Panitumumab-FOLFIRI: Effective Second-line Treatment for Metastatic Colorectal Cancer

By William B. Ershler, MD

Synopsis: A previously reported, industry-sponsored phase 3 trial (Study 20050181¹) showed improvements in progression-free survival, objective response, and a non-significant trend toward increased overall survival with panitumumab-FOLFIRI vs FOLFIRI alone for second-line wild-type KRAS metastatic colorectal cancer. The current report describes long-term outcomes from this same dataset.

Source: Peeters M, et al. Final results from a randomized, Phase 3 study of FOLFIRI ± panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 2014;25:107-116.

Epidermal growth factor receptor (EGFR)-targeted agents have shown efficacy when combined with chemotherapy in first-^2,3 and second-line^1,4,5 settings and as monotherapy in chemorefractory colorectal cancer.^6,7 Tumor KRAS status predicts the efficacy of anti-EGFR agents in metastatic colorectal cancer (mCRC) patients^8,9 and is a well-established biomarker for patient selection. Panitumumab is a fully humanized monoclonal antibody that binds to the EGFR of tumor cells and inhibits downstream cell signaling with antitumor effects of inhibition of tumor growth, induction of apoptosis, and inhibition of angiogenesis.¹⁰

Study 20050181 was a large, internationally conducted, randomized, Phase 3 trial designed to address whether the addition of panitumumab to FOLFIRI would enhance outcomes for second-line treatment of patients with mCRC.¹ Long-term data regarding significant clinical outcomes are now available and are the subject of this current report. Patients receiving one prior mCRC treatment were randomly assigned (1:1) to panitumumab (6.0 mg/kg)-FOLFIRI vs FOLFIRI every 2 weeks. Progression-free survival (PFS) and overall survival (OS) were prospectively analyzed by tumor KRAS status.

Patients (n = 1186) were randomly assigned. In patients with wild-type (WT) KRAS tumors (n = 597), panitumumab-FOLFIRI significantly improved PFS vs FOLFIRI (median 6.7 vs 4.9 months; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.69-0.97; P = 0.023). For this group, response rates improved from 10% to 36% (P < 0.0001) and, once again, there was a trend toward longer OS (median 14.5 vs 12.5 months; HR, 0.92; 95% CI 0.78-1.10; P = 0.37). From post-hoc analyses for patients who had received oxaliplatin-bevacizumab as first-line treatment, panitumumab-FOLFIRI improved PFS (median 6.4 vs 3.7 months; HR, 0.58; 95% CI, 0.37-0.90; P = 0.014). PFS and OS were better for those with more skin toxicity (grade 2-4) vs those with no or minimal toxicity (0-1). Safety results were as previously reported and consistent with the known toxicities with anti-EGFR therapy. Quality-of-life data were incompletely captured (about 60% in all study groups), but did not demonstrate any statistically significant or clinically meaningful differences in changes from baseline between treatments.

COMMENTARY

These data confirm the primary efficacy and safety findings as initially reported and establish panitumumab-FOLFIRI as effective second-line treatment of WT KRAS mCRC. Of additional importance, the data indicate that panitumumab offers no added benefit for patients with mutated variants of KRAS. The updated data strengthen the association between skin toxicity and tumor response. Patients with WT KRAS tumors receiving panitumumab-FOLFIRI experiencing grade 2 or higher skin toxicity had improved PFS and OS, as well as higher overall response rates, compared with those experiencing no or mild (0-1) skin toxicity. In fact, OS and PFS appeared shorter for patients with a mild or no skin toxicity in panitumumab-treated patients compared with those receiving FOLFIRI alone, and the overall response rate was also lower in these patients. Based on these findings, a key question in the management of patients with WT KRAS mCRC is whether therapy discontinuation should be considered in patients who do not mount higher levels of skin toxicity. However, as some panitumumab-treated patients develop skin toxicity later in their treatment course (at or beyond the fourth cycle), discontinuation should be considered with caution. A final note of emphasis can be drawn from the current analysis relating to prior therapy. The panitumumab improvement in PFS was discernible for most subgroups of patients with WT KRAS including those who had received prior oxaliplatin with or without bevacizumab. Thus, panitumumab-FOLFIRI is an effective and safe second-line regimen for patients with recurrent or refractory WT KRAS mCRC.

References

1. Peeters M, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706-4713.
2. Douillard JY, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol 2010;28:4697-4705.
3. Van Cutsem E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408-1417.
4. Cunningham D, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-345.
5. Sobrero AF, et al. EPIC: Phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:2311-2319.
6. Jonker DJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007;357:2040-2048.
7. Van Cutsem E, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:1658-1664.
8. Amado RG, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:1626-1634. De Roock W, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 2008;19:508-515.
9. Hocking CM, Price TJ. Panitumumab in the management of patients with KRAS wild-type metastatic colorectal cancer. Therap Adv Gastroenterol 2014;7:20-37.