ONCAlert | Upfront Therapy for mRCC

The NCI-NRG ALK Master Protocol in NSCLC

Targeted Oncology
Published Online:12:50 PM, Wed August 7, 2019

Mark A. Socinksi, MD: We hear a lot about the National Cancer Institute [NCI]-NRG ALK Master Protocol. Can you walk us through what that protocol is trying to achieve?

Thomas E. Stinchcombe, MD: This is programmed through the NCI, and it’s trying to look at what the role of biopsy is. Patients will undergo a biopsy at the time of disease progression. There are about 10 different cohorts of patients, and you’ll be assigned, based on your mutation type, to either 1 or 2 or 3 drugs that have shown preclinical evidence of activity in that cohort. The other part is, if you don’t have a mutation, you’ll be randomly assigned. I think there are about 5 drugs at this point, or chemotherapy, to really look at in those people without a known ALK tyrosine kinase mutation. The first 200 patients will get ctDNA [circulating tumor DNA] collected.

Mark A. Socinksi, MD: I was going to ask you about blood.

Thomas E. Stinchcombe, MD: This was critical because I think when we look at the ctDNA data, sometimes the biopsy was done 6, 12 months, or 2 or 3 therapies beforehand. This time, we’ll actually be able to pair the tumor biopsy with the ctDNA and get a better sense of the concordance and really see what the negative predictive value is at this point. I think it’s an ambitious trial.

Mark A. Socinksi, MD: It sounds like a very complicated trial.

Thomas E. Stinchcombe, MD: It is complicated. I’ve had to present this several times. I think it’s complicated, but if you take a step back, you can say, “What questions are we trying to ask?” And I think we’re trying to ask what the predictive role of the ALK mutation is. That is something that needs to be addressed. What is the role of ctDNA? And for the mutation-negative, will chemotherapy, if coming back, be the preferred therapy? Maybe ALK inhibition is not as active in those patients as it is in the people with the mutation? And if you boil it down to those 3 very common clinical questions, it’s good. When I look at this trial, I think it’s easy to think of a 2-step process: Get the biopsy and then get the biopsy result. And if you look at your specific mutation cohort, then it becomes either a 2-arm trial, 3-arm trial, and it’s a little bit easier to digest. But it is a complex trial.

Mark A. Socinksi, MD: In these situations, I can’t help but think about a clinical investigator presenting this trial to a patient. Obviously, the number of arms and the complexity of it, and all of a sudden you get into the land of confusion from the patient’s point of view. Any concerns with the committee with regard to feasibility and accrual? Obviously, this is not the most common thing we see in lung cancer, in terms of patients.

Thomas E. Stinchcombe, MD: I think feasibility is a justifiable concern at this point, because it’s a big trial. It is 660 patients. I think when I present it, I’m going to present, first, the biopsy. Keep it simple. Then I’ll discuss the therapeutic when I have the biopsy results back. The analogy I’ve used with patients is sometimes that this becomes like “Alice in Wonderland.” You open 1 door and 2 more doors open. It becomes very confusing to patients. I think it’s also going to be confusing to some of the study teams as they try and work through the logistics of this. So I think it’s going to need a lot of patient education. I’m hoping the patient advocacy groups will also be strong proponents of this trial, because they have a very strong voice and a unique communication set that we don’t have as doctors, frankly.

Mark A. Socinksi, MD: Right. And the trial does require rebiopsy, so there are always issues with rebiopsy and that sort of thing.

Thomas E. Stinchcombe, MD: It will be a biopsy before enrollment, and that’s covered. The testing is also covered. And then, at the time of progression on trial, there’s an optional rebiopsy. We’re going to obviously try and capture that data because having paired biopsies is going to be critical to understand the emergence of resistance mechanisms.

Mark A. Socinksi, MD: It’s a population of patients that I think is very amenable to getting stuff like that done, right?

Thomas E. Stinchcombe, MD: I rarely have a patient refuse a biopsy these days.

Mark A. Socinksi, MD: I agree.

Thomas E. Stinchcombe, MD: I think the culture has changed among medical centers as well as the patients, as they realize the utility of these tests.

Mark A. Socinksi, MD: That’s great. If that trial could complete its accrual and address all of those objectives, I think it would be very informative in terms of how we manage this population.

Transcript edited for clarity.

Mark A. Socinksi, MD: We hear a lot about the National Cancer Institute [NCI]-NRG ALK Master Protocol. Can you walk us through what that protocol is trying to achieve?

Thomas E. Stinchcombe, MD: This is programmed through the NCI, and it’s trying to look at what the role of biopsy is. Patients will undergo a biopsy at the time of disease progression. There are about 10 different cohorts of patients, and you’ll be assigned, based on your mutation type, to either 1 or 2 or 3 drugs that have shown preclinical evidence of activity in that cohort. The other part is, if you don’t have a mutation, you’ll be randomly assigned. I think there are about 5 drugs at this point, or chemotherapy, to really look at in those people without a known ALK tyrosine kinase mutation. The first 200 patients will get ctDNA [circulating tumor DNA] collected.

Mark A. Socinksi, MD: I was going to ask you about blood.

Thomas E. Stinchcombe, MD: This was critical because I think when we look at the ctDNA data, sometimes the biopsy was done 6, 12 months, or 2 or 3 therapies beforehand. This time, we’ll actually be able to pair the tumor biopsy with the ctDNA and get a better sense of the concordance and really see what the negative predictive value is at this point. I think it’s an ambitious trial.

Mark A. Socinksi, MD: It sounds like a very complicated trial.

Thomas E. Stinchcombe, MD: It is complicated. I’ve had to present this several times. I think it’s complicated, but if you take a step back, you can say, “What questions are we trying to ask?” And I think we’re trying to ask what the predictive role of the ALK mutation is. That is something that needs to be addressed. What is the role of ctDNA? And for the mutation-negative, will chemotherapy, if coming back, be the preferred therapy? Maybe ALK inhibition is not as active in those patients as it is in the people with the mutation? And if you boil it down to those 3 very common clinical questions, it’s good. When I look at this trial, I think it’s easy to think of a 2-step process: Get the biopsy and then get the biopsy result. And if you look at your specific mutation cohort, then it becomes either a 2-arm trial, 3-arm trial, and it’s a little bit easier to digest. But it is a complex trial.

Mark A. Socinksi, MD: In these situations, I can’t help but think about a clinical investigator presenting this trial to a patient. Obviously, the number of arms and the complexity of it, and all of a sudden you get into the land of confusion from the patient’s point of view. Any concerns with the committee with regard to feasibility and accrual? Obviously, this is not the most common thing we see in lung cancer, in terms of patients.

Thomas E. Stinchcombe, MD: I think feasibility is a justifiable concern at this point, because it’s a big trial. It is 660 patients. I think when I present it, I’m going to present, first, the biopsy. Keep it simple. Then I’ll discuss the therapeutic when I have the biopsy results back. The analogy I’ve used with patients is sometimes that this becomes like “Alice in Wonderland.” You open 1 door and 2 more doors open. It becomes very confusing to patients. I think it’s also going to be confusing to some of the study teams as they try and work through the logistics of this. So I think it’s going to need a lot of patient education. I’m hoping the patient advocacy groups will also be strong proponents of this trial, because they have a very strong voice and a unique communication set that we don’t have as doctors, frankly.

Mark A. Socinksi, MD: Right. And the trial does require rebiopsy, so there are always issues with rebiopsy and that sort of thing.

Thomas E. Stinchcombe, MD: It will be a biopsy before enrollment, and that’s covered. The testing is also covered. And then, at the time of progression on trial, there’s an optional rebiopsy. We’re going to obviously try and capture that data because having paired biopsies is going to be critical to understand the emergence of resistance mechanisms.

Mark A. Socinksi, MD: It’s a population of patients that I think is very amenable to getting stuff like that done, right?

Thomas E. Stinchcombe, MD: I rarely have a patient refuse a biopsy these days.

Mark A. Socinksi, MD: I agree.

Thomas E. Stinchcombe, MD: I think the culture has changed among medical centers as well as the patients, as they realize the utility of these tests.

Mark A. Socinksi, MD: That’s great. If that trial could complete its accrual and address all of those objectives, I think it would be very informative in terms of how we manage this population.

Transcript edited for clarity.
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