Dermatology update: The dawn of targeted treatment
ABSTRACTDuring the past several years, targeted therapies have significantly improved outcomes in advanced basal cell carcinoma, psoriasis, and metastatic melanoma. This article reviews how advances in our understanding of the molecular pathogenesis of these diseases led to the development of targeted therapies and how these therapies are improving outcomes. Research is ongoing to address continuing challenges of drug resistance, adverse effects, and how best to use the new medications.
KEY POINTS
- Vismodegib, an inhibitor of the “hedgehog” pathway, dramatically shrinks basal cell carcinomas, but resistance and adverse effects remain troublesome. Using it to shrink tumors to operable size may be its best future role.
- Th-17 cells and interleukin 17 are now thought to play central roles in the pathogenesis of psoriasis. Clinical trials of new drugs that block interleukin 17 show striking improvement in skin manifestations with few side effects. Benefits in psoriatic arthritis have not yet been shown.
- About half of patients with melanoma harbor BRAF mutations, and new treatments that target this pathway have improved survival rates. For melanoma not involving BRAF mutations, a better understanding of how tumors evade immune control has led to improved immunotherapies. These targeted medications mark the first major advancements in metastatic melanoma treatment in decades.
IMMUNOTHERAPIES FOR NON-BRAF MELANOMA
Although BRAF and MEK inhibitors represent tremendous advances, their use is limited to the approximately 50% to 65% of patients with advanced melanoma who have BRAF V600 mutations. For others, only the traditional standard medications have been available until recently.
Two of those standard FDA-approved medications, interferon alpha-2b and IL-2, represent immunotherapies. Interferon alpha-2b up-regulates antigen presentation and increases antigen recognition by T cells. Overall, about 20% of patients in clinical trials have achieved responses.
IL-2 is a cytokine that increases T-cell proliferation and maturation into effector T cells. High-dose IL-2 has produced responses in 15% of patients, with a durable complete response in a small proportion.
Though success with these medications was modest, the fact that some patients responded to them indicates that immunotherapy could be a viable strategy for treating metastatic melanoma.30 This is underscored by the fact that some patients can mount an adaptive immune response specifically directed against antigenic proteins expressed in their tumors, resulting in expansion of cytotoxic T cells and control or even elimination of the malignancy.30
Tumors manipulate host immune checkpoints
Molecular biology has provided tremendous insight into tumor immunology over the past several decades, and we now recognize that a hallmark of cancer is escape from immune control.
Cancer cells contain a multitude of mutations that produce proteins that should be recognized by the immune system as foreign but in most individuals are not. This is because T-cell activity is down-regulated in cancer due to cancer cells’ ability to manipulate the host’s normal immunologic inhibitory pathways critical for maintaining self-tolerance.
In general, T-cell activation is initiated when an antigen-presenting cell presents an antigen to a T cell in a major histocompatibility complex-restricted manner. To prevent T cells from being activated by self-antigens and initiating autoimmunity, the interaction between antigen-presenting cells and T cells is regulated by checkpoints (Figure 5). First, for an antigen-presenting cell/T-cell interaction to result in T-cell activation, the T-cell receptor CD28 must bind CD80 on the antigen-presenting cell to drive a “positive” signal. Early in the interaction, the T-cell receptor CTLA-4 is up-regulated and competes with CD28 for binding of CD80. If CTLA-4, and not CD28, binds CD80, a “negative” signal is sent to the T cell and down-regulates it, making the interaction unproductive. Importantly, it is the CTLA-4:CD80 interaction that appears to be crucial for the ability of tumors to dampen T-cell responses to cancer cells.
Ipilimumab is a fully humanized monoclonal antibody that binds to CTLA-4, blocking its ability to bind to CD80 and thereby enhancing T-cell activation. In a phase 3 trial, Hodi et al39 evaluated its use in treating advanced melanoma, with some enrolled patients having failed IL-2 treatment. Patients receiving ipilimumab with or without a glycoprotein-100 peptide vaccine (gp100) had an overall survival benefit of 10.1 months compared with 6.4 months for patients treated with gp100 alone. At 24 months, the survival rate with ipilimumab alone was 23.5%, almost double that of patients receiving gp100 alone.
Ipilimumab received FDA approval for treatment of metastatic melanoma in March 2011. This, and the BRAF inhibitors, were the first drugs approved by the FDA for the treatment of advanced melanoma in more than a decade.
Common adverse effects of ipilimumab include fatigue, diarrhea, rash, and pruritus. As expected, given its mechanism of action, up to about 25% of patients experience severe autoimmune-related events that may variably manifest as colitis, rash, hepatitis, neuritis, hypothyroidism, hypopituitarism, and hypophysitis. Another problem with this medication is that a subset of patients do not respond.
Cancer cells disguised as normal cells
Cancer cells can also manipulate another immunologic checkpoint to evade attack by the host immune system (Figure 5). Cytotoxic T cells may recognize antigens on tumor cells and become activated and primed to directly destroy them. However, tumor cells, like normal cells express the programmed death ligands RTK-L1 and PD-L2. These ligands function to bind to the PD-1 receptor on activated T cells to indicate they are “self” and inhibit the cytotoxic T cells from destroying them.
Evasion of immune system attack by manipulating checkpoints involving CTLA-4 and PD-1 helps explain why malignancies can seemingly be associated with brisk inflammatory responses, such as the tumor in Case 3, yet progress and eventually metastasize (Figure 3).
Two medications—nivolumab and pembrolizumab—have been developed in an attempt to disrupt the ability of tumor cells to trick the immune system into accepting them as “self” by manipulating the PD-L1/PD-L2: PD-1 interaction. Both drugs are monoclonal antibodies that bind to PD-1 and, thus, effectively block the ability of PD-L1 or PD-L2 on tumor cells to bind these ligands and signal to activated T cells that they are “self.” This blocking allows T cells to then carry out their killing of tumor cells they initially recognize as foreign.
Nivolumab. In 2014, a phase 3 trial40 compared nivolumab and dacarbazine in patients with untreated advanced melanoma without a BRAF mutation. Objective response rates were 40.0% in the nivolumab group vs 13.9% in the dacarbazine group. This trial was stopped early because of significantly better survival rates in patients taking nivolumab compared with standard chemotherapy.
Interestingly, only 35% of patients who responded to nivolumab had evidence of PD-L1 expression on the surface of their tumor cells as assessed by immunohistochemical assay. Regardless of PD-L1 status, nivolumab-treated patients had improved overall survival compared with those treated with dacarbazine. The response rate with nivolumab was only slightly better in the subgroup of patients whose tumors expressed PD-L1 than in the subgroup without PD-L1.
On December 22, 2014, the FDA granted accelerated approval to nivolumab for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation-positive, a BRAF inhibitor.
Pembrolizumab. Also in 2014, an open-label, randomized, phase 1b trial of pembrolizumab treatment at two different dosage schedules was conducted in patients with advanced melanoma that had become refractory either to ipilimumab or a BRAF inhibitor.41 Treatment with pembrolizumab had an objective response rate of 26% at both doses.
In September 2014, the FDA granted accelerated approval for the use of pembrolizumab to treat patients with unresectable or metastatic melanoma and disease progression following treatment with ipilimumab or a BRAF inhibitor.
Adverse effects of PD-1 inhibitors are similar to those seen with ipilimumab, the most common (occurring in at least 20%) being fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, muscle pain, and diarrhea. Serious effects from pembrolizumab (occurring in at least 2%) were kidney failure, dyspnea, pneumonia, and cellulitis. As seen with ipilimumab, clinically significant autoimmune adverse reactions occur with PD-1 inhibitors, including pneumonitis, colitis, hypophysitis, nephritis, and hepatitis.
Combination therapy under investigation
A phase 1 trial using combination therapy with both immune checkpoint inhibitors—nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4)—in patients with treatment-resistant metastatic melanoma was published in 2013.42 More than half of patients achieved objective responses, with tumor regression of at least 80% in those who had a response. Tumor response was evident in all subgroups of patients studied—those with pretreatment elevated lactate dehydrogenase levels (one of the strongest prognostic factors in metastatic melanoma), metastases to distant sites, and bulky, multifocal tumor burden. Based on these results, a phase 3 trial is now under way looking at the combination of these two medications vs either one alone.
In summary, targeted treatments are changing the paradigm of how common dermatologic conditions associated with significant morbidity and mortality are treated. Although implementation of the above treatments into everyday clinical practice is exciting, future studies surrounding each are needed to address unanswered issues, such as the optimal dosing and treatment schedules in terms of both disease response and inhibition of resistance, optimal patient/disease characteristics for use, and optimal drug treatment combinations. In the meantime, basic research still utilizing classic molecular biology techniques to uncover pathogenic disease mechanisms in even more detail is ongoing and hopefully will lead to development of even better targeted treatments or even cures for these diseases.
