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ONCAlert | Upfront Therapy for mRCC

Immune Checkpoint Therapy Overview for Stage III NSCLC

Targeted Oncology
Published Online:1:31 PM, Fri February 15, 2019

Mark A. Socinski, MD: The use of checkpoint inhibitors in stage III disease is meant to be curative, although we don’t cure 100% of the patients. One of, I think, one of the important questions is, can you go back to using checkpoint inhibitors if patients do progress to stage IV metastatic disease? It is currently a data-free zone. We don’t have any information. The use of checkpoint inhibitors in stage III disease is a relatively recent phenomenon, which we’ll discuss today. And I think many of us are wondering about those patients who may relapse, can you use this data that we typically use in stage IV disease, the data from Keynote-189, Empower 150, Keynote-407. in other trials. You know, over the past couple of years, we’ve seen a myriad of trials in stage IV disease that have really solidified the use of checkpoint inhibitors in stage IV disease, but all of those patients were naïve to checkpoint inhibition prior to those trials.

So I think as a general guideline in practice today, how I would think about it is the issue of timing. If someone has a relatively long disease-free interval, and I would say at least to 12 months from the time that they had received the checkpoint inhibitor, that I would tend to go back to a checkpoint inhibitor in that particular setting. If someone progressed to stage IV while they were on a checkpoint inhibitor for stage III disease, that would tell me that there’s some inherent resistance to checkpoint inhibition, and I wouldn’t be optimistic that a different checkpoint inhibitor at that point would have much clinical utility.

However, I will point out that we don’t have clinical data at this point to support one argument or the other, and it’s really a very unmet need at this point to generate some of that data so clinicians know what to do.

In stage III disease, we typically do test for those patients, and the reason that we test for those people, or test those people, is because many of them historically have developed stage IV disease. So you want, you would want to have that information if they were to transition from stage III to stage IV disease because that would impact your treatment decision.

The reality with current standards of care, and current guidelines, is that in stage III disease, we don’t necessarily know the significance of what to do with an EGFR mutation or an ALK translocation, or ROS1 or BRAF, or any of these things that we typically test for. We don’t have established paradigms based on phase III trials that would tell us that we should treat differently based upon these molecular findings. Now that is totally opposite in stage IV disease where we know that if you have an EGFR mutation, using one of the EGFR TKIs [tyrosine kinase inhibitors] is superior to chemotherapy, ALK-directed therapy, and ALK-translocated patients is superior to chemotherapy.

So in stage IV disease, it really impacts how you manage the patient. We don’t yet have information from randomized trials; many of them are ongoing at the current time, about to use the molecular markers to alter therapeutic approaches in the stage III disease. And I would also make the argument we don’t have established paradigms in the surgical setting where you’ve had curative resection with surgery. Typically, those are stage I or II patients.

Let’s say you find an EGFR mutation in a patient with stage I adenocarcinoma of the lung. We would give that patient adjuvant chemotherapy. We don’t yet know the role of EGFR TKI–directed therapy in that population. There are ongoing studies that are hoping to define that, but currently in 2019, it shouldn’t impact your management in stage I, II, or III disease.

Transcript edited for clarity.

Mark A. Socinski, MD: The use of checkpoint inhibitors in stage III disease is meant to be curative, although we don’t cure 100% of the patients. One of, I think, one of the important questions is, can you go back to using checkpoint inhibitors if patients do progress to stage IV metastatic disease? It is currently a data-free zone. We don’t have any information. The use of checkpoint inhibitors in stage III disease is a relatively recent phenomenon, which we’ll discuss today. And I think many of us are wondering about those patients who may relapse, can you use this data that we typically use in stage IV disease, the data from Keynote-189, Empower 150, Keynote-407. in other trials. You know, over the past couple of years, we’ve seen a myriad of trials in stage IV disease that have really solidified the use of checkpoint inhibitors in stage IV disease, but all of those patients were naïve to checkpoint inhibition prior to those trials.

So I think as a general guideline in practice today, how I would think about it is the issue of timing. If someone has a relatively long disease-free interval, and I would say at least to 12 months from the time that they had received the checkpoint inhibitor, that I would tend to go back to a checkpoint inhibitor in that particular setting. If someone progressed to stage IV while they were on a checkpoint inhibitor for stage III disease, that would tell me that there’s some inherent resistance to checkpoint inhibition, and I wouldn’t be optimistic that a different checkpoint inhibitor at that point would have much clinical utility.

However, I will point out that we don’t have clinical data at this point to support one argument or the other, and it’s really a very unmet need at this point to generate some of that data so clinicians know what to do.

In stage III disease, we typically do test for those patients, and the reason that we test for those people, or test those people, is because many of them historically have developed stage IV disease. So you want, you would want to have that information if they were to transition from stage III to stage IV disease because that would impact your treatment decision.

The reality with current standards of care, and current guidelines, is that in stage III disease, we don’t necessarily know the significance of what to do with an EGFR mutation or an ALK translocation, or ROS1 or BRAF, or any of these things that we typically test for. We don’t have established paradigms based on phase III trials that would tell us that we should treat differently based upon these molecular findings. Now that is totally opposite in stage IV disease where we know that if you have an EGFR mutation, using one of the EGFR TKIs [tyrosine kinase inhibitors] is superior to chemotherapy, ALK-directed therapy, and ALK-translocated patients is superior to chemotherapy.

So in stage IV disease, it really impacts how you manage the patient. We don’t yet have information from randomized trials; many of them are ongoing at the current time, about to use the molecular markers to alter therapeutic approaches in the stage III disease. And I would also make the argument we don’t have established paradigms in the surgical setting where you’ve had curative resection with surgery. Typically, those are stage I or II patients.

Let’s say you find an EGFR mutation in a patient with stage I adenocarcinoma of the lung. We would give that patient adjuvant chemotherapy. We don’t yet know the role of EGFR TKI–directed therapy in that population. There are ongoing studies that are hoping to define that, but currently in 2019, it shouldn’t impact your management in stage I, II, or III disease.

Transcript edited for clarity.
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