1. Goodwin, Peter M.

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MUNICH- More than 4 years median overall survival (OS) was reported in patients treated with an inhibitor of anaplastic lymphoma kinase (ALK) for their ALK gene rearranged non-small cell lung cancer (NSCLC) in a single-arm phase II study reported at the ESMO 2018 Congress.

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"The information presented here showed that, for patients included in the ASCEND-3 trial-ALK-positive patients previously treated with chemotherapy who received ceritinib as their first ALK inhibitor-there [was] an overall survival of 51 months. This is really encouraging," said lead author Enriqueta Felip, MD, PhD, medical oncologist and Head of the Thoracic Tumors Group at Vall d'Hebron University Hospital in Barcelona.


"Previous information [on OS in these patients was] from the PROFILE trial-the study comparing head-to-head crizotinib versus platinum-pemetrexed. And now this is the second information with long-term survival that we have for patients with ALK-positive tumors. And we have shown overall survival of more than 4 years. I think this is important," Felip noted.

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Study Protocol

A daily fasting dose of 750 mg of ceritinib was tested without randomization in a cohort of 124 patients whose tumors tested positive for the ALK gene rearrangement and had already received chemotherapy for their locally advanced or metastatic ALK-rearranged NSCLC.


Patients recruited had to be naive to ALK inhibitor therapy but could have previously received as many as three prior lines of chemotherapy. More than half of the ASCEND-3 cohort had at least two prior antineoplastic regimens.


Interim analysis had previously reported that two-thirds of the patients responded to ceritinib-consistent with response rates of other ALK inhibitors. And responses were regardless of whether or not patients had brain metastases. In the final analysis, the investigators described the median OS of 51.3 months and also the progression-free survival and the duration of response as "prolonged and clinically relevant" in these "heavily pre-treated" patients.


The safety profile was described as consistent with previous analyses of ceritinib regimens in other clinical settings and as having the known safety profile of ceritinib. Adverse events were "manageable" by means of dose reductions or interruptions. And the researchers did not find any new "safety signals."


Quality of life was generally maintained during ceritinib treatment and the investigators concluded the results further supported the positive benefit-risk profile of ceritinib in ALK inhibitor-naive patients who had ALK gene-rearranged NSCLC.


Treatment Options

"The situation in ALK-positive patients is that in first line we have a number of options," Felip noted. Following the approval of crizotinib [after study comparison with chemotherapy], ceritinib had been approved-also by being compared with chemotherapy. Alectinib and brigatinib had longer progression-free survivals compared to crizotinib," she said. "So in the majority of guidelines, these four options are considered as first line: crizotinib, ceritinib, brigatinib, and alectinib.


"What we have presented here is important information-the updated overall survival with longer follow-up."


When she was asked what the distinguishing feature of ceritinib was in terms of ALK inhibition, she described it as a "second-generation" ALK inhibitor [that had been] known to be an active agent because it had been compared to platinum-pemetrexed chemotherapy in the past showing longer progression-free survival.


Felip acknowledged there were outstanding issues such as toxicity. "So we have presented information here that the toxicity in the clinical trial is mainly GI toxicity and liver toxicity," she said. Dose reductions were permitted in ASCEND-3 to manage toxicity and she said she was interested in the analysis from other investigators (also presenting at ESMO) that found equal efficacy from ceritinib taken at a daily dose of 450 mg with a low-fat meal.


When she was asked to compare the final analysis of ASCEND-3 with historical data from other ALK inhibitors, she emphasized the importance of targeting the ALK rearrangement rather than the specific choice of inhibitor.


"All the ALK inhibitors that we now approve in first line have 60 or 70 percent response rates," she said. "We expect that in patients with ALK-positive tumors treated with an ALK inhibitor. With this information, we cannot say one is better than another. We have a number of possibilities in the first-line setting of patients with ALK-positive tumors."


And in the case of ceritinib, she was persuaded that a dose reduction was likely to be justified. "The results presented here are convincing me to give patients 450 mg or-if it's not possible from a regulatory point of view-to start with 750 mg but reduce the dose according to the toxicity without any problems," Felip explained.


The message for busy oncologists was that testing for ALK variations in patients with NSCLC was important. "There are 4 percent of patients with these molecular alterations and we must treat these patients with an ALK inhibitor because we have shown very good overall survival outcomes," Felip noted.


She said there were not clear rules for deciding which ALK inhibitor was the best to use. "We know that brigatinib and alectinib show longer progression-free survival when compared to crizotinib, and we have to consider the presence of CNS metastases and-probably-the toxicity."


And she explained that clinicians are not in a position to recommend a particular agent for a specific patient. "The important [thing] is to diagnose these patients and to treat them with an ALK inhibitor. We have active agents-not only first line but also in second line. And we are [now] in the situation that we [can] obtain more than 4 years overall survival."


Peter M. Goodwin is a contributing writer.