ONCAlert | Upfront Therapy for mRCC

Case 3: Second-Line Therapy After Chemo/I-O in Stage IV NSCLC

Targeted Oncology
Published Online:12:40 PM, Wed September 26, 2018

Anne S. Tsao, MD: Let’s talk about treatment in this case. That’s the million-dollar question now. What do you do in the immunotherapy-refractory patients? Paul, I’m going to throw this first question to you. She has rapidly progressed off the triplet regimen, which we all feel is a very good, superior regimen. What do you do?

Paul K. Paik, MD: It’s interesting where we are now with chemoimmunotherapy being the standard for most of our non–small cell lung cancer patients. It’s great that there’s an overall survival advantage, but the number of lines of therapies have now collapsed. Paradoxically, we find ourselves with fewer options at the end of the day. What we’re left with, in terms of data that has an overall survival advantage that has a higher response rate than its control arm, is docetaxel/ramucirumab. For me, that really is the standard therapy in the second-line setting.

It’s hard. The subgroup analysis for the REVEL trial, as you had mentioned, wasn’t powered for that. The pattern that we’re seeing in terms of patients who progress more rapidly, and the additional benefit to ramucirumab is interesting. I think it just adds additional data that suggests that you should really consider adding ramucirumab to docetaxel in these settings. So, I think it did help. Yes.

Anne S. Tsao, MD: Ben, let’s list the different options in the second-line setting. In theory, what are our options?

Benjamin P. Levy, MD: There are some incorrect choices, and several correct choices.

Anne S. Tsao, MD: But on NCCN [National Comprehensive Cancer Network], they’re all listed.

Benjamin P. Levy, MD: Yes. What we probably don’t want to give this patient is another checkpoint inhibitor. I think that a single agent PD-L1 [programmed-cell death ligand 1] drug after the triplet therapy has very little activity. I would not give another checkpoint inhibitor off of a clinical trial. I think the second-line chemotherapy options certainly include, as Paul mentioned, docetaxel/ramucirumab. Single-agent docetaxel is a second-line option for me. Gemcitabine is a potential second-line option for me. Navelbine [vinorelbine], again, is another option. I think these are all reasonable. If a patient is fit and is rapidly progressing, or even if they’re not rapidly progressing, I think the best data we have is with docetaxel and ramucirumab. Now, do I start docetaxel at 75 mg/m2? Maybe not. Maybe I start at 60 mg/m2, or even a little bit lower with the ramucirumab. I don’t think the checkpoint inhibitor is the right way to go, but I do think systemic options are varied and you have multiple options on the table.

Anne S. Tsao, MD: Paul, is there ever a patient who you see, that’s rapidly progressing, who you wouldn’t give ramucirumab to?

Paul K. Paik, MD: Yes, it would be the categories that led to exclusion from the REVEL trial, which are largely concerns about bleeding, concerns in terms of the anatomic characteristics of the tumor that might suggest centrally located tumors, or tumors that are capitated that would really make you think about doing that. Also, if there’s any additional renal dysfunction that occurred in the interim. Those are things to be aware of as contraindications to giving ramucirumab.

Benjamin P. Levy, MD: I think this case highlights a couple of things. Second-line treatment options are available for rapidly progressing patients, and not all patients are going to respond to immunotherapy or immunotherapy-based regimens. I think there’s a lot that we need to do, as oncologists, to temper that enthusiasm or set expectations that, “Yes, we’re going to give you a triplet therapy. Yes, that includes immunotherapy.” They’ve seen the TV commercials. They’re very excited. But, I think we need to be optimistic but realistic about the real benefits. Not everyone is going to respond or benefit from immunotherapy in the first-line setting. We have to be ready to make those second-line decisions. There was a very nice editorial in the Journal of Clinical Oncology a few months back that reviewed how to manage expectations with immunotherapy and talk to patients about hoping for the best but preparing for the worst. As oncologists, we’re all optimistic about these drugs and where they can take us. But, in the back of our minds, we have to plan on what that second-line option is going to be for these patients.

Anne S. Tsao, MD: Certainly, there’s also the question of hyperprogression, and that seems to be, according to the Europeans, higher in instance than pseudoprogression in these patients.

Benjamin P. Levy, MD: Yes. I’m waiting to see that phenomenon happen in my own clinic. But I think you’re right—you have to prepare for that as well.

Transcript edited for clarity.

Anne S. Tsao, MD: Let’s talk about treatment in this case. That’s the million-dollar question now. What do you do in the immunotherapy-refractory patients? Paul, I’m going to throw this first question to you. She has rapidly progressed off the triplet regimen, which we all feel is a very good, superior regimen. What do you do?

Paul K. Paik, MD: It’s interesting where we are now with chemoimmunotherapy being the standard for most of our non–small cell lung cancer patients. It’s great that there’s an overall survival advantage, but the number of lines of therapies have now collapsed. Paradoxically, we find ourselves with fewer options at the end of the day. What we’re left with, in terms of data that has an overall survival advantage that has a higher response rate than its control arm, is docetaxel/ramucirumab. For me, that really is the standard therapy in the second-line setting.

It’s hard. The subgroup analysis for the REVEL trial, as you had mentioned, wasn’t powered for that. The pattern that we’re seeing in terms of patients who progress more rapidly, and the additional benefit to ramucirumab is interesting. I think it just adds additional data that suggests that you should really consider adding ramucirumab to docetaxel in these settings. So, I think it did help. Yes.

Anne S. Tsao, MD: Ben, let’s list the different options in the second-line setting. In theory, what are our options?

Benjamin P. Levy, MD: There are some incorrect choices, and several correct choices.

Anne S. Tsao, MD: But on NCCN [National Comprehensive Cancer Network], they’re all listed.

Benjamin P. Levy, MD: Yes. What we probably don’t want to give this patient is another checkpoint inhibitor. I think that a single agent PD-L1 [programmed-cell death ligand 1] drug after the triplet therapy has very little activity. I would not give another checkpoint inhibitor off of a clinical trial. I think the second-line chemotherapy options certainly include, as Paul mentioned, docetaxel/ramucirumab. Single-agent docetaxel is a second-line option for me. Gemcitabine is a potential second-line option for me. Navelbine [vinorelbine], again, is another option. I think these are all reasonable. If a patient is fit and is rapidly progressing, or even if they’re not rapidly progressing, I think the best data we have is with docetaxel and ramucirumab. Now, do I start docetaxel at 75 mg/m2? Maybe not. Maybe I start at 60 mg/m2, or even a little bit lower with the ramucirumab. I don’t think the checkpoint inhibitor is the right way to go, but I do think systemic options are varied and you have multiple options on the table.

Anne S. Tsao, MD: Paul, is there ever a patient who you see, that’s rapidly progressing, who you wouldn’t give ramucirumab to?

Paul K. Paik, MD: Yes, it would be the categories that led to exclusion from the REVEL trial, which are largely concerns about bleeding, concerns in terms of the anatomic characteristics of the tumor that might suggest centrally located tumors, or tumors that are capitated that would really make you think about doing that. Also, if there’s any additional renal dysfunction that occurred in the interim. Those are things to be aware of as contraindications to giving ramucirumab.

Benjamin P. Levy, MD: I think this case highlights a couple of things. Second-line treatment options are available for rapidly progressing patients, and not all patients are going to respond to immunotherapy or immunotherapy-based regimens. I think there’s a lot that we need to do, as oncologists, to temper that enthusiasm or set expectations that, “Yes, we’re going to give you a triplet therapy. Yes, that includes immunotherapy.” They’ve seen the TV commercials. They’re very excited. But, I think we need to be optimistic but realistic about the real benefits. Not everyone is going to respond or benefit from immunotherapy in the first-line setting. We have to be ready to make those second-line decisions. There was a very nice editorial in the Journal of Clinical Oncology a few months back that reviewed how to manage expectations with immunotherapy and talk to patients about hoping for the best but preparing for the worst. As oncologists, we’re all optimistic about these drugs and where they can take us. But, in the back of our minds, we have to plan on what that second-line option is going to be for these patients.

Anne S. Tsao, MD: Certainly, there’s also the question of hyperprogression, and that seems to be, according to the Europeans, higher in instance than pseudoprogression in these patients.

Benjamin P. Levy, MD: Yes. I’m waiting to see that phenomenon happen in my own clinic. But I think you’re right—you have to prepare for that as well.

Transcript edited for clarity.
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