Adjuvant imatinib beneficial for high-risk gastrointestinal stromal tumors

Issue: October 25, 2017

MADRID — Adjuvant treatment with imatinib improved outcomes among patients with high-risk gastrointestinal stromal tumors, according to final results of a randomized phase 3 trial presented at the European Society for Medical Oncology Congress.

Perspective from Sebastian Bauer, MD

At 10 years, results showed improved imatinib failure-free survival, OS and RFS with imatinib compared with no adjuvant therapy.

Paolo G. Casali, MD, medical oncologist and head of the adult mesenchymal tumor unit at National Cancer Institute in Milan, Italy, and colleagues began their open-label, multicenter study in 2004.

The analysis — conducted at 112 hospitals in 12 countries — included 908 patients who underwent R0-R1 surgery for localized, intermediate-risk or high-risk gastrointestinal stromal tumors.

Casali and colleagues randomly assigned 454 patients to 2 years of adjuvant therapy with the tyrosine kinase inhibitor imatinib, administered in 400-mg daily doses. The other 454 patients received no further therapy.

Imatinib failure-free survival served as the primary endpoint. Secondary endpoints included RFS, relapse-free interval, OS and toxicity.

Results of interim analyses were published in 2015.

At ESMO, Casali reported final outcomes data, based on median follow-up of 9.1 years.

Overall, researchers reported 5-year imatinib failure-free survival rates of 87% in the imatinib group and 83% in the control group (HR = 0.87; 95.7% CI, 0.65-1.15). Investigators projected 10-year rates at 75% in the imatinib group and 74% in the control group.

Imatinib-treated patients achieved higher rates of RFS at 5 years (70% vs. 63%) and 10 years (63% vs. 61%; HR =0.71; 95% CI, 0.57-0.89), as well as higher rates of OS at 5 years (93% vs. 92%) and 10 years (80% vs. 78%; HR =0.88; 95% CI, 0.65-1.21).

An analysis of the 526 patients with high-risk gastrointestinal stromal tumors as determined by local pathology showed higher rates of imatinib failure-free survival (69% vs. 61%) and RFS (48% vs. 43%) for imatinib-treated patients. Although these differences did not reach statistical significance, the trends were consistent with results of a previous trial that showed a sustained small but statistically significant long-term OS benefit for patients with high-risk gastrointestinal stromal tumors treated with 3 years adjuvant imatinib.

On the contrary, results of this study should discourage the use of imatinib for patients with low-risk gastrointestinal stromal tumors, Casali said.

In addition, initial TKI failure-free survival is a tentative surrogate endpoint that may be worth exploring as part of molecularly targeted therapy of solid cancers.

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“Of course, it would be best if we had overall survival as an endpoint,” Casali said. “But, as long as this is an aggressive disease, we need to use surrogate endpoints, and imatinib has been proven to extend survival.” – by Chuck Gormley

Reference:

Casali PG, et al. Abstract LBA55. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Disclosures: Novartis funded this study. Casali reports research funding from Amgen, Bayer, Eli Lilly, Daiichi Sankyo, Epizyme, Novartis and PharmaMar; advisory roles with Bayer, Blueprint, Eisai, Eli Lilly, Merck Sharpe & Dohme, Merck Serono, Nektar Therapeutics, Novartis, Pfizer and PharmaMar; and honoraria from Bayer, Novartis, Pfizer and PharmaMar. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Sebastian Bauer, MD

In the ideal setting with adjuvant therapy, people would receive it and be cured. With high-risk gastrointestinal stromal tumors, we reduce the cancer to tiny little cells, and then they go into stop mode. However, when you stop treatment, the tumors start growing again. During treatment with imatinib, you rarely have relapses, but once you stop treatment, you can have them.
What lessons have we learned? There is a trend toward better survival for patients with high-risk gastrointestinal stromal tumors, but imatinib is not recommended for patients with intermediate-risk disease. Patients can become tired of receiving this treatment, as we’ve seen in the PERSIST-5 trial, where 34% of patients discontinued treatment after 3 years and 49% discontinued use after 5 years. The truth is, a vast majority of patients remain imatinib-sensitive after relapse, so the challenge is actually eradicating disease.
Where do we go from here? Maybe prolonged treatment will improve senescence, but we don't konw. Maybe we have to think about other concepts, such as lifelong treatment with imatinib. Maybe we’ll have better molecular and pathological tools to select patients at highest risk. Maybe we can introduce better drugs to increase the cell kill. And maybe we can increase tolerability by using lower doses or shorter treatments in the adjuvant setting.
It’s good news that we finally have a drug developed specifically for high-risk gastrointestinal stromal tumors and we’re closing in on extending survival. Hopefully, we can find drugs that are more potent and potentially less toxic than what we have at the moment. And we still have to figure out agents for those patients who do not respond to imatinib.

Sebastian Bauer, MD

Medical oncologist

West German Cancer Center

Essen University Hospital

Disclosures: Bauer reports no relevant financial disclosures.