In our Ask a Doc series, we sit down with physicians and other clinical experts across Highmark’s health plan networks, including at Allegheny Health Network (AHN), for a chat on an important health topic. In this post, we explore developments in cancer treatments — specifically immunotherapy — with Dr. Gene Finley from AHN.
Traditional treatments for cancer, like chemotherapy, often have the downside of significant side effects. Ongoing advances in cancer research have paved the way for new options like immunotherapy, a non-toxic treatment approach with few side effects that has shown promising results for certain individuals with some types of cancer.
As an oncologist, deputy director of Medical Oncology, system director of Oncology Integration, and clinical leader of Cancer Research and Clinical Trials at Allegheny Health Network (AHN), Dr. Gene Finley is on the front lines of innovation in cancer treatments. He generously took time to talk with me about immunotherapy.
Kristin Antosz (KA): What exactly is immunotherapy and how does it work?
Dr. Gene Finley (GF): The short answer is that immunotherapy is a type of cancer treatment that uses the body’s own immune system to attack the cancerous cells.
As to how it works, there are white blood cells known as T-cells that are part of the immune system. T-cells target and attack infected or cancerous cells in the body. High levels of a gene called PD-L1 tell those T-cells when to stop attacking. For instance, there’s PD-L1 in the human placenta, as you don’t want the immune system attacking the fetus. It’s normal for the body to produce these molecules to control immune response, but tumors sometimes use the same mechanism to protect themselves against the immune system. When a cancer cell expresses PD-L1, it effectively tells the T-cell to lay off. What has happened with immunotherapy is that scientists and pharmaceutical researchers have figured out how to utilize drugs to re-activate T-cells sitting near a cancer cell and allow the body’s immune system to attack those cancer cells.
There are several drugs that do this in slightly different ways. Nivolumab, also known as Opdivo, and pembrolizumab, or Keytruda, are the two most commonly used, FDA-approved immunotherapy drugs. They both block the receptor on the T-cell to which the cancer’s PD-L1 binds. Other drugs like atezolizumab (Tecentriq) block or bind to PD-L1 on the tumor cell.
KA: How do these immunotherapy drugs compare to past approaches to cancer treatment?
GF: It’s been remarkable what’s happened over the last 30 years in cancer treatment. In the last decade especially we’ve seen the development of new, targeted drugs that are more effective for colon cancer, gastrointestinal cancers, and others where we just didn’t have drugs that promised much hope in the past.
Compared to chemotherapy, immunotherapy is non-toxic, and only a small percentage of those taking drugs like Keytruda and Opdivo experience side effects. Being an immune-related treatment, we’re generally talking about diarrhea, autoimmune pneumonia, hypothyroidism, and other side effects that we are able to manage. The majority of patients experience little or no drop in quality of life while taking these drugs.
In many cases, there are also improvements in effectiveness and duration of response. For example, the usual chemotherapy drugs administered for lung cancer still only estimate survival at 9 months to a year. In patients who respond to immunotherapy, the duration of its effects can last for years. One patient I’ve been following, as far as we can tell, has no evidence of disease despite having had cancer in his liver. We’ve never before seen that kind of response while using chemotherapy, so this is a big game-changer.
KA: This kind of treatment is still new — can you talk about how these drugs get from laboratory research to being used with patients?
GF: Clinical trials are the key step. We have a number of clinical trials in place at AHN, including both second-line and first-line advanced lung cancer clinical trials, and we’re also collaborating with Johns Hopkins Kimmel Cancer Center on a research program looking at what happens when a patient becomes resistant to immunotherapy and why that happens. We’re trying to better identify biomarkers in lung cancer patients and then assign treatments based on that.
That’s just a few. The clinical trials space is huge, and that’s truly how we found out these drugs work in the first place. We don’t have any wholely effective treatments in lung cancer, or many other cancers, so randomly assigned clinical trials are how we test whether new drugs are more effective than existing standard treatments. Early trials have been very favorable with the immunotherapy drugs, which is why we’re seeing new FDA approvals occurring — and that then opens the door to going from being a research drug to being something that might eventually become the new standard of treatment.
KA: Could you talk a little more about the value of AHN’s work with the Johns Hopkins Kimmel Cancer Center and the Highmark Cancer Collaborative?
GF: Yes, we’re working with the Kimmel Cancer Center on several levels. For example, we’re able to draw on Johns Hopkins’ expertise to offer AHN cancer patients remote second opinions, and even some in-person visits. We’ve also been able to open some of Hopkins’ clinical trials to AHN patients, including one in prostate cancer and two in esophageal cancer. We’re collaborating on molecular testing in cancers with Johns Hopkins’ head of molecular pathology, Dr. Chris Gocke. One of those studies is looking at subsets of lung cancer patients who can be treated with a pill instead of chemo, due to special mutations.
Johns Hopkins is a leader in immunotherapy and lung cancer, with world renowned clinicians in lung cancer research. They were the first center to publish on effective immunotherapy in lung cancer and there’s tremendous interest in research around immunotherapy there because of scientists like Dr. Drew Pardoll, Dr. Steve Baylin, Dr. Victor Velculescu and many others. So to be able to work with Johns Hopkins on this research, it’s been incredibly rewarding and exciting.
KA: Some coverage of immunotherapy makes it feel like a “miracle cure” — is it that promising, or is this part of a proclivity to “overhype” new treatments?
GF: There’s this sense in some of the coverage that we’re curing cancer now — and the takeaway for the average person might be, “Wow, the vast majority of people will respond to this treatment and everyone will get cured of lung cancer.” Unfortunately, that’s not the case.
For lung cancer patients specifically, response rates are around 20 to 30 percent — and for patients with high levels of PD-L1 in the tumor, the rates are even higher. That’s an enormous improvement over what we were able to accomplish for patients in the past, and we’re doing it with a non-toxic drug that has fewer side effects. But 20 to 30 percent is far short of “everyone will get cured.” It’s a bright future, but it can definitely be overhyped.
KA: In terms of who this approach will work for, are there certain characteristics that make a patient a particularly good candidate for immunotherapy?
GF: The most important biomarker we look at in predicting response to immunotherapy in lung cancer is levels of PD-L1. The more PD-L1 in the tumor cells, the better the response to immunotherapy. About one third of patients have a high level of expression of PD-L1 in their tumors, which makes them good candidates for immunotherapy, and the FDA approved Keytruda this year as a first-line treatment for non-small cell lung cancer where more than half of cancer cells express PD-L1 on their surface.
The other biomarker that’s important is what’s called a mutational burden. Some patients have more mutations in their cancer cells — and they seem to respond better to immunotherapy.
KA: Media coverage and public awareness of immunotherapy is a recent development, but did it always seem this promising for the medical community?
GF: No, even just four or five years ago if you asked most doctors about immunotherapy, it was a bit of a joke. There was evidence of it working for melanoma, but not any of the other common diseases. I remember being at the American Society of Clinical Oncologists (ASCO) conference in 2015. The main speaker said, “I used to give this talk on immunotherapy to about 10 people” — and now thousands of people were listening to his presentation, and they had to open up extra seating.
It was about that time that Nivolumab emerged as really the first drug approved for the treatment of lung cancer in patients for whom chemotherapy was ineffective. This was a seminal moment in cancer care, because prior to that, immunotherapy was only used in melanoma and kidney cancer and had absolutely no role in any of the common solid tumors (lung, colon, prostate, and breast cancer). We started to see remarkable responses to immunotherapy in lung cancers — which was very unexpected — and interest really took off.
KA: Including your own interest?
GF: Sure, I had a patient with lung cancer shortly after I came to AHN. He had a specific mutation in EGFR — the Epidermal Growth Factor Receptor — and was very sick. I put him on the drug that targeted that EGFR mutation, and he got better. He got so well that he left the hospital off all oxygen and was completely well for about 18 months. There have been quite a few good experiences with patients along the way, but that EGFR case started my interest in lung cancer in particular — that was my rallying cry.
KA: What do you think the future of immunotherapy holds?
GF: While we have drugs that interact with the PD-L/PD-L1 pathway, we’re just starting to look at GITR, LAG3, OX40, TIM-3 — there’s a whole laundry list of letters and numbers that describe other receptors or pathways on the T-cell that either inhibit or stimulate it. That’s the goal now — to figure out how to combine the incredible array of regulatory pathways that the immune system has to create clinically useful drugs and get more clinical trials off the ground. Another area is determining why patients who have lots of mutations on their tumors tend to do better with immunotherapy. And then also using medications to enhance the immune reactivity of lung cancers and leveraging that to make immunotherapy more effective.
It’s hard to predict the future — no one would’ve predicted where we are now. It’s a very interesting time where we have this nexus of events. We finally understand the molecular underpinnings of cancer and have targeted drugs that attack specific mutations; simultaneously, we have immunotherapy, which is not specific to a mutation but to this completely different mechanism of immunogenicity. Those two things are really changing how we’re treating cancer, and that will continue to evolve, I’m sure.
The future is bright. But if you have advanced cancer now and the doctor says you have one year to live, that’s still very unsatisfying. To tell a patient that 20 to 30 percent of people have a great response to the immunotherapy treatment you’re recommending — that’s just not enough. We have a long way to go, but we are making progress.
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