ONCAlert | Upfront Therapy for mRCC

Case 3: Chemoimmunotherapy in SCLC

Targeted Oncology
Published Online:1:19 PM, Thu June 20, 2019



EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Benjamin P. Levy, MD: Anshu, your thoughts on another contentious question here: the role of consolidative radiation. Let’s say we give this patient—before the advent of I-O [immuno-oncology] was integrated into the realm—4 cycles of a platinum doublet, and they’re doing well. Do you consolidate all sites of disease with radiation post chemotherapy?

Anshu K. Jain, MD: It’s a great question, and our typical practice pattern has been to really focus on consolidation of patients in the traditional manner when they’ve had an excellent response in any sites of distant disease. If the disease is confined in the thorax, we typically do try to consolidate that disease if they’ve had a good response to systemic therapy. I think the question is really now changing in the advent of systemic chemotherapy and I-O. As you know, consolidation thoracic radiotherapy was not allowed on that trial. And so it’s really brought up a lot of interesting questions about how we manage those patients and in what setting it may be or may not be appropriate.

Benjamin P. Levy, MD: Yeah. So that’s a good segue into the trial. We’ve clearly had a practice changing trial with IMpower133. As thoracic medical oncologists, we generally ask very simple questions in our trials; we’re simple folk. We basically take platinum doublet, and then we add something to platinum doublet and compare it. That’s the way things have gone. We’ve been historically unsuccessful with this, but recently we’ve been quite successful both in non–small cell and small cell, which has raised the question, why let research and science get in the way of progress? Does adding a drug to a platinum doublet and comparing it with platinum doublet alone over the past 12 to 24 months translate into overall survival advantages?

This was extensive-stage small cell patients randomized 1-to-1 to platinum-etoposide therapy versus a maximum of 4 cycles versus platinum-etoposide with PD-L1 [programmed death-ligand 1] inhibitor, atezolizumab. Atezo [atezolizumab] was allowed to be given as a maintenance therapy as well, and I think we were surprised. I think that we’ve tried this before in a small cell case, and nothing has ever worked. For the first time, we saw an improvement in progression-free survival. Perhaps more important, this was presented at World Lung [International Association for the Study of Lung Cancer’s 19th World Conference on Lung Cancer] in Toronto, Ontario, and was subsequently published at the same time.

We saw an improvement in overall survival, and we have to look hard and long for survival advantages in small cell, and in just such an unforgiving disease. Interestingly, small cell is 1 of these tumors that we think would be so sensitive to immunotherapy. It’s fraught with mutations. It’s heavily associated with smoking. It’s rapidly progressing. It’s an aggressive tumor biology. All the hallmarks of a tumor that should predict sensitivity immunotherapy. We did see the same benefit that we saw in non–small cell. Nevertheless, we saw a benefit. It was modest but there.

Most subgroups of patients have benefited. Interestingly, they did an analysis of tumor mutational burden in the blood to see if that predicted efficacy to atezolizumab. It did not. It would be helpful to have some sort of biomarker, but there was no biomarker here that really shook out that helped us select patients who are going to get this. So everybody gets it now. Isabel, your thoughts on this? Do you see a lot of small cell? Are you using this regimen? I’ve used it a couple of times, but I’ve got some mixed stories. But, thoughts?

Isabel Preeshagul, DO, MBS: Unfortunately, I do see a fair amount of small cell, and I think the IMpower133 data are very exciting because finally we have something in this field that have shown some benefit. I think in my little experience with this regimen, because it has not been approved for very long, I have had some success with it. Not only does it offer maintenance therapy, but it also helps alleviate some of the anxiety of the watch-and-wait that the patients have. After the 4 cycles of the platinum doublet, scanning them at that interval to evaluate for disease relapse can be anxiety provoking. But, allowing them to be on this regimen every 3 weeks as tolerated has allowed them to feel that they’re continually fighting against this disease.

Benjamin P. Levy, MD: Yeah. No, I would agree. I think that the drug itself is exciting for patients. I think that the maintenance part is important. You know, before we would tell patients, “You’re getting 4 cycles, and then we’re just going to watch you. Yes, there’s a high likelihood that this will come back pretty quick, but I have nothing really to intervene on at this time.” I think having that maintenance, they’ve started with it. They are continuing with the drug once they’ve completed the 4 cycles. Any issues with toxicity at all with the drug combined with the platinum doublet?

Isabel Preeshagul, DO, MBS: Fortunately, I have not seen toxicity. I think most of the toxicity comes more from the platinum-etoposide, from what I’ve seen, which is what we’ve seen before with the platinum-etoposide. The atezolizumab seemed to have been a nice addition with limited toxicity, in my experience, fortunately.

Benjamin P. Levy, MD: Anshu, as you mentioned, this trial did not allow consolidative radiation, and we’re learning about the role of consolidated radiation even in non–small cell for oligometastatic disease. How do you guys sort this out? Are there still times where a patient could be put on this if they progress on the atezolizumab, and you would then radiate them? Or have you just said, “Look, we can’t really fool with radiation now that we’re integrating immunotherapy routinely for these patients?”

Anshu K. Jain, MD: Yeah, I’ve had discussions with a lot of my colleagues, and some of them practice by the book in terms of what the protocol did, whereas others are really saying, “Well, you know what, we’re still dealing with a disease that has a fairly high mortality.” They struggle with the question, saying “Should I really be withholding something that may also provide a progression-free or an overall survival benefit?” If we look at the recent Ben Slotman data, basically what they’ve done in the consolidative setting for thoracic radiation has really brought the dose down significantly. It’s closer to about 60% of what the original dose used to be, about 50 Gy down to 30 Gy, you’re talking about 10 treatments, 2 weeks.

The question really is, can it be given concurrently with atezolizumab? I think it’s going to depend on the amount of disease, the bulk of the disease, and the distribution of the disease. Ultimately, as we kind of get some data in the real-world setting, we may be able to see if the incidence of pneumonitis is a risk or not. I think we may be able to extrapolate from some of the other studies that are looking at combination of thoracic radiation and I-O to see if radiation therapy given concurrently with I-O is really a risk or not.

Benjamin P. Levy, MD: Yeah, and that’s a good point. We were going to have data in the next 2 years looking at concurrent I-O with radiation, and I think that will help us feel more comfortable.

Anshu K. Jain, MD: Right.

Benjamin P. Levy, MD: Whether that data will be a positive or a negative, we don’t know in terms of toxicity. But the question really is, can you safely give immunotherapy concurrently with radiation? As it stands today, we don’t know. We have good data at least with targeted therapy. It can be given relatively safely, with at least palliative radiation, or even whole-brain radiation. But for immunotherapy, that pneumonitis toxicity is real, and I think we need more data.

Anshu K. Jain, MD: I think that either consolidating or local therapy for extrathoracic disease in the setting of concurrent I-O, there’s some more comfort with that. But in the setting of thoracic disease, looking at the anatomical distribution and how it might impact some of the dose symmetry, those are questions that remain to be answered.

Transcript edited for clarity.



EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Benjamin P. Levy, MD: Anshu, your thoughts on another contentious question here: the role of consolidative radiation. Let’s say we give this patient—before the advent of I-O [immuno-oncology] was integrated into the realm—4 cycles of a platinum doublet, and they’re doing well. Do you consolidate all sites of disease with radiation post chemotherapy?

Anshu K. Jain, MD: It’s a great question, and our typical practice pattern has been to really focus on consolidation of patients in the traditional manner when they’ve had an excellent response in any sites of distant disease. If the disease is confined in the thorax, we typically do try to consolidate that disease if they’ve had a good response to systemic therapy. I think the question is really now changing in the advent of systemic chemotherapy and I-O. As you know, consolidation thoracic radiotherapy was not allowed on that trial. And so it’s really brought up a lot of interesting questions about how we manage those patients and in what setting it may be or may not be appropriate.

Benjamin P. Levy, MD: Yeah. So that’s a good segue into the trial. We’ve clearly had a practice changing trial with IMpower133. As thoracic medical oncologists, we generally ask very simple questions in our trials; we’re simple folk. We basically take platinum doublet, and then we add something to platinum doublet and compare it. That’s the way things have gone. We’ve been historically unsuccessful with this, but recently we’ve been quite successful both in non–small cell and small cell, which has raised the question, why let research and science get in the way of progress? Does adding a drug to a platinum doublet and comparing it with platinum doublet alone over the past 12 to 24 months translate into overall survival advantages?

This was extensive-stage small cell patients randomized 1-to-1 to platinum-etoposide therapy versus a maximum of 4 cycles versus platinum-etoposide with PD-L1 [programmed death-ligand 1] inhibitor, atezolizumab. Atezo [atezolizumab] was allowed to be given as a maintenance therapy as well, and I think we were surprised. I think that we’ve tried this before in a small cell case, and nothing has ever worked. For the first time, we saw an improvement in progression-free survival. Perhaps more important, this was presented at World Lung [International Association for the Study of Lung Cancer’s 19th World Conference on Lung Cancer] in Toronto, Ontario, and was subsequently published at the same time.

We saw an improvement in overall survival, and we have to look hard and long for survival advantages in small cell, and in just such an unforgiving disease. Interestingly, small cell is 1 of these tumors that we think would be so sensitive to immunotherapy. It’s fraught with mutations. It’s heavily associated with smoking. It’s rapidly progressing. It’s an aggressive tumor biology. All the hallmarks of a tumor that should predict sensitivity immunotherapy. We did see the same benefit that we saw in non–small cell. Nevertheless, we saw a benefit. It was modest but there.

Most subgroups of patients have benefited. Interestingly, they did an analysis of tumor mutational burden in the blood to see if that predicted efficacy to atezolizumab. It did not. It would be helpful to have some sort of biomarker, but there was no biomarker here that really shook out that helped us select patients who are going to get this. So everybody gets it now. Isabel, your thoughts on this? Do you see a lot of small cell? Are you using this regimen? I’ve used it a couple of times, but I’ve got some mixed stories. But, thoughts?

Isabel Preeshagul, DO, MBS: Unfortunately, I do see a fair amount of small cell, and I think the IMpower133 data are very exciting because finally we have something in this field that have shown some benefit. I think in my little experience with this regimen, because it has not been approved for very long, I have had some success with it. Not only does it offer maintenance therapy, but it also helps alleviate some of the anxiety of the watch-and-wait that the patients have. After the 4 cycles of the platinum doublet, scanning them at that interval to evaluate for disease relapse can be anxiety provoking. But, allowing them to be on this regimen every 3 weeks as tolerated has allowed them to feel that they’re continually fighting against this disease.

Benjamin P. Levy, MD: Yeah. No, I would agree. I think that the drug itself is exciting for patients. I think that the maintenance part is important. You know, before we would tell patients, “You’re getting 4 cycles, and then we’re just going to watch you. Yes, there’s a high likelihood that this will come back pretty quick, but I have nothing really to intervene on at this time.” I think having that maintenance, they’ve started with it. They are continuing with the drug once they’ve completed the 4 cycles. Any issues with toxicity at all with the drug combined with the platinum doublet?

Isabel Preeshagul, DO, MBS: Fortunately, I have not seen toxicity. I think most of the toxicity comes more from the platinum-etoposide, from what I’ve seen, which is what we’ve seen before with the platinum-etoposide. The atezolizumab seemed to have been a nice addition with limited toxicity, in my experience, fortunately.

Benjamin P. Levy, MD: Anshu, as you mentioned, this trial did not allow consolidative radiation, and we’re learning about the role of consolidated radiation even in non–small cell for oligometastatic disease. How do you guys sort this out? Are there still times where a patient could be put on this if they progress on the atezolizumab, and you would then radiate them? Or have you just said, “Look, we can’t really fool with radiation now that we’re integrating immunotherapy routinely for these patients?”

Anshu K. Jain, MD: Yeah, I’ve had discussions with a lot of my colleagues, and some of them practice by the book in terms of what the protocol did, whereas others are really saying, “Well, you know what, we’re still dealing with a disease that has a fairly high mortality.” They struggle with the question, saying “Should I really be withholding something that may also provide a progression-free or an overall survival benefit?” If we look at the recent Ben Slotman data, basically what they’ve done in the consolidative setting for thoracic radiation has really brought the dose down significantly. It’s closer to about 60% of what the original dose used to be, about 50 Gy down to 30 Gy, you’re talking about 10 treatments, 2 weeks.

The question really is, can it be given concurrently with atezolizumab? I think it’s going to depend on the amount of disease, the bulk of the disease, and the distribution of the disease. Ultimately, as we kind of get some data in the real-world setting, we may be able to see if the incidence of pneumonitis is a risk or not. I think we may be able to extrapolate from some of the other studies that are looking at combination of thoracic radiation and I-O to see if radiation therapy given concurrently with I-O is really a risk or not.

Benjamin P. Levy, MD: Yeah, and that’s a good point. We were going to have data in the next 2 years looking at concurrent I-O with radiation, and I think that will help us feel more comfortable.

Anshu K. Jain, MD: Right.

Benjamin P. Levy, MD: Whether that data will be a positive or a negative, we don’t know in terms of toxicity. But the question really is, can you safely give immunotherapy concurrently with radiation? As it stands today, we don’t know. We have good data at least with targeted therapy. It can be given relatively safely, with at least palliative radiation, or even whole-brain radiation. But for immunotherapy, that pneumonitis toxicity is real, and I think we need more data.

Anshu K. Jain, MD: I think that either consolidating or local therapy for extrathoracic disease in the setting of concurrent I-O, there’s some more comfort with that. But in the setting of thoracic disease, looking at the anatomical distribution and how it might impact some of the dose symmetry, those are questions that remain to be answered.

Transcript edited for clarity.
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