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Ceritinib in Crizotinib-Resistant NSCLC

Insights From:Alice T. Shaw, MD, PhD, Massachusetts General Hospital; Gregory J. Riely, MD, Memorial Sloan Kettering; Mark A. Socinski, MD, UPMC
Published: Monday, Feb 22, 2016



Transcript:

Alice T. Shaw, MD, PhD:
All patients on crizotinib will eventually relapse, and that’s due to acquired resistance. There’s been a real effort to understand resistance and to try to overcome that resistance with new and more potent ALK inhibitors. Ceritinib is one of the first of the next-generation ALK inhibitors. It was developed by Novartis, and it is very potent against ALK. It’s likely in the range of ten- to twenty-fold more potent against ALK than crizotinib.

It also is more selective for ALK compared to crizotinib; it does not have any activity against c-MET, for example. In preclinical studies, we’ve seen that ceritinib is able to overcome many of the known resistance mutations. This includes L1196M, which is the “gatekeeper” mutation and G1269A, another common mutation. It seems all the preclinical studies were promising that ceritinib would show efficacy in patients who had failed on crizotinib.

This is what we saw in the phase I study. This was a global study of ceritinib in patients with ALK-positive lung cancer. Most of them had already failed crizotinib. And what we saw is that in this crizotinib-resistant group of ALK-positive patients, ceritinib was very active, with a response rate of about 55% and a median PFS of close to seven months. So many patients, even though they had failed crizotinib, were able to re-respond to this new, and more potent ALK inhibitor.

This has now become a standard agent for patients who have failed on crizotinib. It was approved by the FDA about a year and a half ago, and it’s also been approved by a number of other regulatory agencies around the world. This has led to a new treatment paradigm for ALK patients, where they receive crizotinib as their first-line therapy, and then when they have a relapse on crizotinib, they move on to a next-generation ALK inhibitor like ceritinib.

That was the phase I data. We also now have some data from phase II studies, so these are follow-up global, confirmatory phase II studies of ceritinib in ALK-positive patients. One of them was also done in a crizotinib-resistant setting. And here, the efficacy wasn’t as striking as what we saw in phase I, but it was fairly good still, with a response rate in the 40% to 50% range, and the median PFS in the six- to seven- month range. So, slightly less remarkable than what we saw in the phase I study, but still confirming the activity of this next-generation ALK inhibitor as being a very active agent in crizotinib-resistant disease.

Gregory J. Riely, MD: Ceritinib has been explored as a single agent in patients who’ve not been previously treated for ALK-positive lung cancer, and those patients who’ve had prior crizotinib for their ALK-positive lung cancer. In those patient populations, ceritinib has shown significant efficacy with response rates of above 50% for patients who have had prior crizotinib, as well as those who have not had prior crizotinib.

Median progression-free survivals are on the order of 7 to 12 months for those patients who have previously received crizotinib and then go on to ceritinib. This is a significant second-line option for patients who have had prior crizotinib. The side effects that we’ve seen so far for patients who are treated with ceritinib are typically GI-related side effects, so some dyspepsia, some nausea, and an occasional patient with diarrhea. These are all quite manageable at the doses that are described, and dose reductions can help significantly for those patients.

In moving ceritinib forward, one of the key things is to do some randomized clinical trials, and there are two big randomized clinical trials that are ongoing. One explores the use of ceritinib as a first-line ALK inhibitor. They’re taking patients who are initially diagnosed with advanced ALK-positive lung cancer and randomizing them to initial ceritinib or treatment with cisplatin or carboplatin along with pemetrexed. These would be considered the standard platinum-based doublets in this setting, and they’re comparing that to ceritinib. I think it’s going to be exciting to look at the results of that and understand how ceritinib’s progression-free, and overall survival compares to those patients who receive conventional chemotherapy as first-line therapy.

In the second-line setting, there’s a similar trial going on. And this second-line trial will take patients who have ALK-positive lung cancer, who have been previously treated with a platinum-based doublet. They’re randomized to either ceritinib or treatment with docetaxel or pemetrexed, depending on the prior therapy they’ve had. This will establish the role of ceritinib as a second-line drug, particularly for patients with ALK-positive non–small cell lung cancer.

Mark A. Socinski, MD: Ceritinib is a second-generation ALK inhibitor. It was initially studied in a combination of crizotinib-pretreated patients, as well as treatment-naïve patients. Its initial emphasis was on crizotinib-pretreated patients because crizotinib was approved for the treatment of ALK-positive patients. So, we needed a second-line choice. In these patients, ceritinib showed response rates in the range of 50% to 65% in previously treated patients, reasonable durability with the progression-free survival times in the eight- to ten-month range—good tolerability.

The primary side effects of ceritinib are namely GI toxicities—nausea, vomiting, and liver function abnormalities. However, with careful attention to dose and dose reductions, and those sorts of strategies—which most oncologists are familiar with—ceritinib is a well-tolerated agent, and is very useful because it was the first, second-generation TKI approved for the use in patients who were progressing on crizotinib, the first-line choice.

Ceritinib does have activity in previously untreated patients. Its activity is a little better if you weren’t priorly exposed to crizotinib. However, in my mind, it’s a very important approval, because it gives you a second option in the ALK population, rather than diverting to standard intravenous chemotherapy options. These patients, who had perhaps been on crizotinib for quite some time, got used to taking a pill every day and dealing with those side effects, which are quite different than IV chemotherapy.

Ceritinib approval gave them an option. Certainly, in my practice, it was a welcomed approval, because we could delay the discussion, and the organization and intrusiveness that intravenous chemotherapy does to a patient and their quality of life. This addition was actually quite important in the management of patients in a busy lung cancer practice.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Alice T. Shaw, MD, PhD:
All patients on crizotinib will eventually relapse, and that’s due to acquired resistance. There’s been a real effort to understand resistance and to try to overcome that resistance with new and more potent ALK inhibitors. Ceritinib is one of the first of the next-generation ALK inhibitors. It was developed by Novartis, and it is very potent against ALK. It’s likely in the range of ten- to twenty-fold more potent against ALK than crizotinib.

It also is more selective for ALK compared to crizotinib; it does not have any activity against c-MET, for example. In preclinical studies, we’ve seen that ceritinib is able to overcome many of the known resistance mutations. This includes L1196M, which is the “gatekeeper” mutation and G1269A, another common mutation. It seems all the preclinical studies were promising that ceritinib would show efficacy in patients who had failed on crizotinib.

This is what we saw in the phase I study. This was a global study of ceritinib in patients with ALK-positive lung cancer. Most of them had already failed crizotinib. And what we saw is that in this crizotinib-resistant group of ALK-positive patients, ceritinib was very active, with a response rate of about 55% and a median PFS of close to seven months. So many patients, even though they had failed crizotinib, were able to re-respond to this new, and more potent ALK inhibitor.

This has now become a standard agent for patients who have failed on crizotinib. It was approved by the FDA about a year and a half ago, and it’s also been approved by a number of other regulatory agencies around the world. This has led to a new treatment paradigm for ALK patients, where they receive crizotinib as their first-line therapy, and then when they have a relapse on crizotinib, they move on to a next-generation ALK inhibitor like ceritinib.

That was the phase I data. We also now have some data from phase II studies, so these are follow-up global, confirmatory phase II studies of ceritinib in ALK-positive patients. One of them was also done in a crizotinib-resistant setting. And here, the efficacy wasn’t as striking as what we saw in phase I, but it was fairly good still, with a response rate in the 40% to 50% range, and the median PFS in the six- to seven- month range. So, slightly less remarkable than what we saw in the phase I study, but still confirming the activity of this next-generation ALK inhibitor as being a very active agent in crizotinib-resistant disease.

Gregory J. Riely, MD: Ceritinib has been explored as a single agent in patients who’ve not been previously treated for ALK-positive lung cancer, and those patients who’ve had prior crizotinib for their ALK-positive lung cancer. In those patient populations, ceritinib has shown significant efficacy with response rates of above 50% for patients who have had prior crizotinib, as well as those who have not had prior crizotinib.

Median progression-free survivals are on the order of 7 to 12 months for those patients who have previously received crizotinib and then go on to ceritinib. This is a significant second-line option for patients who have had prior crizotinib. The side effects that we’ve seen so far for patients who are treated with ceritinib are typically GI-related side effects, so some dyspepsia, some nausea, and an occasional patient with diarrhea. These are all quite manageable at the doses that are described, and dose reductions can help significantly for those patients.

In moving ceritinib forward, one of the key things is to do some randomized clinical trials, and there are two big randomized clinical trials that are ongoing. One explores the use of ceritinib as a first-line ALK inhibitor. They’re taking patients who are initially diagnosed with advanced ALK-positive lung cancer and randomizing them to initial ceritinib or treatment with cisplatin or carboplatin along with pemetrexed. These would be considered the standard platinum-based doublets in this setting, and they’re comparing that to ceritinib. I think it’s going to be exciting to look at the results of that and understand how ceritinib’s progression-free, and overall survival compares to those patients who receive conventional chemotherapy as first-line therapy.

In the second-line setting, there’s a similar trial going on. And this second-line trial will take patients who have ALK-positive lung cancer, who have been previously treated with a platinum-based doublet. They’re randomized to either ceritinib or treatment with docetaxel or pemetrexed, depending on the prior therapy they’ve had. This will establish the role of ceritinib as a second-line drug, particularly for patients with ALK-positive non–small cell lung cancer.

Mark A. Socinski, MD: Ceritinib is a second-generation ALK inhibitor. It was initially studied in a combination of crizotinib-pretreated patients, as well as treatment-naïve patients. Its initial emphasis was on crizotinib-pretreated patients because crizotinib was approved for the treatment of ALK-positive patients. So, we needed a second-line choice. In these patients, ceritinib showed response rates in the range of 50% to 65% in previously treated patients, reasonable durability with the progression-free survival times in the eight- to ten-month range—good tolerability.

The primary side effects of ceritinib are namely GI toxicities—nausea, vomiting, and liver function abnormalities. However, with careful attention to dose and dose reductions, and those sorts of strategies—which most oncologists are familiar with—ceritinib is a well-tolerated agent, and is very useful because it was the first, second-generation TKI approved for the use in patients who were progressing on crizotinib, the first-line choice.

Ceritinib does have activity in previously untreated patients. Its activity is a little better if you weren’t priorly exposed to crizotinib. However, in my mind, it’s a very important approval, because it gives you a second option in the ALK population, rather than diverting to standard intravenous chemotherapy options. These patients, who had perhaps been on crizotinib for quite some time, got used to taking a pill every day and dealing with those side effects, which are quite different than IV chemotherapy.

Ceritinib approval gave them an option. Certainly, in my practice, it was a welcomed approval, because we could delay the discussion, and the organization and intrusiveness that intravenous chemotherapy does to a patient and their quality of life. This addition was actually quite important in the management of patients in a busy lung cancer practice.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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