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Sequencing Through Multiple Relapses in Nondriver mNSCLC

Insights From: Hossein Borghaei, DO, Fox Chase Cancer Center; Corey J. Langer, MD, Perelman School of Medicine; Vassiliki Papadimitrakopoulou, MD, MD Anderson Cancer Center
Published: Thursday, Aug 23, 2018



Transcript: 

Corey J. Langer, MD: The emergence of immunotherapy and this transition from second-line to first-line therapy, either as a single agent or in combination with chemotherapy, has really opened the door for new approaches in the second-line setting. Ironically, I think we will see docetaxel—either alone or more likely in combination with ramucirumab—re-emerge from third-line to second-line treatment. We’re giving immunotherapy in combination with chemotherapy. Our major option at the time of disease progression will be docetaxel/ramucirumab. A question remains: is that really the optimal regimen? Certainly, that combination is better than docetaxel alone. We’ve seen data in rapid progressors that suggest it may even be better, particularly for those whose disease progresses within 9 to 10 weeks of the initiation of treatment. There’s a 3- to 3-and-a-half-month improvement in overall survival, frankly a more pronounced difference than we see in the overall population.
              
But I think the adoption of concurrent immunotherapy and chemotherapy opens the door to additional innovative approaches. For instance, we are about to look at—in a phase II trial of individuals whose disease has progressed on maintenance therapy after 4 and a half months—a unique combination taking a weekly taxane, either paclitaxel or nab-paclitaxel, and combining it with ramucirumab and reintroducing carboplatin. There’s no reason to believe that those folks are inherently carboplatin-refractory. We have, in small-cell disease and ovarian cancer, already defined this notion of platinum-sensitive/platinum-refractory. The same observation potentially applies to non–small cell disease. This gives us an opportunity to actually test new combinations in the second-line setting. A lot of my peers and colleagues are worried that we’re exhausting all our therapies at the very beginning, that we’ll have fewer choices. I’d argue the opposite. I think we have more choices in light of the immunotherapy era and the potential options that exist in the second-line setting.

Hossein Borghaei, DO: The availability of current data with the I-O combinations, to me, suggest that most of the treatment-naïve patients who walk into our clinics now are going to be treated with some sort of an I-O combination. I think at this point, that’s going to be I-O plus chemotherapy. I think the efficacy and safety data support that. At the time of progression, the options are to go back to our standard chemotherapy drugs that we were using: for instance, docetaxel. In that category, obviously the results of docetaxel plus ramucirumab versus docetaxel alone suggest there is a little more clinical efficacy for the combination with docetaxel and ramucirumab.

You can argue the trial that showed docetaxel plus ramucirumab should be better than docetaxel alone was done in a patient population that had not necessarily seen a lot of I-O up front. Maybe the tumor microenvironment is a little different. But I think the combination is still a valid and reasonable option for patients who qualify for ramucirumab plus docetaxel. I think there, you have to worry about whether a patient can tolerate a doublet treatment. After all, these are patients who have been through a chemotherapy/I-O or an I-O/I-O combination. As long as they qualify, given some of the restrictions that come naturally with using a drug like ramucirumab if they’re not candidates, I’m not against using that combination. It’s just that if a patient has a poor performance status because of progression, are they really candidates for a more aggressive approach or not?

I think because I-O has moved to the frontline, in the second-line setting, we’re going to be looking at patients who are probably going to get, outside a clinical trial, some sort of a chemotherapy. Now, interestingly, I think there are going to be patients who get chemotherapy plus I-O and then come off treatment for whatever reason, either duration or some toxicity, and have stable disease for a very long time. We haven’t really decided as a group what that period of time is.

Clearly, I think a patient who progresses while getting treated with immunotherapy has a different tumor and probably requires something different than a patient who got his or her last dose of immunotherapy a year and a half ago and has enjoyed a disease-free interval but now, all of a sudden, has progression. I think you have to identify these patients and see if a patient who comes back a year and a half after treatment is still a candidate for an immuno-oncology drug. Maybe that’s what you want to use instead of going back to traditional chemotherapy. I think we’re going to have to start stratifying these patients by how quickly or how slowly they progressed on their prior lines of immunotherapy-based regimens.

Transcript Edited for Clarity 
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Transcript: 

Corey J. Langer, MD: The emergence of immunotherapy and this transition from second-line to first-line therapy, either as a single agent or in combination with chemotherapy, has really opened the door for new approaches in the second-line setting. Ironically, I think we will see docetaxel—either alone or more likely in combination with ramucirumab—re-emerge from third-line to second-line treatment. We’re giving immunotherapy in combination with chemotherapy. Our major option at the time of disease progression will be docetaxel/ramucirumab. A question remains: is that really the optimal regimen? Certainly, that combination is better than docetaxel alone. We’ve seen data in rapid progressors that suggest it may even be better, particularly for those whose disease progresses within 9 to 10 weeks of the initiation of treatment. There’s a 3- to 3-and-a-half-month improvement in overall survival, frankly a more pronounced difference than we see in the overall population.
              
But I think the adoption of concurrent immunotherapy and chemotherapy opens the door to additional innovative approaches. For instance, we are about to look at—in a phase II trial of individuals whose disease has progressed on maintenance therapy after 4 and a half months—a unique combination taking a weekly taxane, either paclitaxel or nab-paclitaxel, and combining it with ramucirumab and reintroducing carboplatin. There’s no reason to believe that those folks are inherently carboplatin-refractory. We have, in small-cell disease and ovarian cancer, already defined this notion of platinum-sensitive/platinum-refractory. The same observation potentially applies to non–small cell disease. This gives us an opportunity to actually test new combinations in the second-line setting. A lot of my peers and colleagues are worried that we’re exhausting all our therapies at the very beginning, that we’ll have fewer choices. I’d argue the opposite. I think we have more choices in light of the immunotherapy era and the potential options that exist in the second-line setting.

Hossein Borghaei, DO: The availability of current data with the I-O combinations, to me, suggest that most of the treatment-naïve patients who walk into our clinics now are going to be treated with some sort of an I-O combination. I think at this point, that’s going to be I-O plus chemotherapy. I think the efficacy and safety data support that. At the time of progression, the options are to go back to our standard chemotherapy drugs that we were using: for instance, docetaxel. In that category, obviously the results of docetaxel plus ramucirumab versus docetaxel alone suggest there is a little more clinical efficacy for the combination with docetaxel and ramucirumab.

You can argue the trial that showed docetaxel plus ramucirumab should be better than docetaxel alone was done in a patient population that had not necessarily seen a lot of I-O up front. Maybe the tumor microenvironment is a little different. But I think the combination is still a valid and reasonable option for patients who qualify for ramucirumab plus docetaxel. I think there, you have to worry about whether a patient can tolerate a doublet treatment. After all, these are patients who have been through a chemotherapy/I-O or an I-O/I-O combination. As long as they qualify, given some of the restrictions that come naturally with using a drug like ramucirumab if they’re not candidates, I’m not against using that combination. It’s just that if a patient has a poor performance status because of progression, are they really candidates for a more aggressive approach or not?

I think because I-O has moved to the frontline, in the second-line setting, we’re going to be looking at patients who are probably going to get, outside a clinical trial, some sort of a chemotherapy. Now, interestingly, I think there are going to be patients who get chemotherapy plus I-O and then come off treatment for whatever reason, either duration or some toxicity, and have stable disease for a very long time. We haven’t really decided as a group what that period of time is.

Clearly, I think a patient who progresses while getting treated with immunotherapy has a different tumor and probably requires something different than a patient who got his or her last dose of immunotherapy a year and a half ago and has enjoyed a disease-free interval but now, all of a sudden, has progression. I think you have to identify these patients and see if a patient who comes back a year and a half after treatment is still a candidate for an immuno-oncology drug. Maybe that’s what you want to use instead of going back to traditional chemotherapy. I think we’re going to have to start stratifying these patients by how quickly or how slowly they progressed on their prior lines of immunotherapy-based regimens.

Transcript Edited for Clarity 
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