ASCO invited comments on the INTRIGUE study from George D. Demetri, MD, FASCO, Professor of Medicine at Harvard Medical School and Director of the Center for Sarcoma and Bone Oncology, Senior Vice President for Experimental Therapeutics, and Quick Family Chair in Medical Oncology at Dana-Farber Cancer Institute, Boston.
George D. Demetri, MD, FASCO
“I view INTRIGUE as an aspirational, well-designed, and expertly conducted clinical trial. Drug development is hard—even when a cancer is as well understood and relatively simplistic as GIST [gastrointestinal stromal tumor]. Showing superiority over an existing approved therapy is challenging in targeted therapy,” he said.
“INTRIGUE failed to show that ripretinib was superior to sunitinib to control metastatic GIST after imatinib failed. The two drugs gave essentially the same control of disease and very similar progression-free survivals, but there were fewer toxicities with ripretinib than with sunitinib—and that’s good! But toxicity was not the primary endpoint of the trial…. Clinical trials aren’t necessarily judged by what’s good for patients; they are very regulated and codified…. So this trial was an ‘intriguing failure,’” Dr. Demetri commented.
Not a Total Failure
“Though technically INTRIGUE was a failed study,” he continued, “it was not a failure to move our field forward. It adds significantly to the evidence base for both these drugs and will allow me to have thoughtful discussions of this trial with my patients.”
It is, in fact, just one of many studies that fail to show the benefit of targeted agents, he said, and for this there are many possible reasons: for example, the emergence of additional resistance mutations, investigators’ overestimation of the drug’s activity, and the inability of single agents to overcome genomic instability and heterogeneity.
In GIST, the development of resistance has dictated a cascade of tyrosine kinase inhibitors that extend remission for less than 6 months and produce responses in only 5% to 9% of patients, he said.
“Patients with metastatic GIST benefit greatly from current tyrosine kinase inhibitors, but we should aim to improve outcomes further,” he commented. Looking forward, he said, other agents will likely be required to make more significant advances in treatment outcomes for GIST: preferably non–cross-resistant, highly selective drugs that can be combined, with optimal pharmacology and long-term tolerability.
DISCLOSURE: Dr. Demetri has served on the board of directors or the scientific advisory boards of Blueprint Medicines; has served as a consultant to G1 Therapeutics, Caris Life Sciences, Erasca, Relay Therapeutics, Bessor Pharma, CellCarta, Ikena Oncology, Kojin Therapeutics, IDRx, Bayer, Pfizer, Novartis, Roche/Genentech, GlaxoSmithKline, Janssen, PharmaMar, Daiichi Sankyo, EMD-Serono/Merck KGaA, Medscape, Mirati, Synlogic, WCG/Arsenal Capital, MJ Hennessy/OncLive, C4 Therapeutics, McCann Health, and Rain Therapeutics.
