, phase 3 trial data suggest.
The most recent analysis of thetrial shows that, in about 400 patients who underwent surgery and had a high estimated risk of recurrence, there was a 50% increase in overall survival with longer treatment at 10 years on an efficacy analysis.
Moreover, there was a 30% improvement in recurrence-free survival (RFS) with 3 years vs 1 year of imatinib, with an even greater benefit seen in patients with a common tumor mutation.
The research was presented at the 2020 annual meeting of the American Society of Clinical Oncology (), held virtually because of the coronavirus pandemic.
Lead author Peter Reichardt, MD, Helios Klinikum Berlin-Buch, Berlin, Germany, said the results show that “3 years of adjuvant imatinib is highly superior” in terms of RFS and overall survival to 1 year of treatment.
“Overall, approximately 50% of deaths can be avoided during the first 10 years of follow-up after surgery with the longer adjuvant imatinib treatment.”
Study discussant Giovanni Grignani, MD, Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy, said that the “burning question” in the sarcoma space is: “Can we improve overall survival by reducing the risk of relapse with a perioperative treatment?
“We would like to able to identify patients for whom the cost of toxicity is paid off by an improvement in their outcome,” he added, noting that this is not achievable “and this is why perioperative treatment is so controversial in oncology.”
Grignani said the picture is a little different for GIST, as the relapse risk is unevenly distributed, the activity of imatinib is “extraordinary,” and the drug toxicity is “certainly bearable but not negligible.”
RFS is, however, affected by the inability of imatinib to eradicate resistant clones left behind by surgery, and replication resumes once the drug is stopped.
The current study nevertheless shows that overall survival “clearly favors 3-year imatinib therapy…with an impressive median follow-up of 119 months [10 years],” commented Patrick Leavey, MD, University of Texas Southwestern Medical Center, Dallas, in a highlights session.
He added that, in GIST, what might be considered “new progress” with the findings “is clarity over the length of imatinib therapy, which ... seems to be safe.”
Reichardt began by noting that several large randomized trials over the past decade have shown that adjuvant imatinib improves both RFS and overall survival.
However, “it is unknown whether imatinib improves overall survival after extended follow-up,” in addition to which “little is known about the long-term safety” of the drug in this setting.
To offer further insights, the protocol of SSGXVIII/AIO was amended in April 2017 to allow for a third analysis to be carried out once the last patient who entered the trial has been followed up for 10 years.
Reichardt recalled that the study, which was an open-label, multicenter phase 3 trial, involved GIST patients who were randomly assigned following surgery in a 1:1 fashion to imatinib for either 12 months or 36 months.
The patients were required to have a high-risk of recurrence, defined as at least one of the following:
- Tumor size >10 cm
- Tumor mitosis count >10/50 on high-powered microscopy (HPF)
- Tumor size >5 cm and mitosis count >5/50 HPF
- Tumor rupture, either spontaneously or at surgery.
Four hundred patients were recruited between February 2004 and September 2008, and 181 patients who were randomly assigned to 12 months of imatinib and 177 to 36 months were included in the efficacy analysis.
The median age of the patients was approximately 61 years, and half were female. The treatment groups were well-balanced in terms of their baseline characteristics.
Of note, 69% of patients in the 1-year treatment group and 71% of those given imatinib for 3 years had a detectable mutation in the KIT exon 11 site. The mean mitosis count was 10/50 and 8/50, respectively.
Over a median follow-up of 119 months (9 years, 11 months), 53% of 1-year treatment patients experienced a recurrence event, and 30% died, of whom 82% died with metastatic GIST.
In the 3-year treatment group, 44% experienced a recurrence event, and 18% died, with 83% of deaths from metastatic GIST.
On intention-to-treat analysis, RFS at 10 years was significantly higher with 3 years of imatinib than with 1 year, at 53% vs 42% (hazard ratio [HR], 0.66; P = .003).
Overall survival at 10 years was also higher with longer imatinib treatment, at 79% with 3 years of therapy vs 65% with 1 year (HR, 0.55; P = .004).
The team found on subgroup analysis that RFS was significantly better with 3-year than 1-year imatinib in patients with:
- A local mitotic count >10 (HR = 0.42)
- A central mitotic count >10 (HR = 0.50)
- A KIT exon 11 tumor mutation (HR = 0.57).
On the efficacy analysis, which included patients who signed informed consent, had GIST at pathology review, and no overt metastases at study entry, the HR for RFS with 3-year vs 1-year therapy was 0.70, whereas the HR for overall survival was 0.50.
Patients treated with imatinib for 3 years had a higher rate of any new cancer during follow-up, at 17%, vs 12% for those treated with imatinib for 1 year. Prostate cancer was the most common form of the disease in both groups.
Cardiac events were, in contrast, evenly distributed between the two groups, with 5% of 3-year patients and 6% of 1-year patients experiencing an event.
The study was funded by Novartis.
Reichardt reports honoraria from Amgen, Bayer, Lilly, Novartis, Pfizer, and PharmaMar; serving in a consulting or advisory role with Bayer, Clinigen Group, Decipher, Lilly, Novartis, Pfizer, PharmaMar, and Roche; and receiving research funding from Novartis (Inst). Other authors report potential conflicts of interest.
Grignani reports honoraria from Bayer, EISAI, Lilly, Merck Serono, Novartis, Pfizer, and PharmaMar; serving in a consulting or advisory role with Bayer, EISAI, and PharmaMar; receiving research funding from PharmaMar (Inst); and travel, accommodations, expenses from PharmaMar and Tesaro.
Leavey reports receiving research funding from Elison Pharmaceuticals (Inst).
This article first appeared on.