Exciting advances in melanoma treatment

Melanoma represents only about 1% of all skin cancer cases, but accounts for the vast majority of skin cancer deaths. There were approximately 75,000 new melanoma cases diagnosed last year, and approximately 10,000 people died of melanoma (ACS). Excluding non-melanoma skin cancers (which are relatively common but tend not to be life-threatening), melanoma ranks 6th in incidence frequency among all cancers in the U.S.

A positive recent trend is that while the incidence rate of melanoma is increasing, the number of deaths is decreasing. During the period 2013-2017 (ACS): 

"[I]ncidence rates increased for 5 cancers: liver and intrahepatic bile duct (liver; 2.5%); melanoma of the skin (melanoma; 2.2%); kidney and renal pelvis (kidney; 1.5%); oral cavity and pharynx (1.2%); and pancreas (1.1%). [...]

The largest declines in death rates were observed for melanoma of the skin (decreasing 6.1% per year among males and 6.3% among females) and lung (decreasing 4.8% per year among males and 3.7% among females)."

The rise in incidence is likely due to demographics (i.e. aging population), increased exposure to sunlight, and unhealthy habits such as the use of tanning beds. The decline in mortality has been the result of earlier diagnosis and significant advances in treatment. In an old post from 2015, I described former President Jimmy Carter's stage 4 (most advanced stage) melanoma. Previously the five-year survival rate for stage 4 melanoma was as low as 15-20%. But thanks to a new class of treatments called immune checkpoint inhibitors (e.g. anti-PD1) the prognosis has significantly improved. President Carter's melanoma went into remission after the immunotherapy and more than five years later, he is still alive.

A review in The New England Journal of Medicine from last year describes the progress being made to better understand and treat melanoma. The article begins with new insights into the molecular characteristics of melanoma that has informed novel treatment strategies:

"Molecular evaluation also reveals that melanoma is among the solid tumors with the highest mutational burden, which is hypothesized to serve as a source of neoantigens for host immune responses and may predict the response to immunotherapy. Most mutations in melanoma are passenger mutations, but several driver mutations that can be targeted by drugs have revolutionized treatment. Because of a BRAF mutation, first described in 2002, BRAF has become the main target of currently approved targeted therapies. BRAF is a serine–threonine kinase in the RAS–RAF–MEK–ERK pathway. Approximately 50% of melanomas have BRAF mutations resulting in constitutive activation of MEK and ERK signaling, providing a rationale for combined BRAF and MEK inhibition."

One interesting insight is that melanoma has a high mutational burden, i.e. many genes undergo many mutations. This could explain in part the effectiveness of immunotherapy because the melanoma expresses neoantigens which are novel antigens (because of sequence alterations) that are viewed as foreign by the immune system and hence attacked. 

The BRAF gene is a central player in melanoma with mutations found in ~50% of melanomas. Constitutive mutations in BRAF (that keep it in the on-state) likely result in activation of signaling pathways involving the MEK and ERK protein kinases. This molecular characterization has led to the development of BRAF and MEK inhibitors against melanoma which have proved to be effective.

What about the other ~50% of melanomas without a BRAF mutation? In those cancers it appears as though two other oncogenes are primary drivers: RAS (~28%) and NF1 (~14%). 

Turning towards treatment, the primary treatment for melanoma is surgery (removing the lesion), which is very effective and getting even better:

"More than 90% of patients with melanoma have localized or regional disease, and the primary treatment for such patients is surgical. Current standard surgical approaches are now markedly less invasive and associated with lower morbidity than previous approaches yet have equivalent or superior accuracy and effectiveness."

A big advance in the field has been the application of immunotherapy and in particular immune checkpoint inhibitors such as anti-PD-1 antibodies. The PD-1 receptor is expressed on T-cells and triggering it will cause the inactivation or death of these T-cells. The purpose of this pathway is to avoid the accidental attack of normal self tissue by T-cells. The problem is that cancer cells targeted as non-self by T-cells will express the PD-1 ligand (PD-L1) that will inhibit T-cell activity allowing the tumor to grow. A PD-1 inhibiting antibody will prevent this downregulation, increasing the number of active T-cells that can fight the tumor. This immunotherapy has found success against melanoma:

"The paradigm-changing advances in cancer immunotherapy involve inhibitory receptors or checkpoints, including cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) protein, pioneered by Allison and Honjo. They earned a Nobel prize for their achievements, and translation of their basic science insights changed the standard of care for melanoma and many solid tumors."

Early results from 2016 showed that the five-year survival rate for metastatic (Stage 4) melanoma doubled from 16.6% to 34% because of  treatment with the anti-PD-1 antibody Opdivo (QH). More anecdotally as mentioned above, former President Carter announced that he had Stage IV melanoma in 2015.  After three weeks of treatment with the immune checkpoint inhibitor Keytruda (Merck) the cancer appeared to be gone (QH). It is almost 8 years later and President Carter is now 98 and still cancer-free.

Even more exciting are the results from combining two different immunotherapies (Figure 1):

"The outcome for patients with advanced melanoma has been transformed with combined checkpoint antibody therapy. Ipilimumab combined with nivolumab (Opdivo) has been associated with a 53% response rate and is now the standard of care for immunotherapy in most patients with advanced melanoma."

A second major advance has been targeted therapy that inhibits BRAF, which as mentioned above may be an important driver of ~50% of melanomas:

"In 2011, vemurafenib became the first BRAF-targeted therapy approved by the Food and Drug Administration (FDA) for the treatment of melanoma on the basis of a 48% response rate and a 63% reduction in the risk of death, as compared with dacarbazine chemotherapy. Although the initial response to vemurafenib was rapid and clinically meaningful, progression-free survival was only 5.3 months, which is indicative of the rapid development of resistance through mitogen-activated protein (MAP) kinase reactivation with monotherapy. "

It turns out that BRAF inhibitors alone have limited effectiveness likely due to resistance mutations arising quickly in the downstream MEK pathway. Fortunately, the combination of BRAF and MEK inhibitors can erect a double blockade that results in a more potent treatment:

"Combined BRAF and MEK inhibition addresses this mechanism of resistance and is now the standard of care for targeted therapy in patients with melanoma. Treatment with dabrafenib and trametinib, vemurafenib and cobimetinib, or encorafenib and binimetinib is associated with prolonged progression-free and overall survival, as compared with BRAF inhibitor monotherapy, with response rates exceeding 60% and a complete response rate of 10 to 18%."

The good news is that BRAF plus MEK targeted therapy (e.g. encorafenib plus binimetinib)  can achieve disease control that lasts for years (Figure 1), but eventually even this combination may succumb to resistance mutations in the cancer. In that case, immunotherapy can be given as the follow-up treatment. In terms of the order, the targeted kinase (BRAF and MEK) inhibitors are usually given first because they act faster.

In addition to combining different drug treatments, one can combine drug treatments with surgery, with the treatments coming before (neoadjuvant) or just after (adjuvant) the surgery. After resection (surgery), both immunotherapy and targeted therapy have demonstrated effectiveness reducing melanoma spread:

"Both PD-1 blockade and combined BRAF and MEK inhibition have a clear benefit in resected stage IIIB, stage IIIC, and stage IV melanomas. No head-to-head comparisons of the two treatments have been performed or are anticipated, but the relative risk reductions appear to be similar and durable."

The article concludes with the following summary and future directions:

"Treatment and survival for patients with localized or metastatic melanoma have improved dramatically in the past 10 years. Initial surgical treatment is more precise and less invasive, with a lower morbidity. Systemic therapy has undergone remarkable changes. Particular areas of research interest include improving the selection and sequence of therapies that have the highest probability of inducing a durable response, defining the benefit of neoadjuvant therapy, and developing treatments with a higher probability of inducing complete and durable remission. Integration of surgical and medical interventions is likely to be key in improving long-term outcomes for patients with melanoma."

It is encouraging that now there are now three modalities for treating melanoma. The first-line of defense remains surgical removal of the melanoma from the skin, and the procedure has become more effective and less invasive in recent years. If the melanoma has spread, two new drug treatments have become available over the last 10 years, immunotherapy and targeted therapy, with both providing significant durable response even to late stage melanoma. One important future area of research is how best to combine these various modalities in terms of sequencing or even administering together as a mega-combination (if the side-effects can be managed).

Figure 1. Percent two-year survival from clinical trials of various treatments ranging from classic chemotherapy to targeted therapy to immunotherapy. The drug or drug combination is before the slash for each label of bar graph (with abbreviations specified below along with brand name). The name of the clinical trial comes after the slash. Drug abbreviations are as follows: Atezo = atezolizumab (anti-PD-L1, Tecentriq), Bini = binimetinib (MEK inhibitor, Mektovi), Cobi = cobimetinib (MEK inhibitor, Cotellic), Dab = dabrafenib (BRAF inhibitor, Tafinlar), Enco = encorafenib (BRAF inhitor, Braftovi), Ipi = ipilimumab (anti-CTLA-4, Yervoy), Nivo = nivolumab (anti-PD-1, Opdivo), Pembro = pembrolizumab (anti-PD-1, Keytruda), Tram = trametinib (MEK inhibitor, Mekinist), TVEC = talimogene laherparepvec (oncolytic immunotherapy, Imlygic), and Vem = vemurafenib (BRAF inhibitor, Zelboraf) (NEJM).