By Jennifer King, Director of Science and Research for Lung Cancer Alliance
If you happened to read last week’s Weekly Breather, you may have picked up on a few pieces of interesting news. An important one, that also hit major media outlets, was that Opdivo (nivolumab) was approved by the FDA last Wednesday for the treatment of lung cancer – more on that in a minute.
Also mentioned in the Breather last week was my hiring as Director of Science and Research for Lung Cancer Alliance. (I know that at least a few people read all the way down – I really appreciated the welcome emails that I received!) One of my roles will be talking about current research with all of you in the lung cancer community, so why not jump right in… Here’s my perspective on why last week’s decision is a very important, step forward.
The Opdivo approval came months sooner than the scientific community expected and this was due to how significantly the drug improved survival. But if you read the fine print of the news last week, you may have realized that the FDA’s approval of Opdivo was only for patients with a very specific type and stage of disease: squamous, non-small cell lung cancer that has already metastasized and is already resistant to platinum-based chemotherapy (like cisplatin, carboplatin, or oxaliplatin). This is only a small percentage of the patients living with lung cancer.
However, there is hope. The Opdivo approval is actually full of promise. This drug (and many others that are currently in drug company pipelines, including a rival named Keytruda (pembrolizumab)) is in a brand new class of therapeutics called immunotherapies or immuno-oncology drugs. Most cancer-fighting treatments are designed to kill cancer cells. But immunotherapies are different. They are not designed to kill the cancer cells. They are designed to help your own body’s normal immune system work better so that IT can kill the cancer cells.
There are multiple types of immunotherapies being developed and Opdivo and Keytruda are in a class called “checkpoint inhibitors”. The body’s normal immune system has “checkpoints” that stop the immune cells from attacking everything. If the immune system went after all the normal cells in the body, we would all have auto-immune diseases like lupus.
Tumors, including lung cancer, often fool the body’s immune system by producing proteins that activate this safety checkpoint. Then the immune system doesn’t fight the cancer effectively. In this case, the tumor produces a protein called PD-L1 that can bind a protein on the immune cell called PD-1. When the two proteins bind, it activates the checkpoint, halting the immune system.
Opdivo and Keytruda are both anti-PD-1 inhibitors: they bind PD-1, preventing it from binding PD-L1 and thereby surpassing the checkpoint. This keeps the normal immune system active and working to fight the tumor. There are also multiple new drugs in clinical trials that bind PD-L1, which should have a similar effect. PD-1/PDL-1 isn’t the only checkpoint. In fact, there is an FDA-approved drug in metastatic melanoma called Yervoy (ipilimumab) that targets a different checkpoint protein called CTLA-4 and it is being tested in clinical trials in lung cancer.
One of the most interesting things about this class of drugs is the type of response that has been seen in trials. Targeted therapies such as EGFR and ALK inhibitors tend to be very effective for patients with the right mutation; however, the response often doesn’t last very long and the tumors become resistant to the drug. Both in lung cancer and in melanoma (where much of the pioneering immunotherapy work has been done) these immuno-oncology drugs have shown a different pattern. It’s not a high percentage of people that have tumors that respond (15% in the Opdivo study). However, in those patients, the effects of the drug are “durable”- meaning that they last a long time.
In the Opdivo study, approximately 60% of those patients that had a response were still responding to the drug six months later. There were similar findings in other studies of PD1/PDL1 inhibitors and for Yervoy. If your immune system fights the tumor well after a checkpoint inhibitor, it continues to do so for quite a while.
For a researcher like me, now there are tons of fascinating questions that could lead to big breakthroughs in patient care. How do other types of lung cancer respond to immunotherapy? What if you don’t have chemotherapy first? Why do only that small percentage of patients respond to the immunotherapies? If we knew who to treat, it would save money and improve quality of life and we know that these drugs could have long-term effects in the treated patients. How can you best combine immunotherapies with each other and with other cancer treatments? Combinations of PD-1 and CTLA-4 inhibitors are showing promise already in melanoma trials. Researchers are looking at the combination of these drugs with targeted therapies as well. And what about other types of immunotherapy? Could they be just as or more effective for patients with lung cancer?
It’s early days and there are so many questions to be answered. But this is a huge step forward: we have a new type of drug that works very differently approved by the FDA for the treatment of patients with lung cancer. I anticipate the approval of many more immuno-oncology drugs for lung cancer as well as more indications for Opdivo over the next few years. So I’m looking forward to writing more of these blogs with many more advances and success stories to share with all of you.