In patients with RAS/BRAF wild-type metastatic colorectal cancer, FOLFIRI (fluorouracil, leucovorin, irinotecan) plus panitumumab can be given intermittently rather than continuously, without compromising outcomes, according to the results of the IMPROVE study presented at the 2022 ASCO Annual Meeting.1 IMPROVE compared the intermittent strategy with the standard approach of continuous treatment.
“The intermittent strategy seems to be particularly promising in left-sided disease, where median progression-free survival was 20.2 months.”— Antonio Avallone, MD
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“The primary endpoint of the study was met, with a median progression-free survival on treament of 17.1 months. At 1 year, 34 [of 68] patients were alive and without progressive disease. The intermittent strategy seems to be particularly promising in left-sided disease, where median progression-free survival on treatment was 20.2 months,” said Antonio Avallone, MD, of the Istituto Nazionale Tumori Fondazione G. Pascale in Naples, Italy. The intermittent strategy also yielded lower rates of severe skin-related toxicity and fewer treatment discontinuations for adverse events; the study found.
The use of panitumumab in this regimen is supported by the PARADIGM study, reported at the 2022 ASCO Plenary Session, which showed an overall survival benefit vs bevacizumab (hazard ratio [HR] = 0.82; P = .031) in patients with left-sided tumors.2
“We believe the results take on relevant value in the COVID-19 pandemic era.”— Antonio Avallone, MD
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As Dr. Avallone pointed out, continuous treatment with a drug targeting the epidermal growth factor receptor (EGFR) plus FOLFIRI is a first-line standard of care in this population. But the efficacy of continuous treatment is limited by the emergence of resistance and treatment-related toxicity, especially skin rash. IMPROVE tested whether intermittent administration of the regimen could reduce both toxicity and resistance.
About IMPROVE
IMPROVE was a prospective, randomized, noncomparative, open-label, multicenter phase II study conducted across Italy. It randomly assigned 137 patients with unresectable, previously untreated RAS/BRAF wild-type metastatic colorectal cancer to a control arm receiving FOLFIRI plus panitumumab continuously until disease progression/unacceptable toxicity or to the intermittent experimental arm. The intermittent arm received eight cycles of the same regimen followed by a treatment-free interval that extended until progressive disease, when another treatment period of up to eight cycles was restarted—continued until disease progression occurred on treatment.
The primary endpoint was progression-free survival on treatment at 1 year. No formal comparison between the two arms was planned.
Outcomes Better With Intermittent Strategy
At a median follow-up of 20 months, median progression-free survival on treatment was 13.2 months in the continuous arm and 17.1 months in the intermittent arm. These rates at 1 year were 52.1% and 60.8%, respectively, Dr. Avallone reported, noting, “The curves clearly started separating at about 10 months.”
Tumor sidedness was important in the outcomes. In left-sided tumors, the benefit of intermittent therapy was even more striking, with median progression-free survival reaching 20.2 months with intermittent FOLFIRI/panitumumab vs 13.2 months with continuous treatment “and the curves separating at about 6 months,” he said. At 12 months, 64.4% and 52.9%, respectively, remained progression-free.
For right-sided tumors, on the other hand, the continuous strategy was numerically better, with median progression-free survival on treatment of 10.7 months vs 7.9 months with intermittent FOLFIRI and panitumumab. At 12 months, for patients with right-sided tumors, 48.6% of the continuous arm and 40.0% of the intermittent arm were progression-free.
KEY POINTS
- The IMPROVE study evaluated intermittent treatment vs continuous therapy in patients with RAS/BRAF wild-type metastatic colorectal cancer.
- Patients received FOLFIRI plus panitumumab for eight cycles, followed by a treatment-free interval and reintroduction of treatment upon disease progression, or continuous therapy, the standard of care.
- Intermittent therapy resulted in longer progression-free survival on treament at 1 year: 60.8% vs 52.1%; median progression-free survival on treatment was 17.1 vs 13.2 months, respectively. Benefits were even greater in left-sided tumors.
- Skin-related toxicity was greatly reduced with intermittent treatment.
The objective response rate was 66% with continuous therapy and 57% with intermittent therapy, including complete responses in 7% and 3%, respectively. The disease control rate was 94% and 90%, respectively. Overall survival data are not mature, as only 25% of events have occurred.
The main grade 3/4 toxicities were skin-related (occurring in 25% of the continuous arm but only 13% of the intermittent arm) and neutropenia (seen in 23% and 24%, respectively).
“The results of the IMPROVE study suggest that the intermittent FOLFIRI/panitumumab treatment may be an effective strategy for RAS/BRAF wild-type metastatic colorectal cancer and deserves further investigation in a phase III trial. Ongoing translational analysis—in particular, [circulating tumor] DNA—may provide further insights on refining this strategy in individuals. We believe the results take on relevant value in the COVID-19 pandemic era,” Dr. Avallone commented.
DISCLOSURE: Dr. Avallone has consulted for or received honoraria from Eisai, MSD, Amgen, and AstraZeneca.
REFERENCES
1. Avallone A, Giuliani F, Nasti G, et al: Randomized intermittent or continuous panitumumab plus FOLFIRI for first-line treatment of patients with RAS/BRAF wild-type metastatic colorectal cancer: the IMPROVE study. 2022 ASCO Annual Meeting. Abstract 3503. Presented June 6, 2022.
2. Yoshino T, Watanabe J, Shitara K, et al: Panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 as first-line treatment in patients with RAS wild-type metastatic colorectal cancer: Results from the phase 3 PARADIGM trial. 2022 ASCO Annual Meeting. Abstract LBA1. Presented June 5, 2022.
