Evolving Immunotherapy Data Shed Light on Best Practices in Metastatic Melanoma

Jeffrey S. Weber, MD, PhD

Different sequencing strategies may help improve outcomes and mitigate toxicities for patients with metastatic melanoma, according to Jeffrey S. Weber, MD, PhD. Moreover, while the dual immunotherapy combination of nivolumab (Opdivo) and ipilumumab (Yervoy) continues to demonstrate long-term benefit for this patient population, newer regimens are also starting to show promise—potentially expanding the growing number of effective therapies in this setting.

For instance, the phase 3 CheckMate 067 trial (NCT01844505), which randomly assigned patients with previously untreated, unresectable or metastatic melanoma 1:1:1 to receive the combination of nivolumab/ipilimumab, nivolumab alone, or ipilimumab alone, now has available data from 6.5 years of follow-up. “There are not a lot of studies out there in melanoma—in fact, I would say there are none—that have this kind of follow-up,” Weber, the deputy director of the Perlmutter Cancer Center at New York University Langone Health in New York, New York, noted, duing a presentation at the 40th Annual CFS®.¹

The combination elicited a median overall survival [OS] of 72.1 months (95% CI, 38.2-not reached [NR]), compared with 36.9 months (95% CI, 28.2-58.7) for nivolumab alone (HR, 0.84; 95% CI, 0.67-1.04) and 19.9 months (95% CI, 16.8-24.6) for ipilimumab alone (HR, 0.52; 95% CI, 0.43-0.64).2 The 78-month OS rates were 49% for nivolumab/ipilimumab, 42% for nivolumab alone, and 23% for ipilimumab alone.

However, 59% of patients treated in the combination arm (n=313) experienced at least 1 grade 3/4 treatment-related adverse effect (TRAE). “Yes, of course, there is more toxicity [with the combination of nivolumab/ipilimumab], but my feeling is that in routine practice, every patient who has metastatic disease deserves a shot at nivolumab/ipilimumab,” Weber said.

Ways to mitigate the toxicities of the combination of nivolumab and ipilimumab were addressed in the phase 3b/4 CheckMate 511 trial (NCT02714218), which evaluated a flipped dose of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks, compared with the regimen of 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab every 3 weeks used in CheckMate 067.

At 3 years of follow-up in CheckMate 511, grade 3 to 5 TRAEs occurred in 34% of patients given the flipped dose regimen, compared with 48% for those administered the regular regimen. Notably, the 2 regimens elicited numerically similar OS, with 3-year OS rates of 59% in the flipped-dose arm and 61% in the control arm.³

“Given that OS curve, you tell me which [regimen] you would rather get. If I were the patient, I would rather have [the] flipped dose,” Weber said. “Flipped dose nivolumab/ipilimumab has thus entered common practice, certainly at my institution and in the community. The likelihood that you are going to sacrifice a survival benefit would seem incredibly low.”

Weber noted that the full dose of nivolumab plus ipilimumab still has a place in practice for patients with brain metastases or those with rapidly progressive disease.

Sequencing Immunotherapy and Targeted Therapy in BRAF-Mutated Melanoma

CheckMate 067 and CheckMate 511 both evaluated nivolumab/ipilimumab in patients with metastatic melanoma, irrespective of the presence of BRAF mutations. The phase 3 DREAMseq trial (NCT02224781) helped address sequencing questions of nivolumab/ipilimumab vs BRAF-targeted therapy for patients with metastatic melanoma harboring BRAF mutations.

DREAMseq randomly assigned patients with BRAF-mutant metastatic melanoma to receive nivolumab/ipilimumab induction and nivolumab maintenance, followed by continuous dabrafenib (Tafinlar) plus trametinib (Mekinist) at disease progression, or continuous dabrafenib plus trametinib followed by nivolumab/ipilimumab induction and nivolumab maintenance at disease progression.

Weber noted that data from the trial showed an early OS benefit for patients who received dabrafenib/trametinib first, but the survival curves crossed around month 8 or 9. Ultimately, patients who received nivolumab/ipilimumab first achieved a 3-year OS rate of 66.2% (95% CI, 56.0%-74.6%) compared with 42.8% (95% CI, 32.9%-52.4%) for those given dabrafenib/trametinib first (log rank P=.0095).⁴

“This essentially puts to rest the idea that you could either give a BRAF [inhibitor] plus a MEK [inhibitor] or immunotherapy first. In my practice, I will continue to prefer to give immunotherapy first,” Weber explained. “The one caveat...if someone presents with high lactate dehydrogenase, rapidly progressive bulky disease, and they are BRAF mutated, I will probably give them 8 to 12 weeks of BRAF/MEK, then I’ll switch them to nivolumab/ipilimumab [irrespective of disease progression. However], that is a different question not addressed in this trial.”

Role of Nivolumab Plus Relatlimab in Metastatic Melanoma

Following the positive data from the phase 2/3 RELATIVITY-047 trial (NCT03470922) and the FDA approval of relatlimab plus nivolumab (Opdualag) for the treatment of adult and pediatric patients who are 12 years or older and who have unresectable or metastatic melanoma in March 2022, the combination may replace single-agent PD-1 blockade, according to Weber.⁵

RELATIVITY-047 randomly assigned patients with previously untreated, unresectable or metastatic melanoma 1:1 to receive 480 mg of nivolumab once every 4 weeks with or without 160 mg of relatlimab. The combination elicited a median progression-free survival (PFS) of 10.22 months (95% CI, 6.51-14.75) compared with 4.63 months (95% CI, 3.48-6.44) for nivolumab alone (HR, 0.78; 95% CI, 0.64-0.94).⁶

Additionally, the combination produced a median OS that was NR (95% CI, 34.20-NR) vs 34.10 months (95% CI, 25.23-NR) for nivolumab alone (HR, 0.80; 95% CI, 0.64-1.01; P=.0593).

“TRAEs of grade 3/4 are [approximately] doubled from 11.% [with nivolumab alone] to 21.1% [for relatlimab/nivolumab], and the discontinuation rate goes up [with relatlimab],” Weber said. “So yes, [relatlimab plus nivolumab] is more toxic, but it is still within what I would consider reasonable bounds.”

Tumor-Infiltrating Lymphocytes on the Horizon

Weber pointed to tumor-infiltrating lymphocytes (TILs)as the next possible advancement in the treatment paradigm for metastatic melanoma. Data from the phase 2 C-144-01 trial (NCT02360579) showed that among 62 patients treated with lifileucel (LN-44), 81% experienced a reduction in tumor burden.7

Furthermore, data from the phase 3 M14TIL trial (NCT02278887), which evaluated patients with metastatic melanoma who received no more than 1 prior line of therapy and no prior ipilimumab, showed that those treated with TIL therapy experienced a median PFS of 7.2 months (95% CI, 4.2-13.1) and a 6-month PFS rate of 52.7% (95% CI, 42.9%-64.7%).8 Those given single-agent ipilimumab had a median PFS of 3.1 months (95% CI, 3.0-4.3) and a 6-month PFS rate of 21.4% (95% CI, 14.2%-32.2%).

“This has gone to the FDA. We hope that this will get approved in the next few months, and the survival curve of TIL [therapy] vs ipilimumab is also better, but again, very immature without a real P value,” Weber concluded.

References

1. Weber JS. Advances in metastatic melanoma. Presented at: 40th Annual CFS®; November 9-11, 2022; New York, NY and virtual.
2. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol. 2022;40(2):127-137. doi:10.1200/JCO.21.02229
3. Lebbe C, Meyer N, Mortier L, et al. Two dosing regimens of nivolumab (NIVO) plus ipilimumab (IPI) for advanced (adv) melanoma: three-year results of CheckMate 511. J Clin Oncol. 2021;39(suppl 15):9516. doi:10.1200/JCO.2021.39.15_suppl.9516
4. Atkins MB, Lee SJ, Chmielowski B, et al. DREAMseq (doublet, randomized evaluation in advanced melanoma sequencing): a phase III trial—ECOG-ACRIN EA6134. J Clin Oncol. 2021;39(suppl 36):356154. doi:10.1200/JCO.2021.39.36_suppl.356154
5. U.S. Food and Drug Administration approves first LAG-3-blocking antibody combination, Opdualag (nivolumab and relatlimab-rmbw), as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb; March 18, 2022. Accessed November 10, 2022. https://bit.ly/3wk6PDx
6. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab vs nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047). J Clin Oncol. 2022;40(suppl 36):360385. doi:10.1200/JCO.2022.40.36_suppl.360385
7. Larkin J, Sarnaik A, Chesney JA, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced melanoma: evaluation of impact of prior anti-PD-1 therapy. J Clin Oncol. 2021;39(suppl 15):9505. doi:10.1200/JCO.2021.39.15_suppl.9505
8. Haanen JBAG, Rohaan M, Borch TH, et al. Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: results from a multicenter, randomized phase III trial. Ann Oncol. 2022;33(suppl 7):S1406. doi:10.1016/j.annonc.2022.08.036