Treatment Paradigms in NSCLC: Chemo-Based vs Non-Chemo Regimens

Key Takeaways

• Biomarkers now drive first-line decisions: Established oncogenic drivers guide upfront targeted therapy, while emerging biomarkers and resistance markers are shaping combination strategies and future treatment paradigms.
• Non-chemotherapy options bring new benefits and risks: Immunotherapy, targeted agents, and antibody-drug conjugates offer central nervous system (CNS) activity and alternatives to chemotherapy but introduce less predictable, sometimes chronic toxicities that require nuanced counseling and monitoring.
• Convenience-focused delivery is changing care models: Oral and subcutaneous therapies improve access and quality of life for many patients, especially those living far from treatment centers, while creating new challenges in adherence, toxicity detection, and care coordination.

Please introduce yourself by stating your name, title, and any relevant experience you’d like to share.

Rajat Thawani, MD: I am Rajat Thawani. I am a thoracic medical oncologist at the Knight Cancer Institute at OHSU in Portland, Oregon.

How would you describe the biggest shifts in first-line non-small cell lung cancer (NSCLC) treatment over the past few years, particularly in how targeted and immunotherapy-based options are reshaping the role of traditional chemotherapy?

Dr Thawani: It's an evolving question. For frontline treatment, we've seen that biomarkers, especially oncogenes, are not new. Things like EGFR, ELK, ROS1, BRAF, and MET are all tested, reported, and we make treatment decisions with targeted therapies, for the most part, in many of these patients before giving them systemic chemotherapy and immunotherapy.

There are lots of new biomarkers that are being added. They're being added in later lines. There are trials ongoing in that space, and right now they're still considered exploratory and experimental, but we're hoping that they'll come upfront at some point. These include MTAP loss and SMARCA4.

There are other resistance markers for immunotherapy, like STK11 and KP1, where we know that immunotherapy by itself may not be enough, PD-1 inhibitors by themselves may not be enough, and we need to add something else, whether that's chemotherapy or dual checkpoint immunotherapy; that is also something that has shifted over the past couple of years. There are many new novel immunotherapy drugs that are being explored, whether that's TIGIT, VEGF, or bispecifics that target both of those things with PD-1. All of that is still being explored.

Finally, antibody-drug conjugates (ADCs) are also being added upfront in a clinical trial setting, where we're trying to see if they can replace chemotherapy or if they can supplement chemotherapy. All of these shifts are happening as we speak. For the non-chemo options, the benefit that they bring is that we believe that immunotherapy will probably be more CNS penetrant than chemotherapy.

We believe that ADCs probably have some response in the brain, so we will get more CNS-penetrant drugs in non-small cell lung cancer early on. It opens a lot of avenues, realizing that the toxicity is different and we still have a lot to learn about them.

When comparing chemo-based regimens with non-chemo approaches, what clinical factors most often guide your decision-making for an individual patient?

Dr Thawani: That's another great question. The tumor biology plays an important role in these decisions. As of now, we use PD-L1 as the biomarker of deciding whether patients get immunotherapy or immunotherapy and chemotherapy. But there are a lot of other biomarkers that exist that we can use to support our decision, whether that's tumor mutational burden and, as I said, STK11 and KP1, to decide whether we need to boost the immunotherapy with chemotherapy or not.

Another important drug combination we use is dual checkpoint, so a CTLA-4 and PD-1 inhibitor. That has shown a lot of activity in these STK11 and KP1 patients in PD-L1-negative tumors. Those are also options. Another thing that comes into mind is, for CNS metastases, we really want to make sure that the drugs that we give someone with active brain metastases are active agents that go into the brain and work. There are patient-specific factors that also help decide one way or the other.

We don't give immunotherapy in someone with active autoimmune disease requiring immunosuppression and high doses of steroids. There are exceptions to that, but if someone has really bad neuropathy and they're not able to do the activities of daily living, then we'll probably spare some of these agents with chemotherapy which cause neuropathy.

Finally, patient goals are above all of the things that we want to do. We tailor our treatment based on patients’ goals, expectations, and what they want for their treatment and their life, with toxicity and survival benefits. Knowing all of these things, and what options are packaged with patients' goals and wishes right on top, is probably how we go with decision-making for patients.

From your perspective, how do toxicity profiles differ between chemotherapy and newer targeted or immunotherapy regimens, and how does that influence how you counsel patients?

Dr Thawani: This is an evolving thing, even in my practice, as we have newer targets and newer drugs that come into play in how I talk to patients about these toxicities.

Starting with chemotherapy, because we've used it over many decades, in my mind, for chemotherapies that we use for lung cancer upfront, we have a lot of knowledge in their toxicity. They're predictable, they're time dependent, and we know that the cumulative toxicity is dose dependent, so the higher the dose, the more the toxicity.

We've made a lot of progress in managing nausea, for example, for patients who get chemotherapy. What matters here is your functional status—the ECOG or Karnofsky Performance Status—that has been validated and used with chemotherapy.

We know the more robust you are, the better you will tolerate chemotherapy. It might be just because your body has more resilience to fight toxicity. That's exactly how I counsel my patients. We try this chemotherapy and we have flexibility with dose reductions with chemotherapy.

On the other hand, immunotherapy is less predictable in timing. We've seen bad side effects of immunotherapy happen right after giving immunotherapy. We've seen them happen after we've even stopped chemotherapy for a few months, so it's less predictable. There's obviously a commonality between when it happens the most, but it's variable.

The side effects can potentially be more consequential. Physicians who serve on the inpatient oncology service or a consult service see a lot of toxicity from immune checkpoint inhibitors. There is the potential that these toxicities can be more consequential and they can be more long term.

Another difference with chemo is that we don't know how to identify the patients who will get the toxicity. There's no way to know. The way I counsel my patients about it is I talk about an allergy, because an allergy is an immune response to a pollen or an antigen, and there is no way to know beforehand who's going to be allergic to what.

Similarly, it's very hard to know who's going to respond to immunotherapy and who's going to be resistant to immunotherapy, or who's going to get a side effect or not. The immune system is very complex, and we've only scratched the surface in our understanding of immunotherapy. It's a big area of research to identify patients who are amazing responders and long-term responders, or patients who don't respond at all, patients who have no side effects of immunotherapy, or those who have a lot of side effects from immunotherapy. Immunotherapy is starkly different than chemotherapy.

For targeted therapies, it tends to be oral agents—not always, but mostly. The toxicity seems to be chronic and also cumulative rather than episodic. It depends on what target the targeted therapy is going after and where that target is present. The toxicity is from the organ that has that target expressed. In my mind, we have dose reductions here also that are not available in immunotherapy.

Depending on how we grade the side effects or toxicity from these targeted therapies, we can dose reduce and we can offer some modifications in lifestyle just to preserve the quality of life because these patients tend to be on these drugs for a while. We want them to enjoy their quality of life too.

It's also an evolving thing. We've seen that with a lot of good drugs that have a lot of efficacy, there can be a lot of toxicity, which tends to be chronic and can compromise quality of life over time.

Lastly, there are ADCs. ADCs are targeted chemotherapy. The way I say it is that they have the side effects of the target being inhibited, but also the chemotherapy. The biggest risk—it’s not very common, but it is common enough for us to worry about—is pneumonitis, inflammation of the lung. In lung cancer, our patients may not have a lot of lung reserve, especially if they've had lung cancer before and have gotten surgery, if their lungs have been radiated before, or if they have a history of smoking with chronic obstructive pulmonary disease (COPD). Again, it's an area of research where we're exploring how to pre-identify these patients who are at risk of pneumonitis to avoid this risk.

As more patients become eligible for targeted agents or immunotherapy—including subcutaneous or oral options—what real-world trends are you observing in patient experience or treatment adherence?

Dr Thawani: This is, again, evolving, especially for subcutaneous treatments. Subcutaneous treatments are evolving as we speak. There are more and more approvals for immunotherapy, and some targeted therapies as well, that can be given subcutaneously.

In terms of how it's benefiting patients, imagine having a patient who has to drive 3 hours to get treatment. It's a big savior of time for those patients where they don't have to drive 6 hours to get a 30-minute infusion. On the other hand, if you live close enough, then you replace a 30-minute infusion with a 15-minute injection that goes under the skin, so you're getting labs anyway. I'm not sure if timing helps everyone, but it definitely helps a subgroup of patients.

Overall, not having to come to the hospital as often or sitting in an infusion chair—where infusion chairs are under pressure, there's a lot of turnover, and there's a lot of demand—is probably a better experience for patients to be away from infusion for longer and [keeping infusion resources available] for patients who need them quickly.

My worry, honestly, in this is still evolving as we learn more, and I'm sure there will be studies to see how it affects patient outcomes and measures for outcomes, patient-reported outcomes (PROs) and things like that. It'll probably decrease the number of office visits that a patient needs for virtual visits. Patients would probably get labs done locally, especially the ones who live far away, and they'll see us virtually. A nurse is going to come give them this injection and then leave and we probably will not be seeing the patients as often.

It's good and bad. Good because maybe patients get to live a more normal life than they would spending 6 hours traveling back and forth every 3 weeks. But on the other hand, we don't know how it impacts detection of toxicity. We do vitals, we do labs, we see them, we examine them, and we pick up on things. That may change. Eventually, for the subcutaneous part, there's a lot of unknown, and as the uptake increases over time, we'll learn a lot more.

Regarding the oral therapies, from a patient perspective, it's great because you take a pill a couple of times a day. If you have no question for reliability, then patients take care of taking their medication. So, [it's important to have] that trust. As long as they're taking their medication, you'll be able to see the responses. The logistic concern here is usually something that we've seen for many years, which are prior authorizations, specialty pharmacy delays, and copays. Especially early in January, we see patients needing to pay a lot of copays upfront. That can lead to treatment gaps. Overall, these patients can take a pill a day, which is great. This is excellent for patients who live far away who don't need to go back and forth.

The monitoring aspect of it is something similar to subcutaneous in that we're doing it virtually and we're using local labs, but this is something that we are more comfortable with because it's been around for longer. For subcutaneous injections, it's like a switch that suddenly turned on. So, we're still adapting to it to see what's going to happen.

Overall, there are new challenges that will come up, but it's good for patients to have more options, to be at home and around family and loved ones for longer, and to not have to spend time on the road to get their care. I hope it's a positive change. I think it's a positive change, and time will tell us more.