ESMO 2016

Ceritinib following crizotinib relapse for ALK positive NSCLC

Dr Giorgio Scagliotti - University of Turin, Turin, Italy

Today, later today, I will present the final results of a phase III confirmatory study that was assessing the role of ceritinib that is a second generation ALK inhibitor against cytotoxic chemotherapy in patients who were already treated with crizotinib that, as you know, is a first generation ALK inhibitor and also exposed to chemotherapy. So in principle we are talking about third line chemotherapy at minimum.

The study was an international study and, just as a sort of background information for every one of you, you are pretty familiar about the fact that before the development of targeted therapy chemotherapy was the only treatment available for patients with advanced disease. You know also that crizotinib is an ALK inhibitor that became available in 2009 so this is telling you how fast we are moving forward in the field of targeted therapies. Crizotinib is effective in the ALK positive patients as assessed originally using FISH testing. But unfortunately most of the patients develop resistance in progressive disease and ceritinib is among a series of new drugs that we used to call second generation ALK inhibitors that usually are more potent than crizotinib and they are more effective on some metastatic sites, for instance against brain metastasis.

As background information, in the phase I study ceritinib demonstrated a quite robust anti-tumour activity in ALK positive non-small cell lung cancer including both ALK naïve, in terms of treatment, and ALK pre-treated patients who progressed under multiple lines of chemotherapy. Today in another presentation you will see the efficacy of ALK in patients who were not pre- exposed to ALK inhibitors but they were exposed to multiple lines of chemotherapy. In a formal phase II study crizotinib showed durable responses again in the same setting of patients who progressed under chemotherapy and crizotinib, including patients with brain metastases.

Now today I will present the results of this study. The study was done in a pretty short period of time, between July 2013 and November 2015. Just for your information, the overall population with an ALK positive tumour is something between 4-6% of the overall patient population with non-small cell lung cancer. The study was conducted in 99 sites including 20 countries and we were including patients with locally advanced or metastatic ALK positive non-small cell lung cancer as assessed by FISH in local laboratories or in a central laboratory where the FISH diagnostic test was not available at the investigation site. All the patients were in PD at the time of the enrolment, they were spanning from PS0 to PS2, all pre-treated with crizotinib. They received at least one line of systemic chemotherapy or more than one line and they had measurable disease advance line. Patients were randomised one to one to the experimental arm or to the systemic therapy that were represented for the vast majority of the patients in the control arm by docetaxel and for the remaining by pemetrexed at the standard recommended dose. The patients were stratified according to the performance status, this is something that is commonly done in the presence of absence of brain metastases.

I truly believe that this morning you woke up early not to see me but to see this data that will come up in this slide. The primary endpoint, as I said before, was progression free survival as assessed by a blind and independent radiological committee. The benefit is quite striking because the median progression free survival for ceritinib was 5.4 versus 1.6 and the hazard ratio is 0.49. That means that you are cutting in half the hazard ratio and you should also be aware that the study statistics were targeting a hazard ratio of 0.6 so we are below the boundary. The p-value, if you like the p-value, is 0.001.

When you are going down into the study you are looking to the , you are looking to the univariate analysis so you are looking at each individual fact that you were considering. You see that in the vast majority of the cases, or let me say in all the cases, the benefit was clearly in favour of ceritinib and in only one case the 95 confidence intervals were crossing the unit. So in the vast majority, almost universally I would say, there was a benefit in favour of crizotinib.

You can ask me something about the toxicity because, based on your a priori information, you can make questions about the toxicity. The toxicity was exactly what has been seen in previous studies, including the phase I and the phase II studies, having more GI toxicities with ceritinib, including also liver toxicities, that they were mainly paper toxicities. While in the control arms having the vast majority of the patients treated with docetaxel the main toxicity was dermatological toxicity.

So, in conclusion, I would say that this phase III study in patients with ALK positive non-small cell lung cancer previously treated, so we are talking about a later line of therapy, previously treated with one or two prior chemotherapy regimens and crizotinib met the primary endpoint. The message is that ceritinib demonstrated a statistically significant and clinically meaningful improvement in progression free survival compared to chemotherapy. The improvement in PFS is robust, demonstrating consistency across a number of subgroups; I showed you the slide for your information. The clinical benefit was further supported by overall response rate and disease control rate.

So the overall survival data are still immature because we have only 50% of events but you need to be aware that in the control arm the crossover to crizotinib was permitted at the time of clinical progression or radiological progression. 75% of the patients were crossed over to crizotinib. So the current data and the current hazard ratio for overall survival is around the unit but this is something that we saw already, for instance in the vast majority, almost in all the studies with the EGFR TKIs. Because if you have a pretty effective agent when you are crossing the control arm to the experimental arm you don’t see any change or any difference in survival. That is the proof, the evidence, that you are changing the natural history of the disease.

The safety profile with ceritinib was consistent with prior studies with measurable adverse events and no new ceritinib related serious adverse events reported. It’s not part of this presentation because this issue will be addressed and this part of the study will be presented at ESMO  later this year but there was also improvement in the lung cancer specific symptoms and the overall health status, compared to chemotherapy it was improved.

Finally, ceritinib demonstrated superior efficacy compared to standard second line therapy in crizotinib resistant ALK positive patients establishing crizotinib as a preferred treatment option in this patient population. Thank you so much.