Any upside to frontline mFOLFOXIRI-panitumumab in mCRC?

In patients with unresectable RAS and BRAF wildtype metastatic colorectal cancer (mCRC), a modified FOLFOXIRI plus panitumumab (mFOLFOXIRI/PAN*) treatment strategy in the first-line setting did not improve objective response rate (ORR) compared with FOLFOX plus panitumumab (mFOLFOX6/PAN**), results of the phase III TRIPLETE study showed.

“The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit [compared with mFOLFOX6/PAN] in terms of treatment activity … in patients with RAS and BRAF wildtype mCRC,” said the study investigators.

The 435 participants enrolled in this multicentre (57 sites in Italy), open-label trial were aged 18–75 years (median age 59 years) with previously untreated, unresectable RAS and BRAF wildtype mCRC and ECOG performance status ≤2***. They were randomized 1:1 to receive mFOLFOXIRI/PAN (intervention) or mFOLFOX6/PAN (control) for ≤12 cycles. Patients in both groups then received fluorouracil/leucovorin/panitumumab until disease progression, intolerable toxicity, patient refusal, or consent withdrawal.  Eighty-eight percent of patients had a left-sided primary tumour and 52 percent had multiple metastatic sites.

ORR did not significantly differ between patients who received mFOLFOXIRI/PAN and mFOLFOX6/PAN (73 percent vs 76 percent; odds ratio [OR], 0.87, 95 percent confidence interval [CI], 0.56–1.34; p=0.526). [ESMO GI 2022, abstract O-6; J Clin Oncol 2022;40:2878-2888]

Seven percent of patients in each group achieved complete response, 66 and 69 percent of patients in the mFOLFOXIRI/PAN and mFOLFOX6/PAN groups, respectively, achieved partial response, and 18 and 17 percent, respectively, achieved stable disease. The R0 resection rate also did not significantly differ between patients assigned to mFOLFOXIRI/PAN and mFOLFOX6/PAN (25 percent vs 29 percent; OR, 0.81, 95 percent CI, 0.53–1.23; p=0.317), nor did disease control rate (91 percent vs 93 percent; OR, 0.79, 95 percent CI, 0.40–1.57; p=0.496).

Deepness of response was also similar between the mFOLFOXIRI/PAN and mFOLFOX6/PAN groups (median 48 percent vs 47 percent; p=0.845), as was rate of early tumour shrinkage (57 percent vs 58 percent; OR, 0.97, 95 percent CI, 0.66–1.42; p=0.878).

After a median follow-up of 26.5 months, progression-free survival was comparable between the mFOLFOXIRI/PAN and mFOLFOX6/PAN groups (median 12.7 vs 12.3 months; hazard ratio, 0.88, 95 percent CI, 0.70–1.11; p=0.277).

Patients in the mFOLFOXIRI/PAN and mFOLFOX6/PAN groups had overall relative dose intensity rates of 75 and 81 percent, respectively.

Grade 3–4 diarrhoea occurred more frequently in mFOLFOXIRI/PAN than mFOLFOX6/PAN recipients (23 percent vs 7 percent). Other grade 3–4 adverse events (AEs) that were more common with the former than the latter were nausea (5 percent vs 2 percent), neutropenia (32 percent vs 20 percent), febrile neutropenia (5 percent vs 3 percent), and fatigue (7 percent vs 2 percent). Thirty-three and 21 percent of mFOLFOXIRI/PAN and mFOLFOX6/PAN recipients, respectively, experienced serious AEs. There were three deaths due to treatment-related AEs in the mFOLFOXIRI/PAN group and none in the mFOLFOX6/PAN group.

“[The results suggest that] mFOLFOXIRI plus panitumumab should not be recommended as upfront therapy for RAS and BRAF wildtype mCRC patients,” the investigators said.

“FOLFOX plus panitumumab allows [the achievement of] remarkable activity and efficacy results, thus supporting patients’ selection according to the primary tumour side and RAS and BRAF mutational status to optimize the efficacy of anti–EGFR^#-based first-line treatments,” they continued.

“When the use of targeted agents is optimized in a clinically and molecularly selected population, there is no added value from the intensification of the associated chemotherapy backbone,” they added.