Optimizing Pathways in NSCLC With Immunotherapy and Radiation

Joe Y. Chang, MD, PhD, MD Anderson Cancer Center, explores advancements in NSCLC treatment pathways, emphasizing the integration of immunotherapy and precision radiotherapy, the role of value-based care in palliative approaches, and the potential of artificial intelligence to optimize individualized treatment strategies.

Joe Y. Chang, MD, PhD: Hi, I'm Dr Joe Chang. I'm a thoracic radiation oncologist at MD Anderson Cancer Center. I specialize in lung cancer and esophageal cancer, and I'm director of the Stereotactic Ablative Radiotherapy program at MD Anderson Cancer Center and a Texas 4000 Distinguished Professor at MD Anderson Cancer Center. I have focused my clinical research in lung cancer, stereotactic ablative radiotherapy treatment, and now, recently, combined immunotherapy.

Could you outline the most effective treatment pathways currently recommended for patients with non-small cell lung cancer (NSCLC), and how can these vary by stages of diagnosis?

Dr Chang: I think the most important part is to optimize, combined local treatment and systematic treatment. For example, for early-stage lung cancer, we know stereotactic radiation therapy or surgical resection provides wonderful local control. However, we still have one-third to half of patients who recur in the regional lymph nodes or in the distant organs. So, combined with normal treatment, systemic treatment with either targeted therapy, if they have EGFR or other gene mutations, or combined with immunotherapy, which has been shown to improve progression-free survival.

For stage III lung cancer, again, for operable cases, neoadjuvant chemoimmunotherapy followed by surgical resection, followed by adjuvant immunotherapy, or, if patients have a targetable gene mutation, followed by adjuvant targeted therapy. For medically inoperable stage III lung cancer, typically, the standard of care is concurrent chemo and radiation therapy followed by immunotherapy, or followed by targeted therapy if they have an EGFR gene mutation.

For stage IV lung cancer, no doubt, novel systemic treatment is the mainstream for treatment. If patients have EGFR or ALK gene mutations, then targeted therapy is the main treatment. If patients don't have EGFR, ALK, or other targetable gene mutation, a combination of immunotherapy and chemo or immunotherapy alone is standard of care.

Recently, [the question has been] how to combine the local treatment when patients respond well or patients progress with the systematic treatment. That would be a very important question. So I think combining the local and systemic treatment would be the future for lung cancer from stage I to stage IV disease.

How do you approach the integration of radiotherapy with immunotherapy in NSCLC treatment? What are the main challenges or considerations with this combination?

Dr Chang: When we combine immunotherapy with radiation therapy, we needed to know the immune mechanism first.

Historically, we are very good at combining chemotherapy and radiation therapy. However, we cannot apply the same thinking process or similar model when we use immunotherapy because chemotherapy just kills the cancer cell directly, but with immunotherapy, you needed to have an environment to stimulate the immune response, immune status, and microenvironment. That's the first thing. The second is that there is timing—stimulation first, and then lymphocytes come to attack the tumor cell. So timing is important too.

The challenge when you combine those 2 is if we just simply add them together, it may not work. Just like what we recently found for non-small cell carcinoma: when you give concurrent chemoradiation therapy plus concurrent immunotherapy followed by adjuvant immunotherapy, the result is negative. So, what is important for us to learn is how to optimize, what's the best time to give immunotherapy, what's the best time to give radiation therapy, and what kind of dose of radiation therapy. Just be aware that for radiation therapy, when you give different doses to different diseases, or to different organs, they have a different toxicity and a different efficacies, so they are different drugs.

For the same reason, even for immunotherapy, there are different immunotherapy drugs, either CTL-4-based, or PD-L1-based, or other newer immunotherapy-based drugs. When you combine, the strategy and timing will be different. That part needs to be analyzed in detail before we jump to conclusions about whether it works or not and how to interpret the data.

For patients undergoing concurrent chemoradiotherapy, how do you manage the potential increased toxicity, and what strategies are most effective in optimizing tolerability?

Dr Chang: When you treat lung cancer with radiation therapy, I think the fundamental question is which target should we treat. That's very important because if the target is not right or not accurate, then you either miss the target or create unnecessary toxicity. Based on the PET imaging, based on enhanced polymer one-step staining (EPOS) procedure, and your clinical judgment, the targeted delineation is the first crucial part of designing radiation therapy.

You then need to use modern technology to reduce the daily setup uncertainty—what we call image-guided radiation therapy (IGRT)—to reduce the margin for what we call PTV margin, which takes care of uncertainty about motion or daily setup uncertainty. You need to minimize that part.

We have an intensity-modulated radiation therapy. We have an intensity-modulated port for treatment. This technology has been shown to improve the toxicity profile compared with conventional 3D or 2D radiation therapy. So new technology is very crucial for lung cancer treatment. And there is a new concept of target delineation and the new modern technology of IGRT. They are very important to reduce toxicity.

Just be aware that, currently, after concurrent chemoradiation therapy, most of our patients did need adjuvant immunotherapy or adjuvant targeted therapy. So we do need to take that into consideration because, potentially, adjuvant treatment will increase toxicity. The whole field of radiation oncologists needs to have a new idea about how we work together to further reduce toxicity using better indication, better targeted delineation, and better technology.

How do you believe value-based care models can better support palliative radiotherapy approaches in NSCLC, particularly for advanced-stage patients where goals may center on quality of life rather than curative outcomes?

Dr Chang: It's very important to have value-based palliative treatment. Historically, we provided a 30-Gy/10-fraction, which was based on the old data that said we didn’t have precise information about where the tumor was, so we didn't have a very good delivery method. But nowadays, we can treat with hyperfractionated radiation therapy in 5 fractions or sometimes even 1 fraction. Those are very helpful for people who have a very poor quality of life and their survival is not very long. Quality of life is important.

Another aspect of it is with modern technology, sometimes palliative radiation therapy can also integrate into consolidated radiation therapy. When you combine those 2 concepts, and it's for people who have an oligoprogression or oligometastatic disease, in that scenario, you can combine palliative radiation therapy with consolidative radiation therapy with precise delivery of higher doses in a much shorter period of time, such as the use of hypofractionated radiation therapy or stereotactic radiation therapy. Those 2 concepts should be taken into consideration for palliation, quality of life, and also potential improved efficacy of treatment.

How do you approach discussions with payers regarding the value and efficacy of advanced radiotherapy techniques, especially for high-cost treatments like SBRT?

Dr Chang: SBRT is such a precise treatment and such an effective treatment after stereotactic radiation therapy in early-stage lung cancer, for example. The local failure rate is less than 5%. It's such a powerful treatment—this is the best approach for treating early-stage lung cancer.

In addition, because we can deliver radiation therapy very precisely, the side effects are also reduced. In addition to that, more and more data show that when you integrate SBRT with immunotherapy, it can potentially have a synergetic effect to combine with immunotherapy to work better compared with conventional fractionated radiation therapy. Indeed, when we can prove efficacy and better integration with a systematic treatment, and reduce side effects, that high technology should be used.

For other technology it’s a similar concept, if we can prove that it can either improve treatment efficacy, or reduce the toxicity, it's much better compared with people who are treated for longer time. Historically, lung cancer has been treated with 6 weeks of radiation therapy and has much higher toxicity, and toxicity costs money too. So that is important when we talk with insurance companies about efficacy and toxicity, the quality of life for our patients.

What upcoming developments in NSCLC treatment are you most excited about, and how do you foresee these impacting treatment pathways?

Dr Chang: More than 20 years ago, when I joined MD Anderson as a faculty member, the cutting-edge development for lung cancer treatment was technology. The computer based 4-dimensional CT simulation and PET imaging helped us to define the target volume much more precisely than before and deliver a much higher dose to the target. At that time, we developed technologies such as stereotactic radiation therapy, intensity-modulated radiation therapy, imaging-guided radiation therapy, and proton treatment, including intensity-modulated proton treatment.

This technology development really fundamentally changed the way we manage localized disease that is not operable. But about 10 years ago, when molecular profiling was widely used in clinic, the targeted therapy for people who had targetable gene mutations fundamentally changed stage IV lung cancer.

Previously, in lung cancer, when you had stage IV disease, the 5-year survival was sometimes 5% or even lower. But with targeted therapy, in some patients, the 5-year survival is pretty high. They live 5 years and some of them even live without disease for more than 5 years, so that's also changed.

About 5 to 10 years ago, immunotherapy also fundamentally changed the management of stage IV lung cancer for people who do not have EGFR or ALK gene mutations. Again, it changed the concept of cure because some people with stage IV lung cancer, after being treated with targeted therapy or immunotherapy, can have no progression or no evidence of disease for more than 5 years, changing the definition of a cure for lung cancer.

All those things are very important milestones for lung cancer treatment. In recent years, combining immunotherapy and radiation therapy and combining targeted therapy with radiation therapy or local treatment are also changing the management of lung cancer, including early-stage, locally advanced, and/or stage IV disease, particularly for oligometastatic and oligoprogression disease.

But for the future, one of the challenges we're facing now is that we don't know how to optimize or how to combine them together. Just like I mentioned before, if you simply combine them, it may not be the best approach. You need to base it on multiple individualized patient situations, such as the individualized microenvironmental status, disease status, staging status, performance status, radiation dose, regimen, and the sequence to consider.

For human beings, our brains are not good enough to develop a model to predict which patients will benefit from immunotherapy combined with radiation therapy. So in my view, artificial intelligence (AI) can really truly help us to develop individualized treatment for patients who need immunotherapy plus radiation therapy. That's the most exciting thing for me for the future.

We know a lot of models are not single factor-driven. They're also not a linear relationship; it's a multifactorial interaction. AI can really help us to identify people who benefit from combined immunotherapy and radiation therapy. Overall, in the future, AI-based optimization of systemic treatment and local treatment is crucial, and I do believe that will fundamentally change the outcomes of lung cancer and other types of cancer.