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Chemotherapy for Advanced Lung Cancer

Panelists:Benjamin Levy, MD, Mount Sinai Health Systems, ; John W. Longshore, PhD, Carolinas Pathology Group; Gregory J. Riely, MD, PhD, Weill Cornell Medical College; Mark A. Socinski, MD, University of Pittsburgh; Thomas E. Stinchcombe, MD, University of North Carolina at Chapel Hill; Jared Weiss, MD, University of North Carolina School of Medicine
Published: Friday, Apr 15, 2016


Transcript:

Mark A. Socinski, MD:
Let’s turn our discussion now to optimizing chemotherapy in advanced non–small cell lung cancer. We do the molecular testing. More times than not, we’re not going to find an oncogenic driver. We’re going to be talking about the issues for first-line chemotherapy uses. So, Tom, why don’t you walk us through your thought process in that patient?

Thomas E. Stinchcombe, MD: I think there’s initial disappointment when you don’t find an oncogenic driver mutation.

Mark A. Socinski, MD: On the doctor or the patient?

Thomas E. Stinchcombe, MD: Both. I think that’s something that’s changed over the last five or 10 years. I think chemotherapy still is a major contributor to the care of lung cancer patients in terms of, even the people with targeted lesions will get chemotherapy at some point. And many of the people, like you said, who are mutation-negative, start with chemotherapy. When I see a lung cancer patient with advanced disease, I look at their performance status, their comorbidities. And then, after that I talk to them pretty extensively about their preferences and what their goals of the care are, I divide the patients into performance status; 0 to 1 patients will either get carboplatin/pemetrexed or carboplatin/paclitaxel and bevacizumab—my two most commonly used therapies. I think you can make a justification for carboplatin/pemetrexed and bevacizumab. But I just tend to use that third one a little bit less frequently.

Mark A. Socinski, MD: What are your choices in the squamous population of patients?

Thomas E. Stinchcombe, MD: For the squamous patients, I generally will treat with carboplatin/gemcitabine, carboplatin/paclitaxel, and carboplatin/nab-paclitaxel as an option as well.

Mark A. Socinski, MD: So in your choices, at least for the non-squamous, you mentioned bevacizumab. How often is that used in your practice? What are the issues there with recommending it?

Thomas E. Stinchcombe, MD: I think it’s a minority of patients. I’d say maybe one in five or so get it. Some of the issues are the uncontrolled hypertension, the hemoptysis, and some other contraindications. I have a little bit of hesitancy of using it for people over 70, and I think you have to triage those patients very carefully. The thing that changed my practice prescribing is that I think the carboplatin/pemetrexed is very easy to give and patients don’t have to worry about the hypertension or the hemoptysis. And that sometimes sways me a little bit more toward the carboplatin/pemetrexed in some patients.

Mark A. Socinski, MD: I think this is a curious area of oncology for me personally, because we kind of slipped into those two drugs. Carboplatin/pemetrexed are as good as those three drugs, carboplatin/paclitaxel/bevacizumab. And we did a recent survey, I forget where this was, of so-called “thought leaders” and all of them said that if you did a trial of carboplatin/pemetrexed plus or minus bevacizumab, they were convinced that it would show a survival advantage.

Benjamin P. Levy, MD: Which is quite interesting, because bevacizumab in addition to cisplatin and gemcitabine, a la the AVAiL study, did not show a benefit in survival.

Mark A. Socinski, MD: Which was a secondary endpoint. That was a positive trial, Dr. Levy. There was a PFS endpoint.

Thomas E. Stinchcombe, MD: But there are trials, the PRONOUNCE trial that compared carboplatin/pemetrexed to carboplatin/paclitaxel/bevacizumab.

Mark A. Socinski, MD: Oh yes, the PRONOUNCE trial.

Thomas E. Stinchcombe, MD: With admittedly an atypical endpoint, we’ll call it, of PFS and grade 4 toxicity. But outcomes were relatively similar.

Mark A. Socinski, MD: But woefully underpowered to assess outcome, so I don’t think physicians should be drawing the conclusion that those two drugs are as good as those three drugs in this setting. Although, I do think they are in common practice. We’re very dominated by pathways at UPMC, and we’re spot on: 21% of our first-line patients get bevacizumab. Is that similar to others’ practice?

Gregory J. Riely, MD, PhD: Yeah. I think it dramatically varies from doctor to doctor. But I think the average at our place would be around 20% as well.

Jared Weiss, MD: Less controversial, though, is the difference in toxicity profiles, and I see this a little bit from a practical perspective as a case of “pay me now or pay me later.” With pemetrexed/carboplatin, you have a less toxic regimen in the induction period, your initial four or four to six cycles. But you have to continue a cytotoxic in your maintenance, whereas I think paclitaxel is a little more challenging than pemetrexed in that induction setting—but then you’re not using a cytotoxic in your maintenance setting.

Mark A. Socinski, MD: I couldn’t agree more. Often patients’ preferences are driven by the side-effect profile, and alopecia is a big one with many people, that they don’t want to do that. Ben, I’m going to ask you. So we’ve established that in the first-line and the second-line, that cytotoxic chemotherapy has a role. We’ve certainly seen things change with immunotherapy. Talk us through getting from first-line, to second-line, to third-line. Historically, there’s been a huge drop off at each line.

Benjamin P. Levy, MD: For most of my patients—and we didn’t talk about this in the first-line—we are offering these patients who tolerate treatment and who are at least achieving stable disease after four cycles, maintenance chemotherapy. And that affords us the ability to follow these patients every 3 weeks and give an active drug. Most common in my practice has been pemetrexed. With second-line options, you do have a drop off. And I would say that the same formulas that go into deciding on [the] first-line regimens that Tom alluded to, including performance status and patient preferences and comorbidities, should also go into decisions regarding second-line. We try to put every patient who reaches second-line or who has progressed on carboplatin chemotherapy on a clinical trial. I think there’s an urgent need to have more clinical trials in the second-line and third-line space. But outside of a clinical trial, there are competing options.

Certainly checkpoint inhibitors, with nivolumab being the leader, are very reasonable for both the squamous and the non–squamous patient population, irrespective of PD-L1 status of their tumors. So, I think that my default second-line has been nivolumab. It’s well tolerated. Again, outside of a clinical trial. Other options include docetaxel or docetaxel plus ramucirumab for very fit patients. And then we move to third-line. We have very few approved drugs in third-line, and it really gets to be a dicey situation on what patients are going to get third-line. And I think second-line decisions often impact our third-line decisions. When patients are getting a checkpoint inhibitor and they’re doing very well in the second-line, and they don’t want to go back to chemotherapy, it makes third-line decisions, if they progress and when they progress, more challenging.

Mark A. Socinski, MD: Yeah. I’ve always felt that part of that drop off was two things: the fear of toxicity of docetaxel, because that was your choice, and the less than stellar benefit that you would get with docetaxel. Do you think that will change with the immunotherapies? More patients will be getting more lines of therapy because now we have immunotherapy as a second-line treatment? It’s pretty well tolerated.

Benjamin P. Levy, MD: I think so. I think patients may be a little more enthusiastic to go on clinical trials third-line or receive drugs that they’ve gotten reasonable benefit from first-line and second-line and tolerated it okay. I think they may be less reluctant to see a third-line agent, especially if it’s not chemotherapy. But even if it is chemotherapy, I think there’s a little more buy-in from the patient to go on to further therapy.

Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD:
Let’s turn our discussion now to optimizing chemotherapy in advanced non–small cell lung cancer. We do the molecular testing. More times than not, we’re not going to find an oncogenic driver. We’re going to be talking about the issues for first-line chemotherapy uses. So, Tom, why don’t you walk us through your thought process in that patient?

Thomas E. Stinchcombe, MD: I think there’s initial disappointment when you don’t find an oncogenic driver mutation.

Mark A. Socinski, MD: On the doctor or the patient?

Thomas E. Stinchcombe, MD: Both. I think that’s something that’s changed over the last five or 10 years. I think chemotherapy still is a major contributor to the care of lung cancer patients in terms of, even the people with targeted lesions will get chemotherapy at some point. And many of the people, like you said, who are mutation-negative, start with chemotherapy. When I see a lung cancer patient with advanced disease, I look at their performance status, their comorbidities. And then, after that I talk to them pretty extensively about their preferences and what their goals of the care are, I divide the patients into performance status; 0 to 1 patients will either get carboplatin/pemetrexed or carboplatin/paclitaxel and bevacizumab—my two most commonly used therapies. I think you can make a justification for carboplatin/pemetrexed and bevacizumab. But I just tend to use that third one a little bit less frequently.

Mark A. Socinski, MD: What are your choices in the squamous population of patients?

Thomas E. Stinchcombe, MD: For the squamous patients, I generally will treat with carboplatin/gemcitabine, carboplatin/paclitaxel, and carboplatin/nab-paclitaxel as an option as well.

Mark A. Socinski, MD: So in your choices, at least for the non-squamous, you mentioned bevacizumab. How often is that used in your practice? What are the issues there with recommending it?

Thomas E. Stinchcombe, MD: I think it’s a minority of patients. I’d say maybe one in five or so get it. Some of the issues are the uncontrolled hypertension, the hemoptysis, and some other contraindications. I have a little bit of hesitancy of using it for people over 70, and I think you have to triage those patients very carefully. The thing that changed my practice prescribing is that I think the carboplatin/pemetrexed is very easy to give and patients don’t have to worry about the hypertension or the hemoptysis. And that sometimes sways me a little bit more toward the carboplatin/pemetrexed in some patients.

Mark A. Socinski, MD: I think this is a curious area of oncology for me personally, because we kind of slipped into those two drugs. Carboplatin/pemetrexed are as good as those three drugs, carboplatin/paclitaxel/bevacizumab. And we did a recent survey, I forget where this was, of so-called “thought leaders” and all of them said that if you did a trial of carboplatin/pemetrexed plus or minus bevacizumab, they were convinced that it would show a survival advantage.

Benjamin P. Levy, MD: Which is quite interesting, because bevacizumab in addition to cisplatin and gemcitabine, a la the AVAiL study, did not show a benefit in survival.

Mark A. Socinski, MD: Which was a secondary endpoint. That was a positive trial, Dr. Levy. There was a PFS endpoint.

Thomas E. Stinchcombe, MD: But there are trials, the PRONOUNCE trial that compared carboplatin/pemetrexed to carboplatin/paclitaxel/bevacizumab.

Mark A. Socinski, MD: Oh yes, the PRONOUNCE trial.

Thomas E. Stinchcombe, MD: With admittedly an atypical endpoint, we’ll call it, of PFS and grade 4 toxicity. But outcomes were relatively similar.

Mark A. Socinski, MD: But woefully underpowered to assess outcome, so I don’t think physicians should be drawing the conclusion that those two drugs are as good as those three drugs in this setting. Although, I do think they are in common practice. We’re very dominated by pathways at UPMC, and we’re spot on: 21% of our first-line patients get bevacizumab. Is that similar to others’ practice?

Gregory J. Riely, MD, PhD: Yeah. I think it dramatically varies from doctor to doctor. But I think the average at our place would be around 20% as well.

Jared Weiss, MD: Less controversial, though, is the difference in toxicity profiles, and I see this a little bit from a practical perspective as a case of “pay me now or pay me later.” With pemetrexed/carboplatin, you have a less toxic regimen in the induction period, your initial four or four to six cycles. But you have to continue a cytotoxic in your maintenance, whereas I think paclitaxel is a little more challenging than pemetrexed in that induction setting—but then you’re not using a cytotoxic in your maintenance setting.

Mark A. Socinski, MD: I couldn’t agree more. Often patients’ preferences are driven by the side-effect profile, and alopecia is a big one with many people, that they don’t want to do that. Ben, I’m going to ask you. So we’ve established that in the first-line and the second-line, that cytotoxic chemotherapy has a role. We’ve certainly seen things change with immunotherapy. Talk us through getting from first-line, to second-line, to third-line. Historically, there’s been a huge drop off at each line.

Benjamin P. Levy, MD: For most of my patients—and we didn’t talk about this in the first-line—we are offering these patients who tolerate treatment and who are at least achieving stable disease after four cycles, maintenance chemotherapy. And that affords us the ability to follow these patients every 3 weeks and give an active drug. Most common in my practice has been pemetrexed. With second-line options, you do have a drop off. And I would say that the same formulas that go into deciding on [the] first-line regimens that Tom alluded to, including performance status and patient preferences and comorbidities, should also go into decisions regarding second-line. We try to put every patient who reaches second-line or who has progressed on carboplatin chemotherapy on a clinical trial. I think there’s an urgent need to have more clinical trials in the second-line and third-line space. But outside of a clinical trial, there are competing options.

Certainly checkpoint inhibitors, with nivolumab being the leader, are very reasonable for both the squamous and the non–squamous patient population, irrespective of PD-L1 status of their tumors. So, I think that my default second-line has been nivolumab. It’s well tolerated. Again, outside of a clinical trial. Other options include docetaxel or docetaxel plus ramucirumab for very fit patients. And then we move to third-line. We have very few approved drugs in third-line, and it really gets to be a dicey situation on what patients are going to get third-line. And I think second-line decisions often impact our third-line decisions. When patients are getting a checkpoint inhibitor and they’re doing very well in the second-line, and they don’t want to go back to chemotherapy, it makes third-line decisions, if they progress and when they progress, more challenging.

Mark A. Socinski, MD: Yeah. I’ve always felt that part of that drop off was two things: the fear of toxicity of docetaxel, because that was your choice, and the less than stellar benefit that you would get with docetaxel. Do you think that will change with the immunotherapies? More patients will be getting more lines of therapy because now we have immunotherapy as a second-line treatment? It’s pretty well tolerated.

Benjamin P. Levy, MD: I think so. I think patients may be a little more enthusiastic to go on clinical trials third-line or receive drugs that they’ve gotten reasonable benefit from first-line and second-line and tolerated it okay. I think they may be less reluctant to see a third-line agent, especially if it’s not chemotherapy. But even if it is chemotherapy, I think there’s a little more buy-in from the patient to go on to further therapy.

Transcript Edited for Clarity
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