Early Tumor Regression as a Marker of Overall Survival in First-Line Treatment of mCRC

PARADIGM Study

The PARADIGM study included 823 patients with unresectable wt RAS mCRC without previous chemotherapy, aged 20–79 years, and with a performance status (PS) of 0–1. They were randomized to receive either panitumumab + mFOLFOX6 (n = 312) or bevacizumab + mFOLFOX6 (n = 292). 

The primary analysis of the PARADIGM study demonstrated that the therapeutic regimen of panitumumab + mFOLFOX6 significantly improves overall survival (OS) in patients with left-sided mCRC with wt RAS compared to the regimen of bevacizumab + mFOLFOX6. This greater benefit in terms of longer OS was also observed in the overall patient population with panitumumab, consisting of 21.0% (panitumumab + mFOLFOX6) and 25.6% (bevacizumab + mFOLFOX6) patients with right-sided mCRC with wt RAS.

Subsequent Analysis

ETS in the subsequent analysis of data from the PARADIGM study was defined as at least a 30% reduction in tumor size as assessed by a physician after 8 weeks of treatment. DpR corresponded to the maximum percentage reduction in the sum of the diameters of target lesions from baseline. OS and PFS were compared between patients with and without ETS, stratified by treatment arm and primary tumor location (left-sided/right-sided). Data obtained up to January 14, 2022, were analyzed.

Results

With panitumumab, a larger proportion of patients achieved ETS (58.5% of the total study population; 64.4% of patients with left-sided tumors) compared to bevacizumab (38.8% of the total study population; 38.0% of patients with left-sided tumors).

In patients with left-sided tumors treated with panitumumab who achieved ETS, longer OS (median 42.6 vs. 27.1 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.42–0.75; p < 0.001) and PFS (15.7 vs. 9.6 months; HR 0.62; 95% CI 0.48–0.81; p < 0.001) were observed compared to patients without ETS. Similarly, in patients with left-sided tumors treated with bevacizumab, achieving ETS was associated with longer OS (median 41.3 vs. 32.4 months; HR 0.69; 95% CI 0.52–0.91; p = 0.01) and PFS (14.5 vs. 11.5 months; HR 0.81; 95% CI 0.62–1.06; p = 0.094), compared to those who did not achieve ETS.

For right-sided tumors, the correlation between achieving ETS and longer OS was observed only with panitumumab treatment (median OS 34.1 vs. 15.2 months; HR 0.47; 95% CI 0.28–0.79; p = 0.005), but not with bevacizumab treatment (22.3 vs. 25.5 months; HR 0.94; 95% CI 0.60–1.45; p = 0.746). A significant correlation between achieving ETS and longer PFS was not found for right-sided tumors.

Regarding the depth of response, a greater median DpR was observed with panitumumab than with bevacizumab in the entire evaluated population (–57.3 vs. –43.6%) and in patients with left-sided tumors (–59.4 vs. –43.6%). For patients with right-sided tumors, DpR was comparable in both therapeutic groups.

Conclusion

Early tumor regression was associated with longer OS and PFS in patients with mCRC with wild-type RAS treated with panitumumab or bevacizumab (both in combination with mFOLFOX6). For left-sided tumors, more patients achieved early tumor regression and greater depth of tumor response with panitumumab compared to bevacizumab. For right-sided tumors, ETS was a predictor of longer OS only with panitumumab treatment.

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Source: Muro K., Watanabe J., Shitara K. et al. Early tumor shrinkage (ETS) and depth of response (DpR) analyses in metastatic colorectal cancer (mCRC) treated with first-line mFOLFOX6 plus panitumumab (PAN) or bevacizumab (BEV): results from the phase III PARADIGM trial. Ann Oncol 2022; 33 (suppl_7): S136−S196, doi: 10.1016/annonc/annonc1048.