Interesting study where intermittent FOLFIRI + pan was seemingly just as effective as continuous therapy. The ongoing Phase III IMPROVE-2 is the confirmatory trial and if positive could change standard practice. Of note, intermittent meant eight (8) cycles followed by a holiday until progression when it was reinitiated.
To investigate whether intermittent treatment after an induction phase of first-line schedule of fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus panitumumab (PAN) prevents or delays the onset of resistance and improves safety and compliance with treatment in patients with unresectable RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC).
IMPROVE (ClinicalTrials.gov identifier: NCT04425239) was an open-label, multicenter, randomized phase II noncomparative trial. Patients with unresectable RAS/BRAF wt mCRC were randomly assigned (1:1) to receive FOLFIRI plus PAN continuously until progression (arm A) or intermittently, with treatment-free intervals (arm B) until progression on treatment, toxicity, or death. The primary end point was progression-free survival on treatment (PFSot) at 12 months. Assuming a null hypothesis of median PFSot time ≤7 months and target PFSot ≥10 months, 65 patients per arm were needed to achieve 80% power and 10% type I error, according to the binomial test.
Between May 2018 and June 2021, 69 patients were randomly assigned to arm A and 68 to arm B. The median number of treatment cycles was 13 in arm A and 16 in arm B. At a median follow-up of 43.2 months (IQR, 35.0-50.5), median PFSot was 11.2 and 17.5 months with 12-month PFSot rates of 45.7% and 58.5%, for arms A and B, respectively. The overall response rates were 68.1% and 61.2%, and median overall survival rates were 36.3 and 35.1 months in arms A and B, respectively. The overall rate of grade >2 skin PAN-related adverse events was 30.3% in arm A and 17.9% in arm B.
Intermittent FOLFIRI plus PAN after the induction phase was feasible, and the primary end point was met with reduced toxicity while allowing patients more time off treatment.
This PLK1-inhibitor seems extremely promising. This phase II trial studied pre-treated KRAS-mut patients with FOLFIRI + bev + study drug and the response rates and PFS were quite remarkable. Given the compelling results, they went from this study to a phase III 1L study.
Combination beat monotherapy is another option for MSI patients. Is combo better then pembro?
Here is a large phase-III well done study confirming what we knew from earlier studies, that ipilimumab plus nivolumab (Ipi+Nivo) is highly active and effective in the microsatellite instability-high metastatic colorectal cancer (MSI-high met-CRC) population. This is most likely more effective than single agent IO therapy but with higher rates of toxicity. When all things are equal, I would consider this to be the standard of care (SOC) in this context.
This Japanese study showed no benefit with the addition of oxaliplatin to fluoropyrimidine plus bevacizumab (5FU+bev) in patients who were aged 70-74 but unfit, or >=75. Interestingly survival was actually shorter in the patients who received oxaliplatin at 21.3 vs 19.7 months.
Overall survival (OS) improvement was not statistically significant in the study arm but is a non-chemotherapy option. Patients here had tumors with MSS.
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