CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 21, 2023
Expiration: August 20, 2024
Fianlimab (Anti‒LAG-3 mAb) Plus Cemiplimab (Anti‒PD-1 mAb) in Patients With Advanced Melanoma
Jeffrey S. Weber, MD, PhD:
The combination of relatlimab, an anti–LAG-3 therapy, and nivolumab confers a higher ORR and longer PFS compared with nivolumab monotherapy, and this combination has been approved by the FDA.17,18 I think one of the most important presentations in melanoma from ASCO 2023 was a phase I/II trial of a new LAG-3 antibody called fianlimab with cemiplimab, an FDA‑approved PD-1 antibody with indications in cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small-cell lung cancer, but not yet in melanoma.19
This multicohort phase I/II trial of fianlimab in combination with cemiplimab enrolled patients who had metastatic or unresectable melanoma and were naive to anti–PD-1/PD-L1 therapies in the initial cohort and the confirmatory cohort (n = 40 each). A third cohort enrolled patients who received previous anti–PD-1/PD-L1 therapy in the neoadjuvant or adjuvant therapy setting (n = 18).20,21 Fianlimab is given at a dosage of 1600 mg and cemiplimab at 350 mg, both IV every 3 weeks for up to 51 weeks. Patients who respond to therapy can continue treatment for an additional 51 weeks if deemed appropriate by investigators. I would note that this is a fairly high dose of fianlimab.
The primary endpoint is ORR and secondary endpoints include PFS, duration of response, disease control rate, safety, and pharmacokinetics. The subgroup analyses in patients with characteristics of poor prognosis and PD-1/PD-L1–naive status were post hoc analyses.
In the initial report of this phase I trial of fianlimab in combination with cemiplimab, the ORR was 63% in patients with PD-1/PD-L1 inhibitor–naive advanced melanoma.22 The current report presents updated findings in patients with PD-1/PD-L1 inhibitor–naive advanced melanoma, new data from patients who previously received a PD-1 inhibitor in the adjuvant setting, and new pooled data for patients with poor prognosis.20,21
Phase I Trial of Fianlimab Plus Cemiplimab: Baseline Characteristics
Jason Luke, MD, FACP:
Baseline characteristics were similar across most categories.20,21 One could argue that the PD-1 experienced cohort has a lower incidence of M1c, liver metastases, and high LDH, suggesting these patients have slightly lower risk relative to what might be seen in a standard group of patients.
Phase I Trial of Fianlimab Plus Cemiplimab: Efficacy Across Cohorts
Jeffrey S. Weber, MD, PhD:
The efficacy of the combination was very impressive. The ORR for the initial and confirmatory cohorts is 63%.20 For the PD-1–experienced cohort the ORR was 56%. Although cautioning against cross-trial comparisons, this ORR is better than the 43% ORR seen with relatlimab/nivolumab in the phase III RELATIVITY-047 trial.18 There were complete responses in 13% and 15% of the confirmatory and initial PD-1–naive groups, respectively. Seeing complete responses with any regimen other than ipilimumab/nivolumab is striking. In addition, 73% of patients experienced tumor reduction.
Jason Luke, MD, FACP:
What was interesting to me was the PD-1–experienced cohort ORR of 56%, which is quite promising for patients who previously had anti–PD-1.
Phase I Trial of Fianlimab Plus Cemiplimab: Efficacy Compared With Historical Controls
Jeffrey S. Weber, MD, PhD:
The median PFS with the combination of fianlimab and cemiplimab was 15 months for the total study population, remembering that this includes patients with previous PD-1/PD-L1 exposure.20 Compared with 10 months PFS for the combination of relatlimab and nivolumab in RELATIVITY-047 and 11.5 months with ipilimumab and nivolumab in CheckMate-067.18,23 I am quite impressed with these data.
Jason Luke, MD, FACP:
I would view these comparisons with caution. Each of these clinical trials treated different patients at different times. But given that, the response rate with fianlimab and cemiplimab in this small number of patients appears a little higher than that seen with nivolumab alone or in combination with relatlimab or ipilimumab in phase III clinical trials. Again, I would caution against trying to compare randomized phase III clinical trials that enrolled several hundred patients with this small single-arm study. That is quite fraught in terms of bias for the types of patients who are participating in smaller trials. But I think the data for cemiplimab and fianlimab look quite promising and certainly deserve to be investigated in the larger phase III setting.
Phase I Trial of Fianlimab Plus Cemiplimab: Efficacy After Prior (Neo)adjuvant Treatment, Including Anti–PD-1 Therapy
Jason Luke, MD, FACP:
For patients who received previous (neo)adjuvant therapy, the ORR was 61% for patients who had received any previous (neo)adjuvant therapy vs 62% for patients who had received previous adjuvant anti–PD-1 therapy.20 Note that these are small numbers of patients, but the ORR looks promising.
Phase I Trial of Fianlimab Plus Cemiplimab: Efficacy in Subgroups With Poor Prognosis
Jeffrey S. Weber, MD, PhD:
Looking at outcomes for patients with poor prognosis, the response rates are lower, but they are still very respectable in this trial. 20,21 A response was achieved by 43% (n = 9) patients with liver metastases and 53% (n = 17) of patients with LDH higher than the upper limit of normal. Even the patients with ≥2 different metastatic sites and high LDH who normally have poor outcomes have a 45% response rate. That is quite good and makes you think there is something unique about this combination of anti–PD-1and anti–LAG-3 in patients who are resistant to anti–PD-1 alone.
Jason Luke, MD, FACP:
It is interesting that the efficacy seemed to hold up in patients who typically have a poorer outcome because of liver metastases and high baseline LDH. A 43% response rate in patients with liver metastases is quite encouraging. I think these are promising data and make me wonder if fianlimab may be more effective than relatlimab. These data are only hypothesis generating in that regard. I do not think we can definitively answer that question but I think this certainly warrants further analysis.
Phase I Trial of Fianlimab Plus Cemiplimab: Efficacy According to LAG-3 and PD-L1 Tumor Expression
Jason Luke, MD, FACP:
These data emphasize that high tumor expression of LAG-3 does not predict who will respond to a LAG-3 inhibitor.20 The response rates were similar in the LAG-3–positive and LAG-3–negative groups. PD-L1 expression may be a better predictor of response with this combination because patients with PD-L1 expression ≥1% had a 73% ORR vs 56% for PD-L1 <1% and 58% for patients with unknown status. Together, these data suggest that any PD-1–based therapy probably will be effective in melanoma.
Phase I Trial of Fianlimab Plus Cemiplimab: Safety Summary
Jeffrey S. Weber, MD, PhD:
The safety data are reassuring with a 12% incidence of grade 3-5 irAEs.20 That is no different than what you would expect for a PD-1 antibody alone. It does not look like this LAG-3 antibody—at least in the phase II setting—appears to add very much to the overall immune‑related toxicity of the PD-1 antibody.
However, there were more endocrinopathies than you would expect. There were 11 cases of adrenal insufficiency and that is not a trivial number since there are only 98 patients in this trial. Although 7 of these were grade 1/2, the incidence is more than what you would expect, and it differentiates this particular combination from anti–PD-1 alone where you would only expect 2 or 3 cases out of 98 patients.
Jason Luke, MD, FACP:
All cases of adrenal insufficiency were successfully managed, but one case led to treatment discontinuation. Adrenal insufficiency will be something to watch moving forward, and I wonder if this is because of a small patient population or something that we will continue to see over a longer period of time.
Phase I Trial of Fianlimab Plus Cemiplimab: Clinical Implications
Jeffrey S. Weber, MD, PhD:
The combination of fianlimab with cemiplimab showed an impressive response rate of approximately 60% and median PFS of 15 months in patients with advanced melanoma.20 Fianlimab with cemiplimab also performed well in patients we would expect to have poor outcomes, including those who had liver metastases and elevated baseline LDH.21
The overall frequency of irAEs with the combination was similar to what we would expect with cemiplimab alone, but the rate of endocrinopathies, especially adrenal, appear to be increased. I think this combination has promise, and I look forward to the results from the randomized phase III studies that are currently enrolling.
Jason Luke, MD, FACP:
Yes the combination of fianlimab plus cemiplimab looks quite potent. These data have led to the initiation of a frontline randomized phase III clinical trial comparing fianlimab plus cemiplimab vs pembrolizumab as first-line therapy in the metastatic setting, which is currently recruiting (NCT05352672). There is another phase III trial currently recruiting patients with stage IIC or III melanoma to receive adjuvant fianlimab plus cemiplimab (NCT05608291).
RELATIVITY-047 Update at 2 Years: First-line Nivolumab Plus Relatlimab vs Nivolumab in Advanced Melanoma
Jeffrey S. Weber, MD, PhD:
Data from the phase II/III RELATIVITY-047 trial comparing nivolumab plus relatlimab vs nivolumab in patients with previously untreated metastatic or unresectable melanoma led to the approval by the FDA of nivolumab plus relatlimab for the treatment of adults and pediatric patients aged 12 years or older with unresectable/metastatic melanoma.24,25 At ASCO 2023, there was an important 2-year update from this study.25
RELATIVITY-047 is a randomized, double-blind phase II/III study that enrolled 714 patients aged 12 years or older who have unresectable or metastatic melanoma and were treatment naive. Stratification was by LAG-3 expression, PD-L1 expression, BRAF mutation status, and M stage (per AJCC v8) and randomization was 1:1 to nivolumab plus relatlimab or nivolumab alone.
Nivolumab was given at a dose of 480 mg and relatlimab at 160 mg in a fixed-dose combination every 4 weeks. Nivolumab alone was given per the standard-dosing regimen. The primary endpoint is PFS and secondary endpoints are OS and ORR. Exploratory post hoc analyses include PFS2, efficacy outcomes on second-line subsequent systemic treatment, and melanoma-specific survival.
The trial met its primary endpoint at the first analysis after a median follow-up of 13.2 months with a PFS of 10.1 months for the combination vs 4.6 months with nivolumab alone.25 Median PFS has been stable with longer median follow-up of 19.3 months, at 10.2 months vs 4.6 months.18
The current report presents 2-year efficacy and safety updates and exploratory/post hoc analyses from the trial.
RELATIVITY-047 Update at 2 Years: Baseline Characteristics
Jason Luke, MD, FACP:
The trial was well balanced, and there were no major differences between these 2 groups of patients.25
RELATIVITY-047 Update at 2 Years: PFS and OS
Jeffrey S. Weber, MD, PhD:
There is no real change in the median PFS with this update—10.2 months with the combination vs 4.6 months with nivolumab monotherapy (HR: 0.81; 95% CI: 0.67-0.97).25 But when you look at the actual curve, which now extends to 51 months, there appears to be a genuine plateau. The 36-month PFS rate is 31% with the combination vs 27% with nivolumab, which is a modest difference, but remember the median follow-up is 25.3 months.
Median OS was not reached with the combination and 33.2 months with nivolumab monotherapy (HR: 0.82; 95% CI: 0.67-1.02). The curves are not very far apart, but they do stay separated beyond 48 months.
Jason Luke, MD, FACP:
It is important to note that although the trial met its primary endpoint for PFS, it did not meet the statistical threshold for OS. The HR of 0.82, while I would argue is meaningful, did not reach the predefined statistical threshold. That is a caveat about this trial. To me, this 18% reduction is quite meaningful and suggests that this treatment benefits patients over a long period of time.
RELATIVITY-047 Update at 2 Years: Best Overall Response per BICR
Jeffrey S. Weber, MD, PhD:
The median duration of response has not been reached in either arm. The ORR is 44% with the combination vs 34% with the monotherapy, so a difference of approximately10%.25
Jason Luke, MD, FACP:
This 10% difference in ORR is similar to the difference seen with nivolumab plus ipilimumab compared with nivolumab alone. I think response will be an important consideration as we think about how to use nivolumab plus relatlimab vs nivolumab plus ipilimumab in the modern era.
RELATIVITY-047 Update at 2 Years: Subgroup Analyses of PFS, OS, and ORR
Jason Luke, MD, FACP:
Tumor LAG-3 expression does not seem to drive the benefit seen with the combination vs nivolumab alone, although there may be some increase in benefit for patients with high LAG-3 expression.25 In patients with tumor PD-L1 ≥1%, there was similarly no difference in PFS or OS with the combination vs PD-1 monotherapy. This may be an important consideration in the future in terms of biomarker stratification of patients. Because using one drug instead of two might be advantageous from a cost and a toxicity perspective.
RELATIVITY-047 Update at 2 Years: Subsequent Therapy
Jason Luke, MD, FACP:
There was not a large difference in subsequent treatment usage among PD-1/CTLA-4 inhibitors, BRAF/MEK inhibitors, and other therapies.25 Slightly more patients who had received first-line nivolumab monotherapy received subsequent PD-1/CTLA-4 inhibitors compared with patients who had received first-line nivolumab plus relatlimab (49% vs 40%, respectively).
The response rate to immunotherapy in the second-line was approximately 25% for patients who received first-line nivolumab plus relatlimab. I think this is really important because one question that arises is how to sequence our therapies. If we have nivolumab plus relatlimab, and nivolumab plus ipilimumab, which should we use first? These data suggest that in at least a small subset of patients, a clinical meaningful response rate to nivolumab plus ipilimumab can be seen after nivolumab plus relatlimab. We need to see more follow-up than just 25 patients on second-line immunotherapy and research to explore that is ongoing.
RELATIVITY-047 Update at 2 Years: Investigator-Assessed PFS2 and Melanoma-Specific Survival
Jeffrey S. Weber, MD, PhD:
PFS2 examines PFS on therapy received after progression on the clinical trial therapy. The absolute difference in PFS2 is 8.3 months (HR: 0.79; 95% CI: 0.65-0.96).25 The curves separate at approximately 6 months, stay apart, and appear to plateau. I think this is something that will attract a lot of attention in the future.
The melanoma‑specific survival is a post hoc exploratory analysis, and it favors the combination with the median not reached vs 46.7 months for nivolumab. There is a projected 11% absolute difference at 48 months. Not many studies calculate melanoma-specific survival, and I think the most important indicator to a patient is OS.
Jason Luke, MD, FACP:
I think that the PFS2 is really interesting consideration. Some of us in the field think that PFS2 may be a better indicator of long-term outcome than OS because OS is now very difficult to calculate, given the number of different immunotherapies to which many patients with melanoma can be exposed. How well a subsequent line of therapy works and if that is influenced by the current therapy I think will be a very important consideration.
RELATIVITY-047 Update at 2 Years: Safety Summary
Jason Luke, MD, FACP:
Adding relatlimab to nivolumab added a small amount of toxicity, but it is not tremendous.25 Grade 3/4 treatment-related AEs occurred in 22% of the nivolumab plus relatlimab arm vs 12% of the nivolumab monotherapy arm. I can tell you that in clinical practice, using these agents, this difference is hard to observe. Most HCPs I know have not noticed a difference between AEs using nivolumab plus relatlimab vs nivolumab alone, unlike the combination of ipilimumab plus nivolumab that produces more high-grade irAEs than nivolumab. However, on trial, the incidence of any grade treatment-related AEs leading to discontinuation was slightly higher with the combination vs nivolumab alone (17% vs 9%, respectively).
The incidence of treatment-related deaths was also similar between the arms. There were 4 deaths in the combination arm because of 1 case each of hemophagocytic lymphohistiocytosis, acute edema of the lung, pneumonitis, and multiorgan failure. In the nivolumab monotherapy arm, there were 2 deaths: one because of sepsis and myocarditis and the other because of worsening pneumonia.
RELATIVITY-047 Update at 2 Years: Clinical Implications
Jason Luke, MD, FACP:
RELATIVITY-047 is an important clinical trial that led to the FDA approval of nivolumab plus relatlimab, the first LAG-3 inhibitor, which is now a standard frontline therapy.25 The clinical implication here is that the benefits in PFS, OS, and ORR are durable after a longer period of follow-up. That is very important for a novel combination because we have a lot of historical experience using nivolumab plus ipilimumab. I think these data suggest that the outcomes with nivolumab plus relatlimab may end up similar to those for nivolumab plus ipilimumab. I look forward to longer follow-up on this trial.
In my clinical practice, I am using nivolumab plus relatlimab where I previously used nivolumab monotherapy. I still use nivolumab plus ipilimumab for patients with high-risk disease such as brain metastases, liver metastases, and high LDH. But as these data mature from RELATIVITY-047, I think we will become more confident that using nivolumab plus relatlimab is a reasonable option for more patients in the frontline, especially if we see meaningful responses to second-line nivolumab plus ipilimumab. That would allow us to expose fewer patients to the toxicity associated with ipilimumab until it was absolutely necessary. I think this is a very important study and look forward to further updates from it in the future. I think it also highlights how quickly the field of melanoma is moving.
Jeffrey S. Weber, MD, PhD:
In metastatic disease, my personal opinion is that no regimen matches the 72-month median OS seen with nivolumab plus ipilimumab in the CheckMate 067 study.23,26 I think it is still the regimen to beat. If you look at the projected 48‑month survival of the combination in RELATIVITY-047, it was 52%, which means a median of approximately 4.5 years. That does not match 6 years. In my opinion, we still do not have a regimen that beats nivolumab plus ipilimumab. If patients will accept the toxicity, I recommend nivolumab plus ipilimumab.
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