ASCO 2020-3 YEARS OF IMATINIB FOR HIGH RISK GIST

Approximately half of deaths can be avoided with the use of 3 years of adjuvant imatinib in the first decade after surgery for high-risk gastrointestinal stromal tumors (GIST), according to long-term data from the Scandinavian Sarcoma Group XVIII/German trial (Abstract 11503).

“Three years of adjuvant imatinib is highly superior in efficacy with respect to recurrence-free survival (RFS) and, most importantly, overall survival (OS) as compared to 1 year of imatinib,” said Peter Reichardt, MD, of Helios Klinikum Berlin-Buch, Sarcoma Center Berlin-Brandenburg, Germany, who presented 10-year follow-up data as part of the ASCO20 Virtual Scientific Program.

“Three years of adjuvant imatinib is highly superior in efficacy with respect to recurrence-free survival and, most importantly, overall survival as compared to 1 year of imatinib.” - Dr. Peter Reichardt

The trial randomly assigned 400 patients with operable GIST and high risk for recurrence to receive 400 mg imatinib daily for either 12 months or 36 months after surgery. High risk for recurrence was defined according to modified National Institutes of Health Consensus Criteria as:

• Tumor size > 10 cm, or
• Tumor mitosis count > 10/50 high-power field of the microscope (HPFs), or
• Tumor size > 5 cm and mitosis count > 5/50 HPFs, or
• Tumor rupture spontaneously or at surgery.

The primary endpoint of the study was RFS. To date, the trial has found that 3 years of adjuvant imatinib improved OS compared with 1 year of imatinib at 54 and 90 months follow-up.

Dr. Giovanni Grignani

At 119 months follow-up, RFS and OS remained significantly better in patients assigned to 3 years of imatinib compared with 1 year of imatinib, Dr. Reichardt said. The 10-year RFS in the intention-to-treat population was 53% for 3 years of imatinib compared with 42% for 1 year of imatinib (HR 0.66, 95% CI [0.49, 0.87]; p = 0.003).

The 10-year OS in the intention-to-treat population was 79% for 3 years of imatinib compared with 65% in the 1-year group (HR 0.55, 95% CI [0.37, 0.83]; p = 0.004; Figure 1).

Figure 1. OS in the Intention-to-Treat PopulationView larger

The researchers also conducted several subgroup analyses.

“Most importantly, favoring the 3-year group were patients with local mitotic count more than 10, central mitotic count of more than 10, and KIT exon 11 mutation,” Dr. Reichardt said.

Outcomes were also analyzed in an efficacy population of patients who signed informed consent, had GIST at independent pathology review, and had no overt metastases at study entry. Among this group, patients assigned to 3 years of imatinib had significantly improved 10-year RFS (HR 0.70, 95% CI [0.52, 0.94]; p = 0.02) and OS (HR 0.50, 95% [0.32, 0.80]; p = 0.003) compared with 1 year of imatinib (Figure 2).

Figure 2. RFS and OS in the Efficacy Population**Patients who signed informed consent, had GIST at pathology review, and had no overt metastases at study entry.

Abbreviations: OS, overall survival; RFS, recurrance-free survival; GIST, gastrointestinal stromal tumors. View larger

There were some secondary cancers in both arms of the study, with prostate cancer being the most frequent. Cardiac events occurred in approximately 6% of patients.

In his discussion of the data, Giovanni Grignani, MD, of Candiolo Cancer Institute, Italy, said that the key point of this trial was the selection of a group of patients at high enough risk that imatinib activity could induce a reduction of 50% in the risk of death at 10 years.

“These outstanding results raise two questions,” Dr. Grignani said.

First, why was the OS curve more attractive than RFS? The OS plot is more attractive because the tails of the two curves are almost touching in the RFS curve.

“Previous studies may help to explain plot of recurrence-free survival,” he said. “Indeed imatinib cannot eradicate resistant clones left behind by surgeons, and imatinib induces a quiescent state that will end as we stop the drug with replication that will resume.”

In contrast, the tails of the OS curve opened up.

“This could be explained by positive interaction of imatinib with innate immunity, and inhibition of IDO leading to T-cell activation,” Dr. Grignani said.

The last question left open by this trial is whether oncologists treat only certain high-risk patients or whether oncologists can include other patients who have similar risk.

“My personal opinion is, ‘yes,’” he said, patients who have similar risk can be included as well.

— Leah Lawrence