Panitumumab Plus FOLFIRINOX or mFOLFOX6 Elicits Similar Responses in RAS/BRAF V600E Wild-Type Unresectable mCRC

The addition of panitumumab (Vectibix) to FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) or mFOLFOX6 (5-fluorouracil [5-FU], leucovorin, and oxaliplatin) led to comparable overall response rates (ORRs) and complete response (CR) rates in patients with RAS or BRAF V600E wild-type, unresectable, metastatic colorectal cancer (mCRC) without liver-limited disease, according to results from the phase 2 PANIRINOX trial (NCT02980510).

Findings presented at the 2023 ESMO Congress showed that patients with non–liver-limited disease randomly assigned to receive panitumumab plus FOLFIRINOX who were included in the per protocol (PP) population (n = 65) experienced an ORR of 75.4% and a CR rate of 7.7% (95% CI, 2.5%-17.0%) per RECIST v1.1 criteria. Patients in the PP population treated with panitumumab plus mFOLFOX6 (n = 27) achieved an ORR of 77.8% and a CR rate of 7.4% (95% CI, 0.9%-24.3%), respectively.

At a median follow-up of 36.11 months (95% CI, 31.97-not reached [NR]) for the PP population in arm A and 25.92 months (95% CI, 16.85-NR) for the PP population in arm B, the median progression-free survival (PFS) was 9.10 months (95% CI, 8.05-11.66) and 8.97 months (95% CI, 7.52-13.17), respectively. At a median follow-up of 31.97 months (95% CI, 28.68-32.30) for the PP population in arm A and 30.42 months (95% CI, 23.39-35.71) for the PP population in arm B, the median overall survival (OS) was not reached (NR) and 20.44 months (95% CI, 15.11-NR), respectively.

“Panitumumab [plus] triplet chemotherapy can be considered sufficiently effective, according to our initial assumption; [however], except for OS data…the outcomes don’t differ numerically between the 2 arms. In my opinion, [these data] don’t support the use of intensified chemotherapy in combination with anti-EGFR [therapy] in this kind of [patient] population—especially when they are well selected, like we did with a circulating DNA analysis,” lead study author Thibault Mazard, MD, PhD, of the Institut du Cancer de Montpellier Val d'Aurelle in Montpellier, France, said in a presentation of the data.

The multicenter, open-label, non-comparative, randomized study enrolled patients between 18 and 75 years of age with unresectable with curative intent mCRC who were previously untreated, expect for fluoropyrimidine in the adjuvant setting. An ECOG performance status of 0 or 1 was also required.

RAS/BRAF V600E status was assessed by Intplex^® circulating DNA analysis. Patients were considered to have RAS/BRAF V600E–mutated disease if circulating DNA harbored a mutational load higher than 0.5%.

Prior to randomization, patients were stratified based on liver-limited disease status. Patients in each group were then randomly assigned 2:1 to receive panitumumab plus FOLFIRINOX (arm A) or panitumumab plus mFOLFOX6 (arm B) for up to 12 cycles.

The analysis for patients with liver-limited disease is ongoing. Data for patients with non–liver-limited disease were presented at the 2023 ESMO Congress.

CR rate per RECIST v1.1 criteria and carcinoembryonic antigen level normalization after a maximum of 12 cycles of chemotherapy, if applicable, served as the trial’s primary end point. The primary end point was met if 4 of 60 evaluable patients in the FOLFIRINOX arm achieved a CR.

Secondary end points included PFS, OS, R0 secondary resection rate, early tumor shrinkage, depth of response, safety, and diagnostic performance of the circulating DNA analysis.

Between October 2017 and July 2023, 574 patients were assessed for eligibility, and 219 were randomly assigned. A total of 111 patients had non–liver-limited disease; 78 of these patients were assigned to receive panitumumab plus FOLFIRINOX and 33 were assigned to receive panitumumab plus mFOLFOX6.

The panitumumab/FOLFIRINOX arm included an intent-to-treat (ITT) population (n = 78), a safety population (n = 77), and a PP population (n = 65). Patients were excluded from the PP population because they did not receive treatment (n = 1), did not have measurable disease per RECIST v1.1 criteria (n = 1), were deemed to have liver-limited disease after central review (n = 9), or they did not undergo a tumor imaging assessment (n = 2).

The panitumumab/mFOLFOX6 arm included an ITT population (n = 33), a safety population (n = 33), and a PP population (n = 27). Patients were excluded from the PP population because they had liver-limited disease after central review (n = 4) or no tumor imaging assessment was conducted (n = 2).

In the ITT populations, the median age was 64 years (range, 32-80) and 62 years (range, 33-75) for the panitumumab/FOLFIRINOX and panitumumab/mFOLFOX6 arms, respectively. Most patients in the panitumumab/FOLFIRINOX arm were male (67%) and had an ECOG performance status of 0 (63%). In the panitumumab/mFOLFOX6 arm, the majority of patients were female (55%) and had an ECOG performance status of 1 (58%). Across both arms, most patients had a left primary tumor (arm A, 78%; arm B, 79%), synchronous metastases (85%; 87%), and more than 1 metastatic site (82%; 73%). In arm A, liver, lung, and peritoneal involvement was reported in 71%, 56%, and 24% of patients, respectively; in arm B, those rates were 64%, 55%, and 21%, respectively.

Additional data showed that 80% of patients in the PP population in arm A achieved early tumor shrinkage, and the median depth of response was –58.2% (Q1-Q3, –78.5% to –41.2%). Additionally, the R0 resection rate was 6.2%. In the PP population in arm B, the early tumor shrinkage rate was 66.7%, and the median depth of response was –60.5% (Q1-Q3, –74.0% to –37.1%). The R0 resection rate was 7.4%.

Regarding safety, the most common grade 3 or higher treatment-related adverse effects (TRAEs) were diarrhea (arm A, 39%; arm B, 9%), peripheral neuropathy (22%; 24%), and skin TRAEs (18%; 24%).

“We are now awaiting the results [for patients with] liver-limited disease,” Mazard concluded.

Reference

Mazard T, Ghiringhelli F, Winter A, et al. Panitumumab (P) + FOLFIRINOX or mFOLFOX6 in unresectable metastatic colorectal cancer (mCRC) patients (pts) with RAS/BRAF wild-type (WT) tumor status from circulating DNA (cirDNA): First results of the randomised phase II PANIRINOX-UCGI28 study. Ann Oncol. 2023;34(suppl 2):S1270. doi:10.1016/j.annonc.2023.10.022