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Upfront Use of Second-Line Agents in ALK+ NSCLC

Insights From: Corey J. Langer, MD, Perelman Center for Advanced Medicine; Hospital of the University of Pennsylvania; Mohammad Jahanzeb, MD, Univerity of Miami Miller School of Medicine; Shirish Gadgeel, MD, Wayne State University School of Medicine; Karmanos Cancer Institute
Published: Wednesday, Aug 02, 2017


Transcript:

Corey J. Langer, MD: ASCEND-4 was really a landmark trial comparing ceritinib with standard cytotoxic chemotherapy—in this case, pemetrexed combined with either carboplatin or cisplatin in treatment-naive individuals. Progression-free survival was more than double in the ceritinib arm: 16.5 months, compared with about 8 months or so for chemotherapy. We see a striking response benefit, over 70%, using ceritinib, compared with about 25% in the chemotherapy arm. We see fewer treatment dropouts; only about 5% discontinued therapy for adverse events on the ceritinib arm, compared with over 10% receiving chemotherapy. And, as we’ve come to expect with this class of agents, there was much better CNS penetrance: a small percentage of occurrences in the brain and lower incidence of CNS progression in the ceritinib arm.

Based on these data, ceritinib is a very reasonable option for frontline treatment. We do not have, to the best of my knowledge, mature head-to-head phase III data comparing ceritinib with crizotinib, which I think is one of the other crucial issues. In that regard, the J-ALEX trial, a Japanese trial comparing alectinib with crizotinib, is quite informative. There, we observed a median progression-free survival that, at a minimum, will be 20 months. At least, that’s the lower end of the confidence intervals. We haven’t even reached the median at this point.

We see disease control rates that, at least numerically, are higher for alectinib over crizotinib, and a far lower risk of toxicity and treatment dropout. So, it’s going to be a competition. I think in the frontline setting, we’ll see competition between ceritinib and alectinib. And, at least based on the toxicity profiles, many of those who work in thoracic oncology suspect that alectinib may win out. The big issue with ceritinib has been toxicity. The standard starting dose is 750 mg daily. Invariably, individuals require dose reductions to either 600 mg or 450 mg daily, and many of us will start out at a lower dose of 450 mg and try to build up to 600 mg or 750 mg daily. Recent data by Alice Shaw and others suggest a low-fat meal combined with ceritinib may help mitigate the GI toxicity, but, again, this is not yet necessarily a standard approach for individuals who receive ceritinib.

Mohammad Jahanzeb, MD: J-ALEX was a Japanese study that actually showed very impressive results. The international version of J-ALEX, which includes the United States, will be reported at the American Society of Clinical Oncology meeting of 2017. Everybody’s looking forward to that presentation. And if that again shows the same hazard reductions that we had seen in the J-ALEX trial, then I think that we will really be considering alectinib more favorably for first-line use. I should mention that there are now first-line data with ceritinib, as well, and there will be first-line data for brigatinib in the ALTA randomized trial that’s ongoing—crizotinib versus brigatinib—and we are participating in that at the University of Miami.

Shirish Gadgeel, MD: The J-ALEX trial was a study that randomized patients to alectinib versus crizotinib. So, this was head-to-head comparison of 2 different ALK inhibitors, but this study was conducted only in Japan. There were other certain unique features of the study. The study required that the tumor was found to be positive for ALK by both IHC and by FISH, or RD-PCR. So, the tumors were known to be ALK-positive by 2 different tests. Secondly, patients were allowed to have received chemotherapy, and a third of these patients had received chemotherapy, whereas two-thirds of the patients were treatment naïve. And finally, patients were not stratified according to brain metastases, and there were slight imbalances.

The J-ALEX study showed that there was a significant improvement in progression-free survival in patients who received alectinib versus crizotinib. Patients who received crizotinib had a median progression-free survival of 10.2 months. At the time of data analysis, the median progression-free survival in patients who had received alectinib had not been reached, and the hazard ratio was 0.34. What was remarkable about the J-ALEX study was that the hazard ratio among patients who had CNS metastases was 0.08, so that means there was a 92% reduction in the risk of progression in patients who received alectinib, as compared with patients who received crizotinib.

Now, one of the reasons why many experts were hesitant to utilize those data in day-to-day practice, apart from the fact that the drug has not been approved in the frontline setting, is that this study was conducted in Japan. There was a companion study called the ALEX study that was conducted globally and is actually going to be reported at this year’s ASCO. We do have a press release that reported there was a significant improvement in progression-free survival in patients who received alectinib, though we don’t know the full results, and we will learn them at this year’s ASCO. It is expected that, based on these results, alectinib will also be approved by the FDA for frontline use.

We will have now 2 other drugs apart from crizotinib for use as frontline treatment in patients with ALK-positive advanced non–small cell lung cancer. I think the only difference is that alectinib was compared with another ALK inhibitor, whereas ceritinib was compared with cytotoxic chemotherapy, which is no longer used as frontline therapy. And, therefore, I would value the data from J-ALEX—and now the companion study, ALEX—as more relevant to day-to-day practice, as compared with the ASCEND-4 data. My suspicion is that this may lead to alectinib being used more frequently as frontline therapy for patients with ALK-positive advanced non–small cell lung cancer. But we do have, now, 2 other choices for treatment with these patients apart from crizotinib.

Corey J. Langer, MD: The field is going to get very confusing, particularly once we start routinely using agents like alectinib or ceritinib in the frontline setting. We have precious little data for going to other TKIs as second-line, and we’re going to have to generate these data as we go along. Personally, I believe we’re going to need to rebiopsy these individuals, get tissue, and look for unique mutations that may be more sensitive to one TKI over another. This will be supplemented by what I call liquid biopsies, by looking at circulating-free DNA or tumor-free DNA that may similarly help guide our therapeutic decision making.

So, hypothetically, an individual has received alectinib frontline. Should that individual go on to ceritinib, or should they go on to brigatinib? For that matter, should they go on a standard systemic chemotherapy? Biopsies will govern this. The clinical situation will also govern the therapeutic decision. If disease is progressing slowly and the patient is relatively asymptomatic, I will have the luxury of time of looking at another TKI before I pull the trigger on chemotherapy. On the other hand, in an area where we have very little data, the progression is fulminant, and the patient is highly symptomatic, at least I have an established track record with chemotherapy. That individual will more likely go on to a platinum-based combination, given the nature of ALK rearrangements: almost definitely pemetrexed combined with carboplatin, with or without an angiogenesis inhibitor.

Shirish Gadgeel, MD: The study, actually, that is being conducted is a randomized phase III study called the ALTA-2 trial and is randomizing patients to brigatinib versus crizotinib. It is ongoing, but, from what I understand, two-thirds of the planned enrollment has been completed. And so, it is expected that the study will complete enrollment in the near future. The goal of the study is to assess progression-free survival in patients who have received brigatinib, compared with patients treated with crizotinib. The expectation is that the study will be positive and that brigatinib will provide a greater progression-free survival based on the fact that, in preclinical models, it is a more potent ALK inhibitor. In patients who have progressed on crizotinib, it has shown promising activity, as well as activity in the CNS. But once those results become available—and if the study is positive, as expected—we will have to decide how to choose between all the next-generation ALK inhibitors for frontline treatment. So, at the present time, the study is ongoing, and we’ll have to see what the results show.

Transcript Edited for Clarity
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Transcript:

Corey J. Langer, MD: ASCEND-4 was really a landmark trial comparing ceritinib with standard cytotoxic chemotherapy—in this case, pemetrexed combined with either carboplatin or cisplatin in treatment-naive individuals. Progression-free survival was more than double in the ceritinib arm: 16.5 months, compared with about 8 months or so for chemotherapy. We see a striking response benefit, over 70%, using ceritinib, compared with about 25% in the chemotherapy arm. We see fewer treatment dropouts; only about 5% discontinued therapy for adverse events on the ceritinib arm, compared with over 10% receiving chemotherapy. And, as we’ve come to expect with this class of agents, there was much better CNS penetrance: a small percentage of occurrences in the brain and lower incidence of CNS progression in the ceritinib arm.

Based on these data, ceritinib is a very reasonable option for frontline treatment. We do not have, to the best of my knowledge, mature head-to-head phase III data comparing ceritinib with crizotinib, which I think is one of the other crucial issues. In that regard, the J-ALEX trial, a Japanese trial comparing alectinib with crizotinib, is quite informative. There, we observed a median progression-free survival that, at a minimum, will be 20 months. At least, that’s the lower end of the confidence intervals. We haven’t even reached the median at this point.

We see disease control rates that, at least numerically, are higher for alectinib over crizotinib, and a far lower risk of toxicity and treatment dropout. So, it’s going to be a competition. I think in the frontline setting, we’ll see competition between ceritinib and alectinib. And, at least based on the toxicity profiles, many of those who work in thoracic oncology suspect that alectinib may win out. The big issue with ceritinib has been toxicity. The standard starting dose is 750 mg daily. Invariably, individuals require dose reductions to either 600 mg or 450 mg daily, and many of us will start out at a lower dose of 450 mg and try to build up to 600 mg or 750 mg daily. Recent data by Alice Shaw and others suggest a low-fat meal combined with ceritinib may help mitigate the GI toxicity, but, again, this is not yet necessarily a standard approach for individuals who receive ceritinib.

Mohammad Jahanzeb, MD: J-ALEX was a Japanese study that actually showed very impressive results. The international version of J-ALEX, which includes the United States, will be reported at the American Society of Clinical Oncology meeting of 2017. Everybody’s looking forward to that presentation. And if that again shows the same hazard reductions that we had seen in the J-ALEX trial, then I think that we will really be considering alectinib more favorably for first-line use. I should mention that there are now first-line data with ceritinib, as well, and there will be first-line data for brigatinib in the ALTA randomized trial that’s ongoing—crizotinib versus brigatinib—and we are participating in that at the University of Miami.

Shirish Gadgeel, MD: The J-ALEX trial was a study that randomized patients to alectinib versus crizotinib. So, this was head-to-head comparison of 2 different ALK inhibitors, but this study was conducted only in Japan. There were other certain unique features of the study. The study required that the tumor was found to be positive for ALK by both IHC and by FISH, or RD-PCR. So, the tumors were known to be ALK-positive by 2 different tests. Secondly, patients were allowed to have received chemotherapy, and a third of these patients had received chemotherapy, whereas two-thirds of the patients were treatment naïve. And finally, patients were not stratified according to brain metastases, and there were slight imbalances.

The J-ALEX study showed that there was a significant improvement in progression-free survival in patients who received alectinib versus crizotinib. Patients who received crizotinib had a median progression-free survival of 10.2 months. At the time of data analysis, the median progression-free survival in patients who had received alectinib had not been reached, and the hazard ratio was 0.34. What was remarkable about the J-ALEX study was that the hazard ratio among patients who had CNS metastases was 0.08, so that means there was a 92% reduction in the risk of progression in patients who received alectinib, as compared with patients who received crizotinib.

Now, one of the reasons why many experts were hesitant to utilize those data in day-to-day practice, apart from the fact that the drug has not been approved in the frontline setting, is that this study was conducted in Japan. There was a companion study called the ALEX study that was conducted globally and is actually going to be reported at this year’s ASCO. We do have a press release that reported there was a significant improvement in progression-free survival in patients who received alectinib, though we don’t know the full results, and we will learn them at this year’s ASCO. It is expected that, based on these results, alectinib will also be approved by the FDA for frontline use.

We will have now 2 other drugs apart from crizotinib for use as frontline treatment in patients with ALK-positive advanced non–small cell lung cancer. I think the only difference is that alectinib was compared with another ALK inhibitor, whereas ceritinib was compared with cytotoxic chemotherapy, which is no longer used as frontline therapy. And, therefore, I would value the data from J-ALEX—and now the companion study, ALEX—as more relevant to day-to-day practice, as compared with the ASCEND-4 data. My suspicion is that this may lead to alectinib being used more frequently as frontline therapy for patients with ALK-positive advanced non–small cell lung cancer. But we do have, now, 2 other choices for treatment with these patients apart from crizotinib.

Corey J. Langer, MD: The field is going to get very confusing, particularly once we start routinely using agents like alectinib or ceritinib in the frontline setting. We have precious little data for going to other TKIs as second-line, and we’re going to have to generate these data as we go along. Personally, I believe we’re going to need to rebiopsy these individuals, get tissue, and look for unique mutations that may be more sensitive to one TKI over another. This will be supplemented by what I call liquid biopsies, by looking at circulating-free DNA or tumor-free DNA that may similarly help guide our therapeutic decision making.

So, hypothetically, an individual has received alectinib frontline. Should that individual go on to ceritinib, or should they go on to brigatinib? For that matter, should they go on a standard systemic chemotherapy? Biopsies will govern this. The clinical situation will also govern the therapeutic decision. If disease is progressing slowly and the patient is relatively asymptomatic, I will have the luxury of time of looking at another TKI before I pull the trigger on chemotherapy. On the other hand, in an area where we have very little data, the progression is fulminant, and the patient is highly symptomatic, at least I have an established track record with chemotherapy. That individual will more likely go on to a platinum-based combination, given the nature of ALK rearrangements: almost definitely pemetrexed combined with carboplatin, with or without an angiogenesis inhibitor.

Shirish Gadgeel, MD: The study, actually, that is being conducted is a randomized phase III study called the ALTA-2 trial and is randomizing patients to brigatinib versus crizotinib. It is ongoing, but, from what I understand, two-thirds of the planned enrollment has been completed. And so, it is expected that the study will complete enrollment in the near future. The goal of the study is to assess progression-free survival in patients who have received brigatinib, compared with patients treated with crizotinib. The expectation is that the study will be positive and that brigatinib will provide a greater progression-free survival based on the fact that, in preclinical models, it is a more potent ALK inhibitor. In patients who have progressed on crizotinib, it has shown promising activity, as well as activity in the CNS. But once those results become available—and if the study is positive, as expected—we will have to decide how to choose between all the next-generation ALK inhibitors for frontline treatment. So, at the present time, the study is ongoing, and we’ll have to see what the results show.

Transcript Edited for Clarity
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