CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 02, 2023
Expiration: August 01, 2024
CheckMate 067: Nivolumab + Ipilimumab or Nivolumab vs Ipilimumab for First-line Treatment of Melanoma
CheckMate 067 is a randomized double-blind phase III study exploring nivolumab plus ipilimumab or nivolumab plus placebo vs ipilimumab plus placebo in patients with previously untreated, unresectable stage III or IV melanoma (N = 945).16,17 Treatment continued until disease progression or unacceptable toxicity.
The coprimary endpoints are PFS and OS vs ipilimumab plus placebo. The trial was not powered to compare the 2 nivolumab containing arms. Secondary endpoints are ORR, tumor PD-L1 expression and efficacy, and safety.
CheckMate 067: OS and PFS at 7.5-Year Follow-up
The 7.5 year follow-up of this trial found ongoing OS and PFS benefits in the nivolumab containing arms compared with ipilimumab.18 The median OS was 72.1 months, 36.9 months, and 19.9 months for nivolumab plus ipilimumab, nivolumab alone, and ipilimumab, respectively. These results reinforce the SoC for this patient population, which is using an anti–PD 1–containing regimen as upfront therapy.
RELATIVITY-047: Relatlimab + Nivolumab vs Nivolumab in Previously Untreated Advanced Melanoma
The global randomized open-label phase II/III RELATIVITY 047 study is investigating a fixed-dose combination of nivolumab plus relatlimab, which is a LAG 3–targeted monoclonal antibody, vs nivolumab alone.19,20 This study enrolled 714 patients with previously untreated, unresectable, or metastatic melanoma. Each treatment was given every 4 weeks until patient request, unacceptable toxicity, progression, or death.
The primary endpoint is PFS by blinded independent central review (BICR) and secondary endpoints are OS and ORR by BICR.
RELATIVITY-047: PFS by BICR
The study met its primary endpoint of an improvement in PFS with relatlimab plus nivolumab.21 At a median follow-up of 25.3 months, the median PFS was 10.2 months vs 4.6 months with nivolumab alone. These results led to the FDA approval of relatlimab plus nivolumab for adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma in 2022.
RELATIVITY-047: OS
The secondary endpoint of OS did not meet statistical significance, with a median OS not reached with the combination and a 33.2-month median OS with nivolumab alone (HR: 0.82; 95% CI: 0.67-1.02).21
Phase I Trial of Fianlimab (Anti‒LAG-3) + Cemiplimab: Efficacy in Advanced Melanoma
There are other LAG 3–targeting compounds being examined in patients with melanoma, including fianlimab.22 In this phase I trial of fianlimab combined with cemiplimab, which targets PD 1, in patients with advanced melanoma, the ORR was 61% in a combined cohort of 98 patients.
Phase III IMspire150: Anti–PD-L1 + Targeted Therapy in Newly Diagnosed, Advanced Melanoma
The multicenter, double-blind phase III IMspire150 study evaluated atezolizumab plus the BRAF/MEK inhibitors vemurafenib and cobimetinib vs vemurafenib plus cobimetinib and placebo.23 Patients enrolled were newly diagnosed with unresectable stage IIIC-IV BRAFV600-positive advanced melanoma (N = 514). Treatment continued until disease progression, death, unacceptable toxicity, or pregnancy.
The primary endpoint for this study was PFS by investigator assessment and secondary endpoints included PFS by independent review committee (IRC), ORR, duration of response (DoR), OS, and time to deterioration.
IMspire150: Efficacy Outcomes
Median PFS was improved with the triplet, at 15.1 months vs 10.6 months with the doublet (HR: 0.79; 95% CI: 0.64-0.97; P = .022).24 However, there was no significant difference in OS and the ORR was very similar between the arms.
IMspire150: Safety
The rate of grade 3 and grade 4 toxicities with the triplet therapy was quite high, so it is challenging to identify a patient population for whom this regimen is appropriate.24
Interactive Decision Tool Patient Case 2
In this case we are considering which first-line therapy to choose for a patient with metastatic, wild-type BRAF melanoma
In a patient with wild-type BRAF metastatic melanoma who is treatment naive, all 5 expert faculty favored therapy with nivolumab in combination with either ipilimumab or relatlimab. In the absence of biomarkers to inform treatment decision-making, we often consider patient performance status, medical comorbidities, disease volume and the presence/absence of brain metastases. In more frail patients who may not tolerate immune-related toxicities well and who have small disease burden, a regimen associated with a lower likelihood of serious irAEs may be appropriate. Further discussion of central nervous system (CNS) metastases is found later in this module.
Pooled Analysis of COMBI-d and COMBI-v Trials of Dabrafenib + Trametinib: 5-Year OS
Targeted therapy is also an option for patients with BRAF-mutant melanoma and 3 BRAF/MEK inhibitor combinations are approved. The randomized COMBI-d and COMBI-v trials evaluated the efficacy and safety of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib in patients with metastatic BRAF-mutant melanoma.25 A pooled analysis from the studies reported PFS and OS. One important take-home point from these data was that the 5 year OS rate was 34% in this patient population, with a median OS of 25.9 months. The 5-year PFS rate was 19%, with a median PFS of 11.1 months.
coBRIM: OS With Vemurafenib ± Cobimetinib in BRAF-Mutant Advanced Melanoma
The combination of vemurafenib plus cobimetinib was examined in the randomized phase III coBRIM trial vs vemurafenib plus placebo. Patients enrolled had unresectable stage IIIC/IV BRAFV600E/K-mutant melanoma (N = 495).26 Results from this study were similar to those seen with COMBI-d and COMBI-v, with a 5 year OS rate of 31% with the combination and a median OS of 22.5 months.
COLUMBUS: Encorafenib + Binimetinib vs Vemurafenib or Encorafenib for BRAF-mutant Melanoma—PFS
The randomized, open-label phase III COLUMBUS study looked at encorafenib plus binimetinib in comparison with vemurafenib or encorafenib monotherapy in patients with unresectable stage IIIB/C/IV melanoma and a BRAFV600E/K mutation.27 The 5 year PFS was 22.9% with the combination, 19.3% with encorafenib monotherapy, and 10.2% with vemurafenib monotherapy. The median PFS was 14.9 months with encorafenib plus binimetinib, 9.6 months with encorafenib monotherapy, and 7.3 months with vemurafenib monotherapy.
COLUMBUS: OS
The 5 year OS rate with encorafenib plus binimetinib was 34.7%.27 The 5-year OS rate with encorafenib alone was very similar, at 34.9%, while vemurafenib alone was 21.4%. The median OS with the combination was 33.6 months with the combination, 23.5 months with encorafenib monotherapy, and 16.9 months with vemurafenib monotherapy.
DREAMseq: Nivolumab/Ipilimumab → Dabrafenib/Trametinib vs Dabrafenib/Trametinib → Nivolumab/Ipilimumab
A lingering question for patients with BRAF-mutant melanoma has been how to sequence targeted therapy and immunotherapy. An important study in melanoma is the randomized phase III DREAMseq trial, which evaluated the sequencing of nivolumab plus ipilimumab followed by dabrafenib plus trametinib at progression with the reverse sequencing in patients with unresectable stage III or IV melanoma (N = 300).28 Patients enrolled had metastatic BRAFV600E/K-mutant melanoma, were treatment naive and had no active CNS metastases. Treatment continued until disease progression or unacceptable toxicity.
The primary endpoint for this study is the 2 year OS rate and secondary endpoints are PFS, ORR, and safety.
DREAMseq: OS and PFS
Results published in 2023 demonstrate an OS benefit for the sequence beginning with ipilimumab plus nivolumab vs dabrafenib and trametinib.28 The 2-year OS rate was 71.8% and 51.5%, respectively.
It is now the SoC for patients with metastatic BRAF-mutant melanoma to begin with combination immunotherapy rather than targeted therapy. In the absence of biomarkers that inform treatment decision making, we often consider patient performance status, medical comorbidities, disease volume and the presence/absence of brain metastases. In more frail patients who may not tolerate immune-related toxicities well and who have small disease burden, a regimen associated with a lower likelihood of serious irAEs may be appropriate.
Pembrolizumab + Low-Dose Ipilimumab in PD-1 Refractory Melanoma
After progression on an anti‒PD-1‒based therapy the selection of therapy is more challenging. A phase II trial in the second-line setting evaluated pembrolizumab in combination with low-dose ipilimumab (1 mg/kg) in patients who progressed after PD 1/PD-L1–based therapy (N = 70).29
The ORR was 29% in this relatively small patient population with a complete response (CR) rate of 7.2% and a median DoR of 16.6 months. The median PFS was 5.0 months, and median OS was 24.7 months.
SWOG 1616 Trial of Ipilimumab ± Nivolumab in Anti‒PD-1 Refractory Advanced Melanoma
SWOG 1616 is a randomized phase II trial comparing ipilimumab plus nivolumab followed by nivolumab monotherapy vs ipilimumab alone in patients with anti–PD 1 refractory melanoma (N = 92).30
The primary endpoint was PFS, and the combination was found to be superior to ipilimumab alone, with a median PFS of 3.0 months and an estimated 6-month PFS of 34%.
RELATIVITY-020: 2L or Later Relatlimab/Nivolumab in Anti‒PD-1/PD-L1 Refractory Melanoma
The phase I/IIa RELATIVITY-020 trial is evaluating relatlimab plus nivolumab in patients with melanoma refractory to anti–PD 1 therapy (N = 518).31 Cohort D1 eligibility included 1 previous anti–PD 1 therapy, and cohort D2 eligibility included ≥1 previous anti–PD 1/PD-L1 therapy. The question that always arises is whether patients who received anti–CTLA-4 were included, and for this trial the answer is yes. In cohort D1, which included 351 patients, 39.3% of the patients had previously received anti–CTLA-4, and this rate was 59.8% in cohort D2 (which contained 163 patients).
The median PFS was 2.1 months in cohort D1 and 3.2 months in cohort D2. The median OS was 14.7 months and 17.1 months, respectively. ORR was achieved by 42 patients (12.0%) in cohort D1 and 15 patients (9.2%) in cohort D2.
LEAP-004: Pembrolizumab + Lenvatinib for Anti–PD-1/PD-L1–refractory Melanoma
Also in the second line, the open-label phase II LEAP-004 trial examined pembrolizumab plus lenvatinib in patients with unresectable stage III/IV melanoma refractory to anti–PD 1/PD-L1 therapy (N = 103).32 The primary endpoint of this study is ORR by BICR, and secondary endpoints are DoR, PFS, OS, and safety.
LEAP-004: BICR-Confirmed Response (Primary Endpoint)
The ORR was 21.4%, with a best overall response of CR in 3 patients (2.9%) and partial response (PR) in 19 patients (18.4%).32,33 The disease control rate (DCR) was 66.0%, but the median DoR was somewhat lacking at 8.3 months.
Pembrolizumab/low-dose ipilimumab, nivolumab/ipilimumab, nivolumab, relatlimab/nivolumab, and pembrolizumab/lenvatinib are among the treatment options included in NCCN guidelines as possibilities for second line therapy.12
C-144-01 Trial: Lifileucel in Previously Treated Metastatic Melanoma
Next, I will discuss a therapy that is still experimental but is expected to be reviewed by the FDA in late 2023. Lifileucel is a tumor infiltrating lymphocyte (TIL)-based therapy currently in clinical trials and under evaluation by the FDA.34,35 The phase II C-144-01 study is evaluating lifileucel in patients with unresectable/metastatic melanoma refractory to anti–PD 1–based therapy (N = 189). Patients could have previously received BRAF with or without MEK inhibitors if BRAFV600 mutation positive. Lifileucel was manufactured at a centralized facility.
The primary endpoint of C-144-01 is IRC-assessed ORR, and secondary endpoints are DoR, DCR, PFS, OS, and safety.
Lifileucel: Best Objective Response (Primary Endpoint)
Cohorts 2 and 4 (n = 153) had identical enrollment requirements and both received cryopreserved lifileucel. At a median follow-up of 27.6 months, the ORR for the combined cohorts 2 and 4 was 31.4% with the median DoR not reached (range: 1.4+ to 45.0+ months).35 A best overall response of CR was achieved by 8 patients (5.2%).
Lifileucel: DoR in Patients With a Confirmed Response
This DoR curve shows a plateau that appears after the 12 month mark.35 A DoR of ≥18 months was achieved by 41.7% of patients and 39.6% of responses were ongoing at the time of data cutoff.
Lifileucel: Adverse Events
Lifileucel is administered differently than most currently available therapies. It requires surgical resection of a tumor and then processing and development of the TILs in a central facility.35 Once the product is produced, patients are admitted to the hospital and administered myeloablative chemotherapy followed by lifileucel and high dose IL 2.
The most common any-grade adverse events (AEs) associated with lifileucel are thrombocytopenia, chills, and anemia. The most common grade 3/4 AEs were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%). Treatment-emergent AEs were highest in the first 2 weeks after infusion and then rapidly decreased. Overall, the safety profile was consistent with the known safety profiles of the regimens.
Interactive Decision Tool Patient Case 3
This case is a patient with BRAF wild-type melanoma who received first-line ipilimumab/nivolumab and now has progressive disease. Progression may have occurred either while on therapy or <6 months from the end of therapy after achieving a CR.
For this patient, 3 of the 5 melanoma experts recommended transitioning to relatlimab plus nivolumab. The other 2 faculty recommended participation in a clinical trial, which might include TIL therapy, with 1 faculty recommending the use of TIL therapy once approved.
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