Immune Checkpoint Inhibitors in Melanoma: New Directions

The drugs pembrolizumab (Keytruda) and nivolumab (Opdivo) were approved by the U.S. Food and Drug Administration (FDA) in 2014 and 2015, respectively. These two competing blockbuster drugs are already changing the outlook in metastatic melanoma, previously considered to be a fatal disease. Known as ‘immune checkpoint inhibitors,’ they work by releasing ‘brakes’ on a patient’s own immune system, freeing it to attack tumors. In the wake of their success, researchers are now taking immune checkpoint inhibition in new directions.

Keytruda and Opdivo target the immune checkpoint protein PD-1, which is found on tumor-fighting T cells and restrains their activity. Targeting PD-1 frees up the T cells to attack cancer cells. Keytruda and Opdivo have a higher response rate and are less toxic than ipilimumab (Yervoy), a drug that targets another checkpoint protein on T cells called CTLA-4 and that was approved by the FDA in 2011. The investigational drugs MEDI4736 and MPDL3280A bind to and disable the protein PD-L1. PD-L1 is expressed on tumor cells, binds to PD-1 on T cells, and prevents their activation. Much has been written about these immune checkpoint inhibitor drugs, including in this blog.

Here are some of the directions in which immunotherapy for melanoma is developing further:

1. How to identify patients likely to respond to immune checkpoint inhibition?

Melanoma patients treated with either Keytruda or Opdivo may respond with long-lasting disease control, but less than 30% of patients have a good response to these drugs. This percentage is even lower for patients treated with Yervoy. Much work is being done to understand what factors determine whether a melanoma patient will respond to checkpoint inhibition.

Expression of PD-L1 on tumor cells can be a good predictor of response to an anti-PD-1 drug. However, some patients without PD-L1 on their tumors also have a good response. Clearly, PD-L1 alone cannot be used as a predictive factor.

A fairly large sequencing study performed a deep analysis of tumors from patients treated with Yervoy. It found that the ‘mutational load’ of tumors—how many mutations are present—correlates with good response to Yervoy. After treatment with Yervoy, patients whose tumors had more than 100 mutations survived much longer than those whose tumors had fewer mutations. However, this alone could not explain all the responses seen—similar to PD-L1 expression not being 100% reliable in predicting response to anti-PD-1 drugs.

Another study found that melanomas with mutations in the gene NRAS tend to have better responses to immune checkpoint inhibition than tumors in which NRAS is unchanged. It is possible that the higher mutational load of these tumors makes them better targets for immune treatments, but additional factors are most certainly at work.

It is becoming clear that there is no single factor that could predict a patient’s response to immune checkpoint inhibition. The question arises if it might be feasible to analyze multiple factors, including particular tumor features and the patient’s immune system, in order to predict response.

2. What are the most promising treatments to use alongside checkpoint drugs?

It is generally recognized that immunotherapy drugs should be combined with other drugs in order to increase their efficacy. Last October, I wrote about ongoing clinical trials testing such combinations. The list was short enough to fit into a single blog post: a total of 19 trials. Now, there appear to be 13 trials testing combinations with Opdivo, 9 trials with Keytruda, 4 trials with the anti-PD-L1 drugs, and about 50 trials with Yervoy. This is certainly too many to list here, and shows the hope invested in the success of this approach.

One treatment that has already produced remarkable results is the combination of two different checkpoint drugs, Opdivo and Yervoy. This treatment is intended to remove two different brakes on T cell activation, CTLA4 and PD-1, in an approach known as ‘dual checkpoint blockade.’ A study just published showed that treatment with both drugs made tumors shrink or disappear in 61% of patients—a truly outstanding response rate. Yervoy alone produced responses in just 11% of patients.

Researchers continue to combine targeted therapies and immunotherapies in trials. A study in 2013 combined vemurafenib (Zelboraf; a BRAF inhibitor) and Yervoy in BRAF-mutant melanoma, but it had to be stopped because of severe side effects. However, clinical research into a potentially winning combo of immune and targeted therapy is ongoing. Combinations of anti-PD-1 and anti-PD-L1 drugs with BRAF and MEK inhibitors for BRAF-mutant melanoma are being tested in trials in various schemes. In lab studies, combining an anti-PD-1 drug with both BRAF and MEK inhibitors produced remarkable results in a mouse melanoma model.

A recent study reported a much-improved response to Yervoy in patients whose tumors were irradiated prior to receiving the drug. Other studies have shown that adding an anti-PD-1 drug to Yervoy after irradiation essentially cures mice of their melanomas. This approach—radiation and dual checkpoint blockade—is being explored in ongoing trials, including ones for patients with brain metastases of melanoma, in whom the combo could be particularly effective.

Other drugs being tested in combination with checkpoint drugs fall into several categories. Among them are antitumor vaccines, which, on their own, have generally not been successful in melanoma treatment. Some trials are attempting to combine Yervoy with a promising technique called adoptive cell transfer, in which a patient’s own T cells are multiplied in the lab and then infused back into the patient. Adding the checkpoint drug may just deliver a kick to the infused T cells that will transform them into fully armed cancer killers. In addition, although they are newcomers themselves, drugs that are injected directly into tumors (also known as intralesional drugs, eg, T-VEC) are being explored in combination with checkpoint drugs.

3. What else is in the immunotherapy pipeline for melanoma?

There are a few new checkpoint drugs entering trials: MGA271 targets a molecule called B7-H3 that inhibits T cell activation; the drugs IMP321 and BMS-986016 target an inhibitory molecule called LAG-3, found on T cells. Tremelimumab is, like Yervoy, an anti-CTLA4 drug that is still in clinical testing.

Anti-PD-1 and anti-CTLA4 drugs remove brakes on T cells. But there are also several  stimulating molecules on T cells that need to be engaged to allow for maximum activity, and these are now the subjects of intense exploration. The hope is that simultaneously releasing a molecular brake (with a checkpoint drug) and pushing the accelerator pedal (by engaging a stimulating protein) will unleash the full power of T cells.

One of these stimulating proteins is CD40. A new drug called CP-870,893 targets CD40 on T cells. Some very recent results showed that this drug, when combined with the anti-CTLA4 drug tremelimumab, produced responses in 27% of a small group of melanoma patients. CD27 is another stimulating protein on T cells. The anti-CD27 drug varlilumab is being tested in several trials in combination with Yervoy or Opdivo.

Other drugs in early clinical testing aim to engage the stimulating proteins OX40 and GITR. There is also a lot of justified enthusiasm for the promise that immune checkpoint inhibitors hold for melanoma. The number of new drugs and approaches reflect this.