The year 2015 was an explosive one for the field of immuno-oncology, and currently there are more than 35 immuno-oncology agents in clinical development.1 Lee Schwartzberg, MD, FACP is Chief, Division of Hematology Oncology; Professor of Medicine, University of Tennessee; and Executive Director, West Cancer Center, Memphis, TN. He is also the Advisory Committee Chair of the Institute for Clinical Immuno-Oncology (ICLIO).
Here, Dr. Schwartzberg shares his perspective on how changes in the last 12 months will impact the direction of immuno-oncology in 2016, and why these changes make education in the following areas a priority:
- Understanding the toxicity profiles of immuno-oncology agents and how to manage them
- Using immuno-oncology agents in combinations and sequences
- Differentiating progression from pseudoprogression
- Biomarker-driven treatments
- The implications of immunotherapy for survivorship care, especially in terms of long-term toxicity
Given all the research and approval activity in 2015, do you get a sense that clinical awareness is growing in the oncology community about the different mechanisms of action, anti-tumor response, and the toxicity profiles of immuno-oncology agents?
Dr. Schwartzberg: Absolutely. The general mechanism of action of the checkpoint inhibitor is now well established. The field is moving so fast, perhaps faster than anyone could have expected, and the knowledge base is also rising. With all the approvals in 2015, we now have broad swaths of patients who are eligible for treatment.
Data I’ve seen from a couple of different sources lately suggests that, already, approximately 50 percent of lung cancer patients are receiving a checkpoint inhibitor at some point in their therapy. That grew from 10 to 50 percent over the last year, and since that’s a very large group of patients, that means that most oncologists are using immuno-oncology drugs now.
Will drug replacement remain?
Dr. Schwartzberg: There are new challenges that will need education, especially around operational access and patient-oriented issues such as access to treatment. At the moment the two companies with drugs are being very liberal about supplying drugs for non-indicated diseases. So outside of lung and melanoma, if we decide that a checkpoint inhibitor is clinically indicated , even if we get insurance denial, one of the companies will probably supply the drug.
I don’t know how long that’s going to last, especially since we’ll likely soon have more approvals and competition in this area. Once we have four or six [drugs] on the market, will pharmaceutical companies still provide drug replacement? I don’t know. So we need to think about that.
How should these treatments be selected?
Dr. Schwartzberg: We are now having to consider, how do you select agents? Is there any significant difference between pembrolizumab and nivolumab? Is there any difference between anti PD-1s and PD-L1s? Do they all work the same in every disease? These are really interesting questions, and they are practical questions, too, because this is going to come down to: “Taking the drug every two weeks or every three weeks? Is that better for my patient?”
That brings us to the issue of value-based care, which is going to continue to be important. How are the payers looking at this? Is there a value-based reimbursement proposition for immunotherapy?
How do we recognize and manage toxicity?
Dr. Schwartzberg: We need to continue to emphasize the toxicity profiles of immuno-oncology agents. Anecdotally, I’m hearing and seeing that toxicity is more significant than the clinical trials reported. Maybe that is an issue of patient selection or real-world morbidity, but toxicity recognition and management remains a pressing clinical issue for clinicians.
For example, patients being treated with checkpoint inhibitors can get into trouble if they develop diarrhea, especially if they go to their local hospital and see a gastroenterologist who treats them for infectious colitis instead of immune-related colitis. It remains common that non-oncologists are not aware of the different toxicity profiles of immuno-oncology agents.
What are some of the key clinical trial findings that will have a bearing on community practice in 2016?
Clinical Trials in Combination Therapies
Dr. Schwartzberg: Right now what’s happening is combinations, with lung cancer and melanoma leading the way. In lung cancer, chemotherapy is being combined with immunotherapy up front; immunotherapy is being used as maintenance therapy after chemotherapy induction; or targeted therapies are being combined as first-line therapy of choice for the 30 to 50 percent of the population that has an actionable mutation (i.e., EGFR). Moving immunotherapy up in the treatment approach is the current standard in melanoma, and also we’re seeing combination therapies between CTLA-4 and checkpoint inhibitors to try to increase the response rate.
From ongoing clinical trials, we should know within a year whether combinations with the standard therapy are a good or bad thing. Biomarker use is another area where people are scratching their heads in the community. We don’t really know how to select patients. There’s some evidence that PDL-1 expression makes a difference, but it’s very confusing for people in the community and it’s controversial.2-3 We need to think through the different areas of this controversy and explore the extent of its value in clinical practice.
Mutations and Immmunotherapy
Dr. Schwartzberg: The other area besides PD-L1 that’s gotten a tremendous amount of attention this year has been the concept that cancers with microsatellite-instability-high (MSI-high) or large number of neoantigens may be excellent targets for immuno-oncology agents. I spoke on the patient education perspective at an Institute of Medicine meeting addressing policy making for immunotherapy a few weeks ago.4 It was interesting that in the course of a day and a half, we saw the same slide at least three times in different presentations, with the number of somatic mutations in various human cancers demonstrating that certain tumors like lung cancer and melanoma have lots of mutations, possibly generating neoantigens, and others like breast cancer have less.
So there’s a lot of interest in that concept and the community has started to learn about it. An example in clinical medicine that has captured community oncologists’ imagination was a very small but extremely influential trial published last year in the New England Journal of Medicine (Ref) that showed that patients with colon and other cancers that have abnormalities in MSI that cause a lot of mutations seem to derive benefit from immunotherapy.5
What are some of the unanswered questions in terms of how best to use immunotherapies in clinical practice in relation to sequencing treatments, and using them in an economically sustainable way?
Dr. Schwartzberg: There are lots of questions here. First, should patients receive combination immunotherapy in metastatic melanoma or should that be biomarker driven? The second question is how should we sequence targeted therapies in the 50 percent of melanoma that are BRAF mutated? Which one should patients get first? Should they get combination therapy?6 What are the ongoing trials looking at combination therapy with BRAF and MEK inhibitors with immuno-oncology or without? Outside of a trial, how should you sequence them? Those are all good questions.
In lung cancer, currently immunotherapy is not first-line therapy, but the trials, as I mentioned, are ongoing to look at this in the first-line setting. Sequencing in lung cancer tends to be in the second- or third-line setting, probably moving up to the second line in most patients based on the data that I’ve seen, and the fact that even though there is toxicity, it’s generally less than [with] chemotherapy. So it tends to be an attractive choice.
How do we differentiate between progression vs. pseudoprogression?
Dr. Schwartzberg: The issue is how long these agents need to be continued, and that gets to the lingering issue of how best to differentiate between progression and pseudoprogression. I think people are aware of the immune-related response criteria, but I think in the community the greater issue is that as these patients get toxicity, how long do I keep them on treatment? There is not a lot of good information out there.
So my personal feeling is that I’d like an expert to come and say: “Here’s what I do…three cycles of pembrolizumab; if the patient is doing this and the x-ray is doing this, I’m pretty sure it’s real progression. If a patient is doing this, I’m pretty sure it’s pseudoprogression. If the patient is doing this, I’m pretty sure I don’t know what’s going on and I’m going to keep going for another couple of cycles.”6 I think a practical, in-depth walk through of how to differentiate between progression and pseudoprogression would be very helpful.
More people are living longer as a result of these agents. What are the implications of that for therapy and for managing survivorship?
Dr. Schwartzberg: We’re starting to see a substantial number of lung cancer patients who get a response or get stable disease, and they’re now out six months, nine months, 12 months. What do we do for the patients who do well? We don’t have any clinical trial data to guide us. I can tell you what’s done in the community is that patients ask for a therapy break. And this has nothing to do with immunotherapy.
We saw the same thing with anti-HER2 therapy. Patients want a break and ask: “Do I really need to keep taking it? I feel good and now I’m coming in every two or three weeks to get this IV drip. Can I get a break?” We don’t really know yet what clinicians are doing and how we should approach this, and that gets to the expense issue as well.
And finally, under the category of survivorship is the issue of long-term toxicity, which we’re just starting to see now. Clinical trials aren’t designed necessarily to focus on that and typically don’t collect long-term toxicity data. So I think anything we can learn about that would be extremely useful.
- Feinberg B. Where Does Immuno-Oncology Fit in a Value-Based Care Delivery Model? http://www.ajmc.com/journals/evidence-based-oncology/2016/february-2016/where-does-immuno-oncology-fit-in-a-value-based-care-delivery-model. 2016
- Patel SP, Kurzrock R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14(4):847-856.
- Lisberg A, Garon EB. The value of PD-L1 testing in non-small-cell lung cancer. JAMA Oncol. 2016; doi:10.1001/jamaoncol.2016.0043
- Institute of Medicine. Policy issues in the clinical development and use of immunotherapy for cancer treatment. http://www.nationalacademies.org/hmd/Activities/Disease/NCPF/2016-FEB-29.aspx
- Alexandrov DB, Nature 2013
- Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. New Engl J Med. 2015; 372:2509-2520.
- Smalley KS, Eroglu Z, Sondak VK. Combination therapies for melanoma: A new standard of care? Am J Clin Dermatol. 2016;17(2):99-105.