Malignant Melanoma, Targeted Therapy and Immunotherapy - The Road to Success

Thanks to the approval of new therapeutic approaches, the treatment of advanced melanoma has been further developed in recent years. Patients with metastatic melanoma who undergo immunotherapy and/or targeted therapy can now hope for long-term survival. While good biomarkers exist for genetically targeted therapies, research is still needed for immunotherapies. A combination of different markers is probably required. In the future, patients who will benefit long-term from current monotherapy, dual therapy, and new combinations must be clearly identified to further improve efficacy and reduce toxicity.

Metastatic melanoma presents a significant challenge in clinical practice. In the past, the disease, for which few treatment options were available, was considered incurable. Until ten years ago, the median overall survival of untreated patients with metastatic melanoma was nine to twelve months [1]. In a historical cohort of 2100 patients, the median overall survival of patients with advanced melanoma, excluding patients with metastases to the brain, was 6.2 months (95% CI, 5.9 months to 6.5 months). Of these, 25.5% (95% CI, 23.6% to 27.4%) were alive at one year [2]. In another cohort, only 15% of patients were still alive five years after diagnosis [3]. Recently, 152 422 patients with malignant melanoma treated in various randomized clinical trials and monocentric observational studies between 1978 and 2011 underwent a review and were evaluated for stage-specific survival and recurrence rate [4]. The 5-year overall survival in stage IV ranged from 9% to 28% [4]. The occurrence of metastases to the brain in metastatic melanoma is proving to be an additional problem. The prognosis experiences further deterioration, while the quality of life decreases dramatically [5,6].

With the introduction of new treatment options for advanced melanoma, new hope is germinating for patients and their treating physicians. After years of stalemate with therapies having no impact on survival, new agents such as checkpoint and kinase inhibitors are providing a broadening of the therapeutic spectrum for melanoma patients. Today, immunotherapy and targeted therapy are standard treatment for melanoma patients thanks to numerous pivotal trials completed with positive results [7–11].

Targeted cancer therapies

Melanoma is a heterogeneous cancer that can be classified as follows based on its molecular characteristics: Melanomas with (i) BRAF mutation, (ii) NRAS mutation, (iii) NF-1 mutation; and (iv) Absence of these three mutations (triple wild type) [12,13]. The presence of activating BRAF mutations in approximately 50% of all melanoma cases has received considerable scientific attention. In fact, melanoma patients with BRAF mutation have good treatment success by suppression of the MAPK (mitogen-activated protein kinase cascade) pathway using small molecule agents such as selective BRAF and MEK inhibitors. Both BRAF and MEK inhibitors, as monotherapy, have demonstrated beneficial effects on survival in this select population of patients with advanced melanoma [9,10,14–17]. Administered as combination therapy in melanoma with BRAF mutation, they also prolonged both progression-free survival (PFS) and overall survival (OS), while delaying the development of resistance mechanisms [18,19]. Current data for the combination of dabrafenib and trametinib show a 2-year PFS of 30% and a 3-year PFS of 22%, in addition to a 1-year OS of 74%, a 2-year OS of 52%, and a 3-year OS of 44% [20]. This highlights that not only immunotherapy but also targeted therapy can provide durable responses in a subset of patients. In particular, patients with low tumor burden, low LDH levels, and a high overall mutation burden seem to be expected to have a longer OS [20,21]. In addition, the combination of vemurafenib and cobimetinib demonstrated comparable response rates with a median PFS of 9.9 months and 9-month survival rates of 81% [22]. The 2-year OS was 48%, with median OS not yet reached after a mean follow-up of 18.5 months [23]. Finally, the combination of encorafenib and binimetinib has also shown promise; survival data will be presented shortly [24].

Effective alternative

Recent data suggest that targeted therapy may also be an option for patients with NRAS mutation [25]. The selective MEK inhibitor binimetinib was associated with longer PFS compared with dacarbazine in melanoma patients with NRAS mutation [17] and is therefore considered an effective alternative for this population. Interestingly, patients previously treated with immunotherapy seem to respond better to MEK inhibition. This suggests that there is an interaction between targeted therapy and immunotherapy. A number of other publications contain data on the immunostimulatory effect of kinase inhibitors [26,27]. Controlled clinical trials will shed more light on this aspect in the near future and provide further insight into the potentially immunogenic effect of kinase inhibitors. In addition, the aim is to clarify how targeted therapy can best be used in the era of immunotherapy.

Immunotherapies

Melanoma is characterized by genetic and epigenetic abnormalities that give rise to antigens that the immune system can use to distinguish melanoma cells from melanocytes [28,29]. For many years, the biologics IL-2 and interferon-alpha (IFN-alpha) were the only agents that showed modest clinical benefit in a small subset of melanoma patients [30, 31]. Since two phase III studies demonstrated that blockade of the CTLA-4 checkpoint by the monoclonal antibody ipilimumab has a positive effect on long-term survival in patients with metastatic melanoma, a paradigm shift has taken place. A durable response was observed, lasting up to 10 years in approximately 20% of patients [6,7,32]. Since these landmark studies and the approval of ipilimumab by the FDA and EMA, immunotherapy research has boomed, focusing on different checkpoint inhibitors. Of particular interest is the blockade of the PD-1/PD-L1 interaction. PD-1 is an inhibitory receptor on the T cell that alters the effector functions of the T cell as a result of interaction with PD-1 ligand on tumor cells. While CTLA-4 blockade is thought to lead to an increased response of tumor-specific T cells, PD-1 blockade is thought to primarily stimulate the activity of an already tumor-resistant T cell pool. Impressive response rates and more favorable survival curves (compared with ipilimumab) were recorded among the two FDA- and EMA-approved PD-1 inhibitors, pembrolizumab and nivolumab, with a proportion of patients showing longer-term response [11, 33-35]. With pembrolizumab, the 1-, 2-, and 3-year overall survival rates are 73%, 50%, and 40%, respectively, with a median OS of 24 months [36]. Comparable efficacy was demonstrated with nivolumab. Here, 63%, 48%, 42%, 35%, and 34% were reported for 1-, 2-, 3-, 4-, and 5-year overall survival, respectively; median overall survival was 17 months [37].

Combinations of active ingredients

While checkpoint inhibition by blockade of PD-1 also demonstrated clinical activity in mucosal melanoma [38], no effect on uveal melanoma was observed with monotherapy with CTLA-4 or PD-1 blockade [39,40] and should therefore not be used in this disease outside of (combination) trials.

In addition to monotherapies, therapeutic strategies with combinations of active ingredients are now also being intensively researched. In particular, the combinations of PD-1 antibodies and CTLA-4 antibodies have demonstrated a robust and markedly synergistic effect [41]. With an overall response rate of 57% and a PFS rate of 49% and 46% for 12 and 18 months, respectively, this combination therapy proves clearly superior to monotherapy with ipilimumab [41]. Unfortunately, this benefit is associated with a significantly higher and clinically relevant rate of toxicities 3. and 4th degree. Clear markers supporting the preferential use of mono-PD-1 blockade over combination therapy do not exist to date [42] (see also Biomarkers section).

Interestingly, the response to immunotherapy appears to be durable even when therapy is interrupted, either because of toxicity or because patients have achieved complete remission, with a very low recurrence rate [36].

Currently, numerous clinical trials are investigating different combinations of checkpoint inhibitors to achieve even better efficacy and reduce toxic effects. In addition, other combination strategies such as the combination of targeted therapy and immunotherapy are also being explored.

Biomarker

Considerable efforts have been made to describe the mechanism of action of immunotherapies and to identify predictive markers of response in humans. However, solid biomarkers for immunotherapy are still lacking. Data from Phase III trials that include potential biomarkers, as well as retrospective analyses of larger patient cohorts, will provide further important information on the use of biomarkers.

Although tumor expression of PD-L1 seems to indicate a higher response rate, longer PFS, and longer overall survival compared to tumors without PD-L1 expression [17,43], PD-L1 expression, due to its heterogeneous nature and dependence on the biopsy site as well as the numerous staining assays available, needs to be further standardized. In addition, it does not help clinicians make decisions, as PD-L1-positive patients have higher response rates across all treatment options-CTLA-4 blockade, PD-1/PD-L1 blockade, and the combination of these agents.

Due to the multifactorial nature of tumor-immune interactions, only combined biomarker assays are likely to reveal which aspects of these interactions to focus on in a given case [44].

Recently, it has been proposed to use a combination of markers obtained by tumor genomics, immunohistochemistry, and standard peripheral blood compartment assays to individualize treatment choices [45]. Such a cancer immunogram should help facilitate treatment decisions in a dynamic and changing context. Included are parameters that determine tumor foreignness, general immune status, infiltration of immune cells into the tumor, absence of local inhibitory factors and inhibitory tumor metabolism, tumor recognition and sensitivity to immune effectors [45]. Other prognostic models for melanoma patients treated with pembrolizumab have been proposed, including those incorporating baseline factors. In one of these models using four baseline characteristics, namely the pattern of visceral metastases, serum LDH concentration, relative lymphocyte count, and relative eosinophil count, a patient subgroup with excellent prognosis was identified [46]. Another group proposed a similar immune score with the use of clinical characteristics such as serum LDH concentration, pretreatment with ipilimumab, gender, and presence of liver metastases. The aim was to identify patients likely to respond to PD-1 antibody therapy [47,48]. Finally, another group noticed a correlation between performance status, serum LDH concentration, lymphocyte count, and C-reactive protein (CRP) on the one hand and survival in melanoma patients treated with pembrolizumab on the other [49]. CRP is a frequently used marker for the determination of inflammatory processes as they are also observed in tumors. A recent study presented data from mice that blockade of tumor-induced inflammation resulted in alteration of the local tumor environment and improved T-cell-mediated tumor control [50].

All these studies are of great importance against the background of a growing number of therapeutic strategies with drug combinations and they facilitate the counseling of patients with regard to the decision for a mono- or combination therapy. In addition, it is essential to determine whether a change in factors in a more favorable direction is associated with a better response to immunotherapy.

Future

In this highly innovative field, it is difficult to predict upcoming developments. However, some issues need to be addressed to improve long-term benefits and reduce toxic side effects.

We need to develop algorithms for individualized immunotherapy that will enable us to determine which patients will benefit from monotherapy with CTLA-4 or PD-1 inhibitors and which will be candidates for combination therapy. At this time, it is not clear whether long-term surviving patients after ipilimumab therapy belong to the same subgroup as long-term benefiting patients after PD-1/PD-L1 inhibition.

We need to develop an optimal combination scheme. Emerging data suggest that ipilimumab and PD-1 inhibition can be combined at different doses or sequentially [51,52], so that efficacy is maintained while toxicity is reduced. These findings would not only benefit patients receiving treatment, but also open up options for triple or quadruple therapies.

The question will no longer be whether targeted therapy or immunotherapy will be used, but in what order or combination these therapeutic options will be applied. Early clinical data suggest that a combination of BRAF+MEK inhibition with PD-1/PD-L1 blockade is safe [53–55]. However, it is not clear whether the agents should be combined continuously or intermittently. We designed a study to at least partially address this question (ImPemBra study NCT02625337).

Modulation of the tumor environment with the aim of stimulating infiltration of CD8 T cells (this marker is closely linked to a better outcome of PD-1 blockade [56]) could be one of the next steps. Indeed, preclinical models with pancreatic tumors have shown an increase in CD8 infiltration and improved response to PD-1 blockade after targeting the stroma with FAK (focal adhesion kinase) inhibitors [57]; this is currently being investigated in a phase I trial. In addition, modulation of tumor immune infiltrates, such as tumor-associated macrophages (TAM) by CSF-R1 inhibition, regulatory B cells by depletion and maturation inhibition of B cells, or inhibition of tumor-associated neutrophils, has been shown to improve effector functions of T cells in preclinical models, and will be used in the foreseeable future for combination therapies in melanoma, among others [58–60].

If all of these agents are used at an earlier stage of disease, such as ipilimumab, nivolumab, or pembrolizumab in adjuvant therapy [61, 62] (EORTC 1325 trial, NCT02362594) or the combination in a (neo)adjuvant scenario (OpACIN trial, NCT02437279), therapeutic outcomes can be further improved in all melanoma patients.

In summary, there has been a profound change in melanoma therapy within the last decade. Current developments provide further movement in this field and we expect melanoma to be one of the first tumor diseases for which individualized therapies with different combinations of immunotherapies and/or targeted therapies will be used. tumor disease will continue to serve as a model with regard to such approaches over the next ten years. They will gradually be studied in other tumor diseases, as is already being done in lung cancer, renal cell carcinoma, Hodgkin’s disease and others.

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