1 Introduction
Melanoma is still one of the most severe cutaneous malignancies, with a continuously increasing incidence rate [
1]. Its strong invasive capability and high level of genomic alterations account for early metastasis and deadly outcomes [
2]. The identification of signaling pathways in melanoma, as well as tumor immune cell communications, have led to new therapeutic approaches in treating advanced melanoma. In particular, identification of the crucial role of the RAS–RAF–MEK–ERK (MAPK) signaling pathway can be regarded as a milestone for melanoma therapy. About half of all melanoma patients harbor an activating
BRAF mutation (mostly
BRAF V600E), leading to increased proliferation and survival of melanoma cells [
3]. Targeting this signaling pathway has led to a significant improvement in overall survival (OS) and progression-free survival (PFS), with latest results showing a landmark OS rate of 34% after 5 years of initiating such therapy in treatment-naïve patients with unresectable or metastatic melanoma [
4]. Although combined targeted therapy (cTT) with a BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) is associated with a high objective response rate (ORR), most patients relapse during therapy due to acquired mechanisms of resistance. Several resistance mechanisms (primary and secondary) have been described [
5,
6]. Compared with BRAFi monotherapy, cTT showed fewer adverse events (AEs) and delayed occurrence of acquired resistance [
7]. It is still unclear if resistance is truly acquired or represents the outgrowth of resistant clones, with the latter being more likely [
8]. However, long-term PFS and OS can be observed in some patients undergoing cTT. In addition, patients harboring a
BRAF mutation can also receive an immune checkpoint blockade (ICB) as first-line therapy. Recent results showed a 5-year OS of 60% on ipilimumab plus nivolumab.
In this review, we summarize the latest results for patients treated with BRAF and MEK inhibitor combination therapy or ICB. In particular, we discuss baseline characteristics associated with a more favorable outcome, as well as suitable second-line therapies and strategic considerations.
5 Resistance Mechanisms to Combined BRAF and MEK Inhibition and ICB Remain a Major Problem in Melanoma Therapy
Looking at the long-term data of each cTT study (COMBI-d, COMBI-V, coBRIM, and COLUMBUS), most patients progress after approximately 12 months of therapy due to acquired resistance. Primary resistance to TT, i.e. direct lack of therapeutic response, occurs less frequently. There are many possible ways described in the literature regarding resistance mechanisms, one of which is alternative activation of the MAPK signaling pathway due to different receptor tyrosine kinases, e.g. EGFR, PDGFRB, and FGFR1 [
28‐
31]. Additionally, secondary mutations in the
BRAF gene, as well as alternative splicing, have also been identified [
32,
33]. Furthermore, patients harboring an activating NRAS mutation also showed higher rates of BRAFi/MEKi resistance, mostly due to activation of the PI3K/AKT signaling pathway [
30,
34]. Other mutations of the PI3K/AKT signaling pathway have also been associated with a resistance to BRAFi/MEKi, e.g.
PTEN loss-of-function mutations [
35]. Although of diverse nature, all mechanisms share one particular feature—they are unbreakable at this point in time. Unfortunately, cross-resistance to immune checkpoint inhibitions seems to exist on the molecular level [
36].
Hugo et al. identified a transcriptomic signature with an upregulation of genes involved in cell adhesion, mesenchymal transition, angiogenesis, and extracellular matrix remodeling (e.g. AXL, VEGFA, WNT5A, IL10, CCL7) in patients not responding to first-line anti-PD-1 therapy [
37]. These transcriptomic signatures are associated with an innate anti-PD-1 resistance (IPRES). Similar gene upregulation could also be found after MAPK inhibition, suggesting a possible cross-resistance to a subsequent anti-PD-1 therapy.
Kreft et al. demonstrated that patients who have progressed on cTT show a less favorable outcome after second-line ICB [
38]. Here, an objective response (partial or complete response) was achieved in 18.0% (
n = 7/39) of patients receiving second-line anti-PD-1 monotherapy (either nivolumab or pembrolizumab) and 15.0% (
n = 9/60) of patients receiving a combined ICB (ipilimumab plus nivolumab). The ORR for patients without MBMs at baseline was 26.4% (
n = 5/19) and 22.2% (
n = 6/27), respectively. For patients with MBMs prior to second-line ICB, the respective ORRs were 10.0% (
n = 2/20) and 9.1% (
n = 3/33). Additionally, Mason et al. also showed a less favorable survival outcome for patients receiving a combination ICB (ipilimumab plus nivolumab) after not responding to first-line TT compared with first-line combination ICB, with a median PFS of 2.0 months (95% CI 1.4–4.6) and 11.0 months (95% CI 6.0–not reached), respectively, as well as an ORR of 21% in BRAFi/MEKi failure patients [
39]. In agreement, another retrospective study also identified lower response rates for patients treated with second-line ICB (exclusively ipilimumab) after progression on TT compared with patients with second-line TT after progression on ICB [
40]. The median PFS and OS for patients receiving ipilimumab after tumor progression to TT was 2.7 months (95% CI 1.8–3.1) and 5.0 months (95% CI 3.0–8.8), respectively. Another study also demonstrated a reduced response rate to ICB after progression with cTT [
41]. Here, 52/100 patients treated with first-line cTT received a second-line ICB monotherapy (nivolumab or pembrolizumab) after tumor progression, of whom only 4/52 showed an objective response, whereas 36/52 had PD as their BOR.
These data indicate activity of anti-PD-1-based ICB in patients with acquired resistance to cTT. However, response rates are significantly lower than in treatment-naïve patients and might be similar for ipilimumab plus nivolumab and anti-PD-1 monotherapy. The latter raises the question whether trials such as DREAMseq (NCT02224781) and SECOMBIT (NCT02631447) interrogating the optimal sequence of cTT and ICB are appropriately designed to answer this question since they employ combined ICB.
While acquired resistance is the major challenge of cTT, primary refractory disease is a more frequent clinical problem in patients receiving ICB [
18]. Several mechanisms have been described that mostly impair interferon sensitivity [
42,
43] and/or antigen presentation [
44] for anti-PD-1 monotherapy. Recently, association of primary resistance to PD-1 blockade with mutations and losses in JAK1 that can mediate interferon resistance was confirmed [
45]. Mechanisms of resistance to combined ipilimumab and nivolumab remain elusive but might be different from those observed in patients receiving pembrolizumab or nivolumab [
46,
47]. As stated above for cTT, primary resistance to ICB cannot be overcome specifically, but several trials are evaluating new strategies to reach this goal. Cross-resistance to cTT in patients not responding to ICB might exist. Clinical data show that activity of second-line cTT remains high, but PFS might be shorter than in treatment-naïve patients [
40,
48].
6 Summary/Discussion
To date, patients with unresectable or metastatic melanoma, harboring an activating mutation in the BRAF gene, have two different treatment options. As described above, the long-term follow-up data for cTT show promising results, with a 5-year landmark OS of 34% on treatment with D + T in patients harboring a BRAF V600E/K mutation. When looking at the survival outcome for patients with the most favorable baseline characteristics (i.e. normal LDH levels, ECOG PS 0, low tumor burden, no evidence of MBMs) and a CR to D + T, the 5-year landmark OS rate reached up to 71%. In comparison, patients with a BRAF mutation receiving a combined ICB with ipilimumab and nivolumab show a 5-year survival rate of 60% without incorporating additional favorable baseline characteristics. Certainly, these results indicate that long-term survival of BRAF V600-mutated melanoma is possible, both with cTT and ICB. To evaluate if these data indicate a true cure for metastatic melanoma, we first have to define what achieving a ‘true cure’ means.
Appendicitis is cured surgically and cellulitis is cured with antibiotics. In contrast, diabetes and psoriasis are managed, treated, or controlled. The goal of treating patients with metastatic melanoma or other advanced malignancies is to provide palliation by disease control and an extension of the life expectancy without decreasing the quality of life (QoL) by treatment-related AEs. Therefore, a true cure for melanoma means that there is no evidence of the disease and no relapse will ever occur, ideally without continuous treatment. In this perspective, non-adjuvant cTT seems unable to reach this goal. Given the low and still dropping rate of patients without progression after 5 years of cTT, it seems unlikely that this approach will cure patients. In addition, approximately 50% of melanoma patients undergoing cTT will relapse/progress if treatment is discontinued, indicating that clinical activity of these drugs is tightly associated with continuous exposure [
49]. In contrast, ICB can provide clinical benefit even after discontinuation of treatment [
50]. These notions might change when cTT is used adjuvantly: statistical models imply that 12 months of adjuvant cTT with D + T provide sustained benefit to patients.
In 2018, the FDA and EMA approved the use of dabrafenib plus trametinib in an adjuvant setting for stage III melanoma. Hauschild et al. presented extended follow-up data regarding the relapse-free survival (RFS) of the COMBI-AD study (NCT01682083), a randomized, phase III trial, where patients with resected BRAF V600-mutated stage III melanoma were assigned to 12 months of D + T versus placebo [
51]. Here, at a median follow-up of 44 months, patients receiving the cTT showed a 4-year RFS rate of 54% (95% CI 49–59). An estimated statistical cure rate of 54% (95% CI 49–59) for cTT, compared with 37% (95% CI 32–42) in the placebo group, has also been described. These results increase the hope for a real ‘cure’ by cTT, but long-term and OS data are still pending.
Since data indicate that curing patients with advanced
BRAF V600E/K-mutated melanoma using non-adjuvant cTT is unlikely in the overall patient population, it becomes very important to choose the most suitable first-line therapeutic option. Very recently, a 5-year analysis of the pivotal CheckMate 067 trial, performed by Larkin et al., showed a survival benefit for patients with a
BRAF mutation undergoing combined ICB in comparison to
BRAF wild-type patients [
18]. Interestingly, patients harboring a
BRAF V600 mutation showed a 5-year OS rate of 60%, whereas
BRAF wild-type patients reached a 5-year OS rate of 46%. While these findings might have been influenced by second-line therapy, the median PFS of 11.2 months (95% CI 7.0–18.1) for
BRAF wild-type patients and 16.8 months (95% CI 8.3–32.0) for
BRAF-mutated patients, also indicates a direct impact of mutation status on ICB outcomes. In this trial, the median OS for patients receiving nivolumab monotherapy and harboring a
BRAF mutation was 45.5 months (95% CI 26.4–not reached), compared with 34.4 months (95% CI 24.1–59.2) for patients without a
BRAF mutation. The median PFS rates for both cohorts were 5.6 months (95% CI 2.8–9.5) and 8.2 months (95% CI 5.1–19.6), respectively.
Considering an additional subgroup analysis from CheckMate 067 showing a 64% survival rate in all patients with normal baseline LDH and less than three organ sites with metastases, it is likely that combined ICB might show a 5-year survival rate > 64% in
BRAF-mutated patients showing additional favorable baseline characteristics. Although these results should be interpreted with great caution, an indirect comparison by Atkins et al. showed improved survival outcome in
BRAF-mutated melanoma patients receiving ipilimumab plus nivolumab compared with V + C and D + T [
52]. This is also supported by indirectly comparing the 5-year landmark OS rates of COMBI-v/d and CheckMate 067 (34% vs. 60%). These findings are also in line with the results of a retrospective study [
53] in which patients with a
BRAF mutation treated with an anti-PD-1 monotherapy as first-line therapy had longer OS compared with patients treated with first-line cTT. Another retrospective analysis included 567 BRAF-mutated patients with advanced disease stage who received first-line therapy of either cTT (
n = 297;
n = 262 D + T and
n = 35 V + C), anti-PD-1 monotherapy (
n = 162;
n = 69 nivolumab and
n = 93 pembrolizumab), or combined ICB (
n = 108 ipilimumab plus nivolumab) [
54]. After a median follow-up of 22.4 months (interquartile range [IQR] 10.3–32.7), the median OS was 13.2 months (IQR 5.2–41.4), 39.5 months (IQR 8.7–not reached), and not reached (IQR 8.7–not reached), respectively. A 36-month follow-up of the CheckMate 067 trial showed similar results, with a median OS for nivolumab monotherapy of 37.6 months (95% CI 29.1–not reached) and not reached (95% CI 38.2 months–not reached) for ipilimumab plus nivolumab in the entire study population [
55]. In contrast, the presented median OS for first-line cTT was significantly lower than for patients treated within the COMBI-d trial (median OS 25.1 months; 95% CI 19.2–not reached) [
56]). A possible explanation for this difference could be the less favorable baseline characteristics in the real-world setting (e.g. presence of MBMs, elevated LDH levels), as indicated by our own studies [
38,
53].
Another retrospective study analyzed the treatment outcome for ipilimumab plus nivolumab as first-line therapy or after not responding to cTT or anti-PD-1 ICB in advanced (unresectable stage IIIC/IV) melanoma in a real-world setting [
39]. A total of 152 patients were included (
n = 60 first-line;
n = 33 s-line after cTT;
n = 57 s-line after anti-PD-1 ICB). After a median follow-up of 6.1 months (95% CI 5.8–6.7), the median OS for first-line ipilimumab plus nivolumab was 14.2 months (95% CI 8.0–not reached), compared with 3.6 months (95% CI 1.6–not reached) for second-line after not responding to cTT and 9.6 months (95% CI 7.8–not reached) for second-line after not responding to anti-PD-1 monotherapy. Of all patients included in that study, 26% had MBMs, 55% had elevated LDH levels, and 39% had ECOG PS ≥ 1, explaining a less favorable treatment outcome compared with the results of the CheckMate 067 trial. Coming back to biomarkers associated with favorable outcomes, these and other real-life data [
38] show an accumulation of patients with unfavorable baseline characteristics among those receiving first-line cTT. Out of clinical practice, patients presenting with a high tumor burden and/or symptomatic brain metastases are especially in need of immediate disease control. Therefore, patients presenting with these characteristics and harboring a BRAF mutation seem to be preferentially treated with first-line cTT, since palliation by disease control is the primary goal, even if ICB might be superior in the long run. Nonetheless, no definitive recommendations can be made due to the lack of direct comparison of ICB and TT in clinical trials.
Apart from efficacy, safety and QoL are major features of clinical importance. Regarding QoL, prospective clinical trials have shown that cTT and ICB have no significant impact on the QoL of melanoma patients, as previously reviewed by Malkhasyan et al. [
57]; however, relapse and progression are associated with a drop in QoL. Many AEs have been described for cTT and ICB. In patients treated with cTT, AEs of any grade (according to the Common Terminology Criteria for Adverse Events [CTCAE]) occurred in almost all patients, with grade 3–4 AEs occurring in 54%/62% of patients for D + T (COMBI-d, COMBI-v [
4]), 60% for V + C (coBRIM [
13]), and 58% for E + B (COLUMBUS, Part 1 [
12]). In CheckMate 067, combined ICB caused grade 3–4 toxicities in 59% of patients, while anti-PD-1 monotherapy led to grade 3–4 AEs in 23% of patients [
16]. Importantly, long-term exposure to cTT and/or long-term follow-up in patients receiving or having received ICB are not associated with new AEs. In general, the incidence of AEs is dropping with longer follow-up.
Taken together, is there a hope for cure? Yes, certainly. Under favorable circumstances (i.e. low LDH levels at baseline, few metastatic organ sites, no brain metastases, BRAF V600E/K mutation), there is a good chance of long disease control with ongoing PFS and high OS in patients receiving first-line cTT or ICB for the treatment of metastatic disease. As stated above, a true cure means that patients are without a relapse ‘forever’. Two aspects must be considered in this perspective: how long do we have to follow-up patients for relapses and at which point in time do we have to document melanoma-specific survival instead of OS? At present, answering these questions based on evidence is impossible.
With head-to-head data pending, indirect comparison and interpretation of results from prospective studies evaluating first-line ICB in melanoma patients harboring a BRAF V600 mutation indicate that long-term disease control is more likely in patients receiving first-line ICB, particularly ipilimumab plus nivolumab. However, apart from these considerations, concurrent medical conditions, symptoms, shared decision making, and other factors have to be incorporated into the treatment of patients with advanced melanoma.