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1yr
Clinical evidence for RET inhibition in GI malignancies

Gastrointestinal (GI) malignancies such as pancreatic and colorectal cancers (CRCs) are difficult to treat, some of which have poor response to standard of care. Emergence of next-generation sequencing has given patients the opportunity to receive targeted therapy if an actionable oncogenic driver is identified.

One such driver is RET fusion, in which the tyrosine kinase domain of RET fuses with upstream gene fragments, leading to constitutive activation and oncogenesis. RET fusions can occur in non–small-cell lung and thyroid cancers as well as GI malignancies.

Subgroup analysis of a phase 1/2 trial demonstrated durable efficacy of selpercatinib (NCT03157128), a highly selective ret proto-oncogene (RET) kinase inhibitor, in patients with locally advanced or metastatic RET fusion-positive GI tumors. Objective response rates were 53.8% and 30.8% in 13 study patients each (n=26) with pancreatic cancer and CRC, respectively. Median durations of response were 52.1 and 13.3 months for pancreatic cancer and CRC, respectively. Based on its efficacy across multiple histologies, selpercatinib received tissue-agnostic approval for treatment of adults with locally advanced or metastatic RET fusion-positive solid tumors.

In a phase 1/2 trial of pralsetinib (NCT03037385), a highly selective RET kinase inhibitor, all 4 patients with RET fusion-positive pancreatic cancer responded to treatment. Currently, pralsetinib is only approved for non–small-cell lung and thyroid cancers with RET alterations.

Do you order next-generation sequencing for patients with locally advanced or metastatic GI tumors? If a RET fusion is identified, would you consider a highly selective RET kinase inhibitor?

  • 1yr
    I order it in all metastatic patients. I prefer RET testing as part of NGS.
  • 2yr
    Yes, all my patients with advanced cancer have NGS done by both tissue and blood based testing at the time of diagnosis. In absence of other standard treatment options, I would definitely consider using RET directed therapy in second line for such tumors.
  • 2yr
    I order NGS testing in all my stageIv GI cancers. If a RET fusion was found, I would certainly consider its use although likely not use in the front use in second or third line.
  • 2yr
    I do order NGS for all my patients with advanced GI cancers looking for any actionable target. If a RET fusion was found, I would certainly consider its use although likely not in the front line.
  • 2yr
    I ordered the tissue NGS from Tempus as it does both DNA and RNA panels, which is excellent for picking up fusion protein. IF I get RET fusion, I will definitely use Selercatinib as it does have a very high response rate.
  • 2yr
    Yes, I would order NGS testing for all newly diagnosed advanced/metastatic GI cancers. This allows for identification of mutations for targeted therapy which is ofter more efficacious and better tolerated than cemotherapy. For patient's with GI cancer and RET-fusion positive, I would definitely consider RET kinase inhibitors after progression on standard chemotherapy given high response rate and duration of response. I have had positive experiences prescribing RET inhibitors in metastatic lung cancer patients that were positive for RET fusion.
  • 2yr
    I do order NGS testing for my advanced GI cancers. Thankfully most insurances cover the test. I have yet to identify a RET postive GI patient however. If there is an FDA approved drug and endorsed by NCCN, I would use it. I typically order tissue based NGS first and then liquid biopsy if it's QNS
  • 2yr
    I feel NexGen is SOC and targeted treatments are the way to go
  • 2yr
    Agree with NGS testing for all solid tumors. If you don't test you don't know. While some of these molecular alterations are rare they can make a big difference in the treatment and patient outcomes
  • 2yr
    Yes, I order NGS on all my CRC and pancreatic cancer patients. I would absolutely use a RET inhibitor if appropriate.
  • 2yr
    test all my pts with ngs ,havent seen RET mutation in crc or pancreatic cancer
  • 2yr
    I do order. NGS testing on tissue and blood at same time. I haven’t come across any RET mutations in colon cancer yet Is extremely rare. However, given the tumor agnostic indication, I’m encouraged to use this as soon as I find one.
  • 2yr
    I do order a ngs test on my metastatic colorectal patients. If a ret mutation is found then ret inhibitors are used.
  • 2yr
    I order liquid and tissue NGS simultaneously to increase chance of identifying an actionabl e mutation. If RET found, data strongly supports RET inhibitor as first line therapy.
  • 2yr
    I order NGS testing for all my solid tumors. If a ret mutation was found, would use ret directed TKI in front line setting
  • 2yr
    do order NGS both tissue and liquid, broad NGS testing. Waiting to get RET fusion come up but if so then will look up NCCN guidelines and pick the latest RET based therapy and
  • 2yr
    I certainly would order NGS, as I already do looking for resistance mutations, etc. The presence of RET on testing would lead me to strongly consider a RET inhibitor barring any contraindications for the patient based on their comorbidities
  • 2yr
    Yes, Ordering NGS on all my advanced GI cancers is a must in my opinion. If a RET Fusion was found I would absolutely use the RET inhibitor for it
  • 2yr
    I order NGS for all advanced GI cancers and if REt fusion is found, would offer RET targeted therapy
  • 2yr
    definitely order tissue NGS (or liquid NGS if tissue not available) upfront for all advanced GI malignancies as part of our standard protocol. Definitely would offer RET inhibitors for eligible patients due to high response rates and DOR.
  • 2yr
    I typically order NGS panel on most advanced cancers at this time as it could factor into decision making regarding first-line and subsequent lines of therapy. If a driver mutation is identified, I will discuss targeted therapy with patient's either per label if there is FDA approval or on a clinical study.
  • 2yr
    Yes - I get NGS testing on all my stage IV patients including GI malignancies. I would certainly look to use a RET inihibitor in patients with a RET fusion whom there is no standard of care for.
  • 2yr
    I order NGS on all advanced or metastatic GI cancer and if RET fusion is identified I will consider RET kinase inhibitors after I run out of standard treatment options.
  • 2yr
    I use NGS routinely now. If the tumor is RET positive, then I would use targeted RET therapy.
  • 2yr
    yes all advnced pts undergo NGS testing and with fda approval across different malignancies ,will use ret inhibitors
  • 2yr
    I do order NGS for my patients with advanced GI cancers. I would consider a RET inhibitor if a RET fusion was discovered. Determination of the fusion partner and co-occurring genomic alterations is important in the decision making.

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