Celebrating the 10th Anniversary
A decade of discoveries in Cancer Discovery. For the community. By the Community.
Authors
Their impactful studies. In their words.
Foundation Medicine
Memorial Sloan Kettering Cancer Center
MD Anderson Cancer Center
Mass General Cancer Center
Blueprint Medicines
Precision Targeted Therapy with BLU-667 for RET-Driven Cancers
July 2018
Q: What unanswered questions in the field were these studies addressing?
A: (Garrett Frampton) METex14 mutations had been previously described, but their prevalence and mutual exclusivity with other well-known lung cancer drivers was not appreciated. Additionally, the sequence diversity of METex14 mutations was poorly described. Finally, the examples of patients with tumors harboring METex14 alterations responding to targeted therapy provided compelling evidence for further study in randomized trials.
A: (Paul K. Paik) While mutations in the intron sequences flanking MET exon 14 had been previously identified in small series more than a decade prior to our publication, and then more recently in The Cancer Genome Atlas’s Lung Adenocarcinoma analysis, very little work had been done either preclinically or clinically to address whether MET tyrosine kinase inhibition could work as a therapy for patients whose lung cancers harbored these MET exon 14 skipping events. We had started prospectively testing all of our patients with non–small cell lung cancer (NSCLC) with MSK-IMPACT, our next-generation sequencing assay, by that point and so were finding these changes in real time, raising the practical question of what we could potentially do for our patients with these aberrations.
This was an important step to get the best therapies to all patients with lung cancer. When I started this investigation, Foundation Medicine categorized these mutations as VUS (variants of unknown significance). Now they are part of standard diagnostic testing for lung cancer, in approximately 8 years. That’s exciting!
A: (Vivek Subbiah, Justin F. Gainor, Erica K. Evans) These studies were designed to investigate the preclinical activity of selective RET inhibition in RET fusion–positive lung cancer (NSCLC) and RET-mutant thyroid cancer. Through a combination of in vitro, in vivo, and patient-level data, these studies provided early proof of concept that activated RET kinase activity was an oncogenic driver in these tumors and that safe, selective inhibition of RET represented a viable therapeutic option for these patients.
Q: What surprised or excited you most about the findings?
A: (Garrett Frampton) I would love to know why METex14 alterations have such strikingly strong patterns of co-occurrence with MDM2 and CDK4 gene amplification. The signal is so strong, and I have no idea what the cause is.
A: (Paul K. Paik) What was most exciting about our findings was the real benefit that patients were having right from the start. This was very much a clinical translational discovery for us, where the roots can be found in our clinical observations. Much of the research that we do can seem esoteric or far removed from our patients, but this publication was quite the opposite of that. There was a real sense that this could be moved forward quite quickly to benefit the broader community. I think conceptually the study was rewarding because it reflected the impact that bedside to bench research can have, which is another way of saying that we can learn a lot from the day-to-day act of taking care of our patients.
I think the paper’s impact was immediate, helping to kick-start a series of trials of selective MET inhibitors to target MET exon 14 skipping–positive NSCLC. It took just five years from the initial publication of the Cancer Discovery manuscript to the first FDA-approved drug for patients with this disease.
A: (Vivek Subbiah, Justin F. Gainor, Erica K. Evans) Tumors often become resistant to targeted therapies through on-target resistance mutations that affect drug binding. In the development of pralsetinib (BLU-667), the agent was optimized for activity against predicted mutations at the gatekeeper position, a position that is commonly mutated after kinase directed therapies. It was exciting to see that pralsetinib was capable of potently inhibiting both wild-type and RET gatekeeper mutations—activity that we hope extends the duration of benefit for patients.
Q: What has been the greatest impact in the years that followed?
A: (Garrett Frampton) This was an important step to get the best therapies to all patients with lung cancer. When I started this investigation, Foundation Medicine categorized these mutations as VUS (variants of unknown significance). Now they are part of standard diagnostic testing for lung cancer, in approximately 8 years. That’s exciting!
A: (Paul K. Paik) I think the paper’s impact was immediate, helping to kick-start a series of trials of selective MET inhibitors to target MET exon 14 skipping–positive NSCLC. It took just five years from the initial publication of the Cancer Discovery manuscript to the first FDA-approved drug for patients with this disease. A second MET inhibitor was approved earlier this year for the same indication. Much work is now ongoing that seeks to understand the resistance mechanisms to these drugs. We’ve circled back to look at antibody-based therapies for patients with MET exon 14 skipping events as well. The impact is, to be certain, a reflection of timing as well. Our publication came out at a time when sponsors were looking for developmental pathways for their MET inhibitors, and in an era when a wealth of prior and ongoing work had gotten us to the point where routine genomic testing was increasingly being done.
This rapid bench-to-bedside translational research is a milestone in precision medicine for RET-positive cancers. Beyond NSCLC and thyroid cancer, pralsetinib has also shown activity across multiple different cancers driven by RET, and drug development continues in these cancers.
A: (Vivek Subbiah, Justin F. Gainor, Erica K. Evans) This manuscript, published online concurrently with our presentation at the 2018 AACR Annual Meeting, represented one of the first preclinical/clinical reports of a highly selective RET inhibitor. These data established critical proof of concept for the successful development of pralsetinib in the registrational ARROW trial. Just two and a half years following publication, pralsetinib received FDA approval for the treatment of advanced or metastatic RET fusion–positive NSCLC, and on December 1, 2020, pralsetinib received FDA approval for the management of advanced or metastatic RET-mutant medullary thyroid cancer and RET fusion–positive thyroid cancer. This rapid bench-to-bedside translational research is a milestone in precision medicine for RET-positive cancers. Beyond NSCLC and thyroid cancer, pralsetinib has also shown activity across multiple different cancers driven by RET, and drug development continues in these cancers.
