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Douglas B. Johnson, MD, MSCI, discusses the importance of Cancer Immunotherapy Awareness Month and the utility of immunotherapy across tumor types.
Douglas B. Johnson, MD, MSCI
With immunotherapy now serving as a core pillar of cancer treatment—alongside chemotherapy and radiation—across a broad range of tumor types, raising awareness about the distinct safety profiles, response patterns, and other key considerations for treatment selection allows for more effective incorporation into routine clinical practice and maximal therapeutic benefit, according to Douglas B. Johnson, MD, MSCI.
“Increasing awareness [about immunotherapy] remains important because the adverse effects [AEs] are different, the management of those AEs is different, the types of responses are different, and the considerations for using immunotherapy in the adjuvant vs neoadjuvant setting are also distinct,” Johnson said in an interview with OncLive® during Cancer Immunotherapy Awareness Month. “Understanding the nuances of immunotherapy is no longer optional. It is a foundational aspect of modern oncology and will continue to be so.”
During the interview, Johnson discussed the limitations and potential of current biomarkers for guiding immunotherapy; shared evolving clinical approaches, including earlier integration of immunotherapy in melanoma; and emphasized strategies to mitigate immune-related AEs (irAEs) while balancing long-term risks and benefits.
Johnson is a professor of medicine in the Division of Hematology/Oncology and the leader of the Melanoma Clinical Research Program at Vanderbilt University Medical Center in Nashville, Tennessee.
Johnson: So far, across immuno-oncology indications, we've got 3 biomarkers that are FDA approved. High PD-L1 expression in some cancer types is useful, lung cancer being the poster child, where you have high PD-L1 expression in the frontline setting, defined as greater than 50% tumor cells. Unfortunately, if we still look at the long-term survival rates, we're still seeing relatively poor outcomes in those patients. Of course, [many] patients do achieve long-term responses, but it's obviously not the greatest biomarker when you're still having most patients, unfortunately, dying of their disease.
Even PD-L1 expression, while it certainly can remove some patients who really won’t benefit, is not that great in identifying the absolute best responders, and there are so many patients who don’t benefit. I would say one of the [biomarkers] that is most promising, although it unfortunately only applies to a small number of patients, is microsatellite instability [MSI]. In any tumor type where there’s a chance of MSI-high status, that’s something that should be checked at this point, because patients have at least a 50% response rate to immunotherapy.
In [a disease like] like colon cancer, we're seeing almost 100% response rates in the neoadjuvant setting with combination immunotherapy, which is remarkable when patients do have that marker. [Accordingly], that’s something that should be checked. Unfortunately, as we all know, that represents a small proportion of patients in the broader metastatic cancer landscape, so it's great when we have it, but it's a small percentage overall.
The third marker is high tumor mutation burden [TMB]. This one certainly has a role, but it’s a little harder to know exactly how to use it. High TMB often occurs in MSI-high patients and carcinogen-driven tumors like melanoma or non–small cell lung cancer. I would say it's less predictive in that space. A lot of it is more of a surrogate of MSI or tumors that are already responsive. It can be helpful, but I would say it's not the greatest.
As someone who [focuses on] melanoma, we're certainly using immunotherapy all the time. It's kind of our go-to agent. When I was in my training and residency, we would have these conversations with patients that we can treat you, but we can't cure you; that we can do a lot for you, but we're not going to get rid of this cancer. That has turned on its head. Especially with patients with melanoma, even in the metastatic setting, I've got a whole clinic full of patients who are 5 years out, 10 years out, with no evidence of disease, who started with widely metastatic disease. That is a real change.
If you're an oncologist treating a patient with melanoma, that patient is potentially curable, even if they're in the metastatic setting, and certainly on frontline therapy. The other thing is, we're starting to use these therapies a lot earlier; we’re not just [seeing them] in the adjuvant setting, but promisingly in the neoadjuvant setting. We're seeing that even just giving a couple of doses of immunotherapy before surgery can improve the cure rate, even after giving the same treatment after surgery, which is something I would not have predicted.
The way I think about it is that there's a bull’s eye for the immune system to go after if there's a tumor in place. We can activate the immune system against that tumor while it's there, take it out, and then any residual micrometastatic disease can be more effectively targeted. We're seeing improved cure rates, and I expect immunotherapy to move more into the neoadjuvant setting across other disease types, as it already is.
These immune toxicities are quite different from chemotherapy toxicities. They relate to T-cells being activated and attacking host tissue in addition to the tumor, and can affect essentially every organ system. These are certainly important to think about. That’s one of my main research interests.
We know just a few sorts of highlights for irAEs. Certainly, one is that patients are often treated with steroids. There’s been a fair amount of data recently showing that the higher the dose of steroids, the worse the long-term survival and overall survival. Although we have to use steroids in many cases, if there’s a situation where it’s borderline, or the patient’s not very sick, or maybe has asymptomatic liver enzyme abnormalities, it’s certainly reasonable to think about trying a lower dose of steroids, like 0.5 mg/kg instead of 1 mg/kg.
Now, if a patient is sick and you’ve got to do high-dose steroids, please do. We certainly don’t want to get into a situation where the patient dies from toxicity or you end up having to use more steroids after all, because the patient’s not getting better, and you have to escalate to a high dose.
However, in these borderline cases, decreasing steroids is reasonable and helpful. We’ve also found that low-grade toxicities, and maybe high-grade as well, seem to correlate with better survival. There’s probably a sweet spot where patients get AEs, but not too many, that reflects a robust immune system. There may even be some cross-reactivity between certain organs and the tumor itself, where the T-cells are infiltrating both.
We’re also seeing emerging data for non-steroidal options as well. For example, budesonide, while technically a steroid, is not absorbed systemically. I use it for [patients with] mild cases of hepatitis. Budesonide is absorbed in the liver and metabolized there, so it can help with liver inflammation. I’ll also sometimes try budesonide in mild colitis before escalating to systemic steroids.
The other thing worth highlighting is chronic toxicities. We’ve found that a higher number of patients than we previously thought have lingering toxicities after stopping immune therapy. We did a study that showed approximately 40% of patients have AEs that persist for more than 3 months after stopping therapy. When thinking about adjuvant therapy for melanoma, for example, endocrinopathies make up about half of those lingering toxicities—hypothyroidism and hypopituitarism—but also things like arthritis, xerostomia, and other kinds of irAEs.
That’s certainly something to consider. For example, in stage IIIA melanoma with a low risk of recurrence, does a 10% recurrence risk justify 1 year of adjuvant therapy and the potential long-term toxicities that may come with it? Obviously, there’s not a clear-cut right or wrong answer, but these are additional data points I use to help make those decisions with patients.
A number of organizations have done a great job in terms of increasing awareness around cancer immunotherapy. For many years, physicians and patient advocacy organizations were simply not aware of immunotherapy; it was considered a niche product in melanoma and had not moved beyond that. Thankfully, it has now permeated broader clinical consciousness.
Learning as much as possible about immunotherapies is essential. This has become a cornerstone of cancer treatment, on par with chemotherapy and radiation therapy, and is now being used across many tumor types.
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