Panitumumab Plus mFOLFOX6 Improves Survival in RAS Wild-Type mCRC

Kei Muro, MD, PhD

Treatment with frontline panitumumab (Vectibix) and mFOLFOX6 led to a significant improvement in overall survival (OS), plus higher response rates and R0 resection rates, compared with bevacizumab (Avastin) and mFOLFOX6, despite comparable progression-free survival (PFS), in patients with RAS wild-type metastatic colorectal cancer (mCRC), according to findings from the phase 3 PARADIGM trial (NCT02394795) that were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer.

At a median follow-up of 61 months, the median OS was 37.9 months (95.798% CI, 34.1-42.6) with panitumumab vs 34.3 months (95.798% CI, 30.9-40.3) with bevacizumab in patients with left-sided tumors (HR, 0.82; 95.798% CI, 0.68-0.99; P = .031). The median OS was 36.3 months (95% CI, 32-39) with panitumumab vs 31.3 months (95% CI, 29.3-34.1) with bevacizumab in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .030), reflecting statistically significant P values of less than 0.04202 and 0.05, respectively.

“These results support panitumumab plus mFOLFOX6 as a first-line therapy for patients with RAS wild-type and left-sided mCRC,” lead study author Kei Muro, MD, PhD, chief and director of the Department of Clinical Oncology and Outpatient Treatment Center at Aichi Cancer Center Hospital, and coauthors, reported in the presentation.

The addition of an anti-EGFR or anti-VEGF antibody to chemotherapy is associated with an improvement in OS of up to 30 months in patients with unresectable mCRC. However, post-hoc comparative analyses have shown inconclusive results regarding the relative benefit of both approaches in patients with RAS wild-type disease.

Prior data has shown that the benefit of an anti-EGFR antibody may be enriched in patients with RAS wild-type disease with primary tumors originating in the left side of the colon or rectum. As such, investigators designed the first prospective trial to test the superiority of panitumumab vs bevacizumab plus standard chemotherapy in this population.

The study enrolled patients aged 20 to 79 years with chemotherapy-naïve, unresectable, RAS wild-type mCRC; an ECOG performance status of 0 or 1; and at least 1 measurable lesion.

Patients were randomized 1:1 to panitumumab plus mFOLFOX6 (n = 411) or bevacizumab plus mFOLFOX6 (n = 412). The efficacy analysis set included 400 patients in the panitumumab arm (left-sided, n = 312) and 402 patients in the bevacizumab arm (left-sided, n = 292). The safety analysis set included 404 and 407 patients, respectively.

The primary end point was OS, which was tested hierarchically, in the left-sided and overall population. Secondary end points included PFS, response rate, duration of response (DOR), and R0 resection in the left-sided and overall population, and safety.

Exploratory end points included early tumor shrinkage, depth of response, and disease control rate (DCR) in the left-sided and overall population.

Baseline patient characteristics showed that across the left-sided, overall, and right-sided populations, most patients were between the ages of 65 and 79 years; had an ECOG performance status of 0; at least 2 sites of metastasis; the liver as an involved metastatic site; and undergone prior primary tumor resection.

Additional findings from the study showed a median PFS of 13.7 months (95% CI, 12.7-15.3) with panitumumab vs 13.2 months (95% CI, 11.4-14.5) with bevacizumab in the left-sided population (HR, 0.98; 95% CI, 0.82-1.17). In the overall population, the median PFS was 12.9 months (95% CI, 11.3-13.6) and 12.0 months (95% CI, 11.3-13.5), respectively (HR, 1.01; 95% CI, 0.87-1.18).

Higher response rates were observed with panitumumab in the left-sided and overall population, at 80.2% (95% CI, 75.3%-84.5%) and 74.9% (95% CI, 70.3%-79.1%), respectively, vs 68.6% (95% CI, 62.9%-74.0%) and 67.3% (95% CI, 62.4%-71.9%) with bevacizumab.

In the left-sided population, the DCR was 97.4% (95% CI, 94.9%-98.9%) with panitumumab vs 96.5% (95% CI, 93.7%-98.3%) with bevacizumab. In the overall population, the DCR was 94.9% (95% CI, 92.3%-96.9%) and 95.5% (95% CI, 92.9%-97.3%), respectively.

The median DOR was also prolonged with panitumumab in the left-sided and overall population, at 13.1 months (95% CI, 11.1-14.8) and 11.9 months (95% CI, 10.5-13.4), respectively, vs 11.2 months (95% CI, 9.6-13.1) and 10.7 months (95% CI, 9.5-12.2), respectively, with bevacizumab.

Similarly, the R0 resection rate was higher with panitumumab in the left-sided and overall population, at 18.3% (95% CI, 14.1%-23.0%) and 16.5% (95% CI, 13.0%-20.5%), respectively, vs 11.6% (95% CI, 8.2%-15.9%) and 10.9% (95% CI, 8.1%-17.1%) with bevacizumab.

Notably, more patients who received bevacizumab in the left-sided and overall population received subsequent second-, third-, and fourth-line therapy compared with those who received panitumumab.

Additional findings showed that patients with right-sided tumors did not derive OS (HR, 1.09; 95% CI, 0.79-1.51) or PFS (HR, 1.23; 95% CI, 0.91-1.67) benefit with panitumumab. Moreover, the response rate, DCR, and median DOR was numerically higher with bevacizumab, though the R0 resection rate was 10.7% (95% CI, 5.0%-19.4%) with panitumumab vs 9.7% (95% CI, 4.8%-17.1%) with bevacizumab.

Regarding safety, adverse effects (AEs) of any grade reported in at least 20% of patients in the panitumumab and bevacizumab arms, respectively, included acne-like dermatitis (75% vs 3%), peripheral sensory neuropathy (71% vs 74%), stomatitis (62% vs 41%), decreased appetite (56% vs 50%), paronychia (52% vs <6%), decreased neutrophil count (50% vs 55%), dry skin (46% vs <10%), nausea (40% vs 40%), fatigue (40% vs 40%), diarrhea (37% vs 33%), dysgeusia (31% vs 23%), hypomagnesemia (30% vs 2%), constipation (23% vs 27%), and decreased platelet count (22% vs 20%).

“No new safety signals were observed; both treatments had manageable safety profiles,” the authors wrote.

A large-scale biomarker analysis is underway in a phase 3 trial (NCT02394834), using plasma and tumor tissue samples collected before and after treatment, and potential prognostic biomarkers will be reported at an upcoming meeting.

Reference

Muro K, Watanabe J, Shitara K, et al. First-line panitumumab versus bevacizumab in combination with mFOLFOX6 for RAS wild-type metastatic colorectal cancer: PARADIGM trial results. Ann Oncol. 2022;33(suppl 4):S377. doi:10.1016/j.annonc.2022.04.454