IN RECOGNIZING irAES

Health care providers are much more experienced in managing irAEs now than in the past, but the physicians mentioned gaps in management that lead to poor outcomes for patients. Srikar R. Malireddy, MD, of Texas Oncology, said in Johnson’s group that getting more experience has helped with recognizing signs of common AEs, and that members of his support staff now know the right questions to ask patients for early diagnosis.

Johnson said that he provides patients with a wallet card listing 10 symptoms to look out for, along with emergency contact information for the oncology team. Johnson and Malireddy discussed the crucial need for early intervention with high-dose steroids, which may be missed if patients are taken to receive emergency care in a hospital where staff members are unfamiliar with managing IO.

Others expressed concerns that nurses in community oncology practices do not receive enough education on managing nonchemotherapy drugs. “This touches the emergency [department], it touches the hospitalist, it definitely touches our nurses,” said Johnson. “Education is a key goal, and it is improving to some extent…with the increased use across different indications, but it definitely requires vigilance across our whole team to try to optimize patient outcomes.”

Education of patients is also important so they can self-report irAEs. “The more we educate the patients well about the IO, the better feedback we get and the quicker feedback we get so we can manage quickly,” Nadipuram said.

Tan said pneumonitis is one of the more deadly toxicities if it goes unrecognized but can be addressed with steroids, if identified early. “I think the publications on the rates of pneumonitis are highly underrepresented; I think the real-world rate of pneumonitis is more like 20% to 30%,” he said.

SEQUENCING AND OTHER CONSIDERATIONS

The consensus in both events leaned toward nivolumab/ipilimumab over a single agent as the default frontline approach for most patients based on its strong OS benefit. “The long-term data are such that it’s very hard to choose a single agent for someone who is otherwise fit to receive the combination therapy,” Dilip L. Solanki, MD, of Texas Oncology, said in Johnson’s group.

Shunyakov commented that if the patient’s life expectancy is 2 to 3 years or more, they should consider dual IO based on its median OS, which can be 5 years for BRAF-negative and 7 for BRAF-positive disease.² Nivolumab/relatlimab fills a gap for patients who cannot tolerate greater toxicity but, without longer-term OS data, physicians lacked a compelling reason to choose it for more fit patients.

Patients who progress on IO have fewer options. However, those who are positive for BRAF mutations can receive BRAK/MEK inhibitors in the second line. Although it was unclear whether these patients should receive targeted therapy before IO, the phase 3 DREAMseq trial (NCT02224781) shed light on the question of sequencing by randomly assigning patients with BRAF V600-mutant melanoma to receive either nivolumab/ipilimumab or dabrafenib (Tafinlar) plus trametinib (Mekinist) up front, followed by the other regimen.¹⁰ IO showed a progression-free survival benefit and improvement in 2-year OS rate of 71.8% (95% CI, 62.5%-79.1%) for nivolumab/ipilimumab vs 51.5% (95% CI, 41.7%-60.4%) for dabrafenib/trametinib. Tan noted that nivolumab/relatlimab can be used as a second-line agent after other regimens.

Although patients could not have received a LAG-3–directed therapy before relatlimab, the response is only 12.0% in the second line in patients who are already PD-1 refractory.¹¹ While toxicity is a serious concern for many patients receiving IO, the potential survival benefit of these agents generally outweighs tolerability. Providing patients with additional support and monitoring can help mitigate significant toxicities. “I encourage oncologists not to be discouraged, because you’re definitely helping more patients than harming them,” Tan said.

_REFERENCES

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_{9. Tawbi HA, Schadendorf D, Lipson EJ, et al; RELATIVITY-047 Investigators. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970}

_{10. Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: the DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023;41(2):186-197. doi:10.1200/JCO.22.01763}

_{11. Ascierto PA, Lipson EJ, Dummer R, et al. Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1/programmed death ligand 1 therapy: results from the phase I/IIa RELATIVITY-020 trial. J Clin Oncol. 2023;41(15):2724-2735. doi:10.1200/JCO.22.02072}