Next-generation selective RET inhibitor shows initial promise with RET-altered solid tumours

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Published: 5 Jun 2023
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Prof Qing Zhou - Guangdong Provincial People’s Hospital, Guangzhou, China

Dr Zhou talks to ecancer at ASCO 2023 about data she presented from a phase 1 study of novel agent KL590586.

It was found to be well-tolerated, and associated with robust clinical activity in RET-altered tumours regardless of tumour type.

This included NSCLC patients with resistance to first-generation selective RET inhibitor and with CNS mets. Further studies are planned.

This morning I presented the other presentation about a highly selective RET inhibitor. This is a novel drug coming from Sichuan Kelun Biotech company; it is a company from China. So, this morning I presented the phase I data about this novel drug and the name of the drug is A400. 

This drug is a next generation selective RET inhibitor. Why we called it next generation is because, from the structure, this drug is highly selective for RET fusion or RET mutation compared to first generation RET inhibitors. For example, this drug will focus on the RET fusion or RET mutation rather than other candidates like VEGFR or JAK 1/JAK2. So this structure will lead to less toxicity. The second point is this drug can overcome resistance to the first generation TKIs because, from both the preclinical and the clinical data, we can see that this drug can cover the resistant mutation. So in our clinical trial we also enrolled some patients who have received a prior selective RET TKI and after enrolling in our clinical trial, after receiving the A400, this novel drug, most of the patients also achieved a partial response. So we can see from these two aspects we can call the novel drug, A400, a next generation, highly selective RET inhibitor. 

What was the study design?

This is a phase I study. This is a typical dose escalation and dose expansion study. In this study, we enrolled both the RET fusion or RET mutation non-small cell lung cancer or medullary thyroid cancer and some other alteration solid tumours. In this phase I trial, we started the dose level from 10mg and increased to 20mg, 40mg, 60mg, 90mg and up to 120mg. We also did the dose expansion in the 60mg and 90mg cohorts. 

So, from this phase I trial we analysed the safety and the efficacy and the PK data. This is the study data. 

What did you find?

In this study, first of all we found the the next generation RET TKI, A400, has quite a different toxicity profile compared with the first generation RET TKIs because, as we know, the first generation RET TKIs have more haematological toxicity or cardiovascular toxicity. But in the next generation RET TKI, in our study we didn't have such high haematological toxicity and cardiovascular toxicity.

In our clinical trial we found that we had the most common toxicities of liver dysfunction, constipation and such as kidney dysfunction, but not such high hypertension or prolonged QTC that's found in the first generation TKIs. This is the toxicity profile and from the efficacy we can see across different tumour types the overall response rate is more than 60% and the disease control rate is more than 90%. This efficacy is very exciting.

If we focus on the RET fusion positive non-small cell lung cancer patients, in the treatment naïve group the overall response rate is more than 80%, a very high response rate, and the disease control rate is also more than 90%. In the pretreated non-small cell lung cancer patients, the overall response is nearly 70% and the disease control rate is also more than 90%. In both groups the efficacy is both very impressive. 

Finally, in in some patients who have received a previous first generation RET TKI, the response rate is very also very high. In seven patients who received first generation TKI, five patients achieved a partial response. 

Also another good result is in patients with brain metastases. In six patients with brain metastasis, five patients achieved a partial response and in three patients the intracranial lesion completely disappeared. So this is very impressive. 

How could this research impact future treatment?

So far in our clinical practice we have the first generation RET TKI approved both in America and in China. But so far we need to have better efficacy and more tolerability and we need next generation TKIs to overcome the resistance to the first RET TKIs. So our result, maybe in the future we can change now the status so far. So far we can see the pivotal study phase II trial and the other expansion cohort in other solid tumours just ongoing both in China and in America and Europe. I think maybe in the future the result of such kinds of clinical trial will change the clinical criteria.