First-in-human trial results of RET targeted BLU-667

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Published: 25 Apr 2018
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Prof Vivek Subbiah - MD Anderson Cancer Center, Houston, USA

Dr Subbiah speaks with ecancer at AACR 2018 about results from a first-in-human clinical trial of RET targeted therapy.

RET alterations occur in tumours of many origins, and is currently treated with non-selective multi kinase inhibitors.

Among 43 patients with advanced solid tumours, BLU-667 elicited response rates of between 30-45%, depending on disease type.

The results are published in Cancer Discovery, and you can watch Dr Subbiah present the results in a press session here.

RET is a well-established oncogene that is seen less than 1% across all tumour types. It is seen 1-2% in lung cancer patients, 50% of a form of thyroid cancer called medullary thyroid cancer and 100% of another form of medullary thyroid cancer called hereditary thyroid cancer and 10-20% of another cancer called papillary thyroid cancer. So far, as you know, precision oncology has benefitted patients with EGFR, ALK and ROS1 aberration but precision oncology approaches have not benefitted patients with the RET gene aberration. We did not have a highly potent selective RET drug. So this drug, BLU-667, is a designer drug that selectively targets the RET pathway alteration, the RET genes.

What did you find from the trial?

This is the initial results of ARROW, the first-in-human phase I study of BLU-667, the potent RET inhibitor across RET altered cancers. Initial data in the dose escalation of the study showed broad and robust clinical activity in patients with multiple RET alterations. So this drug has broad activity regardless of the tumour type, regardless of the type of RET alteration, regardless of prior therapies that include chemotherapy, immunotherapy and multi-kinase inhibitor therapy and also regardless of the number of prior therapies. 84% of all evaluable patients had some form of radiographic regression. The overall response rate in RET fusion positive non-small cell lung cancer is 50%; the overall response rate in medullary thyroid cancer RET altered patients is 40% and across the board in RET altered cancers the response rate is 45%. This is highly encouraging for a phase I study.

Can you comment on any toxicities?

Absolutely. For a phase I study it’s mainly safety and toxicity. The good news is that we did not see any grade 4 or grade 5 toxicities with this drug. Most of the toxicities were grade 1 and definitely tolerable. The adverse events were 16% across the study which is very reasonable for a phase I study.

What can we see over the next few years?

As of today we completed the phase I dose escalation study so now we have the safety and toxicity of this compound and we have a dose. The dose is 400mg orally every day. As you know, in cancer patients once a day dosing is easier than two or three times dosing. The global expansion phase II portion of the study is open and enrolling globally.

Does this study highlight the importance of molecular profiling?

Absolutely. This is a great question. In our war against cancer we need to divide and conquer and RET, with this study, has become one of the targetable alterations. So even if it’s 1-2% of non-small cell lung cancer these patients have fantastic responses from this drug. So we hope that patients get molecularly profiled, not for just this therapy but for any targeted therapy so that they can be enrolled in clinical trials that offer targeted therapies.

Is there anything you’d like to add?

The results so far have been highly encouraging for a phase I clinical triallist and a drug developer and we hope to continue to see this activity in the expansion portion of the study.