Latest data for managing ALK NSCLC patients

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Published: 11 Dec 2020
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Prof Myung-Ju Ahn - Samsung Medical Center, Seoul, South Korea

Prof Myung-Ju Ahn speaks to ecancer at the ESMO Asia Virtual Congress about the latest data for managing ALK NSCLC patients with a focus on Asian populations.

Much of the information regards a few recent large profile studies including J-ALTA and ALTA-1L , revealing the unmet needs, challenges, and treatment selection in first line (1L), 2L or 2L setting.

Prof Ahn then compares updated Asian vs non-Asian population data from the aforementioned studies and latest data from J-ALEX and ALESIA.

She rounds off by discussing the implications that the results from these 4 studies will have on clinical practise.

This programme has been supported by an unrestricted educational grant from Takeda.

 

This programme has been supported by an unrestricted educational grant from Takeda.

J-ALTA is a single-arm phase II study conducted in Japan. There were 72 patients who were treated with alectinib or crizotinib, with or without crizotinib, were treated with brigatinib which is a CNS active second generation ALK inhibitor. The response rate was 30% and the median progression free survival was 7.3 months. The interesting thing is that brigatinib has an anti-tumour activity even in patients refractory to TKI who have the G1202R or I1171N, V1180L, L1196M mutations. So, even though it’s a small phase II study, this study demonstrated the anti-tumour activity of the brigatinib in patients who are refractory to first and second generation ALK inhibitors. So it’s quite a promising result.

The ALTA-1L study is a randomised phase III study comparing brigatinib with crizotinib. The second interim analysis was presented at ESMO Asia. In brigatinib this study is quite unique because around 30% of patients already received chemotherapy so it reflects more the real world than clinical practice. The progression free survival was significantly improved with brigatinib compared to crizotinib; the hazard ratio was 0.3. The progression free survival for brigatinib was 24 months versus 11 months for crizotinib, which is quite a significant improvement of progression free survival.
Also, the ALTA-1L study is a little different from other studies in that only the independent response evaluation was the primary endpoint. So this study demonstrated that brigatinib significantly improved the progression free survival related to the standard of care for the first line treatment in ALK positive non-small cell lung cancer.

What are the unmet needs, challenges and treatment selection in first line (1L), 2L or 2L setting when treating ALK NSCLC?

Actually the first challenge for the treatment of ALK positive non-small cell lung cancer is that 30% of patients actually at diagnosis have CNS metastasis and around 70-75% of patients develop CNS metastasis. So when you chose the ALK inhibitor in the first line or second line setting you should choose the ALK inhibitor penetrating the brain, that’s the most important part. The second one is that we learned from crizotinib that most of the patients develop progression because of acquired resistance. So when you choose the first line or second line you choose the drug that overcomes those secondary mutations. That’s another unmet medical need.

Could you compare the updated Asian vs non-Asian population data from the main trials coming out of ESMO ASIA 2020?
This year at ESMO ASIA the ALTA-1L comparing the Asian versus non-Asian data was published. Overall there is no difference in terms of progression free survival and overall response rate between the Asians and the non-Asians, such as the progression free survival for brigatinib in Asians was 24 months versus 24 months for the non-Asians. Also the response rate was 75% for Asians versus 68% for non-Asians, suggesting that it’s quite comparable between Asians and non-Asians.

Also in the ALESIA study which was conducted only in Asia comparing alectinib versus crizotinib, this study the median progression free survival has not been reached for alectinib versus only 11 months for the crizotinib, suggesting that this alectinib as a second generation ALK TKI is quite effective in Asian patients.

I should mention the J-ALEX. J-ALEX is the randomised phase III study conducted in a Japanese patient population. Patients were randomised to either alectinib versus crizotinib and then the patients were treated. With alectinib the dose was 300mg which is different from the global trial, the 600mg b.i.d. of alectinib. J-ALEX also showed that the progression free survival was significantly improved compared to crizotinib. The PFS has not been reached versus 10.2 months for the crizotinib. Although it’s not compared with non-Asians but altogether brigatinib and alectinib are quite effective in Asian patients, since there is no comparison between the Asians and non-Asians.

What were the key results from the J-ALEX and ALESIA studies?

The J-ALEX is the Japanese-only randomised phase III study conducted in only a Japanese patient population. The different thing is that the drug dose is 300mg rather than 600mg which was used in the global trial. With J-ALEX and ALESIA both studies showed consistent results that alectinib, a second generation ALK inhibitor, is quite effective compared to crizotinib in the treatment of ALK positive non-small cell lung cancer as a first line.

What is the impact of these results on the future treatment of NSCLC?

So far the second generation ALK inhibitors have been approved, such as ceritinib and alectinib and brigatinib. Those three agents have a longer progression free survival compared to chemotherapy or to crizotinib. So these second generation ALK inhibitors are positioned as a first line treatment in ALK positive non-small cell lung cancer because these drugs can penetrate the brain and give a good overall response rate and they cover many different kinds of ALK mutations which are resistant to crizotinib. However, unfortunately, most of the patients actually develop progression after 24 or 30 months so still there is an unmet medical need to overcome those resistant ALK positive patients.

Recently lorlatinib in a randomised phase III study comparing lorlatinib versus crizotinib, by the name of the CROWN study, it also showed significant improvement in progression free survival. However, given the long-term overall survival in ALK positive patients with second line therapy, in the future we should define what kind of sequence of treatment actually improves the treatment of non-small cell lung cancer with ALK positive patients to overcome resistance and to prolong the overall survival.